endothelin-1 and Heart-Failure

Most studies reported that high plasma endothelin-1 (ET-1), big ET-1, and C-terminal proET-1 (CT-proET-1) were correlated with poor prognosis of heart failure (HF). However, available evidence remains controversial. To help solve the debate, we collected all the available studies and performed a meta-analysis.. We searched the databases covering Embase, PubMed, Ovid, and Web of Science on June 28, 2017. The hazard ratio (HR) or risk ratio (RR) and its 95% confidence intervals (CIs) were collected and calculated by use of a random-effect model. Heterogeneity was assessed by Cochran's Q test, and publication bias was assessed by funnel plots with Egger's and Begg's linear regression test.. Thirty-two studies with 18,497 patients were included in the analysis. Results showed that circulating ET-1, big ET-1, and CT-proET-1 were positively correlated with high risk of adverse outcomes, with pooled RRs (95% CIs) of 2.22 (1.82-2.71, P < .001), 2.47 (1.93-3.17, P < .001), and 2.27 (1.57-3.29, P < .001), respectively. In the subgroup of death as primary outcome, the pooled RRs (95% CIs) were 2.13 (1.68-2.70, P < .001), 2.55 (1.82-3.57, P < .001), and 2.02 (1.39-2.92, P < .001) for ET-1, big ET-1, and CT-proET-1, respectively. No significant publication bias was observed in this study.. Our meta-analysis provided evidence that increased plasma levels of ET-1, big ET-1, and CT-proET-1 were associated with poor prognosis or mortality for HF populations.

Topics: Biomarkers; Endothelin-1; Heart Failure; Humans; Peptide Fragments; Prognosis; Protein Precursors

Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter-regulatory hormones of the RAAS and SNS, and endothelin-1 become over-activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Atrial Natriuretic Factor; Biphenyl Compounds; Chronic Disease; Drug Combinations; Endothelin-1; Heart Failure; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Neprilysin; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Sympathetic Nervous System; Tetrazoles; Valsartan

Topics: Alternative Splicing; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Designer Drugs; Drug Combinations; Drug Therapy, Combination; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Neprilysin; Peptidyl-Dipeptidase A; Protease Inhibitors; Receptors, Angiotensin; Renin-Angiotensin System; Snake Venoms; Tetrazoles; Valsartan

Heart failure is a complex disease in which a careful clinical examination and the measurement of cardiac function may not always be sufficient for making a correct diagnosis. Measuring plasma levels of natriuretic peptides may assist in this process, also offering a good tool for accurate risk stratification. Other alternative biomarkers may give insight into the different pathways of heart failure genesis and pathophysiology, and may help to identify those patients with overt heart failure and a more adverse outcome, or distinguish between those at risk of developing heart failure. Despite a high number of potentially useful biomarkers, only a few will likely be introduced routinely into clinical practice. However, a multi-marker approach might increase the diagnostic accuracy and it might identify different phenotypes of heart failure patients who might benefit from individualized therapy in the future.

Topics: Animals; Biomarkers; Blood Proteins; Endothelin-1; Galectin 3; Galectins; Glycopeptides; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Natriuretic Peptides; Peptide Fragments; Predictive Value of Tests; Prognosis; Receptors, Cell Surface; Troponin

The NO/ONOO-cycle is a primarily local, biochemical vicious cycle mechanism, centered on elevated peroxynitrite and oxidative stress, but also involving 10 additional elements: NF-κB, inflammatory cytokines, iNOS, nitric oxide (NO), superoxide, mitochondrial dysfunction (lowered energy charge, ATP), NMDA activity, intracellular Ca(2+), TRP receptors and tetrahydrobiopterin depletion. All 12 of these elements have causal roles in heart failure (HF) and each is linked through a total of 87 studies to specific correlates of HF. Two apparent causal factors of HF, RhoA and endothelin-1, each act as tissue-limited cycle elements. Nineteen stressors that initiate cases of HF, each act to raise multiple cycle elements, potentially initiating the cycle in this way. Different types of HF, left vs. right ventricular HF, with or without arrhythmia, etc., may differ from one another in the regions of the myocardium most impacted by the cycle. None of the elements of the cycle or the mechanisms linking them are original, but they collectively produce the robust nature of the NO/ONOO-cycle which creates a major challenge for treatment of HF or other proposed NO/ONOO-cycle diseases. Elevated peroxynitrite/NO ratio and consequent oxidative stress are essential to both HF and the NO/ONOO-cycle.

Topics: Endothelin-1; Heart Failure; Humans; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxynitrous Acid; Reactive Oxygen Species; rhoA GTP-Binding Protein

The right ventricle (RV) is not well suited to chronic pressure overload and often fails to adequately compensate. Mechanisms that allow the RV to respond to acute pressure overload often become maladaptive and contribute to its failure, including the effects of pulmonary hypertension on RV myocardial perfusion, the influence of interventricular dependence on RV function, and metabolic shifts in the RV myocardium from fatty acid to glycolysis. Medications to treat pulmonary hypertension have focused on pulmonary vasodilatation. Their effects on RV function may determine their effectiveness. How new medications affect right ventricular performance must be addressed.

Topics: Adaptation, Physiological; Calcium Channel Blockers; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Exercise; Familial Primary Pulmonary Hypertension; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Ventricular Dysfunction, Right; Ventricular Remodeling

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Cell Differentiation; Cell Proliferation; Complement C5a; Endothelin-1; Female; Heart Failure; Heart Transplantation; Hematopoietic Stem Cells; Humans; Hypertension; In Vitro Techniques; Male; Mast Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Myocarditis; Neuropeptides; Reactive Oxygen Species; Sex Characteristics; Ventricular Remodeling

It is now becoming clear that two major systems namely the sympathetic nervous system and the renin-angiotensin system are activated in response to ischemic injury; these result in the elevation of plasma catecholamines and angiotensin II during the development of myocardial infarction as well as congestive heart failure. Although plasma levels of several other hormones including aldosterone, endothelin, vasopressin, natriuretic peptides, growth factors and inflammatory cytokines are also increased in heart failure, their relationship with changes in catecholamine and/or angiotensin levels as well as their significance for the induction of congestive heart failure are poorly understood. In this article we have examined the evidence regarding the role of endothelin and vasopressin in the pathogenesis of cardiac hypertrophy and congestive heart failure in addition to evaluating the significance of their antagonism by using their receptor blockade for treatment of congestive heart failure. Endothelin appears to maintain blood pressure by its vasoconstricting action whereas vasopressin primarily produces similar effect by retention of body fluid. Myocardium is also known to express both ET-A and ET-B receptors in addition to V1 and V2 receptors for vasopressin, which have been shown to induce cardiac remodeling. Out of various ET-1 receptor antagonists, which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an ET-A receptor antagonist, BQ-123, seem most promising for the treatment of congestive heart failure. Likewise, vasopressin antagonists such as a non-selective antagonist, conivaptan, as well as V2 selective antagonist, tolvaptan, may prove highly valuable for the therapy of this condition. Since most of the existing interventions are helpful in treating patients with congestive heart failure only partially, there appears to be a real challenge for developing some combination therapy for the treatment of congestive heart failure.

Topics: Angiotensin II; Animals; Antidiuretic Agents; Antihypertensive Agents; Benzazepines; Biomarkers; Bosentan; Catecholamines; Drug Therapy, Combination; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Renin-Angiotensin System; Sulfonamides; Sympathetic Nervous System; Tolvaptan; Treatment Outcome; Vasopressins

Outcomes of victims of cardiac arrest or acute myocardial ischemic events have improved with advances in medical therapy. Heart failure, however, remains a leading cause of morbidity and mortality after these conditions have occurred. Clinical features may be useful for predicting patients who are at risk of developing such complications, but they lack of sensitivity and specificity. Biomarkers have been therefore suggested as means to provide relevant prognostic information. The more commonly used biomarkers after cardiovascular ischemic events, including cardiac arrest, are creatin kinases and troponins. In addition, natriuretic peptides and C-reactive protein have gained great interest and now sufficient data has been collected such to justify their clinical applicability. Finally, several other novel biomarkers, to be used after resuscitation from cardiac arrest or more generally after a myocardial ischemic event, have been anticipated. Nevertheless, the "perfect" biomarker, able to provide diagnosis and prognosis with high sensitivity and specificity does not exit. A multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation is therefore suggested.

Topics: Adrenomedullin; Arginine Vasopressin; Biomarkers; C-Reactive Protein; Cardiopulmonary Resuscitation; Creatine Kinase; Endothelin-1; Heart Arrest; Heart Failure; Humans; Immunity, Innate; Myocardial Ischemia; Natriuretic Peptides; Serum Amyloid P-Component; Troponin

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Topics: Acute Disease; Atrial Natriuretic Factor; Benzoates; Elapid Venoms; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nitrates; Peptide Fragments; Prognosis; Pyridines; Receptors, Endothelin; Relaxin; Tetrazoles; Vasoconstriction; Vasodilator Agents

The endothelin axis promotes vasoconstriction, suggesting that antagonists of endothelin signaling might be useful in treatment of heart failure. However, promising results from animal trials have not been recapitulated in heart failure patients. Here we review the role of major signaling pathways in the heart that are involved in cell survival initiated by ET-1. These pathways include mitogen-activated protein kinase, phosphatidyl inositol-1,4,5-triphosphate kinase (PI3K-AKT), nuclear factor-kappaB (NF-kappaB), and calcineurin signaling. A better understanding of endothelin-mediated signaling in cardiac cell survival may allow a reevaluation of endothelin receptor antagonists (ETRAs) in the treatment of heart failure.

Topics: Animals; Calcineurin; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Evidence-Based Medicine; Extracellular Signal-Regulated MAP Kinases; Heart Failure; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Myocardium; NF-kappa B; Phosphatidylinositol 3-Kinases; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

Several therapies commonly used for the treatment of acute heart failure syndromes (AHFS) present some well-known limitations and have been associated with an early increase in the risk of death. There is, therefore, an unmet need for new pharmacologic agents for the early management of AHFS that may improve both short- and long-term outcomes.. To review the recent evidence on emerging pharmacologic therapies in AHFS.. A systematic search of peer-reviewed publications was performed on MEDLINE, EMBASE and Clinical Trials.gov from January 1990 to August 2007. The results of unpublished or ongoing trials were obtained from presentations at national and international meetings and pharmaceutical industry releases. Bibliographies from these references were also reviewed, as were additional articles identified by content experts.. Cumulative data from large studies and randomised trials suggest that therapies with innovative mechanisms of action may safely and effectively reduce pulmonary congestion or improve cardiac performance in AHFS patients.. Some investigational agents for the management of AHFS are able to improve haemodynamics and/or clinical status. In spite of these promising findings, no new agent has demonstrated a clear benefit in terms of long-term clinical outcomes compared to placebo or conventional therapies.

Topics: Adenosine; Cardiovascular Agents; Endothelin-1; Etiocholanolone; Heart Failure; Hemodynamics; Humans; Hydrazones; Natriuretic Peptide, Brain; Perhexiline; Pyridazines; Randomized Controlled Trials as Topic; Simendan; Sodium-Potassium-Exchanging ATPase; Syndrome; Vasodilator Agents

Despite the fact that septic patients exhibit altered cardiac function, it is not considered a major pathology during sepsis. Thus, the molecular mechanisms underlying sepsis-induced myocardial dysfunction have not been studied extensively. In a polymicrobial septic rat model, +dP/dt and -dP/dt on day 1 were not altered but found depressed later, i.e., at 3 and 7 days postsepsis. Diastolic dysfunction characterized by an elevation of the time constant of left ventricular relaxation, tau, was evident at 1, 3, and 7 days postsepsis. Recent data from our laboratory demonstrated that sepsis-induced cardiodynamic alterations correlated with upregulation of TNF receptor-associated death domain, Bax, Smac (both mitochondrial and cytosolic fractions), total nuclear factor kappaB expression, p38-mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation, and cytochrome c levels in the rat heart at 3 and 7 days postsepsis. Data from various laboratories emphasized that molecular myocardial alteration, which occurs during early and late stages of sepsis, needs to be elucidated thoroughly. A poor understanding of myocardial signaling during early sepsis could be one of the main reasons for limited success of pharmacotherapeutic options for sepsis. We anticipate that an increased understanding of pathophysiological mechanisms leading to sepsis-induced myocardial dysfunction would generate new enthusiasm among various research groups in this area of research.

Topics: Animals; Apoptosis; Endothelin-1; Heart; Heart Failure; JNK Mitogen-Activated Protein Kinases; Myocardium; p38 Mitogen-Activated Protein Kinases; Rats; Sepsis; Signal Transduction

Topics: Animals; Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Sulfonamides; Ventricular Remodeling

Circulating plasma endothelin (ET)-1 concentrations are substantially elevated, and correlate with the hemodynamic severity and New York Heart Association (NYHA) class, in patients with chronic heart failure (CHF). In early preclinical studies involving different models of experimental heart failure, ET antagonists reduced cardiac pressures, increased cardiac output, and prolonged survival. ET receptor antagonists also impressively improved systemic and pulmonary hemodynamics in patients with CHF, without causing neurohormonal activation. However, recent clinical trials, including the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and EARTH (Endothelin A Receptor Antagonist Trial in Heart Failure) studies, have shown neutral effects in terms of mortality and symptoms. This paper describes the possible reasons why benefit was not seen in these clinical studies, and suggests what lessons can be learnt from the way the studies were undertaken to apply to future studies.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Humans; Treatment Outcome

Activation of the renin-angiotensin system (RAS), with ensuing aldosterone excess, detrimentally affects outcome in patients with hypertension and heart failure (HF). RAS blockade with angiotensin (Ang) 1-converting enzyme inhibitors (ACEIs) or Ang II type 1 receptor blockers (ARBs) is beneficial in such conditions. However, aldosterone secretion can persist despite these treatments. Hence, mechanisms besides Ang II acquire the role of aldosterone secretagogue. The RALES and EPHESUS studies have shown that this aldosterone "escape" or "breakthrough" is an important factor, because it is a determinant of outcome in HF patients. Endothelin (ET)-1, which stimulates aldosterone secretion via both A (ETA) and B (ETB) receptor subtypes, and which is increased in HF, is a candidate for the "aldosterone breakthrough." Moreover, the novel ET peptide ET-1(1-31) is involved in adrenocortical growth. Therefore, findings suggesting a role for the ET-1 system as an aldosterone secretagogue, along with the potential usefulness of endothelin antagonists for the prevention of "aldosterone breakthrough," are discussed.

Topics: Adrenal Cortex; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Endothelin-1; Heart Failure; Humans; Hypertension; Randomized Controlled Trials as Topic; Receptors, Endothelin; Renin-Angiotensin System

Evidence suggests that vascular endothelium plays key role in the regulation of vascular tone, in the process of inflammation and in the thrombotic mechanisms. Recent studies indicate that it is an important component of the pathophysiological mechanisms of heart failure. Heart failure may induce endothelial dysfunction by different mechanisms, such as reduced synthesis and release of nitric oxide (NO), increased degradation of NO or by increased production of endothelin-1. In addition, endothelial dysfunction has been associated with the progression of heart failure. Alterations in neurotransmitters, hormones and also in physiological stimuli are present in heart failure and affect the vascular endothelium. Treatments with beneficial effects on endothelial dysfunction may also improve prognosis in patients with heart failure.

Topics: Animals; Apoptosis; Carnitine; Cell Adhesion Molecules; Endothelin-1; Endothelium, Vascular; Exercise; Heart Failure; Humans; Inflammation; Nitric Oxide; Tumor Necrosis Factor-alpha

Topics: Aspartic Acid Endopeptidases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Heart Failure; Humans; Hypertension, Pulmonary; Metalloendopeptidases; Receptors, Endothelin

Myocardial remodeling invariably occurs in congestive heart failure (CHF) and is a response to a prolonged cardiovascular stress, which is characterized by a cascade of compensatory structural events. Remodeling of the myocardial interstitium occurs in CHF and likely contributes to the progression of the remodeling process. The myocardial matrix can be considered a biological highway in which a large amount of signaling proteins and structural proteins are being moved within the interstitium, entering and exiting the interstitial space, and docking to cellular components. The rates at which these events occur can accelerate and decelerate depending on the particular cardiac disease state and thereby can alter the course of myocardial remodeling. Once considered merely a scaffolding to align cells, the matrix plays a complex and divergent role in influencing cell behavior. For example, the matrix has a functional role in cell migration, proliferation, adhesion, and cell-to-cell signaling. In light of this, the myocardial matrix should not be regarded as merely a static structure, but rather, as a complex system of dynamic interactions between matrix molecules, signaling proteins, and transmembrane proteins. Specific strategies that are targeted at modifying activity along this matrix highway will likely alter the course of myocardial remodeling and heart failure.

Topics: Angiotensin II; Disease Progression; Endothelin-1; Extracellular Matrix; Heart Failure; Humans; Hypertrophy, Left Ventricular; Integrins; Matrix Metalloproteinases; Myocardial Infarction; Myocardium; Transforming Growth Factor beta; Ventricular Remodeling

Topics: Animals; Arteriosclerosis; Biomarkers; Bosentan; Diagnostic Techniques, Endocrine; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Receptors, Endothelin; Reference Values; Sulfonamides

Heart failure (HF) is a clinical syndrome characterized by chronic, persistent activation of the neuroendocrine system, which has been assumed to be linked to disease progression and adverse outcomes. Clinical trials have shown that adrenergic modulators, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, and beta-blockers, improve long-term outcomes in patients with HF. These findings have led to the hypothesis that inhibition of a single neurohormonal or cytokine pathway may continue to provide incremental benefits. However, the results of recent clinical trials, using centrally acting agents--endopeptidase inhibitors or endothelin and cytokine antagonists--suggest that selective inhibition of neurohormonal systems may not be advantageous and actually may have serious adverse effects. The reasons for this lack of benefit may be ascribed to the fact that long-term mortality benefits in patients with chronic HF are primarily the result of treatment of the diseases that have caused HF in the first place rather than treatment of neurohormonal abnormalities.

Topics: Clinical Trials as Topic; Cytokines; Endopeptidases; Endothelin-1; Heart Failure; Humans; Neurotransmitter Agents; Signal Transduction

Topics: Angiotensin-Converting Enzyme Inhibitors; Arginine; Chronic Disease; Diagnosis, Differential; Diuretics; Drug Therapy, Combination; Endothelin-1; Heart Failure; Humans; Hypertension; Prognosis; Renin-Angiotensin System; Vasopressins

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Topics: Adrenomedullin; Angiotensin II; Animals; Apoptosis; Calcium; Cardiomegaly; Cell Division; Cyclic AMP; Endothelin-1; Heart Failure; Humans; Myoblasts, Cardiac; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Peptides; Protein Kinase C; Signal Transduction; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Topics: Animals; Biomarkers; Clinical Trials as Topic; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Heart Failure; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neovascularization, Pathologic; Peptides, Cyclic; Phenylpropionates; Pyrimidines; Transcription Factors; Vasoconstriction; Ventricular Remodeling

Nitric oxide (NO) and endothelin-1 (ET-1) are endothelium-derived mediators that play important roles in vascular homeostasis. This review is focused on the role and reciprocal interactions between NO and ET-1 in health and diseases associated with endothelium dysfunction. We will also discuss the clinical significance of NO donors and drugs that antagonize ET receptors.

Topics: Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Homeostasis; Humans; Nitric Oxide; Receptor, Endothelin A; Receptors, Endothelin; Vasoconstriction

Chemotherapy is an established approach for several malignancies, but its utility may be hampered by induced cardiac toxicity possibly leading to heart failure, with a negative impact on the patient's quality of life and ultimately survival. Prospective left ventricular systolic function monitoring has demonstrated that cardiotoxicity could be subclinically present for many months or years before its overt manifestation. Although considered irreversible, some reports suggested recovery or delayed progression of cardiac dysfunction by preventive cardioactive therapies. Thus, the identification of earlier instrumental or biochemical markers of cardiac injury able to predict heart failure remains a major task. Diastolic indexes as a primary expression of hemodynamic dysfunction after cardiac damage, analyzed by means of conventional or newer Doppler technologies (tissue Doppler, color M-mode, etc.) are discussed. Moreover, brain natriuretic peptides, troponins and endothelin-1, as possible sensitive/specific markers/predictors of subclinical cardiotoxicity are reviewed in order to update and possibly improve the strategy for the detection and clinical management of chemotherapy-related cardiotoxic effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Cardiac Output, Low; Endothelin-1; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Neoplasms; Predictive Value of Tests; Primary Prevention; Prognosis; Quality of Life; Sensitivity and Specificity; Severity of Illness Index; Troponin; Ventricular Dysfunction, Left

Stretch of cardiomyocytes in vivo occurs in response to a number of stimuli, including pressure or volume overload, but it is most clearly seen following relatively large, acute myocardial infarctions. It is in this setting that stretch is most clearly related to the pathogenesis of heart failure. Stretch of the remote, noninfacted myocardium leads to the activation of a large number of cellular signal transduction pathways, which sets into motion a series of what are designed to be compensatory responses to the increased wall stress on the surviving myocardium. Herein, we will discuss the cellular pathways activated by cell stretch, which appear to trigger the initial steps in the pathogenesis of ventricular dilatation following myocardial infarction. We will discuss what is known of the "stretch sensors," which convert the mechanical stimulus into molecular signals. I will then introduce the specific cellular signaling pathways activated by stretch and discuss the evidence for their involvement in remodeling. Since many of these pathways will be covered in more detail in specific sections to follow, this will serve as an introduction to stretch-activated signaling. Finally, we will briefly examine later phases of the response, including advanced heart failure. The goal is to identify molecular modulators that might serve as targets for pharmacologic or molecular intervention.

Topics: Angiotensin II; Animals; Endothelin-1; GTP-Binding Proteins; Heart Failure; Humans; Insulin-Like Growth Factor I; Integrins; Interleukin-6; Myocardial Contraction; Myocytes, Cardiac; Signal Transduction; Ventricular Remodeling

Chronic heart failure (CHF) is associated with an increase in the production and secretion of various regulatory hormones that are initially beneficial, but become deleterious when elevated for prolonged periods. The neurohumoral excitation that occurs in the CHF state is mediated, in part, by abnormal inhibitory cardiovascular reflexes, such as the arterial baroreflex and the cardiopulmonary reflex. In addition, two sympatho-excitatory reflexes have been shown to be enhanced in CHF: the arterial chemoreflex and the cardiac sympathetic afferent reflex. While these reflexes may play a role in the sympatho-excitation of the CHF state, there is an important central modulation of sympathetic outflow by a variety of hormones that are elevated in CHF and have been shown to have neural effects. These include angiotensin II (Ang II), nitric oxide (NO), and endothelin-1. In fact, experimental animal data suggest that a central reciprocal relationship exists between Ang II and NO in their ability to modulate sympathetic outflow. These substances may also participate in the beneficial effects of exercise training in the CHF state. Exercise training lowers sympathetic nerve activity and plasma Ang II, and enhances arterial baroreflex function. This review emphasizes the neurohormonal and reflex regulation of sympathetic outflow in heart failure. While abnormal reflex regulation may predict a poor outcome, new treatment options may emerge from a better understanding of reflex regulation in CHF.

Topics: Angiotensin II; Baroreflex; Endothelin-1; Excitatory Postsynaptic Potentials; Heart Failure; Humans; Nitric Oxide; Sympathetic Nervous System

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.

Topics: Endothelin-1; Endothelium, Vascular; Heart Failure; Humans; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Tumor Necrosis Factor-alpha; Vasoconstriction; Vasodilation

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomize

Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction; Renal Insufficiency

Endothelin (ET) is a peptide composed of 21 amino acids, derived from a larger precursor, the big-endothelin, by action of the endothelin-converting enzyme (ECE) family; three isoforms of endothelin, named ET-1, ET-2 and ET-3, have been identified. Endothelin-1 is generated mainly by vascular endothelial cells and exerts various important biological actions, mediated by two receptor subtypes, ET-A and ET-B, belonging to the G protein-coupled family that have been identified in various human tissues such as the cardiac tissue. Endothelin-1 is a potent vasoconstrictive agent, has inotropic and mitogenic actions, modulates salt and water homeostasis and plays an important role in the maintenance of vascular tone and blood pressure in healthy subjects. Endothelin-1, as well as ET-A and ECE-1, also has an important role in cardiovascular development, as observed by the variety of abnormalities related to neural crest-derived tissues in mouse embryos deficient of a member of the ET-1/ECE-1/ET-A pathway. Various evidence indicates that endogenous endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as heart failure. In heart failure, elevated circulating levels of both endothelin-1 and big-endothelin-1 are observed; in failing hearts an activation of the endothelin system is found: tissue level of ET-1 is increased with respect to non-failing hearts as well as receptor density, due mainly to an upregulation of the ET-A subtype, the prevalent receptor subclass in cardiac tissue. Finally, studies in both humans and animal models of cardiovascular disease show that inhibition of the endothelin function (anti-endothelin strategy) is associated with an improvement of haemodynamic conditions; these observations indicate that endothelin receptor antagonists or endothelin-converting enzyme inhibitors may constitute a novel and potentially important class of agents for the treatment of this disease.

Topics: Animals; Cardiomegaly; Cytokines; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Enzyme Inhibitors; Heart Failure; Humans; Receptors, Endothelin; Signal Transduction; Ventricular Remodeling

Congestive heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3 and ET-4, which cause vasoconstriction, cell proliferation and myocardial effects through activation of ETA receptors. In contrast, endothelial ETB receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ETA-receptor antagonist into the brachial artery in healthy humans leads to vasodilation, whereas infusion of an ETB-receptor antagonist causes vasoconstriction. Endothelin-1 plasma levels are elevated in CHF and correlate both with hemodynamic severity and symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death after myocardial infarction as well as in CHF. Endothelin-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia and renal impairment in CHF. Selective ETA, as well as combined ETA/B-receptor antagonists, have been studied in patients with CHF, and their use has shown impressive hemodynamic improvement (i.e., reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET-receptor antagonists, indeed, have a potential to improve hemodynamics, symptoms and, potentially, prognosis in patients with CHF, which still carries a high mortality.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Forecasting; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Myocardial Contraction; Peptides, Cyclic; Phenylpropionates; Predictive Value of Tests; Prognosis; Pyrimidines; Sulfonamides; Time Factors; Vascular Resistance; Vasoconstriction; Ventricular Function, Left

Initial pharmacologic therapy for hypertension is low-dose thiazide diuretics, beta-blockers, and ACE inhibitors. Increasing data have confirmed that ACE inhibitors have specific benefit in patients with diabetes, atherosclerosis, left ventricular dysfunction, and renal insufficiency. CCBs are alternative agents for ISH in the elderly and appear to decrease stroke with perhaps less protection against progression of renal insufficiency and proteinuria, CAD mortality and new onset heart failure versus other initial agents, especially ACE inhibitors. ARBs are well tolerated and effective blood pressure lowering agents but have not been confirmed as effective as ACE inhibitors for reducing renal progression, clinical events, or mortality from heart failure. Effective pharmacologic antihypertensive therapy may avoid disabling and undetected cerebrovascular disease, cognitive dysfunction, and disturbing symptoms of elevated blood pressure. Vasopeptidase inhibitor, such as omapatrilat, and endothelin-1 antagonist, such as bosentan, may become future agents approved for the reduction of morbidity and mortality with hypertension. The ALLHAT trial continues to examine the potential benefits and harms of amlodipine versus chlorthalidone and lisinopril in a diverse high-risk population. Based on ALLHAT data, however, doxazosin is no longer an acceptable initial pharmacological agent. Intensive pharmacologic treatment with blood pressure lowering to less than 130/85 mm Hg is recommended with diabetes, renal insufficiency, and heart failure with additional goal of less than 125/75 mm Hg with renal failure and proteinuria greater than 1 g/24 h, based on multiple outcome studies.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Bosentan; Bradykinin; Calcium Channel Blockers; Diabetes Complications; Diuretics; Drug Therapy, Combination; Endothelin-1; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Pyridines; Quality of Life; Renal Insufficiency; Renin-Angiotensin System; Risk Factors; Sulfonamides; Systole; Thiazepines; Treatment Outcome

Our understanding of the role of the endothelin system in human cardiovascular physiology and pathophysiology has evolved very rapidly since the initial description of its constituent parts in 1988. Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system and has potent vasoconstrictor, mitogenic and antinatriuretic properties which have implicated it in the pathophysiology of a number of cardiovascular diseases. The effects of ET-1 have been shown to be mediated by 2 principal endothelin receptor subtypes: ET(A) and ET(B). The development of a range of peptidic and nonpeptidic endothelin receptor antagonists represents an exciting breakthrough in human cardiovascular therapeutics. Two main classes of endothelin receptor antagonist have been developed for possible human therapeutic use: ET(A)-selective and nonselective antagonists. Extensive laboratory and clinical research with these agents has highlighted their promise in various cardiovascular diseases. Randomised, placebo-controlled clinical trials have yielded very encouraging results in patients with hypertension and chronic heart failure with more preliminary data suggesting a possible role in the treatment and prevention of atherosclerosis and stroke. Much more research is needed, however, before endothelin receptor antagonists can be considered for clinical use.

Topics: Aged; Animal Population Groups; Animals; Arteriosclerosis; Cardiovascular Diseases; Drugs, Investigational; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Receptors, Endothelin; Stroke

Both ET(A) selective and dual, ET(A/B), receptor antagonists have favourable short- and longer-term haemodynamic actions in patients with acute and chronic heart failure. Their effect on neurohumoral measures is not yet fully determined. Two moderately large, medium-duration studies have examined the effect of dual ET(A/B) receptor antagonists on clinical status, reaching conflicting conclusions. One large scale, long-term, morbidity mortality evaluation is underway with bosentan.

Topics: Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Middle Aged; Receptors, Endothelin

A role of the potent and long-acting vasoconstrictor peptide endothelin-1 and the pathophysiology of chronic human heart failure has been postulated based upon indirect evidence such as elevated plasma endothelin-1 levels and their with the degree of hemodynamic impairment. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity not only to directly evaluate its pathophysiological role but also to assess its potential role as a new approach to heart failure therapy. This brief review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure and the clinical results obtained in patients during acute, intravenous and more prolonged, oral administration with bosentan, a mixed ET(A)/ET(B)-receptor antagonist. Bosentan acutely and during short-term oral therapy markedly improved hemodynamics in patients in addition to standard heart failure therapy, including an ACE-inhibitor. These effects were associated with a reduced responsiveness of the renin-angiotensin system to diuretic therapy and reduced basal plasma aldosterone levels. Although the hemodynamic and neurohumoral profile of short-term bosentan therapy looks promising for the treatment of patients with chronic heart failure appropriate trials will have to be performed to document clinical benefit during long-term therapy. Finally, the question remains open whether mixed endothelin-1 receptor antagonists like bosentan will have similar effects as compared to antagonists which block the ET(A) receptor only.

Topics: Bosentan; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Receptors, Endothelin; Sulfonamides

Congestive heart failure (CHF) is a disease process characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3, and ET-4, which cause vasoconstriction, cell proliferation, and myocardial effects through activation of ET(A) receptors. In contrast, endothelial ET(B) receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ET(A) receptor antagonist into the brachial artery in healthy humans leads to vasodilation whereas infusion of an ET(B) receptor antagonist causes vasoconstriction. ET-1 plasma levels are elevated in CHF and correlate both with the hemodynamic severity and with symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death in patients after myocardial infarction and with CHF. ET-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia, and renal impairment in CHF. Selective ET(A) as well as combined ET(A/B) receptor antagonists have been studied in patients with CHF showing impressive hemodynamic improvements (i.e. reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis of CHF which still carries a high mortality.

Topics: Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Hypertension; Myocardial Infarction; Receptors, Endothelin; Treatment Outcome; Vascular Resistance

There is now considerable evidence to support a role for the endothelin (ET) system in the pathogenesis and progression of chronic heart failure (CHF). As such, the potential exists for this system to be useful in both diagnosis (by measurement of peptide levels in plasma and other body fluids) and treatment (by pharmacological blockade) of this condition. Plasma levels of endothelin-1 (ET-1) are elevated in CHF and the magnitude of elevation correlates with disease severity. ET-1 levels in plasma predict subsequent mortality in patients with CHF. ET-1 may also contribute to symptoms associated with CHF, such as exercise intolerance. In the diagnosis of CHF, plasma levels of ET-1 appear to be a less powerful discriminator between patients with mild disease and control subjects with normal ventricular function on multivariate analyses, compared to brain natriuretic peptide (BNP), or its N-terminal fragment. ET-1 concentrations are also elevated in the saliva of patients with CHF and may represent an alternative approach to assessment of the status of the ET system in these patients. Specific ET receptor antagonists (both mixed and ET(A)-selective) have been developed. Studies with these agents in animal models of CHF have demonstrated beneficial effects via both haemodynamic and non-haemodynamic pathways. A number of short-term clinical studies have been performed demonstrating improvements in haemodynamic parameters without neurohormonal activation. Long-term clinical studies with ET receptor antagonists are currently underway to definitively test the impact of blockade of this system on mortality and major cardiovascular endpoints. Endothelin converting enzyme (ECE) inhibitors represent an alternative strategy of ET blockade, and early data from animal models suggest these agents may be of clinical utility, either alone or, more likely, in combination with other zinc metallopeptidases.

Topics: Animals; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Receptors, Endothelin

Heart failure still carries a high morbidity and mortality, necessitating new approaches for its management. Greater understanding of the pathophysiology of heart failure has opened the way for novel therapeutic approaches, including analogs of natriuretic peptides and drugs that modulate endothelin, cytokine release and endothelial vasoconstriction. Other drugs are undergoing laboratory and clinical trials that will eventually supersede or complement less optimal heart failure treatments. Clinical trials will ascertain if these new strategies in the treatment of heart failure will ultimately be successful in the management of these patients.

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Atrial Natriuretic Factor; Bosentan; Calcium; Cardiotonic Agents; Clinical Trials as Topic; Endothelin-1; Heart Failure; Humans; Hydrazones; Muscle Proteins; Neprilysin; Phosphodiesterase Inhibitors; Pyridazines; Simendan; Sulfonamides; Tumor Necrosis Factor-alpha

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Capillary Permeability; Endothelin-1; Endothelium; Female; Heart Failure; Heart Transplantation; Humans; Leg; Male; Microcirculation; Middle Aged; Posture; Regional Blood Flow; von Willebrand Factor

Endothelin-1 has been appreciated in animals and humans as a potential target for inhibition in patients with acutely decompensated congestive heart failure (CHF), as well as patients with a chronic low-output state. There has been intense interest in determining the effects of endothelin-1 on the cardiovascular system. Elevated plasma levels of endothelin-1 in patients with CHF portend a poorer prognosis than similar patients without elevated levels. Endothelin-1 levels correlate inversely with maximum oxygen consumption, and inhibition of the myocardial endothelin pathway in rats with CHF improves survival. An association between endothelin-1 and the development of CHF has recently been supported. Selectively inhibiting the endothelin A receptors in dogs with CHF produced hemodynamic improvement. Similarly, in rabbits, a structural advantage was demonstrated. Benefits in cardiac remodeling have been demonstrated in several models of CHF by nonselectively antagonizing endothelin receptors. In human trials using nonselective endothelin-1 inhibitors, researchers have demonstrated hemodynamic benefit and improvement in cardiac function in patients with decompensated CHF. Inhibition of endothelin-1 in patients with CHF appears to have potential therapeutic value, and ongoing clinical trials will further investigate the safety, efficacy, and role of this new potential therapeutic target for the treatment of CHF.

Topics: Animals; Disease Models, Animal; Disease Progression; Dogs; Drug Evaluation, Preclinical; Endothelin-1; Heart Failure; Hemodynamics; Humans; Oxygen Consumption; Prognosis; Pyridines; Rabbits; Rats; Survival Analysis; Tetrazoles

Endothelin (ET)-1 is a potent vasoconstrictor with growth promoting and mitogenic properties associated with various cardiovascular diseases (CVD) and has been found to be an important protagonist in congestive heart failure (CHF). The introduction of ET-1 receptor antagonists into the arena of clinical research has amplified our understanding of the ET system: the first human trials with acute and chronic inhibition of the ET system have shown promising results and confirm the findings from experimental models. The availability of oral compounds such as bosentan has raised the hope that these novel drugs might become a new therapeutic class of agents for the treatment of CVD and, in particular, of CHF. The question, however, remains whether the beneficial effects observed so far in patients with CHF go beyond simple hemodynamic improvements and whether these compounds improve long-term survival in these patients.

Topics: Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Sulfonamides; Vasoconstriction

Our understanding of the pathophysiology of chronic heart failure is rapidly expanding. recent investigations suggest a role for various proinflammatory and vasoconstrictive cytokines in the development and progression of the disease. In particular, tumor necrosis factor-alpha, interlukin-6, and endothelin have all been implicated in heart failure desease progression. These cytokines appear to be activated in response to a remodeling, induction of programmed cell death, neurohormonal activation, and hemodynamics, these agents cause a variety of deleterious effects in the setting of ventricular dysfunction. Investigational inhibitors and antagonists of these substances show promise for the future treatment of heart failure.

Topics: Apoptosis; Cytokines; Disease Progression; Endothelin-1; Heart Failure; Humans; Interleukin-6; Nitric Oxide; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin Receptor Antagonists; Cytokines; Disease Progression; Endothelin-1; Heart Failure; Humans

The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Atrasentan; Bosentan; Controlled Clinical Trials as Topic; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Obstructive; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Pyrrolidines; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Time Factors; Vasoconstriction; Vasodilation

The important neuroendocrine systems implicated in heart failure are reviewed here, with special emphasis on their possible role in pathophysiology and the chances of pharmacological intervention. The part played by the sympathetic nervous system and the renin-angiotensin-aldosterone system and the beneficial effects of beta-blockers, ACE inhibitors, and angiotensin II antagonists are well-established. The involvement of vasopressin, endothelin-1, ANP, BNP, and TNF-alpha and the interventional possibilities relating to these hormones are also discussed. It is concluded that, in addition to the known interventional principles of neuroendocrine activation, there is a series of new exciting principles and some of them might become important in the future.

Topics: Atrial Natriuretic Factor; Cytokines; Endothelin-1; Heart Failure; Humans; Nitric Oxide; Receptors, Endothelin; Receptors, Vasopressin; Renin-Angiotensin System; Sympathetic Nervous System

Neurohumoral systems activated in heart failure are reviewed in relation to prognostic and diagnostic information. Plasma levels of noradrenaline, renin, vasopressin, endothelin-1, ANP, BNP, and TNF-alpha are all elevated in heart failure. Most of these factors correlate with the prognosis, but only a minor part seems to possess additional, independent information when other information that is normally available in such patients is taken into account. At present, the diagnosis of heart failure cannot be made on only one blood sample. However, neuroendocrine markers seem: 1) to have a role in the diagnosis and classification of heart failure, 2) to be useful in providing a "neuroendocrine profile", which elucidates different aspects of heart failure, and 3) to be of probable value in the choice and titration of medical treatment for the individual patient in the future.

Topics: Atrial Natriuretic Factor; Endothelin-1; Heart Failure; Humans; Norepinephrine; Prognosis; Tumor Necrosis Factor-alpha; Vasopressins

The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class of agents that are being evaluated for their potential benefits in treating various cardiovascular disorders. Bosentan is an orally active endothelin receptor antagonist that has been studied for the treatment of CHF. Early clinical experience with bosentan has confirmed some benefits on hemodynamic parameters in patients with CHF. Its role in slowing the progression of the disease and improving survival remains to be elucidated.

Topics: Animals; Antihypertensive Agents; Bosentan; Controlled Clinical Trials as Topic; Dogs; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hemodynamics; Humans; Placebos; Rats; Receptors, Endothelin; Sulfonamides; Time Factors

Despite conventional therapy, there is still much room for improvement in the prognosis of patients with chronic systolic heart failure. Evidence supports a role for endothelin-1 (ET-1), a potent vasoconstrictor, in the pathophysiology of heart failure. Given its potentially deleterious effects, the optimal treatment of heart failure may need to include efforts directed toward antagonizing this hormone. In support of this notion, the use of ET receptor antagonists produces a number of beneficial effects in heart failure, including both improvements in hemodynamics and reductions in the levels of other vasoconstricting neurohormones. There are at least 2 receptors for ET-1 (the ET-A and ET-B receptor), and the effects of ET-1 binding differ depending on the receptor involved. It is still unclear whether blockade of the ET-A receptor alone or the combined blockade of both the ET-A and ET-B receptors will be most efficacious as a therapeutic strategy. Long-term benefits have been achieved with the use of a mixed ET-A/B receptor antagonist, when added to standard triple-drug therapy, in patients with severe heart failure. We await the results of ongoing trials to determine if these agents will fulfill the promise of adding substantial incremental benefit to the treatment of the disease.

Topics: Bosentan; Carboxylic Acids; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Indans; Peptides, Cyclic; Prognosis; Pyridines; Pyrimidines; Receptors, Endothelin; Sulfonamides; Treatment Outcome

Pathogenic mechanisms of chronic systolic heart failure are constantly of great interest. In recent years the neurohumoral theory of heart failure has gained attraction. According to this theory, neurohumoral mechanisms play the main role in the pathogenesis of heart failure, especially in its progression. These mechanisms can be divided into 2 categories: vasoconstrictive, mitogenic and antinatriuretic on the one hand and vasodilative, antimitogenic and natriuretic on the other one. The former consists of sympathetic nervous system, renin-angiotensin-aldosterone system, vasopressin, endothelin, cytokines. The latter comprises natriuretic peptides, prostaglandins and nitric oxide. Undoubtedly unfavourable roles of sympathetic system and renin-angiotensin-aldosteron have been shown in the progression of heart failure. Data are being also gathered confirming harmful effects of endothelin and cytokines and possibly of neuropeptide Y and vasopressine. Extensive data exist that demonstrate beneficial influence of natriuretic peptide on heart failure. The roles of nitric oxide as well as recently discovered adrenomedullin and medullipin are far from clear.

Topics: Chronic Disease; Cytokines; Disease Progression; Endothelin-1; Heart Failure; Humans; Natriuretic Agents; Neuropeptide Y; Nitric Oxide; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

1. Brachial artery infusion of endothelin (ET)-1 causes transient vasodilatation followed by sustained vasoconstriction of the forearm vascular bed, whereas ET-1 antagonists cause sustained vasodilatation. These data suggest that ET-1 contributes to basal vascular tone. 2. Systemic infusion of ET-1 increases blood pressure and total peripheral vascular resistance and reduces heart rate and cardiac output. The renal and pulmonary circulations are particularly sensitive to the vasoconstrictor effects of ET-1. Systemic infusion of the ETA/B receptor antagonist TAK-044 reduces mean arterial pressure and peripheral vascular resistance. 3. Plasma ET-1 concentrations are not elevated in essential hypertension; however, insulin resistance may be a major determinant of plasma ET-1 concentrations. Vascular sensitivity to ET-1 is normal or may be increased in essential hypertension. 4. Plasma ET-1 concentrations are increased in moderate and severe heart failure and are correlated with clinical and haemodynamic measures of severity. Endothelin-1 contributes to increased vascular tone in cardiac failure. 5. Plasma ET-1 concentrations increase following myocardial infarction and persistent elevation predicts an increased mortality within the subsequent 12 months. 6. Preliminary data suggest that interventions that reduce the activity of the endothelin system may have a beneficial effect in heart failure and myocardial infarction.

Topics: Cardiovascular Diseases; Endothelin-1; Forearm; Heart Failure; Humans; Hypertension; Myocardial Ischemia

The endothelium is a major regulator of vascular tone, releasing vasoactive substances such as endothelium-derived nitric oxide (EDRF), endothelium-derived hyperpolarizing factor(s), cycloxygenase metabolites, endothelin and other endothelium-derived contracting factors (EDCF). In a number of cardiovascular pathologies, such as hypertension or heart failure, the balance in the endothelial production of vasodilating and vasoconstricting mediators is altered. The resulting apparent decrease in endothelium-dependent relaxations is termed 'endothelial dysfunction'. In hypertensive patients and in animal models of hypertension, endothelium-dependent relaxations are impaired. However, this endothelial dysfunction presents different characteristics depending on the model studied. In Dahl-salt-sensitive rats, the decrease in endothelium-dependent relaxations is associated with impaired constitutive nitric oxide synthase activity. The presence of an endogenous nitric oxide synthase inhibitor and a decreased response of vascular smooth muscle to the mediator may contribute also to the dysfunction observed in this model. In other animal models of hypertension (such as spontaneous hypertension). the contribution of the L-arginine nitric oxide pathway to endothelium-dependent responses appears normal or impaired despite reports of increased nitric oxide synthase activity or expression. In large arteries from SHR, endothelium-dependent relaxations are impaired mainly because of the concomitant augmented release of endoperoxides activating thromboxane-endoperoxide receptors. Superoxide anions may also play a role in some models, but only in the early phase of the disease: whether or not these species contribute to further development of endothelial dysfunction or to increases in blood pressure remains to be examined. The endothelial dysfunction observed in hypertension is likely to be a consequence of high blood pressure. but it could facilitate the maintenance of elevated peripheral resistance at a later stage in the disease and favour the occurrence of complications, such as atherosclerosis.

Topics: Acetylcholine; Animals; Biological Factors; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Heart Failure; Humans; Hypertension; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Rats; Reactive Oxygen Species

Cardiac myocytes and vascular endothelial cells produce endothelin-1, which increases the contractility of cardiac muscles and of vascular smooth muscles. Endothelin-1 also exerts long-term effects, such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. In heart failure, the production of endothelin-1 is markedly increased in the failing heart. Here, evidence that an endothelin receptor antagonist is a useful new drug for the treatment of heart failure is discussed. Long-term treatment with an endothelin receptor antagonist greatly improves the survival rate of animals (rat, hamster, etc.) with chronic heart failure. This beneficial effect is accompanied by amelioration of left ventricular dysfunction. The myocardial endothelin system appears to be a novel and important target for therapeutic intervention in heart failure.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Heart Failure; Hemodynamics; Humans; Myocardial Contraction; Myocardial Ischemia

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.

Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Rats; Vasoconstrictor Agents

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Calcium Channel Blockers; Drugs, Investigational; Endothelin-1; Heart Failure; Hormones; Humans

Topics: Animals; Atrial Natriuretic Factor; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Renin-Angiotensin System

Endothelin-1 (ET-1) is the most potent vasoconstrictor yet described. The active 21-amino-acid peptide is derived from the conversion of the inactive precursor "Big ET-1" by an enzyme called endothelin-converting enzyme. In addition to its potent action as a vasoconstrictor, endothelin promotes growth and proliferation of smooth muscle and myocardial hypertrophy. ET-1 levels are elevated in acute myocardial infarction (MI), atherosclerosis, renal failure, diabetes, pulmonary hypertension, and congestive heart failure (CHF). ET-1 levels correlate extremely well with the seriousness of the pathophysiologic condition. ET-1 levels at 72 h post MI accurately predict long-term survival. In patients with heart failure, ET-1 levels also predict long-term outcome, with the prognosis being severely compromised in patients with elevated ET-1 levels. Levels of plasma big ET-1 have been demonstrated to predict 1-year mortality and have been shown to be a better predictor of 1-year outcome than plasma atrial natriuretic peptide and norepinephrine, NYHA class, age, and echocardiographic left ventricular parameters. Although a small number of studies have reported beneficial effects of ACE inhibitors on ET-1 levels in animal models, most reports in humans have not found an effect of ACE inhibitors on ET-1 levels. Only one ACE inhibitor, fosinopril, has been shown to be effective in normalizing ET-1 levels in clinically relevant situations, such as the long-term study of patients with CHF. This observation may point to a superior role of fosinopril compared with other ACE inhibitors in CHF patients and may indicate beneficial effects of fosinopril beyond blood pressure control.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cardiovascular Diseases; Endothelin-1; Heart Failure; Humans; Prognosis; Receptors, Endothelin

Experimental observations, made over the past two decades, have led to a profound shift in the conceptual paradigms about the syndrome of heart failure. As a consequence, heart failure is nowadays considered as a complex disease, not merely characterized by haemodynamic disturbances. Instead, it is now believed that the syndrome is governed and impelled by neurohumoral imbalances and by intracardiac paracrine processes. The latter processes are mediated by activated cardiac endothelial cells and by cytokines, creating a state of cardiac maladaption and leading to disease progression. The clinical benefit of several therapeutic interventions that could not be satisfactorily clarified by improvements in the haemodynamic status, may, therefore, be explained by an unexpected impact on cytokines and endothelial dysfunction. Further extension of these insights will form the basis for the future treatment of heart failure.

Topics: Animals; Cytokines; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Receptors, Endothelin; Ventricular Dysfunction, Left

Myocardial ischemia results in myocardial dysfunction. Recovery may be delayed ("stunning"), or persistent if perfusion remains reduced ("hibernation") and ischemia may go on to necrosis, thus, contributing to chronic heart failure. In addition, myocardium not directly affected by ischemia may undergo adaptive processes like hypertrophy and dilatation, which may result in chronic left heart failure. This process is characterized by hemodynamic, neurohumoral, and progressive morphologic changes of the heart which are closely interrelated. Hemodynamic changes basically consist of an increase in left ventricular filling pressure and a decrease in global ejection fraction, and, in most cases years after myocardial infarction, in an increase in systemic vascular resistance and right atrial pressure. Neurohumoral changes consist of an increase in plasma catecholamines, atrial natriuretic factor and vasopressin, and in an activation of the renin-angiotensin-system. Plasma endothelin-1 was recently reported to be increased in patients with heart failure, and prognosis was related to endothelin levels. Diminished response of vessels to endothelium (EDRF/NO) dependent vasodilatation suggests impairment of vascular endothelium in heart failure. Local changes of cardiac neurohumoral systems could contribute to structural changes of the heart, e.g., systemic activation to hemodynamic changes. Structural changes of the heart are characterized by an increase in volume and thickness of surviving myocardium and an expansion of ischemic and necrotic myocardium. Molecular control of these processes which include various cell types, such as cardiomyocytes and cardiofibroblasts, are currently an issue of intense research and could result in specific therapeutic importance.

Topics: Chronic Disease; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Myocardial Ischemia; Myocardial Stunning; Myocardium; Necrosis; Nitric Oxide

Topics: Angiotensin II; Animals; Calcium; Cardiomegaly; Endothelin-1; Heart Failure; Humans; Interleukin-1; Neurotransmitter Agents; Receptors, Adrenergic, beta; Ventricular Remodeling

Topics: Animals; Bosentan; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Mice; Myocardial Infarction; Myocardium; Peptides, Cyclic; Rats; Receptors, Endothelin; Stroke Volume; Sulfonamides; Time Factors

Topics: Coronary Disease; Endothelin-1; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Hypertension; Kidney Diseases; Postoperative Period; Time Factors

In congestive heart failure (CHF), low cardiac output decreases the fullness of the arterial circulation. This underfilling of the arterial vascular compartment unloads the baroreceptors, resulting in a sequence of events to maintain arterial circulatory integrity. Among them, the renin-angiotensin-aldosterone axis, the sympathetic nervous system, the non-osmotic release of vasopressin and the endothelins are activated to increase vascular resistance and enhance sodium and water renal retention. Simultaneously, vasodilatory and natriuretic substances such as the natriuretic peptides are activated to counterregulate these vasoconstrictors. In the initial phase of CHF, these events contribute to the cardiorenal adaptation. However, when CHF progresses, they become maladaptive and further depress vantricular performance and increase sodium and water retention. This vicious cycle of CHF provides the rationale for the use of neurohormonal antagonists in CHF. The beneficial effects of angiotensin converting enzyme inhibitors in CHF are well described. Vasopressin V1 receptor antagonists have been associated with peripheral vasodilation and improved cardiac function in some patients with CHF. In CHF animals, the vasopressin V2 receptor antagonist has been demonstrated to reverse the defect in water excretion. Bosentan, an endothelin antagonist, is associated with an increase of cardiac index in patients with CHF. A role for exogenous natriuretic peptides is also under investigation. Modulation of the neurohumoral systems associated with CHF opens a new perspective in the treatment of cardiac edema, principally by improving cardiac performance.

Topics: Animals; Body Water; Endothelin-1; Heart Failure; Homeostasis; Humans; Renin-Angiotensin System; Sodium; Vasopressins

Recent studies have identified the importance of biologically active molecules such as neurohormones as mediators of disease progression in heart failure. More recently it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggests that the cytokines, much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.

Topics: Animals; Cytokines; Endothelin-1; Heart Failure; Hemodynamics; Humans; Interleukin-6; Prognosis; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

The endothelium is involved in cardiac and vascular dysfunction characteristic of heart failure. Vascular dysfunction has been related either to an impaired endothelium dependent vasodilation of both capacitance and resistance vessels, or to an increase in the plasmatic levels of endothelium derived contracting factors, such as endothelin-1. While the former seems to respond favourably to ACE-inhibitors, physical training and L-arginine; the latter will soon be treatable with endothelin-1 A e B receptor antagonists or with inhibitors of its converting enzyme. Cardiac dysfunction may be explained not only by the loss of the positive inotropic effect induced by low concentrations of nitric oxide (produced by the constitutive NO-synthase in the normal endothelium), but also by the negative inotropic effect induced by the high concentrations of nitric oxide, produced as a consequence of the stimulation of the inducible NO-synthase. It is therefore conceivable that cardiac dysfunction would also improve with the administration of drugs presently used to correct endothelium dependent vasodilatation disturbances.

Topics: Endothelin-1; Endothelium, Vascular; Heart; Heart Failure; Humans; Vasodilation

We examined the signal transduction pathway for the development of cardiac hypertrophy induced by high blood pressure. The activities of Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) was examined by passively stretching neonatal rat cardiomyocytes in vitro. Mechanical stretch activated these protein kinases transiently and sequentially: the maximal activation of Raf-1, MAPKK, MAPKs and p90rsk was observed at 2 minutes, 5 minutes, 8 minutes and 10 approximately 30 minutes, respectively. Both angiotensin II (AngII) and endothelin-1 (ET-1) were constitutively secreted from cultured cardiomyocytes, and a significant increase in the concentration was recognized in the culture medium of cardiomyocytes within 10 minutes after stretch. ET-1 mRNA levels were also increased in cardiomyocytes at 30 minutes after stretch. Moreover, ET-1 and AngII synergistically activated Raf-1 and MAPKs in cultured cardiomyocytes. In conclusion, mechanical stretch stimulates secretion and production of AngII and ET-1 in cultured cardiomyocytes, and both vasoconstrictive peptides may play an important role in mechanical stress (high blood pressure)-induced cardiac hypertrophy.

Topics: Angiotensin II; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomyopathy, Hypertrophic; Endothelin-1; Heart Failure; Humans; Hypertension; Proto-Oncogene Proteins c-raf; Rats; Signal Transduction; Stress, Mechanical

Topics: Animals; Arteriosclerosis; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Heart Failure; Humans; Hypertension, Pulmonary; Primary Prevention; Prognosis; Vasoconstriction

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Coronary Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension; Migraine Disorders; Raynaud Disease; Subarachnoid Hemorrhage

The endothelin (ET) family of peptides have potent vascular, cardiac and renal actions which may be of pathophysiological importance in congestive heart failure (CHF). In vivo studies with selective and non-selective ET receptor antagonists are required to clarify the role of ET in the pathophysiology of CHF and determine whether anti-ET drugs may be therapeutically useful in CHF. The impact of angiotensin converting enzyme (ACE) inhibitors on the management of CHF has been such that for any new treatment to be of value it will probably have to offer hemodynamic benefit over and above that already obtained with an ACE inhibitor; anti-ET agents seem to have this potential. The recent formal cloning and characterization of endothelin converting enzyme (ECE) should hasten the development of specific and selective ECE inhibitors and thus provide an alternative investigative, and perhaps therapeutic, tool. Morbidity and mortality from CHF remain unacceptably high even in patients receiving maximal medical therapy, including an ACE inhibitor. Blockade of either the generation (through ECE inhibition) or actions (through receptor blockade) of ET warrant further investigation as potential new therapeutic strategies.

Topics: Endothelin-1; Endothelins; Endothelium, Vascular; Heart Failure; Humans; Prognosis; Severity of Illness Index; Vascular Resistance; Vasoconstriction

To investigate the clinical effects of Xinkeshu combined with levosimendan on perioperative heart failure in oldest-old patients with hip fractures.. Oldest-old patients over 80 years old with perioperative heart failure and hip fractures were randomly divided into the control and observation groups, with 50 patients in each group. All patients in both groups were treated with conventional anti-heart failure therapy and levosimendan, whereas patients in the observation group additionally received Xinkeshu tablets. Clinical manifestations; left ventricular ejection fraction (LVEF); left ventricular end-diastolic dimension (LVEDD); left ventricular end-systolic dimension (LVESD); B-type natriuretic peptide (BNP), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and endothelin-1 (ET-1) levels; and self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores were compared between before and after treatment to evaluate the curative effects of Xinkeshu combined with levosimendan.. After treatment, the efficacy rate was significantly higher in the observation group than in the control group. LVEF and the levels of SOD and NO were higher in the observation group than in the control group after treatment. However, LVEDD; LVESD; BNP, MDA, and ET-1 levels; and the SAS and SDS scores were lower after treatment in the observation group than in the control group.. Levosimendan combined with Xinkeshu can improve cardiac function, alleviate oxidative stress, and relieve anxiety and depression in oldest-old patients with perioperative heart failure and hip fracture.

Topics: Aged; Aged, 80 and over; Drug Therapy, Combination; Drugs, Chinese Herbal; Endothelin-1; Female; Heart Failure; Hip Fractures; Humans; Male; Malondialdehyde; Natriuretic Peptide, Brain; Nitric Oxide; Simendan; Treatment Outcome

Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve.. Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001).. Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype.. NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

Topics: Aged; Arterial Pressure; Atrial Natriuretic Factor; Case-Control Studies; Cross-Sectional Studies; Echocardiography; Endothelin-1; Exercise; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Peptide Fragments; Prospective Studies; Pulmonary Artery; Stroke Volume

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI.. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients.. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint).. Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies.. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.

Topics: Aged; Biomarkers; Endothelin-1; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Spironolactone; Survival Rate; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

Concomitant renin-angiotensin-aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF.. This was an open-label, noncontrolled single-sequence study. After a 24-h run-in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II-IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]).. On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio-to-baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT-proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin-1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100- and 200-mg doses, the Cmax and AUC0-12 h for sacubitril and LBQ657 were approximately dose-proportional while that of valsartan was less than dose-proportional.. Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

Topics: Aged; Aldosterone; Aminobutyrates; Angiotensin Receptor Antagonists; Area Under Curve; Biomarkers; Biphenyl Compounds; Chronic Disease; Drug Administration Schedule; Drug Combinations; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Renin-Angiotensin System; Russia; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Function, Left

Topics: Biomarkers; Body Mass Index; Cachexia; Chronic Disease; Echocardiography; Endothelin-1; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Risk Factors; Time Factors; Troponin I; Weight Loss

The role of inflammatory and hemodynamic stress biomarkers in heart failure (HF) patients treated de novo with beta-blockers has been poorly studied.. A total of 86 patients (age 56 ± 9 years, 81 men) with left ventricular ejection fraction (LVEF) < 40% and previously not treated with beta-blockers were initiated on carvedilol. At baseline and 12 months later we performed echocardiography, cardiopulmonary exercise testing, and determined serum levels of B-type natriuretic peptide (BNP), endothelin-1 (ET-1), C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha (TNF -a). Patients were followed up over a total period of 9 ± 3 years from baseline.. Increased baseline CRP and its on-treatment decrease were associated with improvement of LVEF (est. coefficient per one SD: 1.6; 95% CI: -0.05,3.28; p = 0.056, and -1.80; -3.43, -0.18; p = 0.030, respectively) and diminishing of LV end-systolic volume index [mL/m2] (-6.83; -11.32; -2.34; p = 0.003, and 5.85; 1.23; -10.46; p = 0.014, respectively). Higher baseline ET-1 and on-treatment increase in TNF-a predicted frequent admissions (> 1) for cardiac complications (odds ratio per one SD: 1.98; 95% CI: 1.09-3.59; p = 0.025, and 2.07, 1.12-3.84, p = 0.021, respectively) whereas higher baseline BNP was associated with increased mortality (hazard ratio per one SD: 2.09, 95% CI: 1.26-3.45; p = 0.004).. Serum biomarkers may have different roles in prediction of clinical outcomes among HF patients treated de novo with carvedilol.

Topics: Adrenergic beta-Antagonists; Aged; Biomarkers; C-Reactive Protein; Carbazoles; Carvedilol; Endothelin-1; Female; Heart Failure; Humans; Inflammation Mediators; Interleukin-6; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Poland; Propanolamines; Stroke Volume; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Cardiotoxicity and congestive heart failure are the major factors that limit the use of anti-neoplastic drug adriamycin (ADR). There is increasing experimental evidence that endothelin-1 (ET-1) and nitric oxide (NO) are vasoactive mediators that regulate cardiac performance. The present study was undertaken to investigate the role of ET-1 and NO in ADR-induced acute cardiotoxicity and to evaluate the protective effect of Ginkgo biloba extract (EGb761) in rats. A single dose of ADR (20 mg/kg i.p.) caused a significant increase in the cardiac enzyme activities of aspartate transaminases (AST), lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB) in the serum of animals. This was accompanied by significant increase in cardiac malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor-alpha (TNF-alpha), ET-1 and nitrite/nitrate (NOx) levels. On the other hand, reduced glutathione (GSH) was significantly depressed. Histopathological examination of heart tissues showed hyalinization of the myocardium, with interstitial edema and inflammatory exudates. Pre-treatment of the animals with EGb761 (100 mg/kg, orally) 10 days before and 5 days after ADR treatment reversed the cardiac enzyme levels to normal value, decreased cardiac MDA, TAC, TNF-alpha. ET-1 and NO(x), increased GSH and reversed the histopathological damage induced by ADR. In conclusion, the cardioprotective effects of EGb761 on markers of ADR-induced acute cardiotoxicity appeared to have been mediated by the regulation of inflammatory and vasoactive mediators, as well as the inhibition of membrane lipid peroxidation. Thus, EGb761 may find use as promising adjuvant therapy to ameliorate cardiotoxicity of ADR.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotonic Agents; Doxorubicin; Endothelin-1; Ginkgo biloba; Heart Failure; Male; Nitric Oxide; Plant Extracts; Rats; Rats, Wistar; Treatment Outcome; Up-Regulation

To study the impact of 24-week therapy with nebivolol in a dose of 5 mg/day on the clinical and functional status of patients with idiopathic pulmonary hypertension (IPH), echocardiographic parameters, and blood levels of vasoactive mediators and nitric oxide (NO) metabolite.. During continuous standard therapy comprising dihydropyridine calcium antagonists, warfarin, and diuretics, 12 patients with IPH and functional class (FC) II-III received nebivolol in a dose of 5 mg/day for 24 weeks. According to the data of right heart catheterization, all the patients had a positive acute pharmacological test with a vasodilator (NO). Six-minute walk test (6'WT), estimation of the Borg dyspnea index (BDI) and FC, transthoracic echocardiography (EchoCG), and measurements of the levels of NO metabolites, endothelin-1, (ET-1), thromboxane B2 (TxB2), and 6-keto-prostaglandin F1alpha (6-ketoPG F1alpha) were done at baseline and after 12 and 24 weeks of the therapy.. Following 24-week nebivolol treatment, there was a statistically significant increase in 6'WT distance (from 473 +/- 47.6 to 516.7 +/- 58.4 m; p < 0.0001) and a drop in BDI (from 3.4 +/- 2.2 to 1.1 +/- 0.7; p < 0.05) and FC (from 2.9 +/- 0.4 to 1.7 +/- 0.2; p < 0.05). Doppler EchoCG showed that pulmonary artery systolic pressure statistically significantly decreased (91.6 +/- 30 to 78.3 +/- 39 mm Hg; p = 0.05) at 12 weeks and slightly increased up to 83.2 +/- 32.4 mm Hg at 24 weeks. After 24-week treatment, the anteroposterior dimensions of the right ventricle (RV) statistically significantly reduced (from 4.4 +/- 0.6 to 3.8 +/- 1.2 cm; p < 0.05). The other EchoCG parameters remained substantially unchanged. There was a statistically reduction in the level of ET-1 (from 2.99 +/- 1.1 to 2.17 +/- 0.8 micromol/l; p < 0.05). The concentrations of 6-ketoPG Fla, TxB2, and NO metabolite remained substantially unchanged at 24 weeks of treatment with nebivolol. There were no adverse reactions requiring that the dose of the drug be discontinued or reduced. Heart rate tended to be lower at a 24-week follow-up. All the patients continued taking nebivolol after completion of the study.. Therapy with nebivolol in a dose of 5 mg/day for 24 weeks led to a significant functional improvement in the patients with IPH and reductions in RV dimensions and blood ET-1 levels. The therapy did not cause adverse reactions.

Topics: Adult; Benzopyrans; Drug Monitoring; Echocardiography, Doppler; Endothelin-1; Ethanolamines; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nebivolol; Nitric Oxide; Pilot Projects; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy.. We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012).. In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.

Topics: Adrenomedullin; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Coronary Disease; Death; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Indoles; Male; Middle Aged; Peptide Fragments; Prognosis; Protein Precursors; Risk; Stress, Physiological; Stroke Volume

Beta-blocker therapy has become a mainstay therapy for the over 5 million patients with chronic heart failure in the United States. Variation in clinical response to beta-blockers is a well-known phenomenon and may be because of genetic differences between patients. We hypothesized that variation in genes of the endothelin system mediate the clinical response to beta-blockers in heart failure.. Single nucleotide polymorphisms (SNPs) in six endothelin system genes were genotyped in 309 heart failure patients in a randomized trial of bucindolol versus placebo therapy. We adjusted for multiple comparisons and tested for association between genotype and time to two prospective endpoints.. Nine SNPs were sufficiently common to undergo statistical analysis. The SNPs had no significant effect on prospective outcomes in the placebo group, or on the primary endpoint of time to death in either arm. Two SNPs (IVS-4 G/A and Lys198Asn) in the endothelin-1 gene, however, predicted time to the combined endpoint of heart failure hospitalization or all-cause death in bucindolol-treated patients. The alleles at these SNPs were in tight linkage disequilibrium appearing on either of two complementary haplotypes. A 'dose-response' trend was observed, with participants carrying the rarer haplotype having the highest hazard ratios as compared to the relative 'protective' effect of the common haplotype.. A common endothelin-1 gene haplotype may be a pharmacogenetic predictor of a favorable clinical response to beta-blocker therapy in heart failure patients. The existence of a less common 'high-risk' haplotype could identify a subpopulation of heart failure patients destined to respond poorly to beta-blocker therapies.

Topics: Adrenergic beta-Antagonists; Aged; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Female; Haplotypes; Heart Failure; Humans; Linkage Disequilibrium; Male; Metalloendopeptidases; Middle Aged; Models, Genetic; Pharmacogenetics; Polymorphism, Single Nucleotide; Propanolamines; Proportional Hazards Models; Receptors, Endothelin

The long-term effects of the angiotensin-receptor blocker candesartan, the angiotensin-converting enzyme inhibitor enalapril or their combination have been incompletely studied in a large cohort of patients with heart failure not treated with beta-blockers. The objective of this study was to investigate the changes in neurohormones and LV volumes and ejection fraction in patients treated with enalapril, candesartan, or enalapril plus candesartan without concomitant beta-blocker therapy.. Three hundred and ninety-two patients from the RESOLVD pilot study not treated with a beta-blocker at baseline or at any time during the trial were analyzed. Norepinephrine, endothelin-1, big endothelin-1, angiotensin-II, aldosterone, N-terminal proANP, BNP, and radionuclide angiography were measured before and after 43 weeks of treatment with candesartan alone (n = 162), or enalapril alone (n = 45), or candesartan plus enalapril (n = 185). Endpoints were assessed at baseline and after 43 weeks of therapy.. LV end-diastolic and end-systolic volumes increased significantly at 43 weeks in all groups except for patients treated with enalapril plus candesartan. BNP decreased at 43 weeks only in patients receiving dual angiotensin-II suppression (-6.1 +/- 37.8 pmol/l). Angiotensin-II levels were significantly increased in patients treated with candesartan (+23.6 +/- 47.1 pg/ml; p<0.05).. We conclude that angiotensin-II modulation, with enalapril and candesartan, without concomitant utilization of beta-blocker lead to a decrease in BNP and an attenuation of the increase in LV end-diastolic and end-systolic volumes without a reversal of this process in the long term.

Topics: Aged; Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Double-Blind Method; Drug Therapy, Combination; Enalapril; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Peptide Fragments; Radionuclide Angiography; Stroke Volume; Tetrazoles; Treatment Outcome; Ventricular Function, Left

The urocortins are emerging as potentially important contributors to neurohumoral regulation of the circulation with recent reports attributing a powerful array of hemodynamic, renal, and neurohumoral effects to the urocortins in cardiac failure. These peptides also seem to have cardioprotective effects in the setting of ischemia-reperfusion. Little is known concerning the plasma concentrations of the urocortins in health and disease. We have investigated plasma urocortin 1 as a potential diagnostic marker of heart failure and documented its relationships to symptoms, measures of cardiac function, and concurrent levels of other circulating neurohormones.. In 299 patients with recent onset dyspnea or peripheral edema presenting to primary care, plasma urocortin 1 and other vasoactive hormones were assayed, and echocardiography was performed. Heart failure was present in 74 patients (25%) according to predefined diagnostic criteria. Urocortin 1 levels were increased in patients with heart failure and were related to functional class, clinical signs of heart failure, echocardiographic indicators of left ventricular dimensions and function, plasma creatinine, and concurrent circulating levels of plasma natriuretic peptides, adrenomedullin, and endothelin 1.. Plasma urocortin 1 is elevated in heart failure (in proportion to the degree of cardiac dysfunction) in concert with the generalized neurohormonal activation seen in this condition. Urocortin levels predict heart failure independent of age, history of previous myocardial infarction, diabetes, hypertension, fractional shortening, and N-terminal prohormone brain natriuretic peptide levels.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; Creatinine; Endothelin-1; Female; Heart Failure; Humans; Logistic Models; Male; Middle Aged; Natriuretic Peptides; Predictive Value of Tests; Prospective Studies; ROC Curve; Severity of Illness Index; Ultrasonography; Up-Regulation; Urocortins; Ventricular Function, Left

Both neurohormonal derangements and alterations in the myocardial extracellular matrix are thought to contribute to adverse ventricular remodelling that results in worsening heart failure (HF). There is also emerging preclinical information to suggest that these signalling pathways mutually regulate in HF.. To assess the relationships between plasma levels of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP), and neurohormonal profiles in chronic HF.. In this substudy of 184 HF patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, plasma norepinephrine and epinephrine were measured with HPLC; atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II, aldosterone, and endothelin-1 were measured with immunoassays; MMP-2, MMP-9, and TIMP-1 were measured with 2-site sandwich ELISA assays. We used Spearman's rank correlation to examine the relationships between plasma MMP and neurohormone levels. Circulating ANP, BNP, and endothelin-1 levels were positively correlated with MMP-2 and TIMP-1 levels. Plasma level of aldosterone showed a weak positive correlation with MMP-9, but there was no significant correlation between angiotensin II, epinephrine or norepinephrine and MMP-2, MMP-9, or TIMP-1.. These findings suggest that specific neurohormones and extracellular matrix modulators may play a coordinated role in the pathogenesis of HF.

Topics: Aged; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Chromatography, High Pressure Liquid; Endothelin-1; Extracellular Matrix; Female; Heart Failure; Humans; Male; Matrix Metalloproteinases; Middle Aged; Neurotransmitter Agents; Tissue Inhibitor of Metalloproteinases

Recent studies on the pathophysiology of heart failure indicate the role of neurohormones and immune and inflammatory processes as potential mechanisms involved in the pathogenesis and clinical course of chronic heart failure (CHF).. To analyse the relationship between concentrations of brain natriuretic peptide (BNP), endothelin-1 (ET-1), inflammatory cytokines (TNF-alpha, IL-6) and cardiopulmonary stress test parameters, and to evaluate their changes during carvedilol treatment.. The study included 86 patients (81 men and 5 women) aged from 35 to 70 years (56.8+/-9.19) with symptomatic heart failure and left ventricular ejection fraction <40%, receiving an inhibitor of angiotensin II converting enzyme, diuretic and/or digoxin but not beta-blockers. All patients at baseline, and then at 3 and 12 months after treatment, underwent a panel of studies to assess functional capacity according to NYHA, echocardiographic and cardiopulmonary stress test (CPX) parameters, and serum concentrations of BNP, ET-1, TNF-alpha and IL-6. Before introducing carvedilol we found a weak relationship between concentrations of BNP, ET-1, IL-6 and decreased VO2 peak.. At 12 months exercise tolerance was significantly improved (exercise stress testing prolonged by 143.9 s, p=0.001) and an increase in metabolic equivalent (MET) by 1.41 (p=0.001) was observed. The VO2 peak was nonsignificantly increased by a mean of 0.9 ml/kg/min. In patients with baseline VO2 peak <14 ml/kg/min the concentrations of ET-1 and TNF-alpha were significantly higher than in the remaining ones, and after treatment they were significantly reduced. In these patients VO2 peak%N was also significantly increased (39.5+/-7.5 vs. 50.1+/-15,0; p=0.013). The number of patients with VO2 peak <14 ml/kg/min also significantly decreased from 39 to 21 (p=0.013).. In patients with HF decreased value of VO2 peak is associated with LV systolic function disorders and increased levels of BNP, ET-1, TNF-alpha and IL-6. Chronic treatment with carvedilol improves LV systolic function, exercise tolerance and peak oxygen consumption and is associated with significant decrease of BNP, ET-1, TNF-alpha and IL-6 concentrations.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Carbazoles; Carvedilol; Endothelin-1; Exercise; Exercise Test; Female; Heart Failure; Humans; Interleukin-6; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen Consumption; Propanolamines; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

High-dose cyclophosphamide is a well-known mobilization regimen in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Highly differing rates of cardiac complications associated with high-dose cyclophosphamide have been reported. To date, no systematic clinical study has investigated high-dose cyclophosphamide mobilization regimens in multiple myeloma patients and evaluated its cardiotoxicity. We administered high-dose cyclophosphamide (4 g/m2) to 23 consecutive multiple myeloma patients and followed the patients for 15 days by serially measuring the cardiotoxicity biomarkers troponin I (TnI), brain natriuretic peptide (BNP), and endothelin 1 (ET-1). Systolic and diastolic left ventricular function was assessed by complete echocardiography before and at 6 to 8 weeks after the therapy. Patients younger than 55 years showed significant differences between basal TnI levels and TnI concentrations determined at 15 days after high-dose cyclophosphamide treatment (P = .028). Significant differences between basal BNP concentrations and BNP levels measured at 8 hours after high-dose cyclophosphamide treatment were found in the entire group of patients as well as in 2 subgroups, patients younger than 55 years and those older than 55 years (P <.0001, P <.001, and P = .001, respectively). ET-1 results for the entire group of patients showed a significant difference between baseline ET-1 values and ET-1 values determined 8 hours after high-dose cyclophosphamide administration (P = .004). Echocardiographic measurements revealed a barely nonsignificant decrease in cardiac output after high-dose cyclophosphamide infusion compared with pretreatment values (P = .06), a result in accord with echocardiographically detected increases in mild functional mitral regurgitation (P = .025). TnI levels at 15 days after the completion of treatment correlated with left ventricular diastolic dysfunction, as indicated by the s/d index (r = 0.61; P = .04). In conclusion, the significant neurohumoral activation of heart failure occurring after high-dose cyclophosphamide treatment is manifested by an increase in BNP and ET-1 levels, yet without concomitant cardiomyocyte necrosis. BNP levels and to a lesser extent ET-1 levels are much more sensitive indicators of myocardial injury than functional tests, such as echocardiography, whereas diastolic functional parameters are more sensitive predictors of early cyclophosphamide-induced cardiotoxicity. Mi

Topics: Adult; Aged; Biomarkers; Cyclophosphamide; Diastole; Echocardiography; Endothelin-1; Female; Graft Rejection; Heart Failure; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Myeloma; Natriuretic Peptide, Brain; Transplantation, Autologous; Troponin I

Serial neurohormones may serve as markers of efficacy of congestive heart failure (CHF) therapy. We measured serial plasma big-endothelin (Big-ET), ET-1, N-terminal atrial natriuretic peptide, and brain natriuretic peptide (BNP) in 206 patients randomized to bucindolol or placebo in Beta-Blocker Evaluation of Survival Trial (BEST).. Neurohormones were measured at baseline and 3 and 12 months. At baseline, BNP and Big-ET levels were greater in New York Heart Association (NYHA) Class IV than in Class III patients (median 122 pg/mL versus 447 pg/mL, P = .001; and 20.0 pg/mL versus 9.9 pg/mL, P = .003), and in patients with left ventricular ejection fraction (LVEF) < or = 20% compared with LVEF > 20% (median 211 pg/mL versus 99.1 pg/mL; and 12.9 pg/mL versus 8.0 pg/mL, both P = .003). Big-ET and BNP were the strongest predictors of the composite end point of CHF hospitalization or death. LVEF at 12 months correlated inversely with 12-month BNP levels (r = -0.41, P = .0001). Bucindolol had no effect on neurohormones except that bucindolol treated patients had lower Big-ET levels at 3 months than patients receiving placebo (median 9.1 pg/mL versus 10.9 pg/mL, P = .05). A decline in ET-1 was associated with increased risk of the composite endpoint.. Lack of effect of bucindolol on natriuretic peptide levels appears consistent with its overall lack of efficacy in BEST.

Topics: Adrenergic beta-Antagonists; Aged; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Endothelins; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Propanolamines; Radioimmunoassay; Stroke Volume; Survival Rate; Treatment Outcome

The vasoconstrictor action of endothelin-1 (ET-1) is mediated through ET(A) and ET(B) receptor subtypes on vascular smooth muscle. ET(B) receptors are also present on the vascular endothelium where they mediate vasodilation. Animal studies suggest that the ET(B) receptor also acts as a clearance receptor for endothelin.. To investigate the effects of a selective ET(A) and a selective ET(B) receptor antagonist alone and in combination on haemodynamics and circulating concentrations of ET-1 in patients with chronic heart failure.. Infusion of BQ-123 (n=10), a selective ET(A) receptor antagonist, led to systemic vasodilation and did not change plasma ET-1 concentrations (1.38+/-0.82 to 1.38+/-0.91 fmol/ml, ns). Infusion of BQ-788 (n=8) led to systemic vasoconstriction with a rise in plasma ET-1 (1.84+/-1.06 to 2.73+/-0.99 fmol/ml, p<0.01). The addition of BQ-123 to BQ-788 led to systemic and pulmonary vasodilation with no further increase in plasma ET-1 concentrations (2.80+/-1.14 to 2.90+/-1.20 fmol/ml, ns).. The rise in plasma ET-1 concentrations in response to selective blockade of ET(B) receptors and the associated adverse haemodynamic effects suggest that ET(B) receptors have a role in the clearance of ET-1 in man and that their blockade may not be advantageous for patients with heart failure.

Topics: Aged; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines

Beta-blocker therapy improves symptoms, left ventricular ejection fraction (LVEF), and survival in patients with congestive heart failure, but chronic effects on neurohormones have not been extensively investigated. Therefore, we examined the neurohumoral effects of carvedilol.. Fifty-five patients with New York Heart Association (NYHA) classes II-III congestive heart failure and LVEF < or =35% entered the study with intention to assess LVEF, NYHA class, plasma brain natriuretic peptide (BNP), N-terminal atrial natriuretic peptide (NANP), big-endothelin, endothelin-1, norepinephrine, and angiotensin II at baseline and at 6 and 12 months after initiation of carvedilol.. Forty-six patients completed 12 months of follow-up. Left ventricular ejection fraction improved from 26% +/- 8% at baseline to 39% +/- 14% at 12 months. New York Heart Association class improved from 2.3 +/- 0.4 at baseline to 1.8 +/- 0.7 at 12 months. Brain natriuretic peptide fell from 453 +/- 784 to 208 +/- 393 pg/mL at 6 months and 223 +/- 334 pg/mL at 12 months ( P = .01 vs baseline). N-terminal atrial natriuretic peptide did not change between baseline and 6 months but fell at 12 months (2117 +/- 1678, 2015 +/- 1532, and 1438 +/- 1442 pg/mL, respectively, P = .001 between baseline and 12 months). Angiotensin II was lower at 6 and 12 months than at baseline (12.6 +/- 10, 7.8 +/- 5.5 pg/mL, P < 0.001, and 11.3 +/- 17.1 pg/mL, P = .02, respectively). Left ventricular ejection fraction at 12 months correlated inversely with BNP level at 12 months (r = -0.55, P = .001).. Carvedilol therapy is associated with a sustained decline in BNP and NANP levels. Serial BNP levels can provide some guidance regarding probability of LVEF improvement, but the relationship is not strong enough for BNP levels to supplant measurement of LVEF.

Topics: Adrenergic alpha-Antagonists; Angiotensin II; Atrial Natriuretic Factor; Biomarkers; Carbazoles; Carvedilol; Endothelin-1; Endothelins; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Propanolamines

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Chronic Disease; Cyclic GMP; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Stroke Volume; Time Factors; Treatment Outcome

In observational studies, statins are associated with lower mortality in patients with heart failure (HF), including those with nonischemic HF. Such benefits could be related to anti-inflammatory effects; however, the effects of statins on systemic inflammation in HF are not well-established. We conducted a 16-week, single-center, randomized, double-blind, placebo-controlled, crossover clinical trial of the effects of atorvastatin 10 mg/day on concentrations of systemic inflammatory markers in 22 patients with HF (including 20 with nonischemic HF) with New York Heart Association class II or III symptoms and left ventricular ejection fraction of <40%. The absolute and percentage of changes in inflammatory marker levels were evaluated using analysis of variance. Statin treatment reduced the concentrations of soluble tumor necrosis factor receptor-1 by 132 pg/ml (p = 0.04) and 8% (p = 0.056), C-reactive protein by 1.6 mg/L (p = 0.006) and 37% (p = 0.0002), and, after adjustment for treatment order, endothelin-1 by 0.21 pg/ml (p = 0.007) and 17% (p = 0.01). In post hoc analyses, the reduction in tumor necrosis factor receptor-1 levels was highest among patients with elevated levels at baseline (at or higher than the median of 1,055 pg/ml, p interaction = 0.001), among whom statin therapy reduced the levels by 306 pg/ml (p <0.001) and 22% (p <0.001). Statin treatment did not significantly affect the levels of other inflammatory markers, including interleukin-6 and brain natriuretic peptide. In conclusion, short-term atorvastatin therapy reduced the levels of several important inflammatory markers in patients with HF.

Topics: Adult; Aged; Atorvastatin; Biomarkers; C-Reactive Protein; Cross-Over Studies; Double-Blind Method; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Pyrroles; Receptors, Tumor Necrosis Factor, Type I; Treatment Outcome

Endothelin antagonists represent a new approach to neurohumoral treatment in patients with chronic heart failure. In this study, the new selective endothelin-A receptor antagonist, darusentan, was compared with placebo for 3 weeks in patients with severe heart failure on top of standard treatment that included angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Effects on neurohormones and hemodynamics were evaluated.. Consecutive patients with severe heart failure (New York Heart Association [NYHA] Grade III) were included in this neurohumoral sub-study of an international, multi-center, double-blind, placebo-controlled study of darusentan, and randomized to darusentan (n = 23) or placebo (n = 8). The mean left ventricular ejection fraction was 19 +/- 6% at the beginning of the study. Patients were randomized to different dosage levels of darusentan (30, 100, or 300 mg) for 3 weeks. Hemodynamics were obtained by right heart Swan-Ganz catheterization at entry and end of study. Serial assessment of plasma brain natriuretic peptide (BNP), big-endothelin, and pro-atrial natriuretic peptide (pro-ANP) was performed. In the active treatment group, 1 patient died due to worsening heart failure, 1 patient received elective heart transplantation, and 2 patients stopped taking the medication due to vertigo. In the placebo group, 1 patient was excluded due to non-compliance.. Overall, the mean dose of darusentan was 144 +/- 125 mg/day (30 mg: n = 8; 100 mg: n = 4; 300 mg: n = 7). Significant benefits in hemodynamic variables were found after 3 weeks only in patients receiving darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01). A significant reduction in mean arterial blood pressure was observed with the endothelin antagonist (baseline 80 +/- 8 vs end 73 +/- 8 mm Hg, p < 0.01). BNP decreased significantly in patients with darusentan (90 +/- 87 at entry vs 63 +/- 67 fmol/ml after 3 weeks, p < 0.01), whereas big-endothelin remained unchanged. Pro-ANP tended to decrease in the active treatment group, but did not reach statistical significance.. Significant hemodynamic and neurohumoral benefits were observed in patients with severe heart failure receiving the selective endothelin antagonist darusentan.

Topics: Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin-1; Female; Heart Failure; Heart Function Tests; Hemodynamics; Humans; Liver Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyrimidines

Patients with heart failure have high levels of central sympathetic outflow and also have a high prevalence of sleep-related breathing disorders, predominantly central sleep apnea. The options for treating central sleep apnea in heart failure are limited and include theophylline. Whether theophylline alters sympathetic activity in heart failure patients is not known.. Using a single-blinded, randomized, placebo-controlled study design, we investigated the sympathetic, hemodynamic, neurohumoral, and ventilatory effects of theophylline in patients with congestive heart failure compared with healthy control subjects closely matched for age, sex, and body mass index. Theophylline increased muscle sympathetic nerve activity and lowered transcutaneous CO2 in the control subjects but only lowered transcutaneous CO2 in the heart failure patients. Theophylline nearly doubled plasma renin concentration in both the healthy subjects (P<0.01) and the heart failure patients (P<0.02).. Our study shows that in heart failure patients, there are differential effects of theophylline: in contrast to healthy subjects, theophylline does not increase sympathetic activity in heart failure, whereas increases in plasma renin and ventilation are still evident. These novel findings may have important implications for understanding the potential harmful and beneficial effects of theophylline and related substances in heart failure patients.

Topics: Adolescent; Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Cardiovascular Agents; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Renin; Respiration; Single-Blind Method; Sleep Apnea, Central; Sympathetic Nervous System; Theophylline

Inhaled nitric oxide (iNO) therapy is an effective treatment of pulmonary hypertension following left ventricular assist device (LVAD) implantation. As iNO may also modulate circulating endothelin-1 (ET-1) and big endothelin following LVAD implantation, we investigated the effects of iNO on ET-1 and big endothelin plasma concentration gradients. In order to assist weaning from cardiopulmonary bypass, iNO was administered to 15 consecutive patients with secondary pulmonary hypertension following implantation of a LVAD. Central venous, pulmonary arterial and arterial ET-1 and big endothelin plasma levels were measured preoperatively, on cardiopulmonary bypass prior to iNO administration, 12, 24 and 48 hours postoperatively, and 72 hours after weaning from iNO. The ET-1 gradients between central venous and pulmonary arterial plasma levels decreased significantly with time, and there was a trend for lower arterial-pulmonary arterial plasma concentration gradients. Big endothelin plasma concentration gradients were not altered significantly. The decrease in ET-1 plasma concentration gradients during and after iNO administration may reflect a restoration of the physiologic balance between the different vascular beds. This provides further evidence that intermittent iNO therapy may modulate ET-1 after LVAD implantation.

Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Cardiac Output, Low; Cardiopulmonary Bypass; Central Venous Pressure; Down-Regulation; Endothelin-1; Female; Heart Failure; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Intraoperative Care; Male; Middle Aged; Nitric Oxide; Time Factors; Treatment Outcome; Ventricular Dysfunction, Right

Topics: Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Myocardial Ischemia; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Recurrence; Tetrazoles; Treatment Outcome; Vasodilator Agents

Patients with congestive heart failure (CHF) have a high incidence of ventricular arrhythmias and sudden arrhythmic death. CHF entails profound and complex abnormalities in humoral responses that are thought to promote arrhythmic events. However, it is unknown which of the many endogenous mediators that accumulate as part of neurohormonal activation is important in arrhythmogenesis in the setting of CHF. The study included 83 patients admitted to the hospital for treatment of decompensated CHF. Neurohormonal and cytokine activation was assessed by measuring plasma renin activity, aldosterone, norepinephrine, endothelin-1, tumor necrosis factor-alpha, and interleukin-6 levels. Atrial and ventricular arrhythmic events were assessed by 24-hour Holter monitoring. In a univariate analysis, a highly significant, positive relationship was found between plasma endothelin-1 levels and the average hourly total premature ventricular beats (P = 0.003), the frequency of ventricular pairs (P = 0.0003), and the frequency of ventricular tachycardia episodes (P = 0.001). After inclusion of clinical variables, drug therapies, neurohormones, and cytokine levels in a multivariate analysis, the positive relationship between plasma endothelin-1 level and the average hourly total premature ventricular beats (P = 0.008), the frequency of ventricular pairs (P = 0.007), and ventricular tachycardia episodes (P = 0.009) remained independent. No association between other neurohormones or cytokines and arrhythmic events was demonstrated. The results of the present study suggest that increased endothelin-1 concentrations may be involved in promoting the occurrence of ventricular ectopy in patients with decompensated CHF. Proarrhythmic effects may account, in part, for the poor outcome associated with increased endothelin-1 levels in patients with decompensated CHF.

Topics: Arrhythmias, Cardiac; Cardiotonic Agents; Cytokines; Dobutamine; Electrocardiography, Ambulatory; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Agents; Natriuretic Peptide, Brain; Neurotransmitter Agents; Ventricular Premature Complexes

The present study investigates whether lower-limb dominant exercise training in patients with chronic heart failure (CHF) improves endothelial function primarily in the trained lower extremities or equally in the upper and lower extremities. Twenty-eight patients with CHF were randomized to the exercise or control group. The exercise group underwent cycle ergometer training for 3 months while controls continued an inactive sedentary lifestyle. Exercise capacity (6-min walk test) and flow-mediated vasodilation in the brachial and posterior tibial arteries were evaluated. After 3 months, walking performance increased only in the exercise group (488+/-16 to 501+/-14 m [control]; 497+/-23 to 567+/-39 m [exercise, p<0.05]). The flow-mediated vasodilation in the brachial arteries did not change in either group (4.2+/-0.5 to 4.5+/-0.4% [control]; 4.3+/-0.5 to 4.6+/-0.4% [exercise]), but that in the posterior tibial arteries increased only in the exercise group (4.1+/-0.5 to 4.1+/-0.3% [control]; 3.6+/-0.3 to 6.4+/-0.6% [exercise, p<0.01]). Cycle ergometer training improved flow-mediated vasodilation in the trained lower limbs, but not in the untrained upper limbs. Exercise training appears to correct endothelial dysfunction predominantly by a local effect in the trained extremities.

Topics: Arm; Brachial Artery; Endothelin-1; Endothelium, Vascular; Exercise Therapy; Exercise Tolerance; Female; Heart Failure; Humans; Hyperemia; Leg; Male; Middle Aged; Organ Specificity; Tibial Arteries; Ultrasonography; Vasodilation

Topics: Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Agents; Natriuretic Peptide, Brain; Statistics as Topic

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Cytokines; Double-Blind Method; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Lisinopril; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Predictive Value of Tests; Prospective Studies; Pyridines; Stroke Volume; Thiazepines; Treatment Outcome

We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF).. In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified.. The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months.. Compared with the placebo group, plasma levels of BNP (-23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (-19% at 3 months, p = 0.03; -16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001).. Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.

Topics: Aged; Aged, 80 and over; Angiotensin II; Atrial Natriuretic Factor; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Spironolactone; Treatment Outcome

Effects of loprinone hydrochloride on plasma ET-1 and TNF-alpha levels were assessed in patients with acute heart failure (AHF).. Thirty patients with AHF were divided into 2 groups and treated with loprinone hydrochloride (0.3 pg/kg/min) (n = 15) or placebo (n = 15). Twenty healthy controls were also included. Plasma ET-1 and TNF-alpha were significantly higher in the 30 AHF patients than in the healthy controls. In AHF patients, loprinone hydrochloride lowered plasma ET-1 and TNF-alpha (p < 0.01).. ET-1 and TNF-alpha may play pathophysiological roles in the progression of AHF. Loprinone hydrochloride is effective in reducing plasma ET-1 and TNF-alpha levels in AHF patients.

Topics: Adult; Cardiotonic Agents; Endothelin-1; Female; Heart Failure; Humans; Imidazoles; Male; Middle Aged; Phosphodiesterase Inhibitors; Pyridones; Tumor Necrosis Factor-alpha

Endothelin-1, a powerful mediator of vasoconstriction, is increased in patients with congestive heart failure and appears to be a prognostic marker that strongly is correlated with the severity of disease. However, little is known about the potential immediate beneficial effects of acute blockade of the endothelin system in patients with symptomatic left ventricular dysfunction. We assessed the hemodynamic effects and safety of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with moderate to severe heart failure.. This randomized placebo-controlled study evaluated the hemodynamic effects of 6-hour infusions of tezosentan at 5, 20, 50, and 100 mg/h compared with placebo in 61 patients with New York Heart Association class III to IV heart failure. Plasma endothelin-1 and tezosentan concentrations were also determined. Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo. Tezosentan also dose-dependently reduced pulmonary capillary wedge pressure and pulmonary and systemic vascular resistances, with no change in heart rate. No episodes of ventricular tachycardia or hypotension requiring drug termination were observed during tezosentan infusion. Tezosentan administration resulted in dose-related increased plasma endothelin-1 concentrations.. The present study demonstrated that tezosentan can be safely administered to patients with moderate to severe heart failure and that by virtue of its ability to antagonize the effects of endothelin-1, it induced vasodilatory responses leading to a significant improvement in cardiac index. Further studies are under way to determine the clinical effects of tezosentan in the setting of acute heart failure.

Topics: Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Heart Failure; Heart Function Tests; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Pulmonary Wedge Pressure; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Tetrazoles; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Chronic heart failure (CHF) is associated with impaired endothelium-dependent vasodilation and increased basal vascular tone due, in part, to elevated endothelin-1 plasma levels. In the present study, we investigated whether a reduction of vascular tone using an endothelin A receptor blocker attenuates the impairment of endothelium-dependent, flow-mediated vasodilation (FMD).. Twenty-one patients with CHF randomly received either the endothelin A receptor blocker LU 135252 (30 mg/d, n=7; 300 mg/d, n=7) or a placebo (n=7). Using high-resolution ultrasound, FMD and endothelium-independent, nitroglycerin-induced dilation of the brachial artery were assessed at baseline in the 21 patients with CHF and in 11 controls and after 3 weeks treatment in the 21 patients with CHF. FMD at baseline was impaired in all 21 patients with CHF (3.2+/-2%) when compared with the 11 controls (9.7+/-4.9%; P=0.0005). In comparison with baseline, FMD significantly improved after 3 weeks of treatment with LU 135252 in all 14 patients receiving it (from 3.0+/-2.0% to 4.9+/-2.9%; P=0.04), but FMD remained unchanged with placebo. Subgroup analysis, according to different dosages, revealed a significant increase of FMD compared with baseline (from 2.4+/-1.5% to 5.5+/-2.4%; P=0.03) in the patients treated with the low-dose (30 mg/d), whereas a high dose of 300 mg/d failed to increase FMD significantly. Improvement in the high-dose group, however, may have been masked by reduced vasodilator capacity due to a significant increase in vessel size (from 4.8+/-0.4 to 5.1+/-0.7 mm; P=0.03).. These results suggest that endothelin A receptor blockade improves FMD in CHF patients.

Topics: Blood Flow Velocity; Brachial Artery; Chronic Disease; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Heart Failure; Heart Function Tests; Humans; Linear Models; Male; Middle Aged; Nitroglycerin; Phenylpropionates; Protein Precursors; Pyrimidines; Receptor, Endothelin A; Treatment Outcome; Vasodilation

One of the putative mechanisms for the salutary effects of beta-blockers in patients with congestive heart failure (CHF) is their ability to improve autonomic dysfunction. However, patients with profound neurohumoral abnormalities derive little survival benefit from beta-blockers. The purpose of the current study was to evaluate the effect of beta-blockers on heart rate variability (HRV) in decompensated CHF.. Time and frequency domain HRV indices were obtained from 24-hour Holter recordings and compared to assess the role of beta-blockade in 199 patients (mean age 60 +/- 14 years) with decompensated CHF. Neurohormonal differences were assessed by measuring norepinephrine, endothelin-1, tumor necrosis factor-alpha, and interleukin-6 in a subset of 64 patients.. All HRV indices were markedly suppressed but were substantially higher in patients who were on beta-blockers. Time domain measures of parasympathetic cardiac activity, the percentage of R-R intervals with > 50 ms variation (4.9 +/- 0.6 vs 7.7 +/- 1.2%, P = 0.006) and the square root of mean squared differences of successive R-R intervals (22.7 +/- 2.0 vs 31.6 +/- 4.1 ms, P = 0.004), were higher in the beta-blocker group. Spectral analysis revealed that the total power and the ultra-low frequency power were significantly higher in patients on beta-blockers (82% and 59%, respectively). The high frequency power, a spectral index of parasympathetic modulation, was 41% higher in the beta-blocker group (121 +/- 25 vs 171 +/- 27 ms(2), P = 0.02). Norepinephrine and interleukin-6 levels were substantially lower in patients on beta-blockers (28% and 61%, respectively). However, these differences did not reach statistical significance.. Beta-blockers improve the impaired cardiac autonomic regulation during high sympathetic stress of decompensated CHF. This effect may play an important role in protecting the myocardium and preventing arrhythmias during transient increases in sympathetic activity.

Topics: Adrenergic beta-Antagonists; Aged; Autonomic Nervous System; Disease Progression; Electrocardiography, Ambulatory; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Interleukin-6; Male; Middle Aged; Neurotransmitter Agents; Norepinephrine; Prospective Studies; Tachycardia, Ventricular; Treatment Outcome; Tumor Necrosis Factor-alpha

Endothelin-1, a potent vasoconstrictor, is elevated in congestive heart failure and is postulated to play a major role in the pathogenesis of the disease. Endothelin receptor antagonism may be a specific therapeutic approach. This study was designed to determine the effective dosage range, hemodynamic effects, and tolerability of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with advanced heart failure.. This randomized, double-blind, placebo-controlled multicenter trial enrolled 38 patients with symptomatic stable heart failure (New York Heart Association class III, left ventricular ejection fraction <35%) undergoing right heart catheterization. Patients were equally randomized to a 4-hour intravenous infusion of placebo or tezosentan in ascending doses (5, 20, 50, and 100 mg over 1 hour each). Angiotensin-converting enzyme inhibitors and diuretics were withheld 24hours before the study. Hemodynamics were measured during and for 4 hours after the infusion.. Compared with placebo, tezosentan treatment produced a significant increase in cardiac index (treatment difference 0.59 L/min/m(2), P =.0001) and decreases in pulmonary and systemic vascular resistances (P

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Epinephrine; Female; Heart Failure; Heart Function Tests; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Prospective Studies; Pyridines; Tetrazoles; Vasodilator Agents

The study assessed the relative predictive potency of neurohumoral factors in patients with advanced left ventricular (LV) dysfunction during neurohumoral blocking therapy.. The course of heart failure is characterized by progressive LV deterioration associated with an increase in cardiac (natriuretic peptides) and predominantly extracardiac (norepinephrine, big endothelin [big ET]) hormone plasma levels.. Plasma hormones were measured at baseline and months 3, 6, 12 and 24 in 91 patients with heart failure (left ventricular ejection fraction [LVEF] <25%) receiving 40 mg enalapril/day and double-blind atenolol (50 to 100 mg/day) or placebo. After the double-blind study phase, patients were followed up to four years. Stepwise multivariate regression analyses were performed with 10 variables (age, etiology, LVEF, symptom class, atenolol/placebo, norepinephrine, big ET, log aminoterminal atrial natriuretic peptide, log aminoterminal B-type natriuretic peptide [N-BNP] and log B-type natriuretic peptide [BNP]). During the study, the last values prior to patient death were used, and in survivors the last hormone level, New York Heart Association class and LVEF at month 24 were used.. Thirty-one patients died from a cardiovascular cause during follow-up. At baseline, log BNP plasma level (x2 = 13.9, p = 0.0002), treatment allocation (x2 = 9.5, p = 0.002) and LVEF (x2 = 5.6, p = 0.017) were independently related to mortality. During the study, log BNP plasma level (x2 = 21.3, p = 0.0001) remained the strongest predictive marker, with LVEF (x2 = 11.2, p = 0.0008) log N-BNP plasma level (x2 = 8.9, p = 0.0027) and treatment allocation (x2 = 6.4, p = 0.0109) providing additional independent information.. In patients with advanced LV dysfunction receiving high-dose angiotensin-converting enzyme inhibitors and beta-blocker therapy BNP and N-BNP plasma levels are both independently related to mortality. This observation highlights the importance of these hormones and implies that they will likely emerge as a very useful blood test for detection of the progression of heart failure, even in the face of neurohumoral blocking therapy.

Topics: Adrenergic beta-Antagonists; Atenolol; Atrial Natriuretic Factor; Biomarkers; Double-Blind Method; Endothelin-1; Endothelins; Female; Heart Failure; Hormones; Humans; Male; Middle Aged; Norepinephrine; Placebos; Prognosis; Proportional Hazards Models; Protein Precursors; Random Allocation; Risk Factors; Survival Rate; Treatment Outcome; Ventricular Dysfunction, Left

Endothelin-1 (ET-1) can modulate central and peripheral sympathetic outflow. However, if increased ET-1 levels contribute to autonomic perturbations in the setting of congestive heart failure (CHF) is not known. The purpose of this study was to determine if increased ET-1 levels contribute to the depressed HRV in patients with CHF. Sixty-four patients were admitted to the hospital for treatment of decompensated CHF (mean age 59+/-12 years, NYHA Classes III [72%] and IV [28%]). Time- and frequency-domain HRV measures were obtained from 24-hour Holter recordings. Neurohormonal activation was assessed by measuring plasma renin activity (PRA), aldosterone, norepinephrine, and ET-1 levels. Among the time-domain HRV indices, ET-1 correlated negatively with the standard deviation of RR intervals (SDNN) (r = - 0.38, P = 0.002) and standard deviation of all 5-minute mean RR intervals (SDANN5) (r = - 0.48, P < 0.0001), but not with time-domain indices indicative of parasympathetic modulation. Among the frequency-domain HRV indices, ET-1 correlated negatively with the total power (r = - 0.32, P = 0.01) and ultralow frequency power (ULF) (r = - 0.43, P = 0.0004), but not with indices of parasympathetic (high frequency) or sympathovagal (low frequency) modulation. Using multiple linear regression, adjusting for clinical parameters, drug therapies, and other neurohormones, the strong negative relationship between ET-1 and SDNN (P = 0.027), SDANN5 (P = 0.002), and ULF power (P = 0.017) persisted. In conclusion, ET-1 may play an important role in the autonomic dysfunction characteristic of CHF. The correlation between ET-1 levels and prognostically important indices of overall HRV suggests that these HRV measures are better markers of neurohormonal activation in CHF, which may partially account for their greater discriminatory power for risk stratification.

Topics: Aged; Aldosterone; Clinical Trials as Topic; Electrocardiography, Ambulatory; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Norepinephrine; Radioimmunoassay; Renin; Sympathetic Nervous System

This study is aimed at examining the relative importance of norepinephrine and endothelin-1 in treadmill exercise-induced changes in brachial arterial tone of the non-exercised arm in patients with chronic heart failure (CHF). Brachial artery diameter and blood flow were measured before and after exercise in eight healthy volunteers and 18 patients with stable chronic heart failure by high-resolution ultrasound. Maximal exercise resulted in brachial artery dilatation in controls (4.42+/-0.39 vs. 4.77+/-0.39 mm; P<0. 0001) in contrast to constriction seen in the patients (5.27+/-0.67 vs. 5.12+/-0.66 mm; P=0.07). Both groups demonstrated a significant increase in blood flow after exercise. The pre-exercise (2.83+/-0.76 vs. 1.69+/-0.15 pmol/l; P=0.0004), post-exercise (4.15+/-1.5 vs. 2. 02+/-0.34 pmol/l; P=0.0004) and the percent increase (47.15+/-32.5 vs. 19.0+/-10.5%; P=0.02) in endothelin-1 levels were significantly greater in patients than in controls. In contrast to endothelin-1, the exercise-induced percent increase in norepinephrine was greater in controls than patients (100.7+/-51.8 vs. 49.8+/-43.4%; P=0.01). The percent change in the diameter of the brachial artery in response to maximal exercise was significantly correlated to pre- (r=0.634; P=0.003) and post-exercise (r=0.467; P=0.05) endothelin-1 levels in patients but not in controls [pre-exercise (r=0.07; P=0. 86), post-exercise (r=0.310; P=0.47)]. The change in the diameter of the brachial artery did not correlate with pre- or post-exercise plasma norepinephrine levels in either group. These findings suggest that endothelin-1 is potentially more important than norepinephrine in contributing exercise-induced brachial artery constriction in patients with chronic heart failure.

Topics: Brachial Artery; Endothelin-1; Endothelium, Vascular; Exercise; Heart Failure; Hemodynamics; Humans; Linear Models; Male; Middle Aged; Norepinephrine; Regional Blood Flow; Vasoconstriction; Vasomotor System

To compare hemodynamics and plasma big endothelin levels in patients awaiting heart transplantation who are receiving continuous IV therapy, and to establish their respective potency for predicting future cardiac events.. A randomized, prospective trial of ambulatory continuous treatment with IV prostaglandin E(1) (PGE(1)) vs dobutamine. A subanalysis was conducted of all patients who completed 4 weeks of follow-up in regard to treatment effects on hemodynamics and big endothelin plasma levels.. Thirty-two listed heart transplant candidates who were refractory to oral treatment, 21 patients who were receiving PGE(1), and 11 patients receiving dobutamine.. Hemodynamics and plasma big endothelin levels were measured at baseline and after 4 weeks. The cardiac index increased significantly (PGE(1) group, 1.7 +/- 0.4 vs 2.5 +/- 0.6 L/min/m(2); dobutamine group, 1.8 +/- 0.3 vs 2.3 +/- 0.6 L/min/m(2); p < 0.05), whereas the systemic vascular resistance index (SVRI) decreased significantly only in the PGE(1) group (3,352 +/- 954 vs 2,178 +/- 519 dyne. s. cm(-5)/m(2); p < 0. 05). The plasma big endothelin level decreased significantly (PGE(1) group, 7.6 +/- 3.1 vs 4.7 +/- 2.6 fmol/mL; dobutamine group, 6.5 +/- 3.7 vs 5.0 +/- 2.6 fmol/mL; p < 0.01 for the time effect). Plasma big endothelin (beta = 0.393; chi(2) = 10.8; p = 0.001) and SVRI (beta = 0.003; chi(2) = 6.9; p < 0.01), both measured after 4 weeks of continuous treatment, were the only independent predictors of future outcome.. Continuous treatment over 4 weeks with either PGE(1) or dobutamine in patients awaiting heart transplantation yields an improved hemodynamic state accompanied by a reduction of increased big endothelin levels. Plasma big endothelin measured after 4 weeks of continuous therapy provides prognostic information about future outcome.

Topics: Adult; Aged; Alprostadil; Ambulatory Care; Cardiotonic Agents; Dobutamine; Endothelin-1; Endothelins; Female; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Infusions, Intravenous; Long-Term Care; Male; Middle Aged; Prognosis; Prospective Studies; Protein Precursors; Survival Rate; Vascular Resistance; Vasodilator Agents

We aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the vasopeptidase inhibitor omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome.. We did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40 mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure.. Week 12 ETT increased similarly in the omapatrilat and lisinopril groups (24 vs 31 s, p=0.45). The two drugs were fairly well tolerated, but there were fewer cardiovascular-system serious adverse events in the omapatrilat group than in the lisinopril group (20 [7%] vs 34 [12%], p=0.04). There was a suggestive trend in favour of omapatrilat on the combined endpoint of death or admission for worsening heart failure (p=0.052; hazard ratio 0.53 [95% CI 0.27-1.02]) and a significant benefit of omapatrilat in the composite of death, admission, or discontinuation of study treatment for worsening heart failure (p=0.035; 0.52 [0.28-0.96]). Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV (p=0.035), but not if patients with NYHA class II were included.. Our findings suggest that omapatrilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of vasopeptidase inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Double-Blind Method; Endothelin-1; Exercise Tolerance; Female; Heart Failure; Humans; Lisinopril; Male; Middle Aged; Neprilysin; Norepinephrine; Prospective Studies; Pyridines; Radionuclide Ventriculography; Severity of Illness Index; Survival Rate; Thiazepines; Treatment Outcome

Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure.. With the use of standard-calibrated, competitive reverse-transcription-polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103+/-15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ET(A)) was markedly upregulated in failing human myocardium. This increased ET(A) expression was not affected by ACE inhibitor treatment but was normalized by VAD unloading. ET(A) expression before or after VAD implantation did not correlate with duration of VAD implantation or suppression of Pro-ANP mRNA. ET(B) mRNA expression was unaffected by heart failure or VAD. In contrast, increased ET-converting enzyme-1 mRNA and ET-1 peptide levels in failing myocardium were partially normalized by ACE inhibition but not by VAD unloading.. We conclude that VAD implantation normalizes ET(A) expression in failing human left ventricular myocardium, probably as the result of the beneficial effects of VAD unloading.

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Endothelin-1; Endothelin-Converting Enzymes; Heart Failure; Heart Ventricles; Heart-Assist Devices; Humans; Male; Metalloendopeptidases; Middle Aged; Myocardium; Protein Precursors; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ventricular Function, Left

The aim of this study was to investigate the behavior of plasma endothelin-1 (ET-1) in 23 patients with acute myocardial infarction, complicated and uncomplicated by left ventricular failure, and treated with and without thrombolytic agents. ET-1 was measured on admission; on days 2, 3, and 5; and again on discharge. In addition, on discharge, ET-1 was correlated with left ventricular systolic function. Left ventricular failure was present, on admission, in 14 patients, whereas the other nine did not have any hemodynamic impairment. On discharge, no patients had left ventricular failure, but 11 had moderate to severe left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) < 40%. Fourteen subjects, matched for age and sex, served as a control group. Compared with the control range, ET-1 was highly elevated on the first day, in both uncomplicated (p < 0.01) and complicated patients (p < 0.001). Then it decreased rapidly in the uncomplicated group, reaching the control range within day 5, whereas in the complicated group it remained significantly elevated in comparison with both the control subjects and the uncomplicated patients, until discharge. ET-1 was not correlated with the peak of creatine-kinase MB isoenzyme in any group. In seven patients submitted to thrombolytic treatment ET-1 was always significantly lower than in the nonthrombolyzed patients (p < 0.05), but the pattern of variation across time was no different. On discharge, the difference in plasma ET-1 between patients with LVEF < 40% and the control group was significant (p < 0.001), as was the difference between patients with and without moderate to severe systolic dysfunction (p < 0.01). ET-1 was closely and inversely correlated with LVEF when patients were considered as a whole (p < 0.001). These results suggest that the ET-1 increase in the early phase of myocardial infarction could be due to an ischemic process, to stress reaction, and to cardiac hemodynamic impairment, and therefore, ET-1 may be a good marker of disease. In the following phase the ET-1, being correlated with LVEF, could be a reliable index of systolic function.

Topics: Aged; Aged, 80 and over; Biomarkers; Creatine Kinase; Electrocardiography; Endothelin-1; Female; Fibrinolytic Agents; Follow-Up Studies; Heart Failure; Heart Ventricles; Humans; Isoenzymes; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Prognosis; Radioimmunoassay; Stroke Volume; Thrombolytic Therapy; Ventricular Dysfunction, Left

We have reported that the plasma endothelin-1 (ET-1) level is significantly increased by exercise in healthy athletes and that it is elevated in the circulation of the non-working leg but not the working leg, suggesting that ET-1 plays an important role in redistribution of blood during exercise. This study was designed to compare alterations of neurohumoral substances by exercise in normal subjects and patients with heart disease. Study patients comprised three groups: eight patients with congestive heart failure (CHF) due to Ebstein's anomaly or single-ventricle heart after Fontan operation; six patients with complete transposition of the great arteries (TGA) after an anatomic surgical correction who may be candidates for ischemic heart disease; and five age-matched normal subjects. All patients were in New York Heart Association functional class I. All subjects performed symptom-limited treadmill exercise. It is suggested that patients with CHF or TGA have a manifest or latent exercise intolerance, respectively. In failed to increase plasma ET-1 level, although it caused a greater increase in norepinephrine, angiotensin II, and arginine vasopressin than in the controls. Exercise also caused a delay in the increased response of plasma ET-1 levels in patients with TGA after an anatomic surgical repair. On the other hand, plasma brain natriuretic peptide (BNP) level was augmented by exercise in patients with CHF and patients with TGA but not in the controls. The present results suggest that an increase in ET-1 production during exercise is absent in patients with heart disease. The mechanisms of inhibition of ET-1 production during exercise in patients with heart disease remain to be elucidated. However, the present study suggests that ET-1 plays an important role in redistribution of blood during exercise, and proposes the possibility that failure of an increase in ET-1 production results in exercise intolerance in patients with heart disease.

Topics: Child; Endothelin-1; Exercise; Heart Defects, Congenital; Heart Failure; Heart Rate; Humans; Neurotransmitter Agents; Pulmonary Gas Exchange; Transposition of Great Vessels

Adrenomedullin is a potent vasodilator and natriuretic peptide that may an important role in cardiovascular disease. To investigate the role of adrenomedullin in the pathophysiology of congestive heart disease, plasma levels of adrenomedullin were measured in patients with congestive heart failure. Venous blood samples at rest were obtained before and after treatment from patients with congestive heart failure in New York Heart Association functional class II (n-23), III (n-26) and IV (n-14) and from normal subjects (n-30). Plasma adrenomedullin, endothelin-1,2, and atrial natriuretic peptide were determined by radioimmunoassay, plasma noradrenaline by radioenzymatic assay. Left ventricular ejection fraction was measured by echocardiography. The mean plasma level of adrenomedullin in normal subjects was 8.2 pmol/l, tended to be increased in patients with congestive heart failure those in class II (12.9 pmol/l) and were significantly increased in classes III and IV (21.3 and 29.9 respectively). Plasma adrenomedullin was correlated strongly with endothelin-1,2, atrial natriuretic peptide, and noradrenaline, and relatively weakly with left ventricular ejection fraction. Plasma adrenomedullin levels significantly decreased after treatment. These findings indicate that plasma levels of adrenomedullin are elevated in congestive heart failure and may be involved in the defense mechanism against further peripheral vascular resistance elevation in congestive heart failure.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Echocardiography; Endothelin-1; Endothelin-2; Female; Heart Failure; Humans; Male; Middle Aged; Norepinephrine; Peptides; Radioimmunoassay; Stroke Volume; Vascular Resistance

To determine directly the contribution of angiotensin II to basal and sympathetically stimulated peripheral arteriolar tone in patients with heart failure.. Parallel group comparison.. Nine patients with New York Heart Association grade II-IV chronic heart failure, and age and sex matched controls.. Forearm plethysmography, lower body negative pressure, local intra-arterial administration of losartan, angiotensin II, and noradrenaline, and estimation of plasma hormone concentrations.. Forearm blood flow responses, plasma hormone concentrations.. Baseline blood pressure, heart rate, and forearm blood flow did not differ between patients and controls. In comparison with the non-infused forearm, losartan did not affect basal forearm blood flow (95% confidence interval -5.5% to +7.3%) or sympathetically stimulated vasoconstriction in controls. However, the mean (SEM) blood flow in patients increased by 13(5)% and 26(7)% in response to 30 and 90 micrograms/min of losartan respectively (p < 0.001). Lower body negative pressure caused a reduction in forearm blood flow of 20(5)% in controls (p = 0.008) and 13(5)% (p = 0.08) in patients (p = 0.007, controls v patients). Blood flow at 90 micrograms/min of losartan correlated with plasma angiotensin II concentration (r = 0.77; p = 0.03). Responses to angiotensin II and noradrenaline did not differ between patients and controls.. Losartan causes acute local peripheral arteriolar vasodilation in patients with heart failure but not in healthy control subjects. Endogenous angiotensin II directly contributes to basal peripheral arteriolar tone in patients with heart failure but does not augment sympathetically stimulated peripheral vascular tone.

Topics: Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Endothelin-1; Female; Forearm; Heart Failure; Humans; Infusions, Intra-Arterial; Losartan; Lower Body Negative Pressure; Male; Middle Aged; Norepinephrine; Plethysmography; Regional Blood Flow; Vascular Resistance; Vasoconstrictor Agents

Plasma endothelin levels are increased in patients with moderate and severe CHF. Conflicting data exist about the endothelin-1 (ET) level in patients with mild to moderate CHF and the effect of maximal exercise on plasma ET levels.. We determined the plasma levels of ET and various neurohumoral parameters in 93 patients with CHF in functional class II and III of the NYHA classification at rest and after maximal bicycle exercise. Baseline ET level was increased compared to an age-matched healthy volunteer group (6.95+/-0.31 vs 3.29+/-0.17 pg/ml, mean+/-S.E.M., P<0.05), without significant differences between NYHA class II and III patients. Maximal exercise did not increase the ET level. In contrast, the neurohumoral parameters were significantly increased with maximal exercise. In conclusion, plasma levels of ET are increased in patients with mild to moderate CHF. However, no further increase in response to exercise was observed. Thus, it is highly unlikely that exercise capacity may be limited by ET-mediated peripheral vasoconstriction.

Topics: Aged; Endothelin-1; Exercise; Exercise Test; Female; Heart Failure; Humans; Male; Middle Aged; Neurotransmitter Agents

To investigate the alterations of plasma endothelin-1(ET-1) in patients with congestive heart failure(CHF) and the effects of metoprolol on it, plasma ET-1 and norepinephrine(NE) were measured in 43 patients using radioimmunoassay and high-performance liquid chromatography methods. Twenty-four patients were treated with metoprolol plus the routine therapy while the others were received the routine therapy only. The findings were that levels of plasma ET-1 and NE increased before the treatment, and decreased after the treatment with metoprolol for 1 month. There was no alteration of plasma ET-1 or NE in the control group.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Endothelin-1; Female; Heart Failure; Humans; Male; Metoprolol; Middle Aged; Norepinephrine

We investigated the effects of nasal continuous positive airway pressure (CPAP) on plasma endothelin-1 (ET-1) concentrations in patients with cardiogenic pulmonary edema. Thirty patients were randomly assigned to two groups: 15 patients who received oxygen plus nasal CPAP (CPAP group), and 15 patients who received only oxygen by face mask (oxygen group). The heart rate and the mean pulmonary artery pressure decreased significantly in the CPAP group. The PaO2/ fraction of inspired oxygen (FIO2) ratio increased in the CPAP group (163 +/- 70 to 332 +/- 104, P < 0.01) after 6 h and was significantly higher than that in the oxygen group. Arterial plasma ET-1 concentrations decreased from 6.2 +/- 2.0 pg/mL to 4.8 +/- 1.7 pg/mL (P < 0.05) after 6 h and to 3.3 +/- 0.7 pg/mL (P < 0.01) after 24 h in the CPAP group. Arterial plasma ET-1 concentrations in the CPAP group compared with the oxygen group were significantly lower at 24 h. There was a correlation between the arterial plasma ET-1 concentrations and mean pulmonary artery pressure (r = 0.62, P < 0.001), and PaO2/FIO2 (r = -0.46, P < 0.01). Nasal CPAP led to an early decrease in plasma ET-1 concentrations, and improvement in oxygenation and hemodynamics.

Topics: Aged; Blood Pressure; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Oxygen Inhalation Therapy; Positive-Pressure Respiration; Pulmonary Artery; Pulmonary Edema

This study demonstrated an immediate and short-lasting endothelin-1 release in the circulation of patients with severe chronic congestive heart failure during isometric handgrip exercise, but not in normal subjects. Our data suggest that endothelin-1 levels may increase transiently during daily physical activity, thus contributing to progressive deterioration of left ventricular function.

Topics: Adult; Analysis of Variance; Chronic Disease; Endothelin-1; Exercise; Hand Strength; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Ventricular Function, Left

Previous studies have demonstrated that continuous infusion of furosemide results in increased diuresis and natriuresis compared with bolus administration of the drug in patients with severe heart failure. We reasoned that continuous infusion of furosemide caused less activation of neurohumoral mechanisms, since other studies have shown that bolus administration of furosemide may activate this system. We therefore tested the hypothesis that continuous administration of furosemide would increase water and sodium excretion due to less activation of neurohormones. Eight patients with severe heart failure were studied during continuous infusion over 24 h and bolus injections of furosemide twice daily in a randomized cross-over study. Bolus administration of furosemide increased diuresis and natriuresis significantly in the first 4 h after administration compared with continuous administration, but this was later reversed, resulting in similar 24 h total output. The neurohormones measured at baseline were all markedly elevated. Neither regimens of furosemide caused any further significant changes in neurohumoral response except that pro-ANF decreased more during the first 8 h after bolus administration compared to continuous infusion. This study has demonstrated that bolus administration of furosemide in conventional doses is equally effective as continuous intravenous infusion in patients with severe heart failure. This may be due to maximal neurohormonal activation in severe heart failure (NYHA III-IV) which could not be further activated by bolus administration.

Topics: Atrial Natriuretic Factor; Blood Pressure; Brain; Catecholamines; Cross-Over Studies; Diuresis; Diuretics; Endothelin-1; Endothelins; Female; Furosemide; Heart Failure; Heart Rate; Hormones; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Natriuresis; Neuropeptide Y; Protein Precursors; Vasopressins

Prostaglandin E1 or prostacyclin were randomly infused in 18 patients with severe chronic heart failure who did not respond to oral treatment. Maximally tolerated dosages of both agents increased cardiac index; however, only prostacyclin decreased mean arterial pressure and increased plasma norepinephrine significantly. Twelve hours after 50% peak dose reduction, atrial natriuretic peptide levels, right atrial pressure, mean pulmonary artery pressure, and mean arterial pressure continued to decrease with prostaglandin E1, whereas the increase in cardiac index was sustained; in contrast, at 50% prostacyclin dose reduction, cardiac index decreased toward baseline, suggesting that, with reduced dosages for chronic infusions, desired hemodynamic changes seem to be sustained with prostaglandin E1 only.

Topics: Alprostadil; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Neurotransmitter Agents; Protein Precursors; Pulmonary Wedge Pressure; Vasodilator Agents

Serum levels endothelin-1,2 aldosterone, renin activity were performed in 52 patients with chronic congestive heart failure during captopril therapy. The investigations were done before therapy, after 10-15 days therapy and after disappearance symptoms of heart failure. The levels endotelin-1,2,aldosterone and renin activity were determined using radioimmunologic methods. Fraction ejection and peripheral vascular resistance were determined by echocardiography technics. It was found that serum endothelin levels in patients with chronic congestive heart failure were increased proportionally to functional class of heart failure and decreased after disappearance symptoms of heart failure. An increase in plasma endothelin concentration has not correlated with ejection fraction, aldosterone concentration and renin activity. These studies have demonstrated that in patients with congestive heart failure on captopril therapy endothelin serum levels positively correlates with peripheral vascular resistance. No correlation was found between ejection fraction and activity renin-angiotensin-aldosterone system. These findings indicated that captopril therapy decreases endothelin production.

Topics: Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Captopril; Echocardiography; Endothelin-1; Endothelin-2; Female; Heart Failure; Humans; Male; Middle Aged; Radioimmunoassay; Renin-Angiotensin System; Stroke Volume; Vascular Resistance

Angiotensin converting enzyme inhibitors improve symptoms and prolong life in congestive heart failure, but the dose in the individual patient is uncertain. A randomized, 48-week, double-blind study was performed to investigate the safety and efficacy of 'high' in comparison to continued 'low' angiotensin converting enzyme inhibitor therapy in severe heart failure. Eighty-three patients (56 +/- 1.1 years; 69 men, 14 women) in New York Heart Association functional class III/IV on digoxin, furosemide and 'low' angiotensin converting enzyme inhibitors (captopril < or = 50 mg.day-1 or enalapril < or = 10 mg.day-1) were included. After a > or = 14 day run-in on 10 mg.day-1 enalapril, digitalis and furosemide, right heart catheterization at rest and exercise was performed. All patients presented with atrial pressure > 10 mmHg and/or pulmonary artery pressure > 35 mmHg, and/or cardiac index < 2.5 l.min-1.m-2 at rest. Patients then received enalapril 5 mg twice daily (n = 42), or 20 mg twice daily (n = 41) in random order. Thus, patients randomized to low doses of enalapril actually had no change in therapy from baseline to 48 weeks. Forty-three patients (52%) completed the study, 19 patients on the low dose and 24 patients on the high dose. Both dosages equally influenced survival with 15 (18%) deaths, eight on low dose and seven on high dose. After 48 weeks, functional capacity by New York Heart Association class improved more on the high dose than on the low dose (P = 0.04). In contrast, alterations in invasive haemodynamic variables at rest and exercise as well as maximal exercise capacity were comparable in both groups. Diastolic blood pressure decreased and the change between both groups was statistically significant (P = 0.01). Changes in plasma creatinine levels did not differ between high and low dose treatment and no patients had to be withdrawn because of deterioration in kidney function. With regard to neurohumoral activity, a tendency to a discrepant response to both treatments was observed with a blunted increase in noradrenaline on high versus low enalapril dose. Thus, high-dose enalapril treatment proved superior to low dose as regards symptomatology in severe heart failure after long-term treatment, despite similar effects on haemodynamics and on maximal exercise capacity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Enalapril; Endothelin-1; Endothelins; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Kidney; Male; Middle Aged; Norepinephrine; Protein Precursors; Renin; Treatment Outcome

The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ETA receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ETA and ETB receptors in healthy subjects and patients with CHF.. Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF was measured by venous occlusion plethysmography. In CHF patients (n = 10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ETA receptor antagonist) increased FBF by 52 +/- 10% (P = .0006) and 31 +/- 6% (P = .002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15 +/- 5% (P = .0007). Forearm vasoconstriction to endothelin-1 (an ETA and ETB receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n = 10; CHF versus control subjects, P < .001), whereas vasoconstriction to sarafotoxin S6c (an ETB receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n = 10; CHF versus control subjects. P < .05).. ECE inhibitors and ETA receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ETA and ETB receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Brachial Artery; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Glycopeptides; Heart Failure; Humans; Male; Metalloendopeptidases; Middle Aged; Neprilysin; Peptides, Cyclic; Protease Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Viper Venoms

Congestive heart failure (CHF) is a syndrome characterized by increased levels of angiotensin II (Ang II) and endothelin-1 (ET-1). In vitro, Ang II stimulates ET-1 release. The purpose of the study was to assess the effect of a single dose of an angiotensin-converting enzyme inhibitor (ACEI) captopril versus placebo on plasma endothelin concentration in human congestive heart failure. Captopril (25 mg, given orally) was compared with placebo in a group of 20 patients with systolic dysfunction in a double-blind randomized study. Plasma irET concentration was significantly increased in CHF patients compared with normal subjects (5.59 pg/ml +/- 0.35 vs. 3.58 pg/ml +/- 0.99, p < 0.0002). Despite the decrease in systolic blood pressure and the increase in plasma renin activity, suggesting a significant blockade of the renin-angiotensin system, no difference in plasma irET-1 was observed between captopril and placebo. Our results suggest that captopril does not acutely influence irET-1 plasma concentration in human CHF. These data do not support the hypothesis that the acute vasodilator effect of a single dose of 25 mg of captopril given daily orally involves modulation of the increased plasma concentration of endothelin observed in CHF.

Topics: Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Captopril; Double-Blind Method; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Radioimmunoassay; Renin; Stroke Volume

Evaluation of the effect of endothelin type A (ET A ) receptor blockade on the course of volume-overload heart failure in rats with angiotensin II-dependent hypertension.. Ren-2 renin transgenic rats (TGR) were used as a model of hypertension. Heart failure was induced by creating an aorto-caval fistula (ACF). Selective ET A receptor blockade was achieved by atrasentan. For comparison, other rat groups received trandolapril, an angiotensin-converting enzyme inhibitor (ACEi). Animals first underwent ACF creation and 2 weeks later the treatment with atrasentan or trandolapril, alone or combined, was applied; the follow-up period was 20 weeks.. Eighteen days after creating ACF, untreated TGR began to die, and none was alive by day 79. Both atrasentan and trandolapril treatment improved the survival rate, ultimately to 56% (18 of 31 animals) and 69% (22 of 32 animals), respectively. Combined ACEi and ET A receptor blockade improved the final survival rate to 52% (17 of 33 animals). The effects of the three treatment regimens on the survival rate did not significantly differ. All three treatment regimens suppressed the development of cardiac hypertrophy and lung congestion, decreased left ventricle (LV) end-diastolic volume and LV end-diastolic pressure, and improved LV systolic contractility in ACF TGR as compared with their untreated counterparts.. The treatment with ET A receptor antagonist delays the onset of decompensation of volume-overload heart failure and improves the survival rate in hypertensive TGR with ACF-induced heart failure. However, the addition of ET A receptor blockade did not enhance the beneficial effects beyond those obtained with standard treatment with ACEi alone.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Endothelin-1; Endothelins; Fistula; Heart Failure; Hypertension; Rats; Rats, Transgenic; Receptor, Angiotensin, Type 1; Receptor, Endothelin A

Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient's prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ET. CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation.. The final survival in untreated group was 15%. The treatment with ET. Our results show that treatment with ET

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Endothelin A Receptor Antagonists; Endothelin-1; Fistula; Heart Failure; Kidney; Rats; Rats, Transgenic; Receptor, Endothelin A; Renal Insufficiency, Chronic; Renin-Angiotensin System

Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes.. In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13-31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing.. Baseline cardiovascular protein levels differ between women and men. However, the predictive value of repeatedly measured circulating proteins does not seem to differ except for endothelin-1 and somatostatin.

Topics: Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Proteomics; Sex Characteristics; Stroke Volume; Ventricular Function, Left

The number of patients with heart failure and related deaths is rapidly increasing worldwide, making it a major problem. Cardiac hypertrophy is a crucial preliminary step in heart failure, but its treatment has not yet been fully successful. In this study, we established a system to evaluate cardiomyocyte hypertrophy using a deep learning-based high-throughput screening system and identified drugs that inhibit it. First, primary cultured cardiomyocytes from neonatal rats were stimulated by both angiotensin II and endothelin-1, and cellular images were captured using a phase-contrast microscope. Subsequently, we used a deep learning model for instance segmentation and established a system to automatically and unbiasedly evaluate the cardiomyocyte size and perimeter. Using this system, we screened 100 FDA-approved drugs library and identified 12 drugs that inhibited cardiomyocyte hypertrophy. We focused on ezetimibe, a cholesterol absorption inhibitor, that inhibited cardiomyocyte hypertrophy in a dose-dependent manner in vitro. Additionally, ezetimibe improved the cardiac dysfunction induced by pressure overload in mice. These results suggest that the deep learning-based system is useful for the evaluation of cardiomyocyte hypertrophy and drug screening, leading to the development of new treatments for heart failure.

Topics: Angiotensin II; Animals; Cardiomegaly; Cells, Cultured; Cholesterol; Deep Learning; Drug Evaluation, Preclinical; Endothelin-1; Ezetimibe; Heart Failure; Mice; Myocytes, Cardiac; Rats

Auraptene derived from the peel of Citrus hassaku possesses anti-tumor, anti-inflammatory, and neuroprotective activities. Thus, it could be a valuable pharmacological alternative to treat some diseases. However, the therapeutic value of auraptene for heart failure (HF) is unknown.. In cultured cardiomyocytes from neonatal rats, the effect of auraptene on phenylephrine-induced hypertrophic responses and peroxisome proliferator-activated receptor-alpha (PPARα)-dependent gene transcriptions. To investigate whether auraptene prevents the development of heart failure after myocardial infarction (MI) in vivo, Sprague-Dawley rats with moderate MI (fractional shortening < 40%) were randomly assigned for treatment with low- or high-dose auraptene (5 or 50 mg/kg/day, respectively) or vehicle for 6 weeks. The effects of auraptene were evaluated by echocardiography, histological analysis, and the measurement of mRNA levels of hypertrophy, fibrosis, and PPARα-associated genes.. In cultured cardiomyocytes, auraptene repressed phenylephrine-induced hypertrophic responses, such as increases in cell size and activities of atrial natriuretic factor and endothelin-1 promoters. Auraptene induced PPARα-dependent gene activation by enhancing cardiomyocyte peroxisome proliferator-responsive element reporter activity. The inhibition of PPARα abrogated the protective effect of auraptene on phenylephrine-induced hypertrophic responses. In rats with MI, auraptene significantly improved MI-induced systolic dysfunction and increased posterior wall thickness compared to the vehicle. Auraptene treatment also suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, and expression of hypertrophy and fibrosis response markers at the mRNA level compared with vehicle treatment. MI-induced decreases in the expression of PPARα-dependent genes were improved by auraptene treatment.. Auraptene has beneficial effects on MI-induced cardiac hypertrophy and left ventricular systolic dysfunction in rats, at least partly due to PPARα activation. Further clinical studies are required to evaluate the efficacy of auraptene in patients with HF.

Topics: Animals; Atrial Natriuretic Factor; Biological Products; Cardiomegaly; Citrus; Coumarins; Endothelin-1; Fibrosis; Heart Failure; Myocardial Infarction; Peroxisome Proliferators; Phenylephrine; PPAR alpha; Rats; Rats, Sprague-Dawley; RNA, Messenger

Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF.. We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and heart failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF.. These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Cyclic GMP; Disease Models, Animal; Diuresis; Diuretics; Endothelin-1; Female; Heart Failure; Hemodynamics; Kidney; Natriuresis; Natriuretic Peptide, Brain; Renin; Sheep, Domestic; Vasodilation; Vasodilator Agents; Ventricular Function, Left

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Heart Failure; Humans; Peptide Fragments; Protein Precursors; Risk Assessment; Stroke Volume; Ventricular Function, Left

Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population's rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5-Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance.

Topics: Animals; Animals, Newborn; Autophagy; Autophagy-Related Protein 5; Cardiomegaly; Echocardiography; Endothelin-1; Gene Silencing; Heart Failure; Male; Mice, Inbred C57BL; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Pressure; Sirolimus; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Remodeling

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

Topics: Animals; Cells, Cultured; Dependovirus; Disease Models, Animal; Endothelin-1; Genetic Therapy; Genetic Vectors; Heart Failure; Hypertrophy, Left Ventricular; Mice, Inbred C57BL; Myocytes, Cardiac; NFATC Transcription Factors; Oligonucleotides; Rats, Wistar; Ventricular Function, Left; Ventricular Remodeling

Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured.. ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors.. These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

Topics: Aged; Aged, 80 and over; Biomarkers; Endothelin-1; Ethnicity; Female; Heart Failure; Heart Ventricles; Humans; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Morbidity; Stroke Volume; United States; Ventricular Function, Left

Topics: Endothelin-1; Heart Failure; Humans

Topics: Biomarkers; Endothelin-1; Heart Failure; Hospitalization; Humans; Hypertension, Pulmonary; Prognosis; Stroke Volume

Left ventricular assist devices (LVAD) are implanted in patients with end-stage heart failure (ESHF) as a mechanical support for the failing myocardium, which is characterized by an activation of the neuro-hormonal system, with release of vasoactive mediators, such as endothelin (ET)-1 and relaxin (RLX)-2. The aim of this study was to evaluate whether LVAD is able to modulate the RLX-2 and ET-1 system expression in ESHF patients.. Cardiac tissue was collected from ESHF patients before LVAD implantation (pre-LVAD group, n = 22), at the time of cardiac transplantation with concomitant LVAD removal (post-LVAD group, n = 6), and from stable HF patients on medical therapy at the time of cardiac transplantation (HTx group, n = 7). The expression of RLX-2, ET-1 system and inflammatory markers (IL-8, IL-6, TNF-α) were evaluated by Real-Time PCR.. RLX-2 mRNA resulted similar in pre-LVAD and HTx, but it was significantly increased in post-LVAD (p = 0.02/p = 0.01 respectively). A similar trend was observed for ET-1 and ET-converting enzyme (ECE)-1 while no significant difference was observed for ET-receptors. A positive correlation was found between ET-1 and ET-A (p = 0.031) and ECE-1 (p < 0.0001). The inflammatory markers resulted activated in all the three groups. A significant correlation between RLX-2 and ET-1 in pre-LVAD, as well as between RLX-2 and IL-8/IL-6, was found.. Our research investigates for the first time the involvement of RLX-2 and ET-1 system in ESHF patients supported by LVAD, demonstrating their potential ability to partially recover the failing myocardium, indicating their possible clinical role as biomarkers or pharmacological agents in LVAD patients.. The study of novel biomarkers in patients supported by continuous axial flow devices may be a starting point analysis applicable to patients with centrifugal flow devices.

Topics: Endothelin-1; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Relaxin

Topics: Endothelin-1; Heart; Heart Failure; Humans; Myocardial Contraction

In ST segment elevation acute myocardial infarction (STEMI), the endothelin (ET) system imbalance, reflected by the circulating ET-1:ET-3 ratio has not been investigated. This study's primary objective was to measure the circulating ET-1:ET-3 ratio and correlate it with the risk stratification for 1 year mortality of STEMI based on TIMI score. On admission, the TIMI risk score and at discharge, the dynamic TIMI risk score were calculated in 68 consecutive subjects with STEMI. Subjects with high TIMI risk score were associated with higher mean ET-1 level and ET-1:ET-3 ratio. The ET-1:ET-3 ratio more accurately predicted the high on admission TIMI risk score than the ET-1 level. Subjects with high dynamic TIMI risk score were associated with higher mean ET-1 level and ET-1:ET-3 ratio. The ET-1:ET-3 ratio more accurately predicted the high at discharge dynamic TIMI risk score than ET-1 level. From multivariable analysis, the ET-1:ET-3 ratio was not independently associated with high on admission TIMI risk score but independently predicted high at discharge dynamic TIMI risk score (odds ratio = 9.186,

Topics: Adult; Aged; Cardiotonic Agents; Electric Countershock; Electrocardiography; Endothelin-1; Endothelin-3; Female; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Patient Admission; Patient Discharge; Percutaneous Coronary Intervention; Prognosis; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Shock, Cardiogenic; ST Elevation Myocardial Infarction; Treatment Outcome; Ventricular Fibrillation

This study aimed to explore the correlation of serum brain natriuretic peptide (BNP) and endothelin-1 (ET-1) levels with cardiac pump function and ventricular remodeling in patients with heart failure. Eighty-one patients with chronic heart failure admitted to our hospital from March 2016 to November 2018 were enrolled as the study group, and 80 healthy individuals as the control group. Immunofluorescence was used for the detection of serum BNP, ELISA for serum ET-1, and ultrasound for related indexes of cardiac pump function and ventricular remodeling. Moreover, correlation analysis and prognostic factors analysis were carried out. Both BNP and ET-1 were highly expressed in the serum of patients with heart failure. Cardiac pump function related indexes (left atrial ejection fraction (LAEF), left atrial passive ejection fraction (LAPEF), and left atrial active ejection fraction (LAAEF)) in the study group were significantly lower than those in the control group (P< 0.05). While ventricular remodeling related indexes (left ventricular end-diastolic diameter (LVEDD), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPM), and left ventricular mass index (LVMI) in the study group were significantly higher than those in the control group (P< 0.05). BNP and ET-1 were negatively correlated with LAEF, LAPEF and LAAEF (P< 0.05), and were positively correlated with LVEDD, IVST, LVPM and LVMI (P< 0.05). The expressions of serum BNP and ET-1 were higher in patients with cardiovascular events than those without cardiovascular events. Hypertension, hyponatremia, high BNP, high ET-1, NYHA classification, decreased LAEF and increased LVEDD were independent risk factors for cardiovascular adverse events. Serum BNP and ET-1 are closely related to cardiac pump function and ventricular remodeling in patients with heart failure and can be used as important reference indexes for prognosis evaluation.

Topics: Endothelin-1; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Prognosis; Ventricular Remodeling

Prevalence of major depression in people with chronic heart failure is higher than in normal populations. Depression in heart failure has become a major issue. Psilocybin-containing mushrooms commonly known as magic mushrooms, have been used since ancient times for their mind healing properties. Their safety in cardiovascular disease conditions is not fully known and may pose as a risk for users suffering from these illnesses. Study investigates the effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushrooms use from genus Psilocybe and Panaeolus respectively, in a pathological hypertrophy conditions in which endothelin-1 disorder is a contributor to pathogenesis. We examined the effects of the mushrooms extracts on endothelin-1-induced hypertrophy and tumor necrosis factor-α (TNF- α)-induced cell injury in H9C2 cardiomyocytes. Mushrooms were oven dried and extracted with cold and boiling-hot water. H9C2 cardiomyocytes were induced with endothelin-1 prior to treatment with extracts over 48 h. Cell injury was stimulated with TNF-α. Results proposed that the water extracts of Panaeolus cyanescens and Psilocybe cubensis did not aggravate the pathological hypertrophy induced by endothelin-1 and also protected against the TNF-α-induced injury and cell death in concentrations used. Results support medicinal safe use of mushrooms under controlled conditions and cautioned use of higher concentrations.

Topics: Agaricales; Animals; Endothelin A Receptor Antagonists; Endothelin-1; Hallucinogens; Heart Failure; Humans; Hypertrophy; Myocytes, Cardiac; Phenylpropionates; Psilocybe; Psilocybin; Pyridazines; Rats; Receptor, Endothelin A; Tumor Necrosis Factor-alpha

Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model.. HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-β), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation.. PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-β, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.

Topics: Acetates; Animals; Cells, Cultured; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Fibrosis; Heart Failure; Heart Ventricles; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Interleukin-6; Lung; Male; Phosphorylation; Pulmonary Fibrosis; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; Transforming Growth Factor beta; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

To investigate the effects of ET-1 and TNF-α levels on cardiac function and prognosis in rats with chronic heart failure (CHF), to provide reference for clinical practice.. 120 SD rats were randomly divided into healthy group (n=60) and heart failure group (n=60). Rats from heart failure group were made into CHF models by an intraperitoneal injection of adriamycin. According to the average serum levels of ET-1 and TNF-α, 30 rats with higher level were enrolled in high expression subgroup, while 30 rats with lower level were enrolled in low expression subgroup. The sandwich enzyme-linked immunosorbent assay (ELISA) was employed to determine the ET-1 and TNF-α in rats from healthy group and heart failure group. Doppler echocardiography was used to measure the left ventricular ejection fraction, heart rate, and aortic diameter. After the death of heart failure rats, the total heart mass and left ventricle mass were measured and compared with those of the healthy rats. The serum levels of ET-1 and TNF-α were monitored to explore the influence of ET-1 and TNF-α levels on the prognosis of rats from study group.. The total heart mass and left ventricle mass of the heart failure group were higher than those of healthy group (p<0.05). The total heart mass and left ventricle mass of the low expression subgroup were lower than those of high expression subgroup (p<0.05).. The serum levels of ET-1 and TNF-α are higher than those in healthy rats. CHF rats with higher serum levels of ET-1 and TNF-α have a worse heart function and survival. Serum levels of ET-1 and TNF-α can be used as predictors of cardiac function and prognosis in CHF rats, providing references for clinical practice.

Topics: Animals; Chronic Disease; Endothelin-1; Female; Heart Failure; Male; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Topics: Aged; Biomarkers; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Stroke Volume

The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3' untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3' UTR 158-165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel's activity against chronic heart failure.

Topics: Allyl Compounds; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Heart Failure; HEK293 Cells; Humans; KATP Channels; MicroRNAs; Propylamines; Rats; Rats, Wistar; Signal Transduction; Sulfonylurea Receptors

Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans.. In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02).. Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Topics: Allografts; Biomarkers; California; Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors; ROC Curve; Survival Rate; Ultrasonography, Interventional

Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms.. Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion-mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.. Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II-induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1-promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion-mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.. EC-Foxp1 regulates the TGF-β1-endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC-Foxp1-TGF-β1-endothelin-1 pathway might provide a future novel therapy for heart failure.

Topics: Angiotensin II; Animals; Aorta; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Fibrosis; Forkhead Transcription Factors; Heart Failure; Humans; Mice; Mice, Knockout; Myocardium; Nanotubes, Peptide; Repressor Proteins; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta1; Ventricular Remodeling

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 μg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, β-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.

Topics: Administration, Oral; Animals; Animals, Newborn; Atrial Natriuretic Factor; Cardiomegaly; Cardiotoxicity; Endothelin-1; Environmental Pollutants; Female; Gene Expression; Heart Failure; Humans; Lactation; Mice, Inbred C57BL; Models, Animal; Myosin Heavy Chains; Polychlorinated Dibenzodioxins; Pregnancy

The aim of this study was to assess the predictive role of biomarkers, associated with cardiovascular stress and its neuroendocrine response as well as renal function, in relation to mortality and risk of re-hospitalization among consecutive patients admitted because of heart failure (HF).. Among patients hospitalized for HF, elevated plasma levels of NT-proBNP, MR-proADM, copeptin, and cystatin C are associated with higher mortality after discharge, whereas NT-proBNP is the only biomarker that predicts the risk of re-hospitalization due to cardiac causes.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiovascular System; Cystatin C; Echocardiography; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Patient Discharge; Patient Readmission; Peptide Fragments; Predictive Value of Tests; Protein Precursors; Risk Assessment; Sweden

The aim of this study was to determine if weight loss following Roux-en-Y gastric bypass (RYGB) surgery in morbidly obese patients is associated with a decrease in plasma concentrations of neprilysin, mediators of the renin angiotensin system (RAS), catecholamines and endothelin-1, and also with an increase in the concentrations of vasodilators. Fasting blood samples were obtained from 15 patients with morbid obesity and diabetes prior to and 6 months after RYGB surgery. Circulating levels of neprilysin, vasoconstrictors, vasodilators, and the mRNA expression of related genes in circulating mononuclear cells (MNC) were measured. Six months after RYGB surgery the concentrations of neprilysin, angiotensinogen, angiotensin II, renin and endothelin-1 fell significantly by 27 ±16%, 22 ±10%, 22 ±8%, 35 ±13% and 17 ±6% (P < .05 for all), respectively, while ANP concentrations increased significantly by 24 ±13%. There was no significant change in aldosterone, BNP, cAMP or cGMP concentrations, or angiotensin converting enzyme (ACE) expression. These changes may contribute to the reduction of congestive cardiac failure and blood pressure risks after RYGB surgery.

Topics: Bariatric Surgery; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Endothelin-1; Female; Glycated Hemoglobin; Heart Failure; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Neprilysin; Obesity, Morbid; Postoperative Period; Prospective Studies; Renin-Angiotensin System; Risk; Weight Loss

Serum concentration of big endothelin-1 (ET-1) has prognostic significance in heart failure. However, its prognostic value in cardiac resynchronization therapy (CRT) recipients has not been well-characterized.. A cohort of 367 consecutive patients who received CRT between January 2010 and December 2015 were enrolled, and categorized into three groups according to baseline big ET-1 tertiles: big ET-1 ≤ 0.34 pmol/L (N = 119), big ET-1 between 0.34-0.56 pmol/L (N = 127) and big ET-1 > 0.56 pmol/L (N = 121). The primary endpoints included mortality rate (all-cause) and heart transplantation.. Over a median follow-up of 21 months, 48 (13.08%) patients died, 6 (1.63%) underwent heart transplantation and 100 (27.25%) had heart failure hospitalization (HFH). We found a significant difference in event free survival between the three groups, with high levels of big ET-1 correlating with worse survival (Log-rank test, P < .001). After adjusting for multiple factors in the multivariate model, big ET-1 > 0.56 pmol/L was an independent predictor for primary endpoint event [hazard ratio (HR): 2.005, 95% confidence interval(CI) 1.045-6.2621, P = .040] and HFH (HR = 2.126, 95%CI 1.182-3.827, P = .012).. Baseline big ET-1 > 0.56 pmol/L was independently associated with higher all-cause mortality and HFH among CRT recipients, and therefore can be added to the marker panel used for stratifying high risk CRT patients for priority treatment.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiac Resynchronization Therapy; Cohort Studies; Disease-Free Survival; Endothelin-1; Female; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Treatment Outcome

To investigate the effect of MicroRNA (miRNA)-130a on cardiac function and the expression of tumor necrosis factor-α (TNF-α) in rats with heart failure.. The rat heart failure model (n = 30) were established, then divided into miRNA-130a group, phosphate-buffer saline (PBS) group, rAAV9 group, and sham group (n = 10 in each group). Four weeks after the operation, the cardiac ultrasound and hemodynamic determination were performed. Blood endothelin-1 (ET-1) content was measured by enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (HE) staining was used to observe the morphology of myocardium. The expression levels of miRNA-130a and TNF-α were determined by quantitative Real Time-Polymerase Chain Reaction) (qRT-PCR). And the expression of TNF-α protein was determined by immunohistochemistry and Western blotting.. The rat heart failure model was successfully constructed. The miRNA-130a expression was decreased in rats with heart failure, and miRNA-130a transfection was successful. miRNA-130a improved left ventricular ejection fraction in the rat with heart failure. The blood ET-1 in miRNA-130a group was significantly lower than that of PBS group and rAAV9 group (p < 0.05). RT-PCR, Immunohistochemistry and Western blotting results showed that compared with the sham group, the expression of TNF-α in the model group was increased. And the expression of TNF-α in miRNA-130a group was significantly lower than that of PBS and rAAV9 group.. miRNA-130a could improve cardiac function of heart failure rat by down-regulating TNF-α.

Topics: Animals; Down-Regulation; Echocardiography; Endothelin-1; Female; Heart Failure; Hemodynamics; Male; MicroRNAs; Myocardium; Rats; Rats, Wistar; Transfection; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal diseases, and in the progression of tumour growth in cancer, but current diagnosis and treatment remain inadequate. Peptides derived from the 212 amino acid precursor preproendothelin-1 (ppET-1) may have utility as biomarkers, or cause biological effects that are unaffected by endothelin receptor antagonists. Here, we used specific immunoassays and LC-MS/MS to identify NT-proET-1 (ppET-1

Topics: A549 Cells; Biomarkers; Cell Line; Chromatography, Liquid; Culture Media, Conditioned; Endothelial Cells; Endothelin-1; Heart Failure; Humans; Injections, Intravenous; Peptide Fragments; Protein Precursors; Tandem Mass Spectrometry

Calcium plays an integral role to many cellular processes including contraction, energy metabolism, gene expression, and cell death. The inositol 1, 4, 5-trisphosphate receptor (IP

Topics: Animals; Animals, Newborn; Cardiomegaly; Cell Nucleus; Cells, Cultured; Cytosol; Endothelin-1; Heart Failure; Heart Ventricles; Hyperglycemia; Inositol 1,4,5-Trisphosphate Receptors; Myocardial Contraction; Myocytes, Cardiac; NFATC Transcription Factors; Protein Isoforms; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction

Topics: Aged; Chronic Disease; Complementary Therapies; Endothelin-1; Forests; Heart Failure; Humans; Treatment Outcome

Heart failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan (a nonselective ETA and ETB receptor antagonist) (8 mg·kg(-1)·h(-1)) on resting levels of CSNA, arterial pressure, and heart rate were determined in conscious normal sheep (n = 6) and sheep with pacing-induced HF (n = 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts/100 heartbeats, P < 0.01). Infusion of tezosentan for 60 min significantly decreased resting mean aterial pressure (MAP) in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg, respectively; P < 0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.

Topics: Animals; Arterial Pressure; Baroreflex; Biomarkers; Cardiac Pacing, Artificial; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Heart; Heart Failure; Heart Rate; Hemodynamics; Infusions, Intravenous; Pyridines; Sheep; Signal Transduction; Stroke Volume; Sympathetic Nervous System; Tetrazoles; Time Factors; Up-Regulation

Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET-1 levels and acute heart failure patient outcomes.. We measured plasma ET-1 at baseline, 48-72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND-HF trial (randomized to nesiritide vs. placebo), and its association with 30-day mortality, 180-day mortality, in-hospital death or worsening heart failure, and 30-day mortality or rehospitalization. Median ET-1 was 7.6 [interquartile range (IQR) 5.9-10] pg/mL at baseline, 6.3 (IQR 4.9-8.1) pg/mL at 48-72 h, and 5.9 (IQR 4.7-7.9) pg/mL at 30 days (P < 0.001). Baseline and 48-72 h ET-1 were found to be independently associated with 180-day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3-2.0, P < 0.001 and HR 1.5, 95% CI 1.2-1.9, P = 0.001, respectively, log-transformed]. ET-1 that was measured at 48-72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03-2.4, P = 0.03]. These independent associations remained significant after including NT-proBNP in the multivariable analysis.. We observed an independent association between elevated ET-1 and short-term in-hospital clinical outcomes and 180-day mortality in hospitalized patients with acute heart failure ET-1 provided additional prognostic information which was incremental to that yielded by NT-proBNP.

Topics: Acute Disease; Aged; Biomarkers; Endothelin-1; Female; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Randomized Controlled Trials as Topic

Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling.. Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function.. Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response.

Topics: Animals; Cardiomegaly; Drosophila melanogaster; Endothelin-1; Heart Failure; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Myofibrils; Phenylephrine; Profilins; Sarcomeres

Transcription factor nuclear factor of activated T cells c4 (NFATc4) is the best-characterized target for the development of cardiac hypertrophy. Aberrant microRNA-29 (miR-29) expression is involved in the development of cardiac fibrosis and congestive heart failure. However, whether miR-29 regulates hypertrophic processes is still not clear. In this study, we investigated the potential functions of miR-29a-3p in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. We showed that miR-29a-3p was down-regulated in ET-1-treated H9c2 cardiomyocytes. Overexpression of miR-29a-3p significantly reduced ET-1-induced hypertrophic responses in H9c2 cardiomyocytes, which was accompanied by a decrease in NFATc4 expression. miR-29a-3p targeted directly to the 3'-UTR of NFATc4 mRNA and silenced NFATc4 expression. Our results indicate that miR-29a-3p inhibits ET-1-induced cardiomyocyte hypertrophy via inhibiting NFATc4 expression.

Topics: 3' Untranslated Regions; Animals; Cardiomegaly; Cell Line; Down-Regulation; Endothelin-1; Fibrosis; Heart Failure; MicroRNAs; Myocytes, Cardiac; Nerve Tissue Proteins; NFATC Transcription Factors; Rats; RNA, Messenger

Topics: Biomarkers; Endothelin-1; Heart Failure; Humans; Polysomnography; Sleep Apnea, Obstructive

Topics: Body Mass Index; Cause of Death; Endothelin-1; Heart Failure; Humans; Obesity

Despite pathophysiological links between endothelin-1 and pulmonary vascular remodeling, to our knowledge, the association between plasma endothelin-1 levels and pulmonary hypertension has not been studied in the general population. Also, whether endothelin-1 can predict future heart failure and mortality, outcomes that are associated with pulmonary hypertension, in a population cohort is unclear.. To determine whether elevated plasma endothelin-1 levels are associated with pulmonary hypertension, mortality, and heart failure.. Data from the Jackson Heart Study, a longitudinal, prospective observational cohort study of heart disease in African American individuals from Jackson, Mississippi, were analyzed. The community population sample was limited to participants with detectable tricuspid regurgitation on echocardiography. The study participants included self-identified African American individuals with plasma endothelin-1 levels and tricuspid regurgitation on echocardiogram (n = 3223) at the time of first examination (2000-2004). The analysis of the data began on April 14, 2014, and was completed on February 23, 2016.. Log-transformed plasma endothelin-1 level.. Cross-sectional analysis: presence of pulmonary hypertension (defined as an elevated pulmonary artery systolic pressure >40 mm Hg on echocardiogram). Longitudinal outcomes were all-cause mortality (median follow-up, 7.75 years) and heart failure admissions (median follow-up, 5.32 years).. Of the 3223 participants enrolled in the study, 1051 were men (32.6%). Mean (SD) endothelin-1 levels were 1.36 (0.64) pg/mL; 217 of 3223 cohort members (6.7%) had pulmonary hypertension. After adjusting for potential confounders, log-transformed endothelin-1 levels were associated with increased odds of pulmonary hypertension (adjusted odds ratio per log increment in endothelin-1, 1.66; 95% CI, 1.16-2.37). Log-transformed endothelin-1 levels were associated with mortality (adjusted hazard ratio per log increment in endothelin-1, 1.69; 95% CI, 1.27-2.25; median follow-up, 7.75 years) and heart failure (adjusted hazard ratio per log increment in endothelin-1, 1.57, 95% CI, 1.05-2.37; median follow-up, 5.32 years) in the study cohort. Phenotyping by pulmonary hypertension and endothelin-1 level showed mortality decreasing in order from subgroup with pulmonary hypertension and high endothelin-1 (high endothelin-1: ≥1.7 pg/mL; upper quartile); pulmonary hypertension and low endothelin-1 <1.7 pg/mL; lower 3 quartiles); no pulmonary hypertension and high endothelin-1; and no pulmonary hypertension and low endothelin-1 (log-rank χ2 = 77.16; P < .01 ).. Elevated plasma endothelin-1 levels, especially associated with an elevated pulmonary artery systolic pressure on echocardiogram, may identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies.

Topics: Adult; Aged; Biomarkers; Black or African American; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mississippi; Prospective Studies

Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension.. In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF.. These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF.

Topics: Aged; Animals; Case-Control Studies; Collagen Type I; Connectin; Diastole; Echocardiography; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Heart; Heart Failure; Humans; Hypertrophy; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; MEF2 Transcription Factors; Mice; Middle Aged; Myocytes, Cardiac; Pyrimidines; RNA, Messenger; Stroke Volume; Sulfonamides; Ventricular Dysfunction, Left; Ventricular Remodeling

Biomarkers can help to identity acute heart failure (AHF) as the cause of symptoms in patients presenting to the emergency department (ED). Older patients may prove a diagnostic challenge due to co-morbidities. Therefore we prospectively investigated the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) alone or in combination with other biomarkers for AHF upon admission at the ED.. 302 non-surgical patients aged ≥ 70 years were consecutively enrolled upon admission to the ED. In addition to NT-proBNP, mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and ultra-sensitive C-terminal pro-vasopressin (Copeptin-us) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of AHF after reviewing all available baseline data excluding the biomarkers. We assessed changes in C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) for the multimarker approach.. AHF was diagnosed in 120 (40%) patients (age 81±6 years, 64 men, 56 women). Adding MR-ADM to NT-proBNP levels improved C-index (0.84 versus 0.81; p=0.045), and yielded IDI (3.3%; p=0.002), NRI (17%, p<0.001) and continuous NRI (33.3%; p=0.002). Adding CT-proET-1 to NT-proBNP levels improved C index (0.86 versus 0.81, p=0.031), and yielded robust IDI (12.4%; p<0.001), NRI (31.3%, p<0.001) and continuous NRI (69.9%; p<0.001). No other dual or triple biomarker combination showed a significant improvement of both C-index and IDI.. In older patients presenting to the ED, the addition of CT-proET-1 or MR-proADM to NT-proBNP improves diagnostic accuracy of AHF. Both dual biomarker approaches offer significant risk reclassification improvement over NT-proBNP.

Topics: Academic Medical Centers; Acute Disease; Adrenomedullin; Aged; Aged, 80 and over; Aging; Atrial Natriuretic Factor; Biomarkers; Emergency Service, Hospital; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index

Concentrations of endothelin I (ET1) are elevated in CHF patients and, like other biomarkers that reflect hemodynamic status and cardiac pathophysiology, are prognostic. The Singulex assay (Sgx-ET1) measures the active form of ET1, with a short in vivo half-life and the Brahms assay measures C-terminal endothelin-1 (CT-ET1), a modified (degraded) product with longer half-life. We aimed to determine the prognostic importance of active and modified forms of endothelin 1 (Singulex and Brahms assays) in comparison with other commonly measured biomarkers of inflammation, hemodynamic status and cardiac physiology in CHF.. Plasma biomarkers (Sgx-ET1, CT-ET1, NTproBNP, IL-6, TNFα, cTnI, VEGF, hs-CRP, Galectin-3, ST2) were measured in 134 NYHA class II and III CHF patients with systolic dysfunction. Prognostic importance of biomarkers for hospitalization or death were calculated by both logistic regression and Kaplan-Meier survival analyses.. CT-ET1 (OR=5.2, 95% CI=1.7-15.7) and Sgx-ET1 (OR=2.9, CI=1.1-7.7) were independent predictors of hospitalization and death and additively predicted events after adjusting for age, sex, and other significant biomarkers. Other biomarkers did not improve the model. Similarly, in Cox regression analysis, only CT-ET1 (HR 3.4, 95% CI=1.4-8.4), VEGF (2.7, 95% CI=1.3-5.4), and Sgx-ET1 (HR 2.6, 95% CI=1.2-5.6) were independently prognostic.. Elevated concentrations of endothelin 1 predict mortality and hospitalizations in HF patients. Endothelin 1 was more prognostic than commonly obtained hemodynamic, inflammatory, and fibrotic biomarkers. Two different assays of endothelin 1 independently and synergistically were prognostic, suggesting either complementary information or extreme prognostic importance.

Topics: Adult; Aged; Biomarkers; Endothelin-1; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mortality; Prognosis; Stroke Volume

Increased production of reactive oxygen species has been implicated in the pathogenesis of congestive heart failure. However, emerging evidence suggests a role for reactive oxygen species in regulating various physiological cellular processes in the myocardium. The authors summarize the current understanding of involvement of reactive oxygen species in the regulation of cardiac contractility under physiological conditions.

Topics: Animals; Endothelin-1; Heart Failure; Humans; Myocardial Contraction; Myocardium; Reactive Oxygen Species

To evaluate the effect of high thoracic epidural analgesia (HTEA) in congestive heart failure (CHF).. Rat model of CHF.. Harbin Medical University, Harbin, Heilongjiang, China.. One hundred thirty-five rats.. HTEA involved 5 times daily injections of 0.1% lidocaine at the T3-T4 level.. The authors examined myocardial norepinephrine (NE), angiotensin II (Ang II), endothelin-1 (ET1), and tumor necrosis factor-α (TNF-α) concentrations 2, 4, and 6 weeks after the start of HTEA. They also examined histologic changes in heart tissue and myocardial expression of apoptosis-inducing factor (AIF) and poly (ADP-ribose) polymerase (PARP). Sham rats were used as a control. In the time course, myocardial NE, Ang II, ET1, and TNF-α concentrations were significantly higher in the CHF group compared with the HTEA and sham groups (p< 0.05). Similarly, PARP and AIF protein expression levels were significantly higher in the CHF group compared with the HTEA and sham groups (p< 0.05). Microscopy revealed pronounced damage to myocardial cell structures in the CHF group; this damage clearly was reduced in the HTEA group. In addition, cardiac function evaluation indicated treatment with HTEA resulted in similar heart function as animals that did not have surgically induced CHF.. The findings suggest that HTEA induces changes in sympathetic nervous system, renin-angiotensin system, endothelial, and inflammatory process activity involved in CHF.

Topics: Anesthesia, Epidural; Anesthetics, Local; Angiotensin II; Animals; Apoptosis; Apoptosis Inducing Factor; DNA Repair; Endothelin-1; Heart Failure; Lidocaine; Male; Myocardium; Norepinephrine; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar; Sympathetic Nervous System; Thoracic Vertebrae; Tissue Fixation; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Endothelin-1 participates in the pathophysiology of heart failure. The reasons for the lack of beneficial effect of endothelin antagonists in heart failure patients remain however speculative. The anti-apoptotic properties of ET-1 on cardiomyocytes could be a reasonable explanation. We therefore hypothesized that blocking the pro-apoptotic TNF-α pathway using pentoxifylline could prevent the deleterious effect of the lack of ET-1 in a model for heart failure.. We performed transaortic constriction (TAC) in vascular endothelial cells specific ET-1 deficient (VEETKO) and wild type (WT) mice (n = 5-9) and treated them with pentoxifylline for twelve weeks.. TAC induced a cardiac hypertrophy in VEETKO and WT mice but a reduction of fractional shortening could be detected by echocardiography in VEETKO mice only. Cardiomyocyte diameter was significantly increased by TAC in VEETKO mice only. Pentoxifylline treatment prevented cardiac hypertrophy and reduction of fractional shortening in VEETKO mice but decreased fractional shortening in WT mice. Collagen deposition and number of apoptotic cells remained stable between the groups as did TNF-α, caspase-3 and caspase-8 messenger RNA expression levels. TAC surgery enhanced ANP, BNP and bcl2 expression. Pentoxifylline treatment reduced expression levels of BNP, bcl2 and bax.. Lack of endothelial ET-1 worsened the impact of TAC-induced pressure overload on cardiac function, indicating the crucial role of ET-1 for normal cardiac function under stress. Moreover, we put in light a TNF-α-independent beneficial effect of pentoxifylline in the VEETKO mice suggesting a therapeutic potential for pentoxifylline in a subpopulation of heart failure patients at higher risk.

Topics: Animals; Aorta; Apoptosis; Blood Pressure; Cardiomegaly; Echocardiography; Endothelin-1; Endothelium, Vascular; Female; Gene Expression Profiling; Genotype; Heart; Heart Failure; Heart Rate; Mice; Mice, Knockout; Myocytes, Cardiac; Pentoxifylline; Tumor Necrosis Factor-alpha

Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in N(ω)-nitro-l-arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, heme-arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, heme-arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of heme-arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of heme-arginate, exacerbating inflammatory injury and oxidative insults. We conclude that heme-arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.

Topics: Adiponectin; Aldosterone; Animals; Antioxidants; Arginine; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiomyopathies; Cardiotonic Agents; Chemokine CCL2; Chemokine CCL3; Cyclic GMP; Dinoprost; Endothelin-1; Enzyme Induction; Extracellular Matrix Proteins; Heart Failure; Heme; Heme Oxygenase (Decyclizing); Hypertension; Interleukin-1beta; Interleukin-6; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Tyrosine

Inflammatory, endothelial and neurohormonal biomarkers are involved in heart failure (HF) and pulmonary hypertension (PH) pathogenesis.. To study these biomarkers in PH due to advanced HF.. Thirty adults with HF were included. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), endothelin-1 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured in peripheral vein and pulmonary artery during right heart catheterisation.. IL-6, TNF-α, hsCRP and NT-proBNP correlated with pulmonary pressures independent of ventricular function, HF etiology and vascular bed. IL-6 was independent predictor of systolic pulmonary artery pressure (sPAP).. Inflammatory biomarkers correlate to PH severity. IL-6 predicts sPAP in advanced HF.

Topics: Aged; Biomarkers; C-Reactive Protein; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Interleukin-6; Linear Models; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery; Tumor Necrosis Factor-alpha

To elucidate predictors of unfavorable cardiac events in patients with non-ischemic cardiomyopathy (CMP) complicated by congestive heart failure (CHF) with preserved myocardial coronary reserve (MCR).. We followed 114 patients with non-ischemic MCP and NYHA class III-IV CHF. MCR was estimated by dobutamine stress-echocardiography (SEchoCG). Prior to SEchoCG we measured blood von Willebrand factor (vWF) activity, content of endothelin-1 (ET), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1) and nitric oxide stable metabolites. At peak of dobutamine test blood was collected for measurement of ET, vWF, and NT-proBNP concentrations. Left ventricular ejection fraction (LVEF)sechoCG, ETsechoCG, vWFsechoCG and NT-proBNPsechoCG were calculated as percentage changes of these parameters from baseline at peak dobutamine load.. Groups with low and preserved MCR were not different by relative number of patients with unfavorable course of the disease (41.2 and 34.8%, p = 0.529, respectively). The following parameters were predictors of development of unfavorable cardiac events in patients with preserved MCR (LVEFsechoCG > 10%) during 24 months: initial hsCRP > 5.2 mg/ml, LVEFsechoCG < 19.7% and ETsechoCG > 11.8%. Logistic regression model combined with binary values of LVEFsechoCG and ETsechoCG demonstrated best prognostic efficacy (sensitivity--86.7%, specificity--83.3%, prognostic accuracy--84.6%).

Topics: Adult; C-Reactive Protein; Chronic Disease; Disease Progression; Echocardiography, Stress; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Vascular Cell Adhesion Molecule-1; Ventricular Function, Left; von Willebrand Factor

Topics: Aged; Endothelin-1; Female; Heart Failure; Humans; Male; Myocardial Ischemia; Polymorphism, Genetic; Ventricular Function, Left

High mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload.. Analysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice.. These results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.

Topics: Acetylation; Animals; Atrial Natriuretic Factor; Cardiomegaly; Cell Nucleus; Endothelin-1; Heart Failure; HMGB1 Protein; Humans; Mice; Myocardium; Protein Transport; Rats

Although many obese individuals are normoglycemic and asymptomatic of cardiometabolic complications, this apparent healthy state may be a misnomer. Since heart failure is a major cause of mortality in obesity, we investigated the effects of heme-oxygenase (HO) on heart failure and cardiometabolic complications in obese normoglycemic Zucker-fatty rats (ZFs). Treatment with the HO-inducer, hemin, reduced markers of heart failure, such as osteopontin and osteoprotegerin, abated left-ventricular (LV) hypertrophy/fibrosis, extracellular matrix/profibrotic proteins including collagen IV, fibronectin, TGF-β1, and reduced cardiac lesions. Furthermore, hemin suppressed inflammation by abating macrophage chemoattractant protein-1, macrophage-inflammatory protein-1 alpha, TNF-α, IL-6, and IL-1β but enhanced adiponectin, atrial-natriuretic peptide (ANP), HO activity, insulin sensitivity, and glucose metabolism. Correspondingly, hemin improved several hemodynamic/echocardiographic parameters including LV-diastolic wall thickness, LV-systolic wall thickness, mean-arterial pressure, arterial-systolic pressure, arterial-diastolic pressure, LV-developed pressure, +dP/dt, and cardiac output. Contrarily, the HO-inhibitor, stannous mesoporphyrin nullified the hemin effect, exacerbating inflammatory/oxidative insults and aggravated insulin resistance (HOMA-index). We conclude that perturbations in insulin signaling and cardiac function may be forerunners to overt hyperglycemia and heart failure in obesity. Importantly, hemin improves cardiac function by suppressing markers of heart failure, LV hypertrophy, cardiac lesions, extracellular matrix/profibrotic proteins, and inflammatory/oxidative mediators, while concomitantly enhancing the HO-adiponectin-ANP axis.

Topics: Adiponectin; Animals; Atrial Natriuretic Factor; Blood Glucose; Chemokine CCL2; Dinoprost; Endothelin-1; Heart Failure; Heart Function Tests; Heart Ventricles; Heme Oxygenase (Decyclizing); Hemin; Hemodynamics; Inflammation; Insulin; Insulin Resistance; Macrophage Inflammatory Proteins; Macrophages; Metalloporphyrins; Myocytes, Cardiac; Obesity; Rats; Rats, Zucker; Risk Factors; Tumor Necrosis Factor-alpha; Ultrasonography; Up-Regulation

The mechanisms underlying the reactive component of pulmonary hypertension (PH) in heart failure (HF) are unclear. We examined whether resting systemic oxygen levels are related to pulmonary hemodynamics in HF.. Thirty-nine HF patients underwent right heart catheterization. Subsequently, patients were classified as having: 1) no PH (n = 12); 2) passive PH (n = 10); or 3) reactive PH (n = 17). Blood was drawn from the radial and pulmonary arteries for the determination of PaO(2), SaO(2), PvO(2), SvO(2), and vasoactive neurohormones. PaO(2) and PvO(2) were lower in reactive PH versus no PH and passive PH patients (65.3 ± 8.6 vs 78.3 ± 11.4 mm Hg and 74.5 ± 14.0 mm Hg; 29.2 ± 4.1 vs 36.2 ± 2.8 mm Hg and 33.4 ± 2.3 mm Hg; P < .05). SaO(2) and SvO(2) were lower in reactive PH versus no PH patients (93 ± 3% vs 96 ± 3%; 51 ± 11% vs 68 ± 4%; P < .05), but not different versus passive PH patients. The transpulmonary pressure gradient (TPG) was inversely related to PaO(2), PvO(2), SaO(2), and SvO(2) in the reactive PH patients only (r ≤ -0.557; P < .05). Similarly, plasma endothelin-1 correlated with PaO(2), PvO(2), SvO(2) (r ≤ -0.495), and TPG (r = 0.662; P < .05) in reactive PH patients only.. Systemic hypoxia may play a role in the reactive component of PH in HF, potentially via a hypoxia-induced increase in endothelial release of the vasoconstrictor endothelin-1.

Topics: Adult; Aged; Blood Gas Analysis; Cardiac Catheterization; Cardiac Output, Low; Cohort Studies; Disease Progression; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Multivariate Analysis; Neurotransmitter Agents; Oxygen; Prognosis; Prospective Studies; Regression Analysis; Risk Assessment; Severity of Illness Index; Survival Rate; Vascular Resistance

Although cardiac diseases account for the highest mortality and morbidity rates in Western society, there is still a considerable gap in our knowledge of genes that contribute to cardiac (dys)function. Here we screened for gene expression profiles correlated to heart failure.. By expression profiling we identified a novel gene, termed DHRS7c, which was significantly down-regulated by adrenergic stimulation and in heart failure models. Dhrs7c is a short chain dehydrogenase/reductase (SDR) and is localized to the endo/sarcoplasmic reticulum. Dhrs7c is strongly conserved in vertebrates, and mRNA and protein expression levels were highest in heart and skeletal muscle followed by skin, but were not detectable in other organs. In vitro, both α- and β-adrenergic stimulation repressed Dhrs7c expression in neonatal cardiomyocytes and this could be mimicked by the direct activation of protein kinase C and adenylate cyclase, the respective intracellular targets of these hormones. In contrast, endothelin-1, which also provoked strong hypertrophy development in vitro, did not repress Dhrs7c expression. The latter suggests adrenergic specificity and indicates that down-regulation is not a prerequisite for hypertrophy development. In vivo adrenergic stimulation could also down-regulate Dhrs7c expression. Finally, we confirmed that expression was also down-regulated in two different models of failure and, importantly, also in biopsies from human heart failure patients.. Our results show that the expression of Dhrs7c, a novel endo/sarcoplasmic reticulum-localized SDR, is inversely correlated with adrenergic stimulation and heart failure development.

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Biopsy; Cardiomegaly; Disease Models, Animal; Down-Regulation; Endothelin-1; Gene Expression Regulation, Enzymologic; Heart Failure; Humans; Mice; Myocytes, Cardiac; Oxidoreductases; Phenylephrine; Rats; RNA, Messenger; Sarcoplasmic Reticulum; Sympathetic Nervous System

Previously, we have reported sex differences in the cardiac remodeling response to ventricular volume overload whereby male and ovariectomized (OVX) female rats develop eccentric hypertrophy, and intact (Int) female rats develop concentric hypertrophy. In males, this adverse remodeling has been attributed to an initial cascade of events involving myocardial mast cell and matrix metalloproteinase activation and extracellular collagen matrix degradation. The objective of this study was to determine the effect of female hormones on this initial cascade. Accordingly, an aortocaval fistula (Fist) was created in 7-wk-old Int and OVX rats, which, together with sham-operated (sham) controls, were studied at 1, 3, and 5 days postsurgery. In Int-Fist rats, myocardial mast cell density, collagen volume fraction, endothelin (ET)-1, stem cell factor (SCF), and TNF-α remained at control levels or were minimally elevated throughout the study period. This was not the case in the OVX-Fist group, where the initial response included significant increases in mast cell density, collagen degradation, ET-1, SCF, and TNF-α. These events in the OVX-Fist group were abolished by prefistula treatment with a mast cell stabilizer nedocromil. Of note was the observation that ET-1, TNF-α, SCF, and collagen volume fraction values for the OVX-sham group were greater than those of the Int-sham group, suggesting that the reduction of female hormones alone results in major myocardial changes. We concluded that female hormone-related cardioprotection to the volume stressed myocardium is the result of an altered mast cell phenotype and/or the prevention of mast cell activation.

Topics: Animals; Anti-Inflammatory Agents; Cardiomegaly; Collagen; Endothelin-1; Estrogens; Female; Heart Failure; Mast Cells; Nedocromil; Ovariectomy; Phenotype; Rats; Rats, Sprague-Dawley; Stem Cell Factor; Tumor Necrosis Factor-alpha; Ventricular Remodeling

To investigate the in vivo and in vitro protective effects of pentamethylquercetin (PMQ), a member of polymethoxy flavonoids (PMFs), on cardiac hypertrophy.. An in vivo cardiac hypertrophy model established by abdominal aorta banding technique in rats was treated with PMQ in increasing dosages (2.5, 5, and 10 mg x kg(-1) x d(-1)). An in vitro cardiomyocyte hypertrophy model was induced by treating neonatal cardiomyocytes with endothelin-1 (ET-1, 0.1 μM). An in vitro fibrosis model was developed in cardiac fibroblasts by aldosterone (Ald, 20 nM) and treated with PMQ (0.3, 1, 3 and 10 μM). Hemodynamic, morphological, histological, and biochemical changes were evaluated at corresponding time points.. The abdominal aorta constriction (AAC) rats demonstrated a significantly elevated blood pressure and profound systolic and diastolic cardiac dysfunction. The resultant cardiac hypertrophy and heart failure were characterized by a significant increase in the heart and lung indices (3.51 ± 0.30 vs 2.35 ± 0.24, 5.58 ± 0.85 vs 3.94 ± 0.54; both P < 0.01), cardiomyocyte cross-sectional areas (153 ± 33% vs 100 ± 5%, P < 0.01) and myocardial fibrosis (9.09 ± 1.30% vs 1.49 ± 0.20%, P < 0.01) with concomitant elevation of B-type natriuretic peptide and cardiac collagen mRNA level. Daily oral administration of PMQ (2.5, 5, and 10 mg/kg for 7 weeks) prevented the foregoing histology, gene and protein changes secondary to AAC procedure. In addition, the up-regulated inflammation factors such as TNF-α and IL-6, and the down-regulated PPAR α and PPAR β were normalizd by PMQ treatment.. PMQ has significant protective effects on cardiac hypertrophy through up-regulating the mRNA and protein levels of PPAR α and PPAR β involved in the process of inflammation response and cardiac fibrosis.

Topics: Aldosterone; Animals; Blood Pressure; Cardiomegaly; Cardiotonic Agents; Cells, Cultured; Collagen; Down-Regulation; Endothelin-1; Fibroblasts; Fibrosis; Heart Failure; Hemodynamics; Interleukin-6; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; PPAR alpha; PPAR-beta; Quercetin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation

PTH is related to left ventricular hypertrophy and its circulating levels are associated with worse prognosis in patients with heart failure (HF). The objectives of our study were to measure the circulating levels of bioactive PTH 1-84 through third-generation assay in HF patients, to determine their association with the disease severity as well as their relation with recognized biomarkers of HF worsening and prognosis.. PTH 1-84 concentrations were determined in 76 HF patients and in 49 healthy volunteers. Circulating levels of amino-terminal proatrial natriuretic peptide (Nt-proANP), B-type natriuretic peptide (BNP), Nt-proBNP, proBNP, and big endothelin-1 (Big ET-1) were also measured.. HF patients had in- creased PTH 1-84 levels in comparison to controls. A significant increase of the PTH 1-84 circulating concentrations was observed according to the New York Heart Association functional classes. PTH 1-84 circulating concentrations were also significantly correlated with Nt-proANP, BNP, Nt-proBNP, proBNP, and Big ET-1.. PTH 1-84 circulating levels are significantly increased in HF patients in comparison to healthy individuals. Our study has also demonstrated that circulating concentrations of bioactive PTH are related to HF severity and well-established biomarkers of the worsening of the disease.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Endothelin-1; Female; Heart Failure; Humans; Immunoassay; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Parathyroid Hormone; Regression Analysis

Pathophysiological interactions between heart and lungs in heart failure (HF) are well recognized. We investigated whether expression of different factors known to be increased in the myocardium and/or the circulation in HF is also increased in alveolar macrophages in HF.. Lung function, hemodynamic parameters, gene expression in alveolar macrophages, and plasma levels in the pulmonary and femoral arteries of HF patients (n = 20) were compared to control subjects (n = 16). Our principal findings were: (1) Lung function was significantly lower in HF patients compared to controls (P<0.05). (2) mRNA levels of ET-1, tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) were increased in alveolar macrophages from HF patients. (3) Plasma levels of ET-1, TNFα, IL-6 and MCP-1 were significantly increased in HF patients, whereas our data indicate a net pulmonary release of MCP-1 into the circulation in HF.. Several important cytokines and ET-1 are induced in alveolar macrophages in human HF. Further studies should clarify whether increased synthesis of these factors affects pulmonary remodeling and, directly or indirectly, adversely affects the failing myocardium.

Topics: Adult; Cytokines; Endothelin-1; Female; Heart Failure; Humans; Immunoenzyme Techniques; Inflammation Mediators; Macrophages, Alveolar; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction

Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown.. Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB + AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment.. Contractile performance was significantly improved in the PAB + AO group versus the PAB group for both ventricles. Relative to sham-operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB + AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor β genes.. Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV.

Topics: Animals; Aorta; Arterial Pressure; Chronic Disease; Collagen; Collagenases; Connective Tissue Growth Factor; Constriction; Disease Models, Animal; Endothelin-1; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Myocardial Contraction; Myocardium; Pulmonary Artery; Rabbits; Receptors, Endothelin; Recovery of Function; Time Factors; Transforming Growth Factor beta; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure; Ventricular Remodeling

Binary transgenic (BT) mice with doxycycline (DOX)-suppressible cardiac-specific overexpression of endothelin-1 (ET-1) exhibit progressive heart failure (HF), QRS prolongation, and death following DOX withdrawal. However, the molecular basis and reversibility of the electrophysiological abnormalities in this model were not known. Here, we assess the mechanisms underlying ET-1-mediated electrical remodelling, and its role in HF.. BT vs. non-BT littermate controls were withdrawn from DOX and serially studied with ultrasound biomicroscopy, octapolar catheters, multielectrode epicardial mapping, histopathology, western blot, immunohistochemistry, and qRT-PCR. Abnormalities in ventricular activation and -dV/dt were detected as early as 4 weeks after transgene activation, when the structure and function of the heart remained unaffected. By 8 weeks of ET-1 overexpression, biventricular systolic and diastolic dysfunction, myocardial fibrosis, and cardiomyocyte hypertrophy were observed. Intracardiac and epicardial electrograms revealed prolonged conduction and ventricular activation, reduced -dV/dt, and abnormal atrioventricular nodal function. Within 4 weeks of ET-1 induction, connexin 40 (Cx40) protein and Cx43 mRNA, protein, and phosphorylation levels were reduced by 36, 64, 93, and 69%, respectively; Na(v)1.5 mRNA and protein levels were reduced by 30 and 50%, respectively, as was Na(+) channel conductance. Importantly, the associated electrophysiological abnormalities at this time point were reversible upon suppression of ET-1 overexpression and completely prevented the development of structural and functional remodelling.. ET-1-mediated electrical remodelling correlates with reduced Cx40, Cx43, and Na(v)1.5 expression and decreased Na(+) channel conductance and precedes HF. The sequence and reversibility of this phenotype suggest that a primary abnormality in electrical remodelling may contribute to the pathogenesis of HF.

Topics: Animals; Cardiomyopathies; Connexin 43; Connexins; Disease Models, Animal; Electrophysiologic Techniques, Cardiac; Endothelin-1; Gap Junction alpha-5 Protein; Gene Expression; Heart Conduction System; Heart Failure; Mice; Mice, Transgenic; Myocardial Contraction; NAV1.5 Voltage-Gated Sodium Channel; Phenotype; Sodium Channels; Ventricular Remodeling

We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP).. We examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay.. Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01) than adding NT-proBNP (p<0.01). Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02).. Plasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.

Topics: Aged; Biomarkers; Chronic Disease; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Mortality; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Risk

Chronic myocardial ischaemia (CMI) has become an important cause of heart failure (HF). The aim of this study was to examine the effects of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) gene transfer in large HF animal models induced by CMI.. HF was induced in mini pigs by proximal left anterior descending coronary (LAD) ameroid constrictors. After confirmation of myocardial perfusion defects and cardiac function impairment, animals were divided into 4 groups (each including 4 animals): the HF group; the HF+enhanced green fluorescent protein (EGFP) group; the HF+SERCA2a group; and sham animals as a control group, rAAV1-EGFP and rAAV1-SERCA2a were injected intramyocardially to animals of the HF+EGFP and HF+SERCA2a groups separately. Sixty days after gene transfer, expressions of SERCA2a were examined, cardiac functions and changes of serum inflammatory and neuro-hormonal factors were determined. The results demonstrated that 60 days after gene transfer, LVEF, Ev/Av and +/- dp/dtmax of the HF+SERCA2a group increased significantly (P < 0.05), along with an increase in SERCA2a protein expression (P < 0.05) compared with the HF/HF+EGFP groups. Serum concentrations of inflammatory and neuro-hormonal factors were also decreased in the HF+SERCA2a group (P < 0.05).. Restoration of SERCA2a in myocardium of HF model induced by CMI could significantly improve cardiac function, suggesting its potential therapeutic significance in CMI-related heart failure.

Topics: Adenoviridae; Angiotensin II; Animals; Disease Models, Animal; Endothelin-1; Fluorescent Dyes; Gene Transfer Techniques; Genetic Therapy; Green Fluorescent Proteins; Heart Failure; Interleukin-6; Male; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stroke Volume; Swine; Swine, Miniature; Tumor Necrosis Factor-alpha

Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 μg/kg per hour; n=6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P<0.001) and output (2.6±0.1 versus 3.8±0.3 L/min; P<0.001), together with reductions in left atrial pressure (28±1 versus 12±1 mm Hg; P<0.001) and peripheral resistance (30±2 versus 20±2 mm Hg/L per min; P<0.001). In contrast, urocortin 2-induced falls in mean arterial pressure were not established until the second day (day 4: 74±2 versus 72±2 mm Hg; P<0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33±0.27 versus 0.73±0.20 nmol/L per hour; P<0.001), aldosterone (970±383 versus 396±96 pmol/L; P<0.05), vasopressin (2.4±0.8 versus 1.3±0.1 pmol/L; P<0.05), endothelin 1 (7.2±0.7 versus 4.5±0.4 pmol/L; P<0.01), and atrial (269±27 versus 150±19 pmol/L; P<0.001) and B-type (65±9 versus 29±6 pmol/L; P<0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P<0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P<0.001) and creatinine (1.4-fold; P<0.001) excretion and creatinine clearance (1.5-fold; P<0.01) compared with control. Food consumption was temporarily suppressed (P<0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure.

Topics: Aldosterone; Animals; Blood Pressure; Cardiac Output; Creatinine; Endocrine System; Endothelin-1; Female; Heart; Heart Failure; Hemodynamics; Infusions, Intravenous; Kidney; Mice; Oligopeptides; Renin; Sheep; Sodium; Time Factors; Urocortins; Vascular Resistance; Vasopressins

Acutely decompensated heart failure (ADHF) leads to neurohumoral activation potentially affecting vascular tone and organ perfusion and may be linked to unfavourable outcome. Global haemodynamic, clinical, and laboratory parameters may severely underestimate tissue hypoperfusion. Therefore, the purpose of this study was to evaluate microvascular flow index (MFI) in patients with ADHF and to assess the effect of standard pharmacological therapy using Sidestream Dark Field (SDF) imaging.. Twenty-seven patients (mean age 75.5 ± 10.1 years, 48% male) with ADHF in New York Heart Association functional class ≥III were included. Serum markers of neurohumoral activation [brain natriuretic peptide (BNP)], endothelin-1 (ET-1), noradrenaline (NA), and echocardiographic parameters of left ventricle-function were determined at hospital admission and the day before discharge. Using SDF imaging, MFI was evaluated at both time-points in semi-quantitative vessel categories (small: 10-25 μm; medium: 26-50 μm; and large: 51-100 μm). At admission, increased serum levels of BNP, NA, and ET-1 and a severely reduced MFI were observed in association with ADHF. Serum levels of BNP, NA, and ET-1 decreased significantly with standard pharmacological therapy (BNP: 2163 ± 1577 vs.1006 ± 945 pg/mL, P< 0.05; NA: 349 ± 280 to 318 ± 265 pg/mL, P< 0.05; ET-1: 5.08 ± 0.72 to 4.81 ± 0.59 pg/mL; P< 0.01). Standard pharmacological treatment also had a profound impact on tissue perfusion by significantly improving median MFI in small [2.6; inter-quartile range (IQR) 2.3-2.9 vs. 2.9; IQR 2.8-3.0; P= 0.01) and medium-sized (2.0; IQR 1.9-2.5 vs. 2.7; IQR 2.5-2.8; P< 0.01) vessels.. In patients with ADHF, microvascular tissue perfusion is impaired even when global haemodynamic or laboratory signs of hypoperfusion are absent. Effective pharmacological treatment to decrease neurohumoral activation significantly improves microflow. Hypoperfusion in ADHF is potentially linked to neurohumoral activation with increased plasma levels of vasoconstrictors and sympatho-adrenergic activity.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Disease Progression; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Microcirculation; Myocardial Perfusion Imaging; Natriuretic Peptide, Brain; Norepinephrine; Prognosis; Regional Blood Flow; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Statistics, Nonparametric; Stroke Volume; Ventricular Function, Left

Endothelin-1 (ET-1) induces cardiac hypertrophy, whereas adiponectin may elicit protective effects in the vasculature and myocardium. We therefore evaluated the relationship between plasma ET-1 and adiponectin levels in heart failure (HF) patients, and the association between adiponectin expression and ET-1-induced hypertrophy of human cardiomyocytes (HCM) in vitro.. One hundred seventeen patients with chronic HF were enrolled into this study. A group of 7 patients with end-stage HF undergoing heart transplantation was included in the histopathological study. Baseline clinical evaluations and laboratory measurements were performed. HCM cultures were studied to investigate the effect of ET-1 on cell size and adiponectin expression.. Plasma ET-1, adiponectin, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased with the severity of HF. Higher New York Heart Association functional class, plasma ET-1, adiponectin, and NT-proBNP levels were significant predictors of adverse outcomes in these patients. The myocardial expression of adiponectin was significantly higher in the recipient hearts of patients undergoing emergency or urgent heart transplantation. In cell culture, ET-1 significantly increased cell size and adiponectin expression in HCM.. Adiponectin was significantly elevated in HF and was significantly associated with ET-1. The study provides a basis for further investigation of ET-1 and adiponectin modulation as a therapeutic strategy for ventricular remodeling in HF.

Topics: Adiponectin; Body Mass Index; Cardiomegaly; Cell Size; Cells, Cultured; Endothelin-1; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis

Topics: Adiponectin; Endothelin-1; Female; Heart Failure; Humans; Male; Myocardium

Tyrosine-phosphorylated focal adhesion kinase (FAK) is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. The aims of the present study were to characterize FAK serine phosphorylation in cultured neonatal rat ventricular myocytes (NRVM), analyse its functional significance during hypertrophic signalling, and examine its potential role in the pathogenesis of human dilated cardiomyopathy (DCM).. Endothelin-1 (ET-1) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation. ET-1-induced FAK-S910 phosphorylation required ET(A)R-dependent activation of PKCδ and Src via parallel Raf-1 → MEK1/2 → ERK1/2 and MEK5 → ERK5 signalling pathways. Replication-deficient adenoviruses expressing wild-type (WT) FAK and a non-phosphorylatable, S910A-FAK mutant were then used to examine the functional significance of FAK-S910 phosphorylation. Unlike WT-FAK, S910A-FAK increased the half-life of GFP-tagged paxillin within costameres (as determined by total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching) and increased the steady-state FAK-paxillin interaction (as determined by co-immunoprecipitation and western blotting). These alterations resulted in reduced NRVM sarcomere reorganization and cell spreading. Finally, we found that FAK was serine-phosphorylated at multiple sites in non-failing, human left ventricular tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM.. FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.

Topics: Angiotensin II; Animals; Animals, Newborn; Blotting, Western; Cardiomyopathy, Dilated; Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Activation; Fluorescence Recovery After Photobleaching; Focal Adhesion Kinase 1; Heart Failure; Humans; Immunoprecipitation; Insulin-Like Growth Factor I; Microscopy, Fluorescence; Mutation; Myocytes, Cardiac; Paxillin; Phenylephrine; Phosphorylation; Protein Kinase C-delta; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Sarcomeres; Serine; Signal Transduction; src-Family Kinases; Time Factors; Transfection

Endothelin-1 levels in patients with chronic congestive heart failure were evaluated with respect to the severity of cardiac dysfunction. The relationships between three neurohormones, brain natriuretic peptide (BNP), human atrial natriuretic peptide (HANP), and endothelin-1,were evaluated.. Forty patients (17 men and 23 women, aged 64-98 years) with chronic congestive heart failure were evaluated. Echocardiography was performed for each patient, and the left ventricular ejection fraction (EF) was calculated. Titers of HANP, BNP and endothelin-1 in serum were measured. Exclusion criteria included acute myocardial infarction, unstable angina, and renal dysfunction (serum creatinine >1.6 mg/dl).. Endothelin-1 levels were correlated with HANP (r = 0.675, p < 0.0001) and BNP (r = 0.616, p < 0.0001) levels. Endothelin-1 levels were not correlated with the left ventricular ejection fraction or end-diastolic volume. BNP levels were correlated with the left ventricular ejection fraction (r = 0.315, p = 0.057).. These findings indicate that endothelin-1 interacts with HANP and BNP in patients with chronic congestive heart failure. Endothelin-1 is suggested to play an important role in chronic congestive heart failure with preserved ejection fraction.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Reproducibility of Results; Sensitivity and Specificity; Ventricular Dysfunction, Left

Serial measurements of neurohormones have been shown to improve prognostication in the setting of acute heart failure (HF) or chronic HF without therapeutic intervention. We investigated the prognostic role of serial measurements of emerging neurohormones and BNP in a cohort of chronic HF patients undergoing increases in HF-specific therapy.. In this prospective study we included 181 patients with chronic systolic HF after an episode of hospitalization for worsening HF. Subsequently, HF therapy was gradually increased in the outpatient setting until optimized. We measured copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide before and after optimization of HF therapy. The primary endpoint was all-cause mortality at 24 months.. Angiotensin-converting enzyme/angiotensin receptor blocker and beta-blockers were increased significantly during the 3-month titration period (P < 0.0001 for both). In a stepwise Cox regression analysis adjusted for age, sex, glomerular filtration rate, diabetes mellitus, and ischemic HF, baseline and follow-up neurohormone concentrations were predictors of the primary endpoint as follows (baseline hazard ratios): copeptin 1.92, 95% CI 1.233-3.007, P = 0.004; midregional proadrenomedullin 2.79, 95% CI 1.297-5.995, P = 0.009; midregional proatrial natriuretic peptide 2.05, 95% CI 1.136-3.686, P = 0.017; C-terminal endothelin-1 precursor fragment 2.24, 95% CI 1.133-4.425, P = 0.025; B-type natriuretic peptide 1.46, 95% CI 1.039-2.050, P = 0.029.. In pharmacologically unstable chronic HF patients, baseline values and follow-up measures of copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide were equally predictive of all-cause mortality. Relative change of neurohormone values was noncontributory.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Prognosis; Protein Precursors

The available data suggest that Urocortin (UCN), a cardioprotective and vasoactive peptide known from fish neuroendocrinology, is involved in cardiac regulation. The aim of this study was to determine UCN plasma concentrations in patients with heart failure (HF). Plasma concentrations of UCN, measured in 42 fully treated HF patients. UCN, were determined using a specific ELISA assay after acidic extraction with Sep-Pak C18 columns. Circulating levels of other neurohormones Nt-proBNP, Nt-proANP and Big ET-1 were also determined. Reference values were obtained from 20 healthy age- and sex-matched subjects. In comparison with controls, UCN plasma concentrations (geometric mean [95% CI]) were significantly increased in HF patients (88 pmol/L [75-105] vs 46 [39-54], p<0.001). As expected, the other neurohormones were also significantly increased in HF patients (Nt-proBNP: 3501 pg/ml [2356-5202] vs 35 [24-51], Nt-proANP: 5498 pg/ml [4336-6971] vs 324 [255-411] and Big ET-1: 15.8 pg/ml [13.6-18.4] vs 5.9 [5.2-6.8]; p<0.01 for all vs controls). No significant correlation was observed between UCN and the other HF biomarkers. Our results demonstrate that plasma concentrations of UCN are significantly increased in patients with HF and that UCN may participate in the neurohumoral response of HF.

Topics: Aged; Aging; Atrial Natriuretic Factor; Endothelin-1; Glomerular Filtration Rate; Heart Failure; Humans; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Urocortins

Topics: Adrenomedullin; Arginine Vasopressin; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Prognosis; Risk Adjustment; Vasodilator Agents

Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence.. Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR) was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis.. Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.

Topics: Aged; Atrial Appendage; Atrial Fibrillation; Atrial Function, Left; Cardiomegaly; Echocardiography; Endothelin-1; Female; Fibrosis; Heart Diseases; Heart Failure; Humans; Hypertension; Linear Models; Male; Middle Aged; Mitral Valve Insufficiency; Receptor, Endothelin A; Receptor, Endothelin B; Risk Assessment; Risk Factors; RNA, Messenger; Up-Regulation

We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.

Topics: Allyl Compounds; Animals; ATP-Binding Cassette Transporters; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Epoprostenol; Heart Failure; Hypertension; In Vitro Techniques; KATP Channels; Male; Myocardium; Nitric Oxide; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Wistar; Receptors, Drug; Sulfonylurea Receptors; Tail; Vasodilator Agents; Ventricular Remodeling

We determined parameters of elasticity of peripheral arteries in patients with heart failure (HF) including those with pulmonary arterial hypertension. We also investigated pulmonary artery responses to vasoconstricting factors in vitro. Reactivity of the aorta and carotid artery was studied on the model of experimental HF. Lowering of elasticity of small arteries progressed with worsening of HF functional class and increase of pulmonary arterial hypertension. In the genesis of pulmonary hypertension definite role played elevated constrictor response of pulmonary artery to endothelin 1 at the background of dysfunction of endothelial ETB receptors. Endothelial dependent reactivity of the aorta and carotid artery was impaired and their constrictor effect augmented.

Topics: Comorbidity; Disease Progression; Elasticity; Endothelin B Receptor Antagonists; Endothelin-1; Endpoint Determination; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Artery; Receptor, Endothelin B; Vascular Resistance; Vasoconstrictor Agents

Circadian rhytmus have long been recognized to occur in many biologic phenomena, including secretion of hormones as well as autonomic nervous system. There is increasing evidence that circadian rhythms have been also found in cardiovascular events, for example, myocardial infarction, sudden cardiac death as well as stroke have shown a circadian pattern of the distribution. The pathophysiology and the mechanism underlying these variations are the focus of much investigation, while i tis not full understood up to date. Heart rate, blood pressure, neurohumoral vasoactive factors, such as plasma norepinephrine levels and renin activity, and probably also contractility are increased in the morning hours.. To evaluate the circadian variability of plasma big endothelin and NT-proBNP level in patients with severe heart failure.. 13 patients with severe heart failure, stable for at least one month, male/female--8/5, NYHA III/IV--11/2, mean left ventricle ejection fraction 23 +/- 5%, mean cardiothoracic ratio 59 +/- 7%, all treated with RAAS blocade (11 x ACE-I, 2x ARB), all treated with diuretics, 12 patients treated with beta-blockers, 7 with digoxin. The cause of heart failure was ischemic heart disease (9) or dilated cardiomyopathy (4).. Blood samples for big endothelin and NT-proBNP were taken every two hours during a standartised daily regime.. Mean plasma level of big endothelin (ranging from 1.25 to 1.71 pmol/l) had significant diurnal variability (upper limit of normal values 0.7 pmol/l). Mean plasma level of NT-proBNP (ranging from 782 to 934 pmol/l) had no diurnal variability (upper limit of normal values of 350 pmo/l).. Plasma level of NT-proBNP is stable during 24 hours and shows no circadian variability. Plasma big endothelin showed a morning peak after a systematic increase during bed rest. NT-proBNP could be evaluated any time during the day, big endothelin sample should be taken during standartised condition.

Topics: Aged; Circadian Rhythm; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments

The aim of this study was to evaluate the prognostic value of chromogranin A (CgA) and C-terminal endothelin-1 precursor fragment (CT-proET-1) in patients with acute destabilized heart failure.. 137 consecutive patients with acute destabilized heart failure attending the emergency department of a tertiary care hospital were prospectively enrolled. Plasma concentrations of CgA, CT-proET-1, and amino-terminal proBNP (NT-proBNP) were measured at baseline. The endpoint was defined as all-cause mortality; the study participants were followed up for 365 days.. Decedents (n=41) had higher median plasma concentrations of CgA (9.7 vs. 6.0 nmol/L; p=0.002), CT-proET-1 (120 vs. 72 pmol/L; p=0.006), and NT-proBNP (5112 vs. 2610 ng/L; p<0.001) at baseline than survivors (n=96). Applying Cox proportional-hazards regression analyses, increased CgA (>6.6 nmol/L), CT-proET-1 (>79 pmol/L), and NT-proBNP (>3275 ng/L) revealed significant risk ratios of 1.96 (95% CI, 1.04-3.70) for CgA, 2.56 (95% CI, 1.33-4.95) for CT-proET-1, and 2.05 (95% CI, 1.09-3.87) for NT-proBNP. When the cohort was stratified according to median CgA and NT-proBNP concentrations, and to median CT-proET-1 and NT-proBNP concentrations, respectively, Cox proportional-hazards regression analyses showed the highest risk for death in patients with both increased CgA and NT-proBNP (risk ratio, 3.65; 95% CI, 1.44-9.28), and increased CT-proET-1 and NT-proBNP (risk ratio, 4.03; 95% CI, 1.61-8.88).. Our study demonstrates that increased CgA and CT-proET-1 plasma concentrations at the initial presentation of patients with acute destabilized heart failure in the emergency department add independent prognostic information in addition to NT-proBNP measurement.

Topics: Aged; Aged, 80 and over; Biomarkers; Chromogranin A; Data Collection; Endothelin-1; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Survival Rate

The identification of chronic heart failure (CHF) patients at high risk of adverse outcome remains a challenge. New peptides are emerging that may give additional information. In CHF patients, endothelin (ET) levels predict mortality risk. Adrenomedullin has been shown to predict mortality in ischaemic heart failure, but not in unselected or non-ischaemic CHF patients. Moreover, ADM and ET have never been assessed in one model. The aim of the present study was to assess the prognostic value of midregional-pro-adrenomedullin (MR-proADM) and C-terminal-pro-endothelin-1 (CT-proET-1) in outpatients with CHF.. We measured plasma MR-proADM and CT-proET-1 levels in 786 consecutive CHF outpatients and compared them with B-type natriuretic peptide (BNP) levels. At 24-month follow-up, 233 patients had died. A stepwise forward Cox regression model with age, sex, estimated glomerular filtration rate, NYHA > II, left ventricular ejection fraction (LVEF), MR-proADM, CT-proET-1, and BNP as possible predictors revealed that MR-proADM levels [hazard ratio (HR) = 1.77, P < 0.001] in addition to age (HR = 1.02, P = 0.004), ejection fraction (HR = 0.98, P = 0.004), and NYHA > II (HR = 1.86, P < 0.001) were predictors of death at 24 months. When the analysis was repeated dependent on NYHA-stage, MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers, but only in patients with mild/moderate CHF.. Our data suggest that MR-proADM may be an important prognostic humoral marker, especially in mild/moderately symptomatic and non-ischaemic CHF patients.

Topics: Adrenomedullin; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Heart Ventricles; Humans; Luminescent Measurements; Male; Middle Aged; Outpatients; Prognosis; Protein Precursors; Retrospective Studies; Stroke Volume; Survival Rate; Time Factors

Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers.. A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminometric assay.. Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p

Topics: Adrenomedullin; Aged; Biomarkers; Chronic Disease; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Ventricular Dysfunction, Left

We investigated the effects of iptakalim, a new ATP-sensitive potassium channel (K(ATP)) opener providing endothelial protection, on the progression of cardiac hypertrophy to failure in a rat model of pressure overloading caused by abdominal aortic banding (AAB). Endothelial dysfunction is central to cardiac hypertrophy and failure induced by pressure overload. It would be useful to clarify whether iptakalim could prevent this.. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, evidence of left ventricular hypertrophy (LVH), and transition to heart failure. LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These could be prevented by treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg for 6 weeks. Progression to cardiac failure, demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial and B-type natriuretic peptide mRNA, could also be prevented. The downregulated nitric oxide signalling system was enhanced, whereas the upregulated endothelin signalling system was inhibited, resulting in normalization of the balance between these two systems.. Iptakalim protected the endothelium and prevented progression of cardiac hypertrophy to failure induced by a pressure overload.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Fibrosis; Heart Failure; Heart Rate; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; KATP Channels; Male; Myocardium; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Ventricular Remodeling

Several studies have analyzed big endothelin-1 as a marker of mortality in patients with severe heart failure (HF). However, it has not proven prognostic value in patients with moderately symptomatic functional class. Our objective was to evaluate, in a 24 months follow-up, the prognostic power of big endothelin-1 in patients with HF and moderately deteriorated functional class.. Big endothelin-1 levels were measured in a cohort of 90 outpatients (age 64 (13), 70% males) diagnosed with HF. Patients were functionally classified (NYHA).. For the whole population, big endothelin-1 was 0.86 (0.61-1.20)fmol/ml. We evaluated its predictive value in detecting cardiovascular mortality, obtaining an AUC of 0.68 (0.08) (P=.02), and a cut-off value of 0.98 fmol/ml (sensitivity 69%, specificity 75%). When a logistic regression analysis was performed, big endothelin-1 was also an independent predictor of mortality (OR=5.851, P=.009).. Big endothelin-1 predicts cardiovascular mortality in patients diagnosed of HF and moderately symptomatic functional class.

Topics: Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies

The venous endothelium is a key regulator of central blood volume, organ perfusion, and hemostasis in heart failure (HF). We previously reported activation of the inflammatory/oxidative program in venous endothelial cells collected from decompensated HF patients. The underlying causes are unknown. We tested the hypothesis that the pro-inflammatory state of HF and vascular strain associated with congestion can activate the endothelial inflammatory/oxidative and hemostatic programs.. We studied 6 normal (NL) dogs (left ventricular ejection fraction [LVEF] >50%, central venous pressure [CVP] = 8 +/- 2 mm Hg) and 6 dogs with HF (LVEF approximately 30%, CVP 8 +/- 2 mm Hg) produced by intracoronary microembolizations. Normal dogs were studied at baseline and 1 hour after fluid load to a target CVP >or=20 mm Hg. Endothelial cells were scraped from jugular veins; mRNA expression was analyzed by reverse transcription polymerase chain reaction. The endothelial inflammatory/oxidative and hemostatic programs were significantly activated in HF dogs compared with NL. In NL dogs, fluid load significantly activated the endothelial inflammatory/oxidative and hemostatic programs, and, concurrently, caused a significant increase in plasma neurohumoral indices to levels that approached those of HF dogs.. The pro-inflammatory state of HF and vascular strain associated with congestion can both activate venous endothelial cells in dogs in a manner consistent with that seen in HF patients.

Topics: Animals; Blood Volume; Disease Models, Animal; Disease Progression; Dogs; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Heart Failure; Interleukin-6; Jugular Veins; Polymerase Chain Reaction; RNA; Stroke Volume; Tumor Necrosis Factor-alpha; Vasodilation

Topics: Animals; Cardiovascular Agents; Disease Progression; Endothelin-1; Endothelium, Vascular; Fibrosis; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; KATP Channels; Mice; Myocardium; Nitric Oxide; Propylamines; Signal Transduction; Ventricular Remodeling

Congestive heart failure (CHF) causes lung remodelling with thickening of the alveolar septa and proliferation of myofibroblasts (MYF). Endothelin-1 (ET-1) is increased in CHF and may contribute to this process. CHF was induced in rats by myocardial infarction. After three weeks there was lung remodelling with thickening of alveolar septa and increases in 5'-bromodeoxyuridine uptake and vimentin expression (P < 0.05). The mitogenic and protein synthesis response of MYF to ET-1 (10 nM) were assessed by H-thymidine and H-leucine incorporation respectively. The mitogenic response in CHF (19.0 +/- 3.0%, mean +/- SEM) was less than for sham rats (35 +/- 5.4%, P < 0.05). This was associated with a lower production of ET-1 by CHF MYF (15.15 +/- 5.67 fmol/ml) compared to sham (33.66 +/- 13.22 fmol/ml; P < 0.05). Additionally, protein expression of ETA (0.36 +/- 0.038 AU) and ETB receptors (0.24 +/- 0.075 AU) were reduced in CHF compared to shams (0.65 +/- 0.086 AU and 0.81 +/- 0.21 AU respectively; P < 0.05). There is a downregulation of the ET system of lung MYF in CHF with reduced proliferation in response to ET-1. This may represent a protective adaptation to counteract lung remodelling in response to chronic exposure to high levels of ET-1.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Down-Regulation; Endothelin-1; Fibroblasts; Heart Failure; Lung; Male; Myocardial Infarction; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B

Evidence is emerging to support the concept that the failing heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-gamma coactivator-1alpha, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown.. In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-gamma coactivator-1alpha protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-gamma coactivator-1alpha and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (-30%) and, to a lesser degree, angiotensin II (-20%) decreased proliferator-activated receptor-gamma coactivator-1alpha mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline).. Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Down-Regulation; Endothelin-1; Female; Heart Failure; Heat-Shock Proteins; Humans; Male; Middle Aged; Mitochondria, Heart; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Transcription Factors

Children with single ventricle physiology have increased ventricular work and are at greater risk of developing heart failure than other children with congenital heart disease. However, the diagnosis of heart failure is difficult because few objective measures have been validated for this cohort. Plasma proteins have been identified as biomarkers of heart failure in adults with structurally normal hearts. However, whether these correlate similarly with heart failure in children with single ventricle physiology is unknown, because the etiology of adult heart failure is typically ischemic heart disease, but heart failure in these children is presumed to be due to primary myocardial dysfunction. We conducted a single-site, cross-sectional observational study of young, single-ventricle patients. Clinical heart failure was defined as a Ross score >2. The association of several candidate biomarkers with heart failure was assessed using logistic regression analysis and receiver operating characteristic curves. Of the 29 included children, 9 (31%) were in clinical heart failure. A doubling of plasma B-type natriuretic peptide was associated with an odds ratio for heart failure of 2.17. The area under the receiver operating characteristic curve was 80.3%. A threshold value of > or =30 pg/ml showed both sensitivity and specificity for heart failure. Three other candidate biomarkers were not associated with clinical heart failure in this sample. In conclusion, plasma B-type natriuretic peptide is a sensitive biomarker for clinical heart failure in young children with single-ventricle heart disease. The use of this plasma biomarker might facilitate detection of heart failure in these complex patients.

Topics: Biomarkers; C-Reactive Protein; Child; Child, Preschool; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Heart Ventricles; Humans; Infant; Infant, Newborn; Logistic Models; Male; Natriuretic Peptide, Brain; ROC Curve; Sensitivity and Specificity; Troponin I

Endothelin 1 (ET-1) is increased in heart failure, both in plasma and within the central nervous system. Centrally, ET-1 induces sympathetic hyperactivity and arginine vasopressin (AVP) secretion. Both sympathetic activity and AVP secretion are regulated by the arterial baroreflex, which is typically impaired in heart failure. We hypothesized that central blockade of ETA receptors (ETAR) alters the baroreflex response of heart rate, renal sympathetic nerve activity (RSNA), and plasma AVP levels in a cardiomyopathic model of heart failure. Female Sprague-Dawley rats received weekly intraperitoneal injections of doxorubicin 2.5 mg x kg(-1) (doxorubicin heart failure, doxo-HF) or saline vehicle (control). After 8 weeks, they were instrumented, conditioned to the study environment, and then studied in the awake, non-restrained state. Baseline mean arterial pressure (MAP), RSNA, and plasma osmolality were similar in both groups, but heart rate (p<0.02), left ventricular pressure (p<0.001), and plasma AVP (p<0.01) were higher in the doxo-HF group. ET-1 dose dependently increased MAP, but the rise was significantly attenuated in doxo-HF rats at all doses. Baseline baroreflex control of heart rate and RSNA was similar in both groups. ETAR blockade with 4 nmol BQ123 i.c.v. significantly decreased both the upper plateau (p<0.05) and the range (p<0.05) of the baroreflex response of both heart rate and RSNA in doxo-HF but not in control rats. Despite higher basal plasma levels of AVP, ET-1 evoked a rise in plasma AVP of 13.6+/-3.2 pg x mL(-1) in doxo-HF compared with 0.4+/-0.4 pg x mL(-1) in control rats (p<0.001). To account for the blunted pressor response to ET-1 in the doxo-HF rats, gain of AVP release was calculated as DeltaAVP/DeltaMAP and was also found to be significantly greater in the doxo-HF rats (p<0.001). BQ123 prevented the rise in AVP and restored the gain in doxo-HF rats to that seen in controls. Thus, central ETAR contribute to the sympathoexcitation and AVP responses observed in heart failure due to doxorubicin cardiomyopathy.

Topics: Animals; Arginine Vasopressin; Baroreflex; Doxorubicin; Endothelin A Receptor Antagonists; Endothelin-1; Female; Heart Failure; Kidney; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

To examine the role of endothelin ETA and ETB receptors in congestive heart failure due to cardiomyopathy, the effect of chronic treatment with selective ETA- and ETB-receptor antagonists (atrasentan and A-192621, respectively), alone and in combination, was assessed on functional and biochemical parameters of 52-week-old Bio 14.6 cardiomyopathic hamsters. Compared with control animals, cardiomyopathic hamsters treated for 9 weeks with atrasentan showed no variation in MAP; however, selective ETB- and combined nonselective ETA- and ETB-receptor antagonists increased systemic blood pressure. After selective ETB-receptor blockade, plasma endothelin levels were augmented. Importantly, this increase was highly enhanced (more than 8-fold) by concomitant ETA-receptor antagonism. Furthermore, the left ventricle:body weight ratio of cardiomyopathic hamsters treated with A-192621, alone or in combination with atrasentan, was significantly increased. On the other hand, decreased left ventricular end-diastolic pressure was observed in cardiomyopathic hamsters after selective ETA- or combined nonselective ETA/ETB-receptor antagonism, while only selective ETA-receptor blockade reduced left ventricular endothelin levels. Our results suggest that, in congestive heart failure, ETB receptors are essential to limit circulating endothelin levels, which may argue for improved cardiac benefits after long-term treatment with highly selective ETA-receptor antagonists.

Topics: Animals; Atrasentan; Blood Pressure; Cardiomyopathies; Cricetinae; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Mesocricetus; Nitrates; Nitrites; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Function, Left

Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.. In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.. Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).. Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

Topics: Adult; Aged; Atherosclerosis; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Heart Failure; Homozygote; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Severity of Illness Index

This study investigated whether endothelin (ET)-1-induced increase in myocardial distensibility is preserved in heart failure (HF) and whether it is modulated by nitric oxide (NO) and prostaglandins. New Zealand white rabbits were treated with doxorubicin (1 mg/kg, intravenously twice a week for 8 weeks, DOX-HF group) or saline (control group). Effects of ET-1 (0.1, 1, 10 nM) were tested in papillary muscles from the DOX-HF group and a control group in the presence of: i) intact endocardial endothelium (EE); ii) damaged EE; iii) N(G)-nitro-L-arginine (L-NNA; NO synthase inhibitor), and iv) indomethacin (INDO; cyclooxygenase inhibitor). In the presence of an intact EE, ET-1 promoted concentration-dependent positive inotropic and lusitropic effects that were maintained after damaging the EE, in the presence of L-NNA or INDO and in the DOX-HF Group. ET-1 reduced resting tension at the end of the isometric twitch (increased diastolic distensibility) by 3.2+/-1.3 %, 6.0+/-1.6 % and 8.8+/-2.7 % (at 0.1, 1 and 10 nM, respectively), in muscles with intact EE, effect that was completely abolished after damaging EE, in the presence of L-NNA or INDO or in the DOX-HF Group. This study demonstrated that the increase in myocardial distensibility induced by ET-1 is absent in HF and is dependent of NO and prostaglandin release.

Topics: Animals; Cardiotonic Agents; Diastole; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Endothelin-1; Heart Failure; Hemodynamics; In Vitro Techniques; Male; Nitric Acid; Papillary Muscles; Prostaglandins; Rabbits; Statistics, Nonparametric

Heart failure is a cause of pulmonary vasoconstriction and remodelling, leading to pulmonary hypertension (PH) and decreased survival. The pathobiology of PH in heart failure remains incompletely understood. We investigated pulmonary vascular function and signalling molecules in early stage PH secondary to experimental heart failure. Eight beagle dogs with overpacing-induced heart failure underwent haemodynamic assessment and postmortem pulmonary arterial reactivity, morphometry and quantification of genes encoding for factors involved in vascular reactivity and remodelling: endothelin-1 (ET-1), ETA and ETB receptors, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), endothelial nitric oxide synthase, angiopoietin-1, bone morphogenetic protein receptors (BMPR1A and BMPR2), serotonin transporter (5-HTT) and the 5-HT(2B) receptor. Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures. However, there were no changes in pulmonary vascular resistance or in arteriolar medial thickness. There were increased expressions of genes encoding for ET-1, ETB, VEGF and VEGFR2, while expression of the other genes analysed remained unchanged. In vitro, pulmonary arteries showed decreased relaxation and increased reactivity, while systemic mammary arteries were unaffected. Early PH in heart failure is characterized by altered vasoreactivity and increased ET-1/ETB and VEGF/VEGFR2 signalling.

Topics: Animals; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Endothelin-1; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Male; Polymerase Chain Reaction; Pulmonary Artery; Pulmonary Circulation; Receptor, Endothelin B; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Resistance; Vasoconstriction; Vasodilation

Ucn2 (urocortin 2) is a recently discovered peptide with therapeutic potential in heart failure. As any new treatment is likely to be used in conjunction with standard ACEI (angiotensin-converting enzyme inhibitor) therapy, it is important that the combined effects of these agents are assessed. In the present study, we investigated the effects of Ucn2 and an ACEI (captopril) administered for 3 h, both separately and together, in eight sheep with pacing-induced heart failure. Ucn2 and captopril alone both increased CO (cardiac output; Ucn2>captopril) and decreased arterial pressure (captopril>Ucn2), left atrial pressure (Ucn2>captopril) and peripheral resistance (Ucn2=captopril) relative to controls. Compared with either treatment alone, combined treatment further improved CO and reduced peripheral resistance and cardiac preload, without inducing further falls in blood pressure. In contrast with the marked increase in plasma renin activity observed with captopril alone, Ucn2 administration reduced renin activity, whereas the combined agents resulted in intermediate renin levels. All active treatments decreased circulating levels of aldosterone (Ucn2+captopril>Ucn2=captopril), endothelin-1 and the natriuretic peptides (Ucn2+captopril=Ucn2>captopril), whereas adrenaline (epinephrine) fell only with Ucn2 (Ucn2+captopril=Ucn2), and vasopressin increased during captopril alone. Ucn2, both separately and in conjunction with captopril, increased urine output, sodium and creatinine excretion and creatinine clearance. Conversely, captopril administered alone adversely affected these renal indices. In conclusion, co-treatment with Ucn2 and an ACEI in heart failure produced significantly greater improvements in haemodynamics, hormonal profile and renal function than achieved by captopril alone. These results indicate that dual treatment with these two agents is beneficial.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Captopril; Cardiac Output; Cardiac Pacing, Artificial; Drug Therapy, Combination; Endothelin-1; Epinephrine; Female; Heart Failure; Models, Animal; Renin; Renin-Angiotensin System; Sheep; Urocortins; Vascular Resistance

The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect on acute and chronic heart failure (AHF/CHF) induced by ligation of the left anterior descending coronary artery for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CAL+HSYA (100 mg kg(-1) by gavage) and CAL+diltiazem (20 mg kg(-1) by gavage). In the AHF model, heart function, as determined by haemodynamic studies and echocardiography, was improved significantly by pretreatment with HSYA or diltiazem. Significant reductions in elevated serum creatine phosphokinase, lactate dehydrogenase, malondialdehyde (MDA), glutamic oxalacetic transaminase, glutamic pyruvic transaminase and blood viscosity were observed, and the activity of serum superoxide dismutase (SOD) was enhanced (all P<0.01). In the CHF model, HSYA and diltiazem restored abnormal heart function, and completely suppressed the elevated plasma atrial natriuretic polypeptide (ANP) and endothelin-1 (ET-1), serum and left-ventricular tissue inducible nitric oxide (NO) synthase (iNOS), NO and MDA, and improved the decrease in SOD. HSYA and diltiazem improved cardiac performance in AHF and reduced cardiac remodelling in CHF by reducing tissue weight indices: left ventricular weight/body weight (BW), right ventricular weight/BW, kidney weight/BW and lung weight/BW, and attenuating increases in infarct size, inner diameter of the left ventricle and collagen volume fraction in non-infarcted areas, and the decrease in mean wall thickness of infarcted myocardium. These results suggest that HSYA exerted beneficial actions in cardiac performance in models of both AHF and CHF, mainly by suppressing ET-1, iNOS and oxidative stress in infarcted tissue.

Topics: Acute Disease; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Viscosity; Cardiotonic Agents; Chalcone; Chronic Disease; Coronary Vessels; Creatine Kinase; Diltiazem; Disease Models, Animal; Echocardiography; Endothelin-1; Heart Failure; Hemodynamics; L-Lactate Dehydrogenase; Ligation; Malondialdehyde; Nitric Oxide Synthase; Oxidative Stress; Quinones; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Cardiac hypertrophy and heart failure (HF) are associated with reactivation of fetal cardiac genes, and class II histone deacetylases (HDACs) (eg, HDAC5) have been strongly implicated in this process. We have shown previously that inositol trisphosphate, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and protein kinase (PK)D are involved in HDAC5 phosphorylation and nuclear export in normal adult ventricular myocytes and also that CaMKIIdelta and inositol trisphosphate receptors are upregulated in HF. Here we tested whether, in our rabbit HF model, nucleocytoplasmic shuttling of HDAC5 was altered either at baseline or in response to endothelin-1, which would indicate HDAC5 phosphorylation and transcription effects. The fusion protein HDAC5-green fluorescent protein (HDAC5-GFP) was more cytosolic in HF myocytes (F(nuc)/F(cyto) 3.3+/-0.3 vs 7.2+/-0.4 in control), and HDAC5 was more phosphorylated. Despite this baseline cytosolic HDAC5 shift, endothelin-1 produced more rapid HDAC5-GFP nuclear export in HF versus control myocytes. We also find that PKD and CaMKIIdelta(C) expression and activation state are increased in both rabbit and human HF. Inhibition of either CaMKII or PKD in HF myocytes partially restored the HDAC5-GFP F(nuc)/F(cyto) toward control, and simultaneous inhibition restored F(nuc)/F(cyto) to that in control myocytes. Moreover, adenovirus-mediated overexpression of PKD, CaMKIIdelta(B), or CaMKIIdelta(C) reduced baseline HDAC5 F(nuc)/F(cyto) in control myocytes (3.4+/-0.5, 3.8+/-0.5, and 5.2+/-0.5, respectively), approaching that seen in HF. We conclude that chronic upregulation and activation of inositol trisphosphate receptors, CaMKII, and PKD in HF shifts HDAC5 out of the nucleus, derepressing transcription of hypertrophic genes. This may directly contribute to the development and/or maintenance of HF.

Topics: Active Transport, Cell Nucleus; Adult; Animals; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carbazoles; Cell Nucleus; Cells, Cultured; Cytosol; Disease Models, Animal; Endothelin-1; Enzyme Activation; Female; Heart Failure; Heart Ventricles; Histone Deacetylases; Humans; Indoles; Male; Middle Aged; Myocardium; Myocytes, Cardiac; Phosphorylation; Protein Kinase C; Protein Kinase Inhibitors; Rabbits; Recombinant Fusion Proteins; Sulfonamides; Time Factors; Transcription, Genetic; Transduction, Genetic; Up-Regulation; Ventricular Function, Left

Urotensin II-related peptide (URP) is a novel endogenous ligand for urotensin II receptor (UT-R). To investigate the pathophysiological role of URP in heart failure, we examined URP, UII and UT-R expression in hearts and kidneys of rats with congestive heart failure due to coronary ligation by quantitative RT-PCR and immunocytochemistry. Significantly increased expression levels of URP mRNA were found in the atrium, the right ventricle and the infarcted part of left ventricle of heart failure rats, when compared with sham-operated rats (about 2.2-fold, 2.7-fold and 3.9-fold, respectively). Expression levels of UII mRNA in the heart were about 10% of URP mRNA, and were slightly increased only in the infarcted part of left ventricle of heart failure rats, when compared with sham-operated rats. The expression levels of UT-R mRNA were increased in the atrium of heart failure rats. There was no significant change of URP, UII and UT-R mRNA expression levels in the kidney between heart failure and sham-operated rats. The myocardium was diffusely immunostained with URP in both rats. The blood vessels in the heart were positively immunostained with URP in heart failure rats, but not in sham-operated rats, whereas they were positively immunostained with UT-R in both rats. These findings suggest that the expression of URP, UII and UT-R is enhanced in failing heart, and the UII/URP/UT-R system has important pathophysiological roles in the progression of heart failure.

Topics: Animals; Endothelin-1; Gene Expression; Heart Failure; Male; Myocardium; Peptide Hormones; Rats; Rats, Inbred WKY; Receptors, G-Protein-Coupled; Urotensins

The study objective is to prove an association among plasma concentration of big endothelin and endothelin-1, other clinical parameters and two frequent polymorphisms - G8002A and -3A/-4A - in the endothelin-1 (EDN-1) coding gene (6p21-23), and among plasma concentration of TNF alpha and gene polymorphisms TNF alpha -308 A/G, -238 A/G, TNF beta Ncol and 3'TACE (tumour necrosis factor alpha converting enzyme) in patients with chronic heart failure (CHF). The second objective is to find an association between polymorphisms G8002A and -3A/4A EDN-1 with diabetes mellitus (DM), peripheral artery disease (PAD) and myocardial infarction (MI) in patients with chronic heart failure (CHF). The study population included 266 patients with symptomatic CHF and proven dysfunction of the left ventricle (LV). Genotyping and plasma concentrations of humoral substances were examined in 224 patients with ejection fraction (EF) below 40%. No associations between plasma concentrations of endothelin-1 and big endothelin and polymorphisms G8002A (p=0.87, p=0.81) and -3A/-4A (p=0.871, p=0.749) in the gene coding endothelin-1 were found. No associations were observed between plasma concentration of TNF alpha and genotypes in four polymorphisms in TNF alpha, beta and TACE genes. A significant correlation was seen between plasma concentration of big endothelin and pulmonary congestion. Patients with ischemic heart disease (IHD) and previous MI showed a difference in the distribution of genotype G8002A for endothelin-1: allele G 0.718 and A 0.282 vs those without MI: allele G 0.882 and A 0.118, (p<0.05). Patients with IHD and DM had allele G in 0.67 and A 0.33, while those without DM had allele G in 0.790 and A in 0.209 (p<0.03). Patients with IHD and concomitant PAD had allele G in 0.718 and A in 0.282 vs those without PAD allele G in 0.882 and A in 0.118 (p<0.0004). Patients with dilative cardiomyopathy (DCMP) showed no differences in genotype G8002A and presence of DM or PAD. It might be speculated that in the case of endothelin-1 and TNF alpha in CHF the genetic determination is not important, and plasma concentrations are influenced more by the disease severity. Ischemics with previous MI, concomitant DM or PAD showed more frequently allele A and less often allele G than those without these diseases. A genotype with allele A is associated with higher risk of concomitant diseases.

Topics: Biomarkers; Chronic Disease; Cytokines; Diabetes Mellitus; Endothelin-1; Female; Genetic Predisposition to Disease; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Vascular Diseases; Polymorphism, Genetic; Risk Assessment

Atrial fibrillation (AF) is a common comorbidity in heart failure (HF) patients and is classically associated with acceleration in the rate of HF progression. The precise mechanism for this interaction is unclear, but comprises "bidirectional" aspects in which AF promotes HF and HF also increases the likelihood of AF. We therefore studied the relationship between AF in an ovine model of pacing-induced congestive HF, in an attempt to identify the mechanisms that underpin the apparent synergistic relationship between AF and HF.. Sixteen adult sheep were paced at 190 beats/min for 21 days (HF). AF was induced in 8 of these animals at 14 days' pacing using programmed extrastimuli (HF + AF). Left ventricular hemodynamics and the pattern of cardiac neurohormonal activation, via coronary sinus (CS) sampling, were determined at rest and during submaximal exercise testing in both groups at 21 days and after AF reversion (by atrial defibrillation) at 21 days. CS norepinephrine (NE), endothelin (ET-1), and brain natriuretic peptide (BNP) levels were significantly increased in HF + AF animals, whereas LV end-diastolic pressure (EDP) and LV dP/dt max were significantly reduced compared with moderate HF alone. Cardioversion significantly reduced CS NE and BNP levels and improved contractility in AF + HF animals. In a further 6 animals, we explored the mechanism by which HF increases susceptibility to AF, with specific emphasis on the influence of functional mitral regurgitation. The elimination of MR in HF animals using a percutaneous mitral annular reduction device significantly decreased the inducibility of AF.. AF induction significantly depresses left ventricular function and causes activation of myocardial neurohormones. In conjunction, the presence of functional MR increases susceptibility to AF and this may be attenuated by MR reduction by percutaneous mitral annular reduction.

Topics: Animals; Atrial Fibrillation; Biomarkers; Blood Pressure; Comorbidity; Disease Progression; Electric Countershock; Endothelin-1; Heart Failure; Heart Rate; Models, Animal; Natriuretic Peptide, Brain; Norepinephrine; Risk Factors; Sheep; Time Factors

Heart failure (HF) may be produced by sustained beta-adrenoceptor stimulation by causing changes in the expression of endothelin-1 (ET-1), the leptin system, calcineurin and sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) underlying cardiac dysfunction. The aim of this study was to verify whether isoprenaline (ISO)-induced HF is attributed to changes in the above molecular markers, and whether the dual ET-receptor antagonist CPU0213 could reverse the cardiac dysfunction caused by ISO treatment, focusing on these molecular markers. HF was induced in rats by administration of ISO (2 mgkg(-1) s.c.) for 10 days. CPU0213 (30 mgkg(-1) s.c.) and propranolol (4 mgkg(-1) s.c.) were administered on days 7-10. HF developed after 10 days' ISO administration and was manifest as impaired cardiac performance, increased heart weight index, oxidative stress, elevated serum enzymes, and disordered expression of the endothelin system, leptin system, calcineurin and SERCA2a. All these abnormalities were significantly reversed by CPU0213, and the effectiveness of this ET-receptor antagonist was comparable to that of propranolol. Thus, antagonism of ET receptors by CPU0213 normalizes these changes in molecular markers, alleviating HF.

Topics: Animals; Calcineurin; Cardiotonic Agents; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Heart Failure; Isoproterenol; Leptin; Male; Propranolol; Pyrazoles; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Angiotensin II (Ang II) and endothelin-1 (ET-1) share their effects on growth of myocardial cells but have been shown to elicit different effects on myocardial function. However, these effects vary markedly among species, cardiac regions (atrium or ventricle) and failing or non-failing myocardium. We therefore investigated the effects of both peptides on contractile function of isolated human myocytes from failing and non-failing hearts.. Cardiomyocytes were enzymatically isolated and electrically stimulated (15 V, 0.2 Hz). Ang II elicited a positive inotropic effect (PIE) mediated by activation of protein kinase C (PKC) in atrial but no effect in ventricular myocytes. ET-1 (10(-8) M) increased cell-shortening by 146+/-9.3% (p<0.05) in atrial myocytes, by 99.1+/-16.5% (p<0.05) in non-failing ventricular but only by 40.5+/-6.4% (p<0.05) in failing ventricular myocytes. The PIE of ET-1 in failing myocytes was more pronounced at low extracellular pH (+112.6+/-27% at pH 7.0 vs. +40.5+/-6.4% at pH 7.4, p<0.05). Amiloride, a sodium-hydrogen-exchange inhibitor, inhibited two thirds of the PIE of ET-1 in failing myocytes. The PKC-inhibitor decreased the PIE by 50% from 113% to 64% in ventricular myocytes under acidotic conditions.. Ang II and ET-1 elicited PIE in atrial myocytes, whereas in ventricular myocytes Ang II did not induce PIE in contrast to ET-1. The PIE of ET-1 was markedly attenuated in failing myocytes. Under acidotic conditions, the PIE of ET-1 was more pronounced in failing myocytes, indicating that ET-1 may activate signaling processes in failing myocytes, which are not activated in normal myocytes.

Topics: Angiotensin I; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Muscle Contraction; Myocytes, Cardiac

Cardiomyocyte hypertrophy and extracellular matrix remodeling, primarily mediated by inflammatory cytokine-stimulated cardiac fibroblasts, are critical cellular events in cardiac pathology. The molecular components governing these processes remain nebulous, and few genes have been linked to both hypertrophy and matrix remodeling. Here we show that p8, a small stress-inducible basic helix-loop-helix protein, is required for endothelin- and alpha-adrenergic agonist-induced cardiomyocyte hypertrophy and for tumor necrosis factor-stimulated induction, in cardiac fibroblasts, of matrix metalloproteases (MMPs) 9 and 13-MMPs linked to general inflammation and to adverse ventricular remodeling in heart failure. In a stimulus-dependent manner, p8 associates with chromatin containing c-Jun and with the cardiomyocyte atrial natriuretic factor (anf) promoter and the cardiac fibroblast mmp9 and mmp13 promoters, established activator protein 1 effectors. p8 is also induced strongly in the failing human heart by a process reversed upon therapeutic intervention. Our results identify an unexpectedly broad involvement for p8 in key cellular events linked to cardiomyocyte hypertrophy and cardiac fibroblast MMP production, both of which occur in heart failure.

Topics: Animals; Atrial Natriuretic Factor; Basic Helix-Loop-Helix Transcription Factors; Chromatin; Endothelin-1; Enzyme Induction; Fibroblasts; Gene Expression Regulation, Enzymologic; Heart Failure; HeLa Cells; Humans; Hypertrophy; Matrix Metalloproteinase 13; Matrix Metalloproteinase 9; Myocardium; Myocytes, Cardiac; Neoplasm Proteins; Phenylephrine; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-jun; Rats; RNA, Messenger; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

The failure of endothelin antagonists to show benefit in heart failure cannot be understood until all the clinical trials are fully published.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Endothelin A Receptor Antagonists; Endothelin-1; Evidence-Based Medicine; Heart Failure; Humans; Publishing

Emerging evidence indicates that leptin may be a potential new target in chronic heart failure (CHF) treatment. We hypothesized that hyperleptinemia may correlate with abnormal expression of SERCA2a, PLB (phospholamban), and the endothelin (ET) pathway in CHF. An activated ET pathway is involved in CHF that is suppressed by CPU86017 (p-chlorobenzyltetrahydroberberine chloride), a complex class III antiarrhythmic agent with an antioxidant effect. Thus, relief of CHF may be mediated by a reversal of abnormalities of the leptin system, the ET-reactive oxygen species (ROS) pathway, SERCA2a, and PLB by CPU86017. CHF was produced by coronary artery ligation for 6 weeks in rats. The rats were divided into 3 groups: sham, CHF untreated, and CHF+CPU86017 (4 mg/kg per day, s.c.). Hemodynamic changes, cardiac morphology, serum biochemistry, messenger ribonucleic acid (mRNA) and protein expression of the leptin pathway, ET pathway, and redox were measured. In CHF rats, hemodynamic abnormalities, cardiac remodeling, and histological changes with features of cardiac failure were associated with hyperlipidemia accompanied by oxidative stress and upregulated OB-Rb, ECE, pp-ET-1, ET(A)R, and ET(B)R mRNA expression in the myocardium. Protein expression of leptin and ET(A)R in the myocardium was markedly increased in CHF rats. An activated leptin pathway was associated with downregulation of SERCA2a and upregulation of PLB in mRNA and protein expression in CHF. CPU86017 downregulated the leptin system and reversed the above changes in the myocardium. An activated leptin pathway correlates with abnormal expression of SERCA2a and PLB and an activated ET-ROS system in the affected myocardium. The multi-ion-channel-blocking and antioxidative effects of CPU86017 downregulate the leptin pathway and ET system, resulting in reversal of the abnormalities of expression of SERCA2a and PLB and cardiac performance in CHF.

Topics: Alkyl and Aryl Transferases; Animals; Anti-Arrhythmia Agents; Antioxidants; Aspartic Acid Endopeptidases; Berberine; Calcium-Binding Proteins; Creatine Kinase; Endothelin-1; Endothelin-Converting Enzymes; Gene Expression; Heart Failure; Heart Rate; L-Lactate Dehydrogenase; Leptin; Male; Metalloendopeptidases; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Transferases (Other Substituted Phosphate Groups); Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

We have followed 99 patients with end stage renal failure, treated by regular haemodialysis. Chronic renal failure is frequently accompanied by chronic heart failure (over 50%), especially by heart failure with preserved ejection fraction. Patients treated by regular haemodialysis had a tendency to cardiomegaly (51%), mild systolic dysfunction of the left ventricle (mean LVEF 53%) and diastolic dysfunction (88%) of the hypertrophic left ventricle. They had also activated endothelin and neurohumoral system. Only 3% of the patients had normal values of Nt-proBNP and big endothelin. The plasma level of Nt-proBNP in haemodialysed patients correlated with cardiothoracic ratio and with ejection fraction. The plasma level of big endothelin correlated only with cardiothoracic ratio.

Topics: Biomarkers; Endothelin-1; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis

Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing beta(3)-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [(125)I]-metaiodobenzylguanidine and [(3)H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.

Topics: Adrenergic Fibers; Animals; Dopamine; Endothelin-1; GAP-43 Protein; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Kinetics; Male; Monocrotaline; Myocytes, Cardiac; Nerve Growth Factor; Neural Cell Adhesion Molecule L1; Norepinephrine; Rats; Rats, Wistar; Sialic Acids; Tubulin; Tyrosine 3-Monooxygenase; Up-Regulation

Cardiomyocyte loss is involved in the transition from compensatory left ventricular hypertrophy (LVH) to heart failure (HF). Our aim was to investigate the status of the leukaemia inhibitory factor receptor (LIFR)/gp130 survival pathway and its cytoprotective activity in intact cardiac tissue and in cardiomyocytes obtained from adult spontaneously hypertensive rats (SHR) with LVH (non-failing SHR) and from aged SHR with overt HF (failing SHR).. Cardiac morphometry was assayed by planimetry in an image analysis system. mRNA and protein expression were quantified by real time RT-PCR and Western blotting. Receptors were localized by immunocytochemistry. Trypan blue staining, TUNEL, and MTT cell viability assays were employed to study the cytoprotective activity of cardiotrophin-1 (CT-1) in isolated caridomyocytes.. Compared to non-failing SHR, failing SHR exhibited enhanced myocardial cell death (p<0.01) demonstrated by the increase in Bax/Bcl-2 ratio, caspase-3 activation and poly (ADP-ribose) polymerase (PARP) fragmentation. Failing SHR had a 7-fold diminished expression (p<0.01) of LIFR, no changes in gp130, and 1.6-fold increased myocardial expression (p<0.01) of CT-1. In cardiomyocytes isolated from non-failing SHR, recombinant CT-1 inhibited apoptotic and non-apoptotic cell death induced by angiotensin II or hydrogen peroxide. LIFR protein was entirely absent in cardiomyocytes isolated from failing SHR, which were resistant to the cytoprotective effects of CT-1. Finally, stimulation of non-failing SHR cardiomyocytes with angiotensin II, aldosterone, norepinephrine or endothelin-1 significantly decreased (p<0.01) LIFR expression.. These data suggest that loss of CT-1-dependent survival mechanisms may contribute to the increase of cell death associated with HF in SHR. Neurohumoral activation may contribute to this alteration via suppression of LIFR.

Topics: Aldosterone; Angiotensin II; Animals; Apoptosis; Cells, Cultured; Cytokines; Cytoprotection; Endothelin-1; Heart Failure; In Situ Nick-End Labeling; Leukemia Inhibitory Factor; Myocardium; Myocytes, Cardiac; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, OSM-LIF; RNA, Messenger

Topics: Adrenergic Fibers; Angiotensin II; Animals; Calcium; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Mice; Nerve Growth Factor; Rats; Tyrosine 3-Monooxygenase; Vasoconstriction; Ventricular Dysfunction, Right

We hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal function in pediatric patients.. We analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 mcg.kg.min without a bolus and titrated to a maximum of 0.03 mcg.kg.min, in 0.005-mcg.kg.min increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly (P = .001). Urine output increased significantly on Days 1 and 3 (P < or = .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL (P < or = .001). In the substudy, aldosterone levels decreased from 37.5 +/- 57.1 to 20.5 +/- 41.9 ng/dL (P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension.. Nesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.

Topics: Adolescent; Adult; Aldosterone; Biomarkers; Cardiac Output, Low; Cardiomyopathies; Child; Child, Preschool; Creatinine; Diuresis; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Infant; Infant, Newborn; Kidney; Male; Natriuretic Agents; Natriuretic Peptide, Brain; Norepinephrine; Prospective Studies; Renin; Treatment Outcome

To examine effects of endotheline-1 (ET-1) and nitric oxide (NO) on endothelium-dependent mechanisms of vascular tonicity regulation in patients with chronic cardiac failure (CCF) of FC I-IV (NYHA).. Vascular reactions of 94 patients with CCF of FC I-IV were examined according to D.S. Celermajer method using ultrasound of high resolution. Tissue oxygenation was studied with transcutaneous polarography (TCM-2, Radiometer). Parameters of circulating erythrocytes were studied by impurity spectrum. Endothelial NO-synthase expression was determined with application of monoclonal antibodies to endothelial NO-synthase. NO metabolites were studied with colorimetric method using Griss reagent. ET-1 was measured in plasma by enzyme immunoassay. The control group consisted of 28 healthy men aged 20 to 54 years.. Patients with CCF of FC I-IV have reduced endothelium-dependent vascular reactions progressing with aggravation of CCF. The causes of the disorders lie in altered metabolism of ET-1 and NO in CCF.. CCF patients demonstrate changes in endothelium-dependent mechanisms of vascular tonicity regulation caused by disturbed metabolism of ET-1 and NO developing in abnormal regime of tissue oxygenation and depending on CCF severity.

Topics: Adult; Brachial Artery; Colorimetry; Endothelin-1; Endothelium, Vascular; Heart Failure; Humans; Immunoenzyme Techniques; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Polarography; Prognosis; Severity of Illness Index; Ultrasonography; Vascular Resistance

Topics: Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis

Inter-dialysis variability in levels of big endothelin and NT-proBNP in plasma were studied in 22 patients with established systolic and/or diastolic dysfunction of the left cardiac ventricle assigned to a chronic haemodialysis programme. The plasmatic level of NT-proBNP in all patients was practically unchanged. There was a falling trended between haemodialysis treatments but this was not statistically significant and in absolute values clinically insignificant. Fluctuations were found between individuals but on average all values were stable and high in the pathological range. No significant changes in the plasmatic level of big endothelin were found either. The average levels were again stable and insignificant and the indicated trend did not achieve clinical or statistical significance. The values were once again high in the pathological range. Plasmatic levels of NT-proBNP and big endothelin do not vary according to the phase of the dialysis cycle and mainly reflect the long-term condition of endothelium failure and long-term stress in the left ventricle. Concentrations are not affected by changes in volume or uraemia between dialysis treatments and the suggested trend towards a fall in NT-proBNP and a rise in big endothelin does not have a clear explanation. In any case, this trend remained within the pathological range and is probably not clinically significant.

Topics: Aged; Endothelin-1; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Natriuretic Peptide, Brain; Peptide Fragments; Renal Dialysis

Peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of lipid and energy metabolism in cardiomyocytes, have recently been proposed to modulate cardiovascular pathophysiological responses in experimental models. However, there is little information about the functional activity of PPARs in human heart failure.. To investigate PPAR-alpha and -gamma expression and activity, and the association with ET-1 production and fibrosis, in cardiac biopsies from patients with end-stage heart failure due to ischemic cardiomyopathy (ICM) in comparison and from non-failing donor hearts. All samples were obtained during cardiac transplantation.. Morphological analysis (by Masson trichrome and image analysis) did not detect fibrosis in the left atrium from non-failing donors (NFLA) or from ICM patients (FLA). However, left ventricles from failing hearts (FLV) contained a greater number of fibrotic areas (NFLA: 3.21+/-1.15, FLA: 1.63+/-0.83, FLV: 14.5+/-3.45%; n = 9, P<0.05). By RT-PCR, preproET-1 expression was similar in the non-failing and failing atrium but was significantly higher in the ventricles from failing hearts (NFLA: 1.00+/-0.06, FLA: 1.08+/-0.11, FLV: 1.74+/-0.19; n = 9, P<0.05). PPAR-alpha and PPAP-gamma mRNA (by RT-PCR) and protein (by Western blot) levels were higher in the ventricles from failing hearts compared with the atrium from failing and non-failing hearts. Electrophoretic mobility shift assays showed that PPAR-alpha and PPAP-gamma were not activated in the ventricles (NFLA: 1.00+/-0.11, FLA: 1.89+/-0.24, FLV: 0.95+/-0.07; n = 9, P<0.05).. These data suggest that PPAR-alpha and PPAP-gamma are selectively activated in the atria from ICM patients and might be functionally important in the maintenance of atrial morphology.

Topics: Adolescent; Adult; Biopsy; Blotting, Western; Case-Control Studies; Child; Endothelin-1; Female; Fibrosis; Gene Expression; Heart Atria; Heart Failure; Humans; Male; Middle Aged; Myocardial Ischemia; PPAR alpha; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Endothelin-1; Genetic Predisposition to Disease; Heart Failure; Humans; Polymorphism, Genetic

Objective of the work is to determine the relation of G8002 polymorhism in endothelin 1 gene to the incidence of diabetes mellitus (DM), ischemic disease of lower limbs (ID LL) and myocardial infarction (MI) at the patients with heart failure. METHODICS: There were observed 224 patients, 176 males, 48 females, average age 55 +/- 12 years, NYHA II/III/IV 82/131/11, average EF LK 25 +/- 7 %, diagnosis ischemic heart disease (IHD) 133, dilatation cardiomyopathy (DCMP) 91.. Patients with IHD had higher incidence of hypertension (p < 0.0007), diabetes mellitus (p < 0.00007) and hyperlipoproteinemy (p < 0.0006) than patients with DCMP. Patients with IHD who experienced MI had a difference in the distribution of G8002A genotypes for endothelin 1 gene: G 0.718 and A 0.282 alleles vs ischemic patients without MI G 0.882 and A 0.118 (p < 0.05) alleles. Ischemic patients with DM had G allele in 0.67 and A 0.33 unlike ischemic patients without DM G allele 0.791 and A 0.209 (p < 0.03). Ischemic patients with synchronous ID LL had G allele in 0.718 and A 0.282 vs ischemic patients without ID LL G allele 0.882 and A 0.118 (p < 0.0004). At the patients with DCMP there was not found a difference in G8002A genotype and the presence of DM or ID LL.. At the patients with heart failure on the basis of ischemic heart disease there was found a difference in endothelin G8002A genotype distribution depending on other accessory diseases. There was more frequently present an A allele and less present G allele in the ischemic patients with DM, who had experienced MI or ID LL than in the ischemic patients without these diseases. Genotype with A allele is connected with higher risk of all accessory diseases.

Topics: Alleles; Diabetes Mellitus; Endothelin-1; Female; Genetic Predisposition to Disease; Genotype; Heart Failure; Humans; Ischemia; Leg; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Polymorphism, Genetic

The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ET(A) (T/C in exon 6, H323H) could predispose carriers to heart failure (HF).. Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) < or =40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26).. The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ET(A) variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ET(A )polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = -0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = -0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis.. The ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.

Topics: Aged; Alleles; Analysis of Variance; Case-Control Studies; Chi-Square Distribution; Codon; Coronary Angiography; Echocardiography; Endothelin-1; Female; Gene Frequency; Genotype; Heart Failure; Humans; Male; Middle Aged; Polymorphism, Genetic; Receptor, Endothelin A; Regression Analysis; Risk Factors

Endothelin-1 (ET-1), a potent vasoconstrictor, is difficult to measure because of its instability and its binding to receptors and plasma proteins. We report a rapid, robust way to indirectly quantify ET-1 release by measuring the C-terminal ET-1 precursor fragment (CT-proET-1) without an extraction step.. In plasma samples from healthy individuals, patients with congestive heart failure (CHF), and patients with sepsis, we measured CT-proET-1 with a sandwich immunoluminometric assay that uses 2 polyclonal antibodies to amino acids 168-212 of pre-proET-1. We also correlated CT-proET-1 concentrations with bigET-1 measurements.. The assay yielded results within 3 h and showed linear dilution with an analytical detection limit of 0.4 pmol/L and an interlaboratory CV <10% for values >10 pmol/L. Ex vivo CT-proET-1 was stable (<10% loss of immunoreactivity) in EDTA-, heparin-, and citrate-plasma for at least 4 h at room temperature, 6 h at 4 degrees C, and in EDTA-plasma for at least 6 months at -20 degrees C. CT-proET-1 values followed a gaussian distribution in healthy individuals (mean, 44.3 pmol/L; range, 10.5-77.4 pmol/L) without significant differences between males and females. The correlation coefficient for CT-proET-1 vs age was 0.25 (P <0.0001). CT-proET1 was significantly (P <0.0001) increased in patients with CHF (median, 104 pmol/L; range, 50.8-315 pmol/L) and patients with sepsis (median, 189 pmol/L; range, 34.6-855 pmol/L). The correlation between CT-proET-1 and bigET-1 for 43 samples was 0.80 (P <0.0001).. CT-proET-1 measurement is a rapid and easy method for indirectly assessing the release of ET-1 in critically ill patients.

Topics: Endothelin-1; Female; Heart Failure; Humans; Immunoassay; Luminescent Measurements; Male; Peptide Fragments; Protein Precursors; Reference Values; Sepsis

The endothelin-1 (ET-1) plasma concentration was measured in dogs with spontaneous cardiac or respiratory diseases. Plasma samples were obtained from 76 healthy control dogs and 73 dogs, of which 58 were suffering from heart disease and 15 were suffering from respiratory disease. Dogs were evaluated using echocardiography, thoracic radiography, biochemical evaluation and a radioimmunoassay for ET-1. ET-1 plasma concentrations were significantly higher in dogs with spontaneous cardiac or respiratory diseases (mean [se] 5.3 [0.3] and 5.3 [0.6] pg/ml, respectively) than in healthy dogs (1.9 [0.1] pg/ml) (P<0.0001). ET-1 plasma concentrations increased with the class of heart failure (International Small Animal Cardiac Health Council classification) (P<0.0001) and with the severity of pulmonary disorders. ET-1 plasma concentrations were positively correlated with the extent of systolic pulmonary hypertension measured by Doppler echocardiography (P<0.05; r=0.75) and with the clinical outcome of dogs with respiratory disease. Evaluation of the ET-1 plasma concentration allowed differentiation between heart and respiratory disorders in dogs exhibiting clinical signs at exercise, but not in patients exhibiting clinical signs at rest.

Topics: Animals; Case-Control Studies; Dog Diseases; Dogs; Echocardiography; Endothelin-1; Female; Heart Failure; Male; Predictive Value of Tests; Radiography, Thoracic; Radioimmunoassay; Respiratory Tract Diseases; ROC Curve

Cardiac hypertrophy is an adaptive process to an increased hemodynamic overload. However, the adaption may lead to the fragility of myocardium facing pathological stimuli. In the present study, experiments were designed to explore the susceptibility of hypertrophic myocardiocytes to apoptotic stimuli and the role of protein kinase Cdelta (PKCdelta) during the transition from hypertrophy to apoptosis. Endothelin-1 (ET-1)-treated cardiomyocytes were used as model of cardiac hypertrophy. Angiotensin II (Ang II) was used as an apoptotic stimulus. Cell surface area was measured to determine the extent of hypertrophy. The apoptotic rate in cardiomyocytes was detected by Hoechst 33258. (1) Cell surface area was increased by 42.5% and 67.3% following 1 nmol/L and 10 nmol/L ET-1 treatment, respectively, as compared with serum-free cultured myocytes. So the mildly and moderately hypertrophic myocyte models were set up. (2) Apoptotic rates in serum-free cultured, mildly and moderately hypertrophic myocytes after Ang II treatment were (15.54+/-1.32) %, (20.65+/-1.40) % and (29.33+/-3.52) %, respectively. It is suggested that hypertrophic myocytes are more susceptive to apoptotic stimulus. (3) Rottlerin, a specific inhibitor of PKCdelta depressed apoptotic rates induced by Ang II to (15.88+/-2.25) % in mildly hypertrophic myocytes and to (15.01+/-1.37) % in moderately hypertrophic myocytes; but rottlerin did not affect apoptotic rate induced by Ang II in serum-free cultured myocytes. These results suggest that inhibition of PKCdelta can reduce Ang II-induced apoptosis of hypertrophic cardiomyocytes and that PKCdelta is possibly involved in the apoptotic process of hypertrophic cardiomyocytes.

Topics: Angiotensin II; Animals; Animals, Newborn; Apoptosis; Cardiomegaly; Cell Enlargement; Endothelin-1; Heart Failure; Myocytes, Cardiac; Primary Cell Culture; Protein Kinase C-delta; Rats; Rats, Sprague-Dawley

The AMPD1 gene C34T polymorphism has previously been associated with prolonged survival in small cohorts of heart failure (HF) and coronary artery disease patients. This study aimed to corroborate the association of the AMPD1 C34T polymorphism with survival in larger myocardial infarction (MI) and HF cohorts.. Genotypes were obtained for 935 post-MI (PMI) and 433 patients with established HF, with median follow-up times of 5.4 and 3.1 years, respectively. At admission, cardiac function was assessed by nuclear ventriculography (PMI) and echocardiography (HF) and plasma cardiac neurohormones were assayed.. Differences in mortality by AMPD1 genotype did not achieve significance, either for the overall HF (P = .07) or the overall PMI group (P = .28), but AMPD1 genotype predicted mortality in patients of both cohorts with a history of MI (HxMI). In contrast to previous studies, the mutant T allele was associated with poorer outcome. Mortality in HF HxMI patients was significantly different between genotype groups (n = 144, mortality CC 56.5%, CT/TT 77.8%, P = .027), but not in patients without HxMI. In PMI patients, the association of genotype with survival in the HxMI subgroup trended toward significance (n = 147, mortality CC 29.8%, CT/TT 45.5%, P = .093). Multivariate analysis of combined PMI and HF cohorts showed that HxMI patients with CT/TT genotype were at greater risk than all other groups (P < .001).. This study suggests that AMPD1 C34T genotype is not a predictor of survival in heart disease patients, except possibly those with HxMI.

Topics: Aged; Aldosterone; AMP Deaminase; Angiotensin II; Atrial Natriuretic Factor; Endothelin-1; Epinephrine; Female; Genotype; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Natriuretic Peptide, Brain; Norepinephrine; Polymorphism, Genetic; Proportional Hazards Models; Retrospective Studies

Endothelial dysfunction has been shown to correlate with severity of congestive heart failure (CHF) and recent data suggest morphological changes of peripheral vasculature to be associated with the syndrome. We therefore investigated the hypothesis that vascular remodeling is associated with functional changes in peripheral conduit arteries and with systemic overexpression of ET-1 in patients suffering from CHF.. 57 consecutive patients referred to the Innsbruck Heart Failure and Transplantation Program (EF=23+/-7%) and 16 matched controls (EF=60+/-5%) were studied. Flow-mediated vasodilation (FMD), nitroglycerin-mediated vasodilation (NMD), wall thickness (WT), and incremental elastic modulus (Einc) were assessed by high-resolution ultrasound of the brachial artery. FMD (P=0.004) and NMD (P=0.02) were significantly higher in controls as compared to moderate and severe CHF patients. In contrast, brachial artery-wall thickness (BA-WT) was increased in severe CHF patients (P=0.038). BA-WT was significantly correlated with both FMD (r=-0.28; P=0.049) and NMD (r=-0.38; P=0.003), and with the Einc (r=0.45, P=0.001). Lumen diameter was not different among groups. In patients with BA-WT>0.31 mm, bigET-1 was higher compared to BA-WT<0.31 mm (P<0.05).. CHF is associated with remodeling of the brachial artery, which is characterized by morphological, mechanical and functional changes of the vessel wall. Endothelin-1 may play a role in the vascular remodeling process.

Topics: Adult; Aged; Brachial Artery; Case-Control Studies; Elasticity; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Tunica Intima; Tunica Media; Ultrasonography; Vasodilation

The selection of patients for cardiac transplantation is notoriously difficult. We have demonstrated that N-terminal brain natriuretic peptide (NT-proBNP) is a powerful predictor of mortality in advanced heart failure and is superior to the traditional markers of chronic heart failure (CHF) severity. However, the comparative prognostic power of endothelin-1 (Et-1), adrenomedullin (Adm) and tumour necrosis factor-alpha (TNF-alpha) in this patient group is unknown.. We prospectively studied 150 consecutive patients with advanced CHF referred for consideration of cardiac transplantation. Blood samples for NT-proBNP, Et-1, Adm and TNF-alpha analysis were taken at recruitment and patients followed up for a median of 666 days. The primary endpoint of all-cause mortality was reached in 25 patients and the secondary endpoint of all-cause mortality or urgent cardiac transplantation in 29 patients. The median values for NT-proBNP, Et-1, Adm and TNF-alpha were 1494 pg/ml [interquartile range 530-3930], 0.39 fmol/ml [0.10-1.24], 94 pg/ml [54-207] and 2.0 pg/ml [0-18.5] respectively. The only univariate and multivariate predictor of all-cause mortality (chi(2)=26.95, p<0.0001), or the secondary endpoint of all-cause mortality or urgent transplantation (chi(2)=31.23, p<0.0001), was an NT-proBNP concentration above the median value.. A single measurement of NT-proBNP in patients with advanced CHF can help identify patients at the highest risk of death, and is a better prognostic marker than Et-1, Adm and TNF-alpha.

Topics: Adrenomedullin; Adult; Aged; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Peptides; Predictive Value of Tests; Prospective Studies; ROC Curve; Tumor Necrosis Factor-alpha

Elevated plasma concentrations of big endothelin-1 (big ET-1) are related with severity and prognosis in patients with heart failure, and N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of ventricular remodeling. The purpose of this study was to investigate the relationship between plasma levels of big ET-1 and NT-proBNP, and between the former and ventricular function.. We studied 103 patients with heart failure (75 men, mean age 63 [13] years). Each participant completed a questionnaire and underwent Doppler echocardiographic study to measure ejection fraction (EF), mitral flow propagation velocity (Vp) and atrioventricular plane displacement (AVPD). Blood samples were also taken to determine plasma levels of big ET-1, aldosterone and NT-proBNP.. For the whole population big ET-1 concentration was 1.03 [0.75] fmol/m, NT-proBNP 619 (307-1328) pg/mL, aldosterone 168 [102] pg/mL, EF 37 [10], Vp 37 [11] cm/s, and AVPD 8.0 [1.7] mm. Plasma big ET-1 correlated positively with plasma NT-proBNP (r=0.50, P<.0001). However, a negative correlation was found between big ET-1 and EF (r=-0.30, P<.01), Vp, (r=-0.30, P<.01) and AVPD (r=-0.21, P<.05). When ET-1 levels were divided into quartiles and the corresponding NT-proBNP, EF, Vp and AVPD values were compared, we found significant differences (ANOVA P<.0001, P<.01, P<.05 and P<.05, respectively).. Plasma levels of big ET-1 correlated positively with NT-proBNP levels and inversely with EF, Vp and AVPD. These findings help clarify the relationships between ventricular function and the neurohormonal activation involved in heart failure, and may aid the search for therapeutic interventions.

Topics: Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Ventricular Function

The term "biochemical marker" of heart failure is used to define a biochemical substance whose plasma levels correlate with the clinical and hemodynamic status and predict the prognosis of patients with heart failure. The aim of this study was to prospectively evaluate, in a single population of patients with heart failure, the correlations between the plasma levels of brain natriuretic peptide (BNP), big endothelin-1 (BET-1), tumor necrosis factor-alpha (TNF-alpha), cardiac troponin I (cTnI) and T (cTnT), the clinical presentation, and the left ventricular function.. The study population included a series of 120 patients (97 males, 81%, mean age 56+/-12 years) in NYHA functional class I (49%), II (20%), III (26%), IV (5%) who were admitted to our institution or followed up as outpatients. All patients underwent cardiologic evaluation, standard electrocardiography, two-dimensional echocardiography, and venous blood sampling on the same day.. At univariate analysis the following correlations were found to be significant: all the laboratory parameters correlated with the NYHA class (BNP r = 0.63, BET-1 r = 0.56, cTnI r = 0.25, cTnT r = 0.24, TNF-alpha r = 0.23); BNP (r = -0.39) and BET-1 (r = -0.27) with left ventricular ejection fraction; BNP (r = 0.37) and BET-1 (r = 0.21) with the degree of mitral insufficiency; BNP (r = -0.39), BET-1 (r = 0.25) and TNF-alpha (r = -0.19) with systolic blood pressure; cTnT (r = 0.34), cTnI (r = 0.33), BNP (r = 0.22) and BET-1 (r = 0.19) with heart rate; BNP with age (r = 0.33) and body mass index (r = -0.28). The plasma levels of BNP, BET-1, cTnT and cTnI were significantly higher in case of systemic or pulmonary congestion. At multiple regression analysis the following correlations were still present: BNP with the NYHA functional class (p < 0.005) and with pulmonary venous congestion (p < 0.05); BET-1 with the presence of pulmonary venous congestion (p < 0.005); TNF-alpha with the NYHA class (p < 0.05) and systolic blood pressure (p < 0.001); cardiac troponins with heart rate (p < 0.05).. The plasma concentrations of BNP and BET-1 showed the best and comparable correlations with parameters describing the clinical status of patients with heart failure, in particular with the presence of pulmonary venous congestion. The value of the plasma concentration of TNF-alpha and those of cardiac troponins were found to be limited in patients with relatively stable heart failure.

Topics: Biomarkers; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Troponin I; Tumor Necrosis Factor-alpha

1 The calcineurin (CaN) enzyme-transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. 2 Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 M, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. 3 ET-1 increased contractile force in all 13 patients (P<0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P>0.1). FK506 had no effect on contractile force (P=0.12). 4 ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). 5 There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKC(epsilon) compared to samples incubated without PKC(epsilon). 6 Endogenous cardiostimulants which activate G(alpha)q-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate.

Topics: Adult; Angiotensin II; Blotting, Western; Calcineurin; Endothelin-1; Female; Heart Failure; Heart Ventricles; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Contraction; Peptides; Phosphates; Protein Kinase C; Tacrolimus; Urotensins

Human Urotensin II (hU-II) is the most potent vasoconstrictor known to date. HU-II receptors are predominant in the human heart and arterial vessels, suggesting hU-II to be of importance as a cardiovascular mediator.. We studied 32 consecutive patients (60+/-12 years) with chronic heart failure (CHF) and 10 control subjects (54+/-12 years, n.s.) with cardiopulmonary exercise testing. Blood samples for the measurement of plasma hU-II and big-endothelin-1 (big-ET1) were obtained at rest and at peak exercise.. Peak VO(2) was significantly higher in controls than in CHF patients (19.8+/-3.8 vs. 14.7+/-3.6 ml min(-1) kg(-1), P<0.001). Big-ET1 levels were increased in CHF compared to controls at rest (2.8+/-1.8 vs. 1.7+/-0.1 fmol/ml, P<0.01) and at peak exercise (2.7+/-1.7 vs. 1.6+/-0.2 fmol/ml, P<0.005). HU-II concentrations were comparable in patients with CHF and controls at rest (2990+/-1104 vs. 3290+/-508 pg/ml, n.s.) and peak exercise (3063+/-1185 vs. 3213+/-1188 pg/ml, n.s.). Resting hU-II levels demonstrated no correlation with peak VO(2) in controls or CHF patients.. The measurement of circulating plasma levels of hU-II does not seem to be very helpful in studying the effects of hU-II in human cardiovascular regulation. A local paracrine or autocrine mediator effect of hU-II in CHF is possible.

Topics: Aged; Endothelin-1; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Oxygen Consumption; Stroke Volume; Urotensins

Endothelin-1 (ET-1) potentiates norepinephrine (NE)-induced contractile responses. An impairment of cardiac NE re-uptake by the neuronal NE transporter (NET) contributes to an increased NE net release in failing hearts. We hypothesized that both phenomena are caused by ET-1-mediated inhibition of NET.. [3H]-NE-uptake, electrical field stimulation-evoked NE overflow and left ventricular contractility (LV-dp/dt(max)) were measured in isolated perfused rat hearts. NET density on cardiac plasma membranes was determined by [3H]-mazindol binding. Experimental heart failure in rats was induced by transverse aortic constriction (TAC).. ET-1 inhibited cardiac [3H]-NE-uptake in a concentration- and time-dependent manner. The endothelin A receptor (ET(A)) antagonist BQ123 but not the endothelin B receptor (ET(B)) antagonist BQ788 abolished ET-1-induced reduction of [3H]-NE-uptake. Likewise, ET-1, but not the ET(B) agonist sarafotoxin S6c, enhanced the stimulated overflow of endogenous NE. In contrast, ET-1 inhibited the stimulated NE overflow during NET blockade (exocytotic NE release) via activation of ET(B). In isovolumically contracting healthy hearts, ET-1 potentiated the NE- but not isoprenaline-induced increase in LV-dp/dt(max). Since isoprenaline is not a NET substrate, the enhanced LV-dp/dt(max) response to NE thus depends on NET. In TAC rats, ET(A) antagonism by darusentan improved both impairment of cardiac [3H]-NE-uptake and reduction of [3H]-mazindol binding sites.. ET-1 inhibits cardiac NE re-uptake via ET(A) but attenuates exocytotic NE release via ET(B), resulting in opposite effects on cardiac NE net release. In healthy hearts, ET(A)-mediated inhibition of NE re-uptake exceeds ET(B)-mediated silencing of NE release and potentiates the NE-induced increase in left ventricular contractility. In TAC rats, endogenous ET-1 impairs NE re-uptake and promotes sympathetic overstimulation of failing hearts.

Topics: Animals; Biological Transport; Carrier Proteins; Endothelin-1; Heart Failure; Male; Mazindol; Myocardial Contraction; Myocardium; Neurons; Norepinephrine; Perfusion; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar

The mitogen-activated kinase kinases (MEK)-extracellular signal-regulated kinases (ERK) signaling pathway is activated by agonists like catecholamines or endothelin-1 (ET-1) and has been implicated in cardiac pathology, such as the progression from cardiac hypertrophy to failure. The purpose of the present study, performed in an in vitro model of contractile failure, was to evaluate whether MEK inhibition prevents functional deterioration.. Contractile dysfunction was induced in reconstituted rat heart tissue by concomitant treatment with ET-1 (10 nmol/l) and isoprenaline (ISO, 10 nmol/l) for 5 days. While basal force of contraction was unchanged, contractile responsiveness to beta-adrenoceptor agonists was markedly impaired (active force declined to 51% of controls) and was associated with decreased lusitropy. Moreover, in ET-1+ISO-treated heart tissues, reprogramming of gene expression was observed with an increased ratio of beta-myosin heavy chain (MHC) to alpha-MHC mRNA and increased transcript levels of ANF and skeletal/smooth muscle alpha-actin isoforms. The MEK inhibitor U0126 (10 micromol/l) almost completely prevented the reduction in beta-adrenergic responsiveness and the negative lusitropic effect of ET-1+ISO co-stimulation. In addition, U0126 completely normalized ANF gene expression, but did not affect or only marginally affected expression of MHC and alpha-actin isoforms.. These results suggest that interruption of the MEK-ERK signaling pathway with a specific MEK inhibitor prevents, in part, the occurrence of a pathologic phenotype secondary to excessive stimulation with neurohumoral factors. The MEK-ERK pathway seems to be an important but not exclusive regulatory pathway responsible for the development of contractile dysfunction.

Topics: Actins; Animals; Atrial Natriuretic Factor; Butadienes; Depression, Chemical; Endothelin-1; Gene Expression Regulation; Heart Failure; Isoproterenol; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Myocardial Contraction; Myocardium; Myosin Heavy Chains; Nitriles; Protein Isoforms; Rats; Rats, Wistar; RNA, Messenger; Stimulation, Chemical; Tissue Engineering

In order to characterize the changes of five neurohormones in pediatric patients with varying degrees of congestive heart failure (CHF) secondary to congenital heart disease (CHD), we measured plasma neurohormone levels by using radioimmunoassay or high-performance liquid chromatography in 81 subjects including 13 normal children and 68 pediatric patients with CHD. Patients with CHF (n=27) had elevated levels of big endothelin-1 (big ET-1) (29.5+/-1.6 vs. 18.1+/-2.1 pg/ml, p<0.001), endothelin-1 (ET-1) (17.9+/-1.7 vs. 7.8+/-1.7 pg/ml, p<0.001) and norepinephrine (505.6+/-65.6 vs. 219.6+/-23.3 pg/ml, p<0.01) as compared with healthy control subjects (n=13). Plasma norepinephrine levels (505.6+/-65.6 vs. 230.0+/-8.0 pg/ml, p<0.001) and atrial natriuretic peptide (35.5+/-4.2 vs. 7.6+/-0.6 pg/ml, p<0.001) in the 27 patients with CHF were significantly higher than in the 41 patients without CHF. There was also a highly significant stepwise increase in big ET-1, atrial natriuretic peptide and norepinephrine according to the severity of heart failure. Our results suggest that increased circulating neurohormonal activity in CHD relates to the presence and clinical severity of heart failure in children. Plasma levels of big ET-1 and ET-1 were not only significant markers of CHF but also correlated well with the severity of CHF in CHD with left-to-right shunt.

Topics: Adolescent; Atrial Natriuretic Factor; Biomarkers; Child; Child, Preschool; Chromatography, High Pressure Liquid; Endothelin-1; Female; Heart Defects, Congenital; Heart Failure; Humans; Infant; Male; Norepinephrine; Prospective Studies; Radioimmunoassay; Severity of Illness Index

Plasma concentrations of endothelin-1 and big-endothelin are increased in heart failure patients. However, the precise contribution of endothelin secretion from the cardiopulmonary system remains unresolved. The aim of this study was to investigate whether the cardiopulmonary system contributes to the circulating endothelin-1 and big-endothelin concentrations in heart failure patients.. Blood samples were obtained at right heart catheterization from different cardiovascular regions including the coronary sinus in chronic heart failure patients (n=12) and from age-matched control subjects (n=12).. The peripheral plasma concentrations of endothelin-1 were almost 3-fold higher in heart failure patients compared with the control subjects (1.25 pmol/l, 0.30-8.20 pmol/l (median, range) versus 0.46 pmol/l, 0.10-0.88 pmol/l, p<0.01). However, the endothelin-1 concentration was approximately 25% lower in plasma samples from the coronary sinus than in plasma from the inferior caval vein (p<0.05) in the heart failure patients. There were no differences in big-endothelin concentrations between any of the cardiovascular regions.. In heart failure patients, increased plasma concentrations of endothelin-1 and big-endothelin mainly reflect an increased secretion from the peripheral endothelium.

Topics: Adult; Aged; Cardiac Catheterization; Cardiomyopathy, Dilated; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Female; Heart Failure; Humans; Male; Middle Aged; Vena Cava, Inferior; Ventricular Dysfunction, Left

Although echocardiographic ejection fraction (EF) is frequently used for the estimation of left ventricular contractility in patients with acute heart failure, its exact role and correlations with clinical, hemodynamic, and neurohormonal variables of cardiac contractility is not known.. Patients (343) with acute heart failure, enrolled into two prospective placebo-controlled hemodynamic studies of tezosentan, and in whom EF was available at baseline, were included. Outcome was evaluated in a subset of 94 patients who were enrolled in the placebo arms of the studies.. Higher echocardiographic EF was correlated with older age, increased incidence of hypertension and atrial fibrillation, and female gender. We observed weak correlation between EF and cardiac output or cardiac power and no correlation with wedge pressure, and the change in hemodynamic variables over time. Higher EF was correlated with more baseline leukocytosis and higher plasma levels of endothelin-1 and blood urea nitrogen, while lower EF was related to higher baseline B-type natriuretic peptide (BNP). We observed no overall correlations between EF and outcome.. In patients with acute heart failure, echocardiographic EF is weakly correlated with hemodynamic measures of left ventricular contractility and outcome; hence, it should be interpreted cautiously when evaluating patients admitted due to acute heart failure.

Topics: Aged; Blood Urea Nitrogen; Cardiac Output; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Retrospective Studies; Stroke Volume; Treatment Outcome; Ultrasonography

In heart failure, the coronary flow reserve (CFR) measured by positron-emission tomography (PET) is reduced. As neurohormone and cytokine levels are also altered in patients with the condition, our aim was to determine whether there is a correlation between CFR and neurohormone and cytokine levels.. The study included 40 patients with heart failure but without ischemic heart disease. Myocardial blood flow was measured by PET using nitrogen-13 ammonia at baseline and during ATP infusion. The CFR was calculated for each patient. In addition, levels of the following were determined: norepinephrine, endothelin-1, angiotensin-II, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), tumor necrosis factor-alpha, interleukin (IL)-1beta, soluble IL-2 receptor, and IL-6.. All neurohormone levels were elevated above reference values. The levels of all cytokines, except IL-1beta, were also elevated. There was a significant negative correlation between CFR and the levels of several neurohormones: ANP (r=-0.476), BNP (r=-0.442), and IL-6 (r=-0.509).. In heart failure, the decrease in CFR is correlated with increases in the levels of certain neurohormones (i.e., ANP and BNP) and cytokines (i.e., IL-6), with vasodilatory effect. These increases are probably are related to compensatory mechanisms that are unable to correct for the endothelial dysfunction present in these patients.

Topics: Coronary Circulation; Cytokines; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Neurotransmitter Agents; Norepinephrine

While both the endothelin-1 (ET-1) and renin-angiotensin systems (RAS) are activated in congestive heart failure (CHF), the temporal sequence of this activation remains unclear. Understanding this pattern of neurohumoral activation may aid in understanding the significance of ET-1 in CHF and provide strategies for ET-1 antagonism. Although acute endothelin (ET) receptor antagonism improves systemic hemodynamics in CHF, clinical trials with chronic ET receptor antagonism report worsening CHF symptoms.. In a canine model of progressive left ventricular dysfunction, we demonstrated activation of myocardial and plasma ET-1 without activation of the RAS during transition to overt CHF, suggesting that ET-1 contributes to this transition. We next evaluated the effects of chronic oral ET-A receptor antagonism on neurohumoral function, renal hemodynamics, and sodium excretion in pacing-induced CHF. After 7 days of treatment (n=7) with ET-A receptor antagonism (with LU135252), sodium excretion did not improve in treated versus untreated CHF (n=6). Furthermore, both plasma renin activity and plasma ET-1 increased with ET-A receptor blockade.. Activation of the myocardial and plasma ET-1 systems precedes activation of the myocardial and plasma RAS in CHF. ET-A receptor antagonism in experimental CHF further activates the RAS without improving sodium excretion. These findings suggest an important role for ET-1 in the progression of CHF and a potential mechanism for the exacerbation of CHF symptoms observed in clinical trials with chronic ET receptor antagonism. Further studies with combined modulation of the ET and other neurohumoral systems in CHF are required.

Topics: Animals; Disease Progression; Dogs; Endothelin A Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Kidney; Male; Phenylpropionates; Pyrimidines; Renin; Renin-Angiotensin System; Sodium

Topics: Animals; Disease Progression; Endothelin A Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Models, Cardiovascular; Renin-Angiotensin System; Ventricular Remodeling

Endothelin-1 (ET-1) concentrations are elevated in patients with congestive heart failure (CHF), although the cause of this increase remains uncertain. We hypothesized that abnormalities in ET-1 production, clearance, or a combination of these may be the cause of elevated ET-1 concentrations in chronic CHF. The kinetics of clearance of ET-1 were measured with (125)I-labeled ET-1 in eight patients with CHF and five age-matched normal individuals. In both normal subjects and the CHF group, the kinetics of ET-1 clearance were best described by a three-compartment model. The steady-state volume of distribution of ET-1 was significantly greater in the CHF group compared with normal subjects (25.2 +/- 3.9 vs. 13.8 +/- 2.1 l/kg; P < 0.05). The total clearance rate from plasma was greater in the CHF group (0.119 +/- 0.018 vs. 0.047 +/- 0.013 l.kg(-1).min(-1); P = 0.05). The total body production rate of ET-1 was also significantly higher in patients with CHF (0.21 +/- 0.03. vs. 0.06 +/- 0.02 ng.kg(-1).min(-1); P < 0.05). It appears that increased ET-1 production rather than decreased clearance is the cause of elevated ET-1 concentrations in patients with chronic CHF.

Topics: Blood Pressure; Chronic Disease; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Iodine Radioisotopes; Kinetics; Male; Middle Aged; Models, Biological

This study assessed alterations in expression of pulmonary endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in rats with pulmonary hypertension (PH) after the ascending aorta had been banded. Rats were studied 12 weeks after banding, which resulted in left heart failure with elevated pulmonary arterial pressure (banded: 31.3 +/- 5.9 (mean +/- SD) mmHg; sham: 20.0 +/- 4.7 mmHg, P<0.05). Competitive reverse transcription-polymerase chain reaction demonstrated significant increases in pulmonary expression of preproET-1 mRNA and eNOS mRNA. Western blot analysis indicated increased pulmonary eNOS protein. Radioimmunoassays indicated increased plasma ET-1 concentrations in the pulmonary artery (banded: 12.4 +/- 1.5 pg/ml; sham: 9.0 +/- 1.3 pg/ml, P<0.01) and increased ET-1 content in lungs (banded: 240 +/- 21 ng/g protein; sham: 203 +/- 20 ng/g protein, P<0.05). There was increased immunohistochemical staining of eNOS and ET-1 in the pulmonary vascular endothelium of aorta-banded rats. Even in the presence of increased eNOS expression, it was not clear how nitric oxide (NO) production (decreased, unchanged, or increased) was involved in the compensatory mechanism to offset pulmonary vasoconstriction. Increased ET-1 expression may be important in mediating PH secondary to aortic banding, and may offer insights into the use of ET-1 antagonists in treating patients with PH secondary to heart failure.

Topics: Animals; Aorta; Disease Models, Animal; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Nitric Oxide Synthase; Rats; Rats, Wistar; Up-Regulation

Topics: Adult; Arrhythmias, Cardiac; Cardiovascular Diseases; Child; Comorbidity; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epidemiologic Studies; Genetic Predisposition to Disease; Heart Failure; Humans; Hypertension; Male; Obesity; Risk Factors; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Thrombophilia

Neuroendocrine activation is a pathophysiological response and an important prognostic marker in patients with chronic heart failure (CHF). Although chronic activation is well described, data on the responsiveness of the hormone systems are more limited. Most previous studies have looked at activation during maximal exercise, whereas we believe that activation at a submaximal level might be more pathophysiologically relevant.. To compare exercise-induced neurohormonal activation between CHF patients and normal subjects using the same relative and submaximal workload.. Twenty-three newly-diagnosed CHF patients and 18 age- and gender-matched healthy subjects were exercised at two workloads, which were calculated to correspond to 50 and 75% of each individual's heart rate response.. In CHF patients, baseline levels of ANP, BNP, AVP, PRA and ET-1 were elevated compared to healthy subjects. Exercise induced an increase in ANP, A and NA in both CHF patients and in normal subjects, however BNP was only increased in CHF patients and not in normal subjects.. When CHF patients exercise at the same relative and submaximal level as age-matched healthy subjects, the relative increases in ANP, A and NA were similar, however, BNP levels only increased in the CHF group.

Topics: Aged; Aged, 80 and over; Arginine Vasopressin; Case-Control Studies; Endothelin-1; Exercise; Exercise Tolerance; Female; Heart Failure; Humans; Male; Natriuretic Peptides; Neurosecretory Systems; Norepinephrine; Renin

Hospitalization for decompensated heart failure is associated with high mortality after discharge. In heart failure, renal function involves both cardiovascular and hemodynamic properties. We studied the relation between renal dysfunction and mortality in patients admitted for decompensated heart failure.. The prognostic importance of four measures of renal function-blood urea nitrogen, serum creatinine, blood urea nitrogen/creatinine ratio, and estimated creatinine clearance-was evaluated in 541 patients (mean [+/- SD] age, 63 +/- 14 years; 377 men [70%]) with a previous diagnosis of heart failure (96% with New York Heart Association class III or IV symptoms) who were admitted for clinical decompensation.. During a mean follow-up of 343 +/- 185 days, 177 patients (33%) died. In multivariable Cox regression models, the risk of all-cause mortality increased with each quartile of blood urea nitrogen, with an adjusted relative risk of 2.3 in patients in the upper compared with the lower quartiles (95% confidence interval [CI]: 1.3 to 4.1; P = 0.005). Creatinine and estimated creatinine clearance were not significant predictors of mortality after adjustment for other covariates. Blood urea nitrogen/creatinine ratio yielded similar prognostic information as blood urea nitrogen (adjusted relative risk = 2.3; 95% CI: 1.4 to 3.8; P = 0.0007 for patients in the upper compared with the lower quartiles).. Blood urea nitrogen is a simple clinical variable that provides useful prognostic information in patients admitted for decompensated heart failure. In this setting, elevated blood urea nitrogen levels probably reflect the cumulative effects of hemodynamic and neurohormonal alterations that result in renal hypoperfusion.

Topics: Aged; Biomarkers; Blood Urea Nitrogen; Cause of Death; Creatinine; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Kidney; Male; Middle Aged; Multivariate Analysis; Patient Admission; Predictive Value of Tests; Prospective Studies; Renin; Statistics as Topic; Survival Analysis

The plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins have been reported to correlate with the severity of heart failure.. In a single population of 80 outpatients with mild to moderate chronic heart failure the correlation between the patient's functional capacity, as evaluated at a 6-min walk test, the clinical parameters and plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins was evaluated.. A significant inverse correlation was found with the patient's age (p < 0.0001), NYHA functional class (p < 0.0001), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.0005), heart rate (p < 0.05), plasma levels of brain natriuretic peptide (p < 0.05) and of tumor necrosis factor-alpha (p < 0.0005). At multiple regression analysis a correlation was found between the 6-min walk test results and the patient's age (p < 0.05), NYHA functional class (p < 0.01), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.05) and tumor necrosis factor-alpha plasma levels (p < 0.05).. In our patients with mild to moderate heart failure, a significant correlation was found between the results of the 6-min walk test and only the plasma concentrations of tumor necrosis factor-alpha among the laboratory parameters analyzed in this study.

Topics: Adult; Aged; Biomarkers; Cardiomyopathy, Dilated; Coronary Artery Disease; Endothelin-1; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Multivariate Analysis; Natriuretic Peptide, Brain; Severity of Illness Index; Statistics as Topic; Troponin; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Walking

Overall, doxorubicine-congestive heart failure (CHF) (male Wistar rats and NMRI mice; 6 challenges with doxorubicine (2.5 mg/kg, i.p.) throughout 15 days and then a 4-week-rest period) is consistently deteriorating throughout next 14 days, if not reversed or ameliorated by therapy (/kg per day): a stable gastric pentadecapeptide BPC157 (GEPPPGKPADDAGLV, MW 1419, promisingly studied for inflammatory bowel disease (Pliva; PL 10, PLD-116, PL 14736)) (10 microg, 10 ng), losartan (0.7 mg), amlodipine (0.07 mg), given intragastrically (i.g.) (once daily, rats) or in drinking water (mice). Assessed were big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) before and after 14 days of therapy and clinical status (hypotension, increased heart rate and respiratory rate, and ascites) every 2 days. Controls (distilled water (5 ml/kg, i.g., once daily) or drinking water (2 ml/mouse per day) given throughout 14 days) exhibited additionally increased BET-1 and aggravated clinical status, while enzyme values maintained their initial increase. BPC157 (10 microg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC157 (10 ng/kg) reduces AST and ALT serum values. Clinical status of CHF-rats and -mice is accordingly improved by the BPC157 regimens and amlodipine.

Topics: Amlodipine; Animals; Doxorubicin; Endothelin-1; Gastric Mucosa; Heart Failure; Losartan; Male; Mice; Peptide Fragments; Peptides; Proteins; Rats; Rats, Wistar; Stomach

Circulating levels of the potent vasoconstrictor peptide endothelin-1 (ET-1) are increased in congestive heart failure (CHF). Coronary blood flow and myocardial oxygen consumption (MVO2) are decreased in some models of CHF. This study tested the hypothesis that ET-1 induced coronary vasoconstriction limits oxygen availability in the failing heart. The effects of selective ET-A receptor blockade with BQ610 (5 microg/min, intracoronary) and selective ET-B receptor blockade with BQ788 (5 microg/min, intracoronary) on coronary blood flow were examined at rest and during graded treadmill exercise in 8 dogs in which congestive heart failure (CHF) had been produced by rapid ventricular pacing for three to four weeks. In animals with CHF, ET-B receptor blockade caused no change in left ventricular (LV) pressure or coronary blood flow. In contrast, ET-A blockade with BQ610 resulted in modest significant increases of coronary blood flow at rest (from 22.4 +/- 2.1 to 27.9 +/- 3.0 mL/min) and during two exercise stages (from 26.9 +/- 2.0 to 30.7 +/- 1.9 during stage 1 exercise and from 28.5 +/- 2.0 to 31.7 +/- 1.3 mL/min during stage 2; all P < 0.05), with an upward shift in the relationship between coronary flow and rate-pressure product. The increase in coronary flow produced by ET-A blockade was not associated with an increase of either myocardial oxygen uptake or LV dP/dt. Thus, although ET-A receptor blockade caused a modest increase in coronary flow, this did not result in an increase of MVO2, implying that ET-A-mediated coronary vasoconstriction did not limit oxygen uptake by the failing heart.

Topics: Animals; Coronary Circulation; Dogs; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Heart Failure; Oligopeptides; Receptor, Endothelin A

Topics: Animals; Endothelin-1; Endothelium, Vascular; Heart Failure; Humans; Lung

The pulmonary circulation may contribute to elevated plasma levels of endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present study were to determine the mechanisms of increased secretion of ET-1 from the pulmonary circulation in CHF.. Juvenile pigs were subjected to sham operation (n=9) or rapid cardiac pacing-induced CHF (215-240 bpm, n=15).. Three weeks of rapid pacing led to significant left ventricular dilatation, increased cardiac filling pressures, and reduced contractility (CHF pigs). Arterial plasma ET-1 levels in the CHF pigs were increased 4-fold compared to sham pigs (P<0.001). Single-bolus multiple indicator-dilution experiments revealed that pulmonary synthesis and release of ET-1 was increased in CHF, while pulmonary clearance of plasma ET-1 remained unaltered despite significant reduction of pulmonary fractional extraction of plasma ET-1. Pulmonary ECE-1 isozyme activity (pmol.min-1.mg protein-1) was selectively increased in lower lobe segments of CHF pigs (2.0+/-0.3) compared to lower lobe segments of controls (1.1+/-0.1, P<0.02), and to upper lobe segments of CHF pigs (1.1+/-0.1, P<0.005), and correlated significantly with the wet/dry weight ratios of the pulmonary tissue samples (R=0.75, P<0.001), i.e. a marker of pulmonary congestion. Furthermore, alveolar macrophages in congested lobe segments were identified as likely sites of increased synthesis and release of ET-1.. In rapid pacing-induced CHF, a complex cardiopulmonary interaction revealed by pulmonary congestion causes increased pulmonary production and secretion of ET-1 due to enhanced pulmonary ECE-1 activities. Pulmonary secretion of ET-1 during evolving CHF is an important contributor to elevated plasma ET-1 levels in the systemic circulation.

Topics: Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Enzyme-Linked Immunosorbent Assay; Heart Failure; Immunohistochemistry; Lung; Macrophages, Alveolar; Metalloendopeptidases; Models, Animal; Pulmonary Circulation; Swine

Aldosterone is produced not only in the adrenal gland but also in the extra-adrenal tissues, including failing human heart. This study examined the production of dehydroepiandrosterone (DHEA) in human heart and elucidated the possible physiological significance. Method and Results- Using left ventricular tissues obtained at autopsy, reverse transcription-polymerase chain reaction followed by Southern blot analysis revealed the gene expressions of CYP17. By measuring plasma aldosterone and DHEA levels at the coronary sinuses and aortic roots during cardiac catheterization, we found that DHEA but not aldosterone was secreted from control subjects (P<0.0001 and P=0.74, respectively), whereas aldosterone but not DHEA was secreted from patients with heart failure (P=0.0017 and P=0.67, respectively). To examine the significance of DHEA, we measured myocyte cell sizes and the gene expression of B-type natriuretic peptide (BNP), using a neonatal rat cardiocyte culture system. We found that DHEA (10(-8) mol/L) significantly inhibited the increase in myocyte cell sizes and BNP mRNA levels upregulated by endothelin-1 (P=0.031 and P<0.0001, respectively).. CYP17 gene expression and production of DHEA were demonstrated in human control heart. Also, we found that cardiac production of DHEA was suppressed in failing heart. We postulated that DHEA and/or its metabolites exert a cardioprotective action through antihypertrophic effects.

Topics: Adult; Aged; Aldosterone; Animals; Blotting, Southern; Cardiac Catheterization; Cell Size; Cells, Cultured; Dehydroepiandrosterone; Endothelin-1; Female; Heart Failure; Heart Ventricles; Humans; Hypertrophy; Male; Middle Aged; Myocytes, Cardiac; Natriuretic Peptide, Brain; Neoplasms; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase

Endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF) in relation with the severity of pulmonary hypertension. We evaluated whether a reduced pulmonary ET-1 clearance could contribute to this elevation.. We determined pulmonary ET-1 clearance in 24 patients with CHF in relation with hemodynamics, plasma ET-1, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Pulmonary ET-1 extraction, measured by the single bolus indicator-dilution technique, was reduced to 32 +/- 14% in comparison to historic controls (47 +/- 7%). Plasma ET-1 clearance by the lungs (924 +/- 588 mL/min) was also much lower than in controls (1424 +/- 79 mL/min). Clearance correlated inversely with mean pulmonary artery pressure (PAP, r = -.47, P = .017) and pulmonary capillary wedge pressure (r = -.47, P = .017) and positively with the rate of left ventricular (LV) relaxation LV -dP/dt (r = .593, P = .004). After multivariate analysis, only mean PAP and LV -dP/dt were independently correlated with ET-1 clearance (r = -.40, P = .03, and r = .55, P = .005, respectively). Plasma ET-1 levels did not correlate with clearance (r = .038, P = .86), and there was no significant arteriovenous ET-1 gradient. There was a mild nonsignificant correlation between plasma ET-1 and pulmonary artery systolic pressure (r = .38, P = .06), but a strong correlation with right atrial pressure (r = .696, P < .0001) and NT-proBNP levels (r = .51, P = .001), which were maintained after multivariate linear regression (r = .60, P = .001, and r = .32, P = .04, respectively).. Pulmonary ET-1 clearance is reduced in CHF in relation with the severity of pulmonary hypertension. This reduced clearance does not significantly modulate plasma ET-1 levels. Whether this is only a marker of secondary pulmonary hypertension or could modulate pulmonary vascular tone will require further studies.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Endothelin-1; Female; Heart Failure; Humans; Hypertension, Pulmonary; Indicator Dilution Techniques; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protein Precursors; Pulmonary Circulation; Pulmonary Wedge Pressure; Regression Analysis; Ventricular Function

Plasma concentrations of atrial and brain natriuretic peptides (ANP, BNP), of their N-terminal pro-peptides, of endothelin-1 (ET-1), and big endothelin-1 (big ET-1) have diagnostic and prognostic significance in congestive heart failure (CHF). However, their respective values as a predictor of survival remain controversial and have never been directly compared in severe CHF.. We analyzed, in 47 patients with severe CHF (New York Heart Association [NYHA] class III to IV; age 66 +/- 8 years, ejection fraction 20 +/- 6%), the prognostic performance of a panel of neurohormones and assays (N-terminal pro-ANP 1-25, 68-98 by radioimmunoassay [RIA], and 1-98 by enzyme-linked immunosorbent assay [ELISA], BNP by RIA and immunoradiometric assay [IRMA], N-terminal pro-BNP by Elisa, ET-1 by RIA, and big ET-1 by RIA and Elisa. Data were compared with 40 patients with mild to moderate CHF [NYHA I-II] and 30 healthy subjects. After a follow-up of 81 +/- 15 months, there were 34 deaths and 1 heart transplant. All neurohormones were significantly higher at baseline in patients with severe than in mild to moderate CHF or healthy subjects (all P < .001). Although all neurohormones but BNP IRMA were significant predictors of survival in univariate analysis, only big ET-1 RIA and ET-1 were independent predictors of survival (improvement chi(2): 7.5 and 4.6, P < .01 and P < .05). Using medians as cutpoints of big ET-1 RIA and ET-1, 2 severe CHF populations were defined with a different outcome (5-year survival: 55 versus 18%, P < .01).. Big ET-1 and ET-1 are strong independent predictors of survival in patients with severe CHF and better for this purpose than natriuretic peptides or their pro-peptides. These markers allow easily to identify a population with a very high risk mortality eligible for more aggressive therapies.

Topics: Atrial Natriuretic Factor; Endothelin-1; Female; Heart Failure; Humans; Immunoradiometric Assay; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis

In vivo models of myocardial infarction induced by coronary artery ligation (CAL) in rats usually suffer from high early mortality and a low rate of induction. This study investigated the time course initiation of chronic myocardial infarction (CMI) in albino rats and the possibility of reducing early mortality rate due to myocardial infarction by modification of the surgical technique. CAL was carried out by passing the suture through the epicardial layer around the midway of the left anterior descending coronary artery including a small area of the myocardium to avoid mechanical damage to the heart geometry. In addition, the role of endothelin-1 (ET-1) in rat heart with congestive heart failure was critically assessed. Time course initiation experiments were designed by sacrificing the animals at different time intervals and by carrying out physiological, biochemical, histopathological, electron microscopical and immunohistochemical studies. Specific markers of myocardial injury, viz. cardiac troponin-T (cTnT), high sensitivity C-reactive protein, lactate dehydrogenase and fibrinogen were measured at different time points. Serum marker enzymes and activities of lysosomal hydrolases were found to be elevated on the eighth day post-ligation. Histopathological studies demonstrated focal areas showing fibrovascular tissue containing fibroblasts, collagenous ground substance and numerous small capillaries replacing cardiac muscle fibers. Transmission electron micrographs exhibited mitochondrial changes of well-developed irreversible cardiac injury, viz. swelling, disorganization of cristae, appearance of mitochondrial amorphous matrix densities, significant distortion of muscle fibers and distinct disruption of the intercalated discs. Immunoblotting studies confirmed the presence of alpha 2-macroglobulin which supported the inflammatory response. The severity of the CMI was inferred by the measurement of the level of ET-1 in plasma and left ventricle which was significantly higher in the CMI rats than in the sham-operated rats. Immunohistochemical studies at different time intervals showed that there was a significant immunoexpression of ET-1 on the eighth day post-ligation. This study conclusively showed that ligation of left anterior descending artery minimized mortality and ET-1 was expressed during CMI.

Topics: alpha-Macroglobulins; Animals; Biomarkers; Blood Pressure; Blotting, Western; C-Reactive Protein; Disease Models, Animal; Electrocardiography; Electrophoresis, Polyacrylamide Gel; Endothelin-1; Heart Failure; Hydrolases; Immunohistochemistry; Kinetics; L-Lactate Dehydrogenase; Ligation; Lysosomes; Male; Mitochondria, Heart; Myocardial Infarction; Rats; Rats, Wistar; Severity of Illness Index; Troponin T

In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Collagen; Disease Models, Animal; Dogs; Enalapril; Endothelin-1; Fibrosis; Heart Failure; Hemodynamics; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Quinolines; Receptor, Bradykinin B2; Renin; RNA, Messenger

To clarify the functional role of endothelin-A/endothelin- B (ETA/ETB) receptors in congestive heart failure (CHF), we examined the effects of a non-selective endothelin receptor agonist, endothelin-1 (ET-1), and a selective ETB receptor agonist, sarafotoxin S6c. CHF was induced in dogs by rapid ventricular pacing and resulted in decreased left ventricular dp/dtmax, decreased cardiac output and increased pulmonary vascular resistance. Sarafotoxin S6c (0.3 nmol/kg) resulted in decreased left ventricular dp/dtmax (-26 +/- 2%), decreased cardiac output (-47 +/- 3%) and increased pulmonary vascular resistance (+48 +/- 10%) in dogs without CHF. The effects of sarafotoxin S6c were attenuated in dogs with CHF (-12 +/- 5% in left ventricular dp/dtmax, -19 +/- 5% in cardiac output and +7 +/- 5% in pulmonary vascular resistance). In contrast, ET-1 (0.5 nmol/kg) had no effect on left ventricular dp/dtmax in dogs without CHF and increased left ventricular dp/dtmax by 16 +/- 3% in dogs with CHF. These data indicate that reduced cardiac contractile and pulmonary vasoconstrictor responses via the ETB receptor are attenuated and that responses mediated by the ETA receptor are more prominent in the context of CHF. This suggests a functional shift of endothelin receptor subtypes in CHF.

Topics: Animals; Cardiac Output; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Endothelin-1; Heart Failure; Lung; Male; Myocardial Contraction; Myocardium; Receptor, Endothelin A; Receptor, Endothelin B; Up-Regulation; Vascular Resistance; Vasoconstriction; Ventricular Pressure; Viper Venoms

While left ventricular (LV) reduction surgery (LVR) is a novel treatment for severe heart failure, alteration of signal transduction pathways by this surgery is unknown. LV endothelin-1 plays a critical role in LV remodeling following myocardial infarction (MI). Another possible mechanism of remodeling is myocardial cell loss due to apoptosis. The purpose of the present study was to determine whether the LV endothelin-1 level and apoptosis signaling change after LVR. Adult rats were divided into two groups: non-MI group and MI group, and the MI group was subjected to permanent ligation of the left anterior descending artery. Four weeks later, rats in the MI group were subjected to LVR (LVR group) or a sham operation (OMI group). Two weeks after the second operation, echocardiography revealed that LVR improved LV systolic function and remodeling. Upregulation of LV endothein-1 was detected only in the OMI group but not in the non-MI group nor in the LVR group. The percentage of terminal deoxynucleotidyl transfer-mediated end-labeling of fragmented nuclei (TUNEL)-positive cardiac myocytes was significantly higher in the OMI group than in the LVR group or the non-MI group. Western blotting of extracts from the left ventricle showed that bcl-2 and bcl-xL levels were restored and caspase-3 activation was repressed after LVR. Thus, LVR modulates the expression of endothelin-1 and apoptosis signaling in failing hearts. These alterations of signal transduction pathways might contribute to the beneficial effects of LVR on systolic function in heart failure.

Topics: Animals; Apoptosis; bcl-X Protein; Cardiac Surgical Procedures; Caspase 3; Disease Models, Animal; Down-Regulation; Echocardiography; Endothelin-1; Heart Failure; Heart Ventricles; In Situ Nick-End Labeling; Male; Myocardium; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Signal Transduction; Ventricular Function, Left; Ventricular Remodeling

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.

Topics: Animals; Atrasentan; Blood Pressure; Cardiomegaly; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Infusion Pumps, Implantable; Kidney; Male; Natriuresis; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Vasoconstriction; Vasodilation

Endothelin-1[1-31] is a recently discovered member of the endothelin family with vasoactive properties in several animal models and in man in vivo. It is generated from big endothelin-1 by human mast cell chymase and may be a novel intermediary peptide in the production of endothelin-1[1-21]. Given that both big endothelin-1[1-38] and chymase activity are increased in chronic heart failure, the aim of this study was to determine whether plasma endothelin-1[1-31] concentrations are elevated in patients with chronic heart failure. Plasma endothelin-1[1-31] concentrations were measured by enzyme-linked immunosorbent assay in nine patients with chronic heart failure, and nine age- and sex-matched control subjects. Consistent with previous studies, plasma concentrations of big endothelin-1[1-38] were elevated in patients compared with controls (17.1 +/- 4.4 pg/mL vs 8.9 +/- 3.4 pg/mL, P = 0.002), although there were no differences in plasma endothelin-1[1-21] (3.3 +/- 0.4 pg/mL vs 3.4 +/- 0.7 pg/mL, P = 0.7) or endothelin-1[1-31] (both 1.1 +/- 0.1 pg/mL, P = 0.2) concentrations. We have demonstrated that patients with chronic heart failure have normal plasma endothelin-1[1-31] concentrations. This suggests that, in contrast to big endothelin-1[1-38], plasma endothelin-1[1-31] is unlikely to be a useful prognostic marker in patients with chronic heart failure.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Chronic Disease; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Heart Failure; Humans; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Reproducibility of Results

Topics: Aged; Cytokines; Endothelin-1; Female; Heart Failure; Humans; Life Tables; Male; Middle Aged; Neurotransmitter Agents; Patient Discharge

Topics: Cardiotonic Agents; Endothelin-1; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Morphine; Neprilysin

In chronic heart failure, myocardial expression of the inducible isoform of nitric oxide (NO) synthase (NOS2) is enhanced, leading to a sustained production of NO. We postulated that NO modulates expression of genes in cardiac myocytes that may be functionally important in the context of cardiac hypertrophy and failure.. As revealed by cDNA expression array analyses, the NO donor SNAP, which has been shown previously to inhibit agonist-induced cardiac myocyte hypertrophy, downregulates expression of the cytoskeleton-associated muscle LIM protein (MLP) in endothelin-1 (ET-1)-stimulated neonatal rat cardiac myocytes. Northern blotting and immunoblotting experiments confirmed this finding and established that SNAP negatively controls MLP mRNA (-49%, P<0.01) and protein (-52%, P<0.01) abundance in ET-1-treated cardiomyocytes via cGMP-dependent protein kinase and superoxide/peroxynitrite-dependent signaling pathways. Treatment of cardiac myocytes with IL-1beta and IFN-gamma downregulated MLP expression levels via induction of NOS2. Moreover, expression levels of NOS2 and MLP were inversely correlated in the failing human heart, indicating that NOS2 may regulate MLP abundance in vitro and in vivo. Antisense oligonucleotides were used to explore the functional consequences of reduced MLP expression levels in cardiac myocytes. Like SNAP, antisense downregulation of MLP protein expression (-52%, P<0.01) blunted the increases in protein synthesis, cell size, and sarcomere organization in response to ET-1 stimulation. Conversely, overexpression of MLP augmented cell size and sarcomere organization in cardiac myocytes.. NO negatively controls MLP expression in cardiac myocytes. Because MLP is necessary and sufficient for hypertrophy and sarcomere assembly, MLP downregulation may restrain hypertrophic growth in pathophysiological situations with increased cardiac NO production.

Topics: Animals; Cell Size; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Cytokines; Cytoskeletal Proteins; Down-Regulation; Endothelin-1; Gene Expression Regulation; Heart Failure; Humans; LIM Domain Proteins; Muscle Proteins; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oligonucleotides, Antisense; Peroxynitrous Acid; Rats; Rats, Sprague-Dawley; Sarcomeres; Superoxides

Topics: Acute Disease; Aged; Aged, 80 and over; C-Reactive Protein; E-Selectin; Endothelin-1; Female; Heart Failure; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Neurotransmitter Agents; Norepinephrine; P-Selectin; Pulmonary Edema; Sympathomimetics; Tumor Necrosis Factor-alpha

Proinflammatory cytokines are capable of modulating cardiovascular function by a various mechanisms. The aim of the study was to evaluate the influence of the selected cytokines: tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (L-6), endothelin 1 (ET-1) on the remodeling of the heart in patients with congestive heart failure (1-year follow-up). The study was made in 45 patients with congestive heart failure treated in the Department of Cardiology. Of these, 31 were men aged from 44 to 77 and 14 were women aged from 48 to 79. Ischaemic heart disease was diagnosed in 22 patients and ischaemic heart disease and hypertension in 10 patients, dilated cardiomyopathy was diagnosed in 6 patients and postinflammatory cardiomyopathy in 7 patients. Blood samples for determination of TNF-alpha, IL-1, IL-2, IL-6, ET-1, aldosterone, catecholamines, brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels were obtained prior to the treatment and in 3 and 6 and 12 month follow-up. At the same time were estimated: NYHA functional class, structure, systolic and diastolic left ventricle function of the heart using echocardiography and 24-hour ECG Holter monitoring (HR, supraventricular and ventricular arrhythmias). TNF-alpha, IL-1, IL-2, IL-6, ET-1, aldosterone, catecholamines, BNP and ANP plasma levels were determined with radioimmunological assay. In patients with progression of congestive heart failure (worsening of NYHA class and ejection fraction of left ventricle) the plasma concentrations of TNF-alpha and ET-1 significantly increased in following observations. In this group patients we determined a correlation between ejection fraction of the left ventricle and serum concentration of TNF-alpha and ET-1. In patients with improving of NYHA functional class and ejection fraction of left ventricle the plasma concentrations of cytokines were not altering. In all patients the plasma concentration of TNF-alpha correlated with ANP and BNP concentrations.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Dilated; Catecholamines; Cytokines; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Interleukin-1; Interleukin-2; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Radioimmunoprecipitation Assay; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Chronic congestive heart failure (CHF) is a complex clinical syndrome characterized by marked neurohormonal activation which may lead to further decompensation of the circulatory system. This study was undertaken to establish the role of certain hormones in pathogenesis of congestive heart failure. Plasma levels of brain natriuretic peptide (BNP), cyclic 3'5'-guanosine monophosphate (c-GMP), endothelin 1 (ET-1), and noradrenaline (NA) were examined in patients in patients with CHF and with decompensation of circulatory system. The survey was made in 92 patients with CHF, among them there were 42 females aged 50-76 years (mean 66 years) and 50 males aged 53-76 years (mean 68 years). All patients were divided into 3 groups according to NYHA classification. On admission blood samples were taken from all patients to determine plasma levels of BNP, c-GMP, ET-1, and NA. Then patients received captopril and furosemide. Next blood samples were taken between 5 and 7 day of the treatment, after entire remission symptoms of decompensation. Plasma levels of BNP, c-GMP, ET-1, and NA were estimated with radioimmunoassay. Our study showed that plasma levels of ET-1, BNP, c-GMP, and NA were increased in patients with CHF. 5-7 days of the treatment with ACE inhibitor and diuretic caused significant decrease of ET-1, BNP, and c-GMP levels, but did not influence NA plasma levels. Determination of ET-1, BNP, c-GMP, and NA plasma levels may be a noninvasive method useful in estimation of degree of CHF and efficacy of the treatment.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Case-Control Studies; Cyclic GMP; Diuretics; Dose-Response Relationship, Drug; Endothelin-1; Female; Furosemide; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Radioimmunoassay; Time Factors

Recent studies showed higher plasma levels of several cytokines, such as interleukines or tumour necrosis factor in patients with congestive heart failure. Cytokines play a very important role in pathogenesis of congestive heart failure, because they impair contractility of heart muscle and cause damage of endothelium and myocytes due to their proinflammatory effects. One of the treatment modalities of heart failure might be administration of drugs inhibiting production of cytokines. The study was undertaken to evaluate whether beneficial effects of amlodipine in congestive heart failure are due to inhibition of synthesis of cytokines. The plasma levels of interleukine 6 (IL-6), tumour necrosis factor (TNF-alpha), neuropeptide Y (NPY) and endothelin-1 (ET-1) were determined in patients with congestive heart failure (NYHA II and III) before and after 30 days of treatment with amlodipine. 40 patients with congestive heart failure (CHF) treated in the Department of Cardiology of Medical University in Wrocław participated in this study. In all patients CHF developed in the course of ischaemic heart disease and coexisting hypertension. Patients were divided into 2 groups dependingly on the NYHA classification. The first group consisted of 24 patients in II NYHA class, the other one--of 16 patients in III NYHA class. At 8 am, on the second day after admission and before treatment with amlodipine blood samples were taken from examined patients to determine plasma levels of IL-6, TNF-alpha, NPY and ET-1. Then patients were administered amlodipine at the dose of 5-10 mg per day. The next blood samples were taken on 5th and 30th day of treatment. Plasma levels of TNF-alpha, IL-6, NPY and ET-1 were estimated with radioimmunoassay using Medgerix kits. Our findings showed that plasma levels of TNF-alpha, IL-6, NPY and ET-1 in patients with CHF are increased. 30-days treatment with amlodipine caused significant decrease of TNF-alpha and IL-6 levels, but did not influence the plasma levels of NPY and ET-1. Amlodipine causes improvement of circulatory efficiency assessed according to NYHA classification. Treatment with amlodipine may be an additional way of therapy in CHF.

Topics: Aged; Amlodipine; Calcium Channel Blockers; Endothelin-1; Female; Heart Failure; Humans; Interleukin-6; Male; Middle Aged; Neuropeptide Y; Tumor Necrosis Factor-alpha

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, and patients with chronic heart failure (CHF) are reported to have high plasma ET-1 levels. The aim of this study was to investigate the relation between plasma ET-1 levels and clinical correlates in patients with CHF. The effects of maximal exercise on plasma ET-1 levels were also investigated.. Plasma concentrations of ET-1, norepinephrine, and atrial and brain natriuretic peptide (ANP and BNP) both at rest and after maximal cardiopulmonary exercise test were determined in 100 patients with CHF (60 +/- 12 years, New York Heart Association [NYHA] class I-III, left ventricular ejection fraction [LVEF]=36 +/- 8%, peak oxygen uptake [VO2] = 18.2 +/- 5.0 mL/min/kg) and 27 controls.. Patients with NYHA class II and III CHF had higher ET-1 levels (controls, NYHA class I, II, III: 2.1 +/- 0.6, 2.1 +/- 1.0, 2.6 +/- 0.9, 3.4 +/- 0.8 pg/mL, analysis of variance P <.0001). Maximal exercise did not alter ET-1 levels in controls or in each CHF subgroup. When all CHF patients were analyzed together, cardiothoracic ratio (P<.01), peak VO2 (P<.001), plasma norepinephrine (P<.01), plasma ANP (P<.01), and plasma BNP (P<.001) were significantly related with resting ET-1 levels on univariate analysis. Multivariate analysis revealed peak VO2 and plasma BNP levels showed an independent and significant relationship with the resting plasma ET-1 levels.. Resting ET-1 levels were increased in symptomatic patients with CHF, and maximal exercise did not increase ET-1 levels. Peak VO2 and plasma BNP levels were independently associated with resting plasma ET-1 levels in patients with CHF.

Topics: Aged; Anaerobic Threshold; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Endothelin-1; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Norepinephrine; Severity of Illness Index; Statistics as Topic; Systole; Ventricular Dysfunction, Left

Peak oxygen consumption is a cornerstone for prognostic determination in patients with congestive heart failure. The purpose of this study was to assess whether plasma B-type natriuretic peptide (BNP) provided any additional prognostic information.. Plasma concentrations of atrial natriuretic peptide, N terminal pro-atrial natriuretic peptide, BNP, endothelin-1, norepinephrine, and peak VO2 were measured in 250 consecutive outpatients with mild to moderate heart failure (96% in New York Heart Association [NYHA] class II or III) and left ventricular ejection fraction (LVEF) <45%.. During a median follow-up of 584 days, 42 patients died (19 from sudden death) and 5 underwent urgent heart transplantation. Multivariate stepwise regression analysis showed that, among 13 variables including NYHA and LVEF, plasma BNP (chi2 = 11.9, P =.0001) was the strongest independent predictor of death or urgent transplantation, followed by serum sodium (chi2 = 8, P =.0046), resting heart rate (chi2 = 7.5, P =.0062), plasma endothelin-1 (chi2 = 7.2, P =.007), and peak VO2 (chi2 = 6.2, P =.012). Patients with plasma BNP above the upper quartile value (260 pg/mL) had a 1-year rate of death or urgent transplantation of 31%. The 1- and 2-year survival rates without urgent transplantation in patients with a peak VO2 < or =14 mL x kg(-1) x min(-1) were 71% and 59%, respectively, when plasma BNP was >137 pg/mL (median value), compared with 100% and 89%, respectively, when plasma BNP was < or =137 pg/mL (P =.008). Furthermore, plasma BNP was the only independent predictor of sudden death (chi2 = 19.9, P =.00001).. Plasma BNP provides additive independent prognostic information compared to peak VO2 alone in outpatients with mild to moderate heart failure.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Heart Failure; Heart Transplantation; Humans; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Oxygen Consumption; Prognosis; Protein Precursors; Regression Analysis; Risk; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

In ventricular myocardium, the T-type Ca2+ current (ICa,T), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated.. We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of ICa,T (measured in the freshly isolated LV myocytes) nor an increase in alpha-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased, ICa,T was recorded in most of the cells (-0.87+/-0.18 pA/pF at -30 mV, P<0.01 versus LVH). This was associated with a significant increase in the alpha-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of alpha-1G mRNA level and ICa,T from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced ICa,T in normal adult myocytes in culture from Sprague-Dawley rats.. ICa,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Bosentan; Calcium Channels, T-Type; Cells, Cultured; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Heart Ventricles; Male; Myocytes, Cardiac; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sulfonamides

We investigated the time course of the expression of cardiac and renal endothelin systems in tachycardia-induced heart failure in dogs. Eleven beagles underwent rapid pacing at a progressively increased rate over a period of 5 wk, with a weekly clinical examination, echocardiography, measurement of circulating and urinary endothelin-1 (ET-1), and myocardial and renal tissue biopsies. Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA. Cardiac and renal tissue ET-1 contents were evaluated by immunostaining and measured by radioimmunoassay at autopsy. Rapid pacing caused a progressive increase in end-systolic and end-diastolic ventricular volumes (P < 0.05) from week 2 together with a decrease in ejection fraction and in mean velocity of circumferential shortening (P < 0.05) from week 1. These changes were tightly correlated to myocardial ppET-1 and renal ETA receptor mRNA and less so to myocardial ECE-1 mRNA, and they occurred before any increase in plasma and urinary ET-1 (P < 0.05 from week 4) and clinical signs of heart failure. Renal ppET-1 did not change. Both cardiac and renal ET-1 peptide contents were increased at autopsy. We conclude that tachycardia-induced heart failure in dogs is characterized by an early activation of the cardiac and renal tissue endothelin systems, which occurs before any changes in circulating and urinary ET-1 and is closely related to altered ventricular function.

Topics: Animals; Aspartic Acid Endopeptidases; Biopsy; Blood Pressure; Dogs; Endothelin-1; Endothelin-Converting Enzymes; Gene Expression; Heart Failure; Heart Rate; Kidney; Male; Metalloendopeptidases; Myocardium; Pacemaker, Artificial; Receptor, Endothelin A; Receptor, Endothelin B; Respiration

Salivary endothelin (ET) concentrations have been shown to correlate with disease severity in patients with chronic heart failure (CHF). We undertook the present study to evaluate the stability of salivary ET under different handling conditions to assess its suitability as a biochemical marker in screening, diagnosis, and management of CHF.. Saliva samples were collected from healthy individuals and/or CHF patients, subjected to different handling conditions, and then stored at -80 degrees C until assayed by an ELISA for ET.. Salivary ET concentrations showed a time-dependent increase during storage at room temperature. After 72 h of incubation at room temperature, ET increased approximately 2.8-fold (P = 0.03). Simultaneously, salivary big ET showed a time-dependent 11.2-fold decrease (P <0.0001). This activity was blocked by an ET-converting enzyme (ECE) inhibitor, suggesting that these changes were attributable to ECE-dependent cleavage of endogenous big ET in saliva. Ex vivo conversion was also observed when samples were stored at 4 degrees C, but the magnitude of these changes was markedly smaller (P <0.0001). Posture also affected salivary ET concentrations in CHF patients. With a change from supine to seated rest, salivary ET concentrations increased 1.5- and 1.8-fold after 20 and 40 min, respectively (P = 0.01). With a return to supine rest, salivary ET concentrations returned to baseline concentrations (P = 0.008).. These data suggest that saliva sampling and handling conditions could markedly affect measurement of salivary ET. In particular, care should be taken to minimize ECE-dependent enzymatic conversion of endogenous big ET in saliva.

Topics: Adult; Aspartic Acid Endopeptidases; Biomarkers; Chronic Disease; Circadian Rhythm; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme-Linked Immunosorbent Assay; Heart Failure; Humans; Luminescent Measurements; Metalloendopeptidases; Middle Aged; Posture; Saliva; Specimen Handling; Temperature

The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ET(A) and ET(B)) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ET(B) endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Drímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ET(B)-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors. The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ET(B1/B2) selective BQ788 (in molar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ET(A)-selective PD155080 partially protected the rat heart on reperfusion.

Topics: Amino Acid Sequence; Animals; Coronary Circulation; Dioxoles; Endothelin-1; Endothelins; Heart; Heart Failure; Heart Rate; Humans; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligopeptides; Peptide Fragments; Perfusion; Piperidines; Rats; Rats, Wistar; Ventricular Function, Left; Ventricular Pressure

to compare the acute effect of ACEI and ARB's upon the plasmatic endothelin level in heart failure patients.. There were studied 30 patients with congestive heart failure, III-IV functional NYHA class, that were not under ACEI or ARB's treatment. In all the patients the endothelinl-21 plasmatic level was determined. After this, 20 patients, representing group I, received a single dose of 1 mg trandolapril, and 10 patients, representing group II, received a single dose of 40 mg telmisartan. After 24 hours, the plasmatic endothelin 1-21 level was determined again.. The mean endothelial plasmatic level was similar in both groups (group I: 0.358+/-0.04 fmol/ml; group II: 0.345+/-0.038). After 24 hours, the endothelin level decreased to 0.295+/-0.03 fmol/ml for group I (p<0.05) and to 0.287+/-0.029 fmol/ml for group II (p<0.05), suggesting that both ACEI and ARB's are equally efficient in decreasing endothelin. The initial endothelinl-21 level was inversely correlated with LVEF (r = -0.989), and the degree of the decrease of endothelinl-21 after both ACEI and ARB's is directly correlated with the initial endothelinl-21 level (r =0.64).. The acute administration of ACEI and ARB's in heart failure patients decreases the endothelin level, both categories of drugs having the same effects.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Endothelin-1; Endothelins; Heart Failure; Humans; Indoles; Middle Aged; Telmisartan

Endothelin-1 (ET-1) is considered to be involved in the development and progression of heart failure. Therefore, we analysed the expression of endothelin-converting enzyme-1 (ECE-1), endothelin receptors A (ET(A)) and B (ET(B)) mRNAs by standard-calibrated, competitive reverse transcriptase-PCR using an internal-deleted in vitro-transcribed cRNA standard. ET-1 peptide levels were measured using isoform-specific rabbit antibodies against synthetic ET-1. mRNA and protein expression was determined in the right atrial myocardium of New York Heart Association class I patients and class IV patients undergoing aorto-coronary bypass surgery. ECE-1 mRNA was upregulated in failing atrial myocardium. Furthermore, ET-1 peptide levels were increased in failing atrial myocardium. Atrial ET(A) mRNA expression was not changed, while ET(B) mRNA was downregulated in the failing atrial myocardium. Our results support an upregulation of ET-1 synthesis by induction of ECE-1 in failing atrial myocardium. Pharmacological inhibition of augmented ECE-1 expression might provide a new therapeutic perspective in the treatment of heart failure.

Topics: Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Activation; Gene Expression; Heart Atria; Heart Failure; Humans; Metalloendopeptidases; Myocardium; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n=5; 270 beats/min) compared with normal dogs (n=5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56+/-0.16 compared with 2.93+/-0.25 litres/min; P<0.01) and systemic vascular resistance had increased (4653+/-374 compared with 3227+/-396 dyn.s.cm(-5); P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95+/-0.83 compared with 2.12+/-0.39 pg/ml; P<0.05) and ADMA (3.27+/-0.49 compared with 1.91+/-0.25 nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r=0.72, P<0.05). Secondly, we chronically administered an ET(A) receptor antagonist, TA-0201 (0.3 mg/kg; n=5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58+/-0.24 litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36+/-0.30 nmol/ml and 2423+/-188 dyn.s.cm(-5) respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ET(A) receptor antagonist can prevent the inhibition of NO production and the increased peripheral

Topics: Animals; Arginine; Cardiac Output; Cardiac Pacing, Artificial; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Heart Failure; Models, Animal; Nitric Oxide Synthase; Pyrimidines; Random Allocation; Receptor, Endothelin A; Sulfonamides; Vascular Resistance

The present study examined the effects of two highly selective endothelin-1 (ET-1) receptor antagonists, ABT-627 (ET(A) blocker) and A-192621 (ET(B) blocker), on the systemic and renal haemodynamic effects of ET-1 in normal rats and in rats with experimental congestive heart failure (CHF) produced by aortocaval fistula. Intravenous injection of ET-1 (1.0 nmol x kg(-1) of body weight) to anaesthetized normal rats produced sustained decreases in renal blood flow (RBF) (assessed by ultrasonic flowmetry) and glomerular filtration rate (GFR), and significant increases in renal vascular resistance (RVR) and mean arterial pressure (MAP). Pretreatment with ABT-627 (1 mg x h(-1) x kg(-1) of body weight) abolished the pressor response to ET-1 without affecting the depressor phase, and significantly impaired the renal vasoconstriction. The systemic and renal vasoconstrictive effects of ET-1 in normal rats were significantly augmented by pretreatment with 3.0 mg x h(-1) x kg(-1) of A-192621. Baseline RBF and GFR in rats with CHF were reduced significantly compared with control rats, whereas RVR was elevated. The hypertensive effect of ET-1 was attenuated in rats with CHF. In the presence of ET(A) blockade, the pressor response to ET-1 was completely abolished in CHF rats. Furthermore, pretreatment with ABT-627 enhanced the recovery from ET-1- dependent vasoconstriction and remarkably reversed the ET-1-induced hypofiltration. Blockade of ET(B) receptors in rats with CHF further exposed the exaggerated ET-1-induced renal vasoconstriction. Our data demonstrate that experimental CHF is associated with altered responsiveness to ET(A)- and ET(B)-mediated systemic and renal effects of ET-1. Furthermore, in CHF, as in control rats, the ET(B)-mediated vasodilatory response may serve as an important compensatory counterbalance to the adverse ET(A)-mediated effects.

Topics: Animals; Atrasentan; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Heart Failure; Kidney; Male; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Renal Circulation; Vascular Resistance

Endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) play important roles in the regulation of body fluid balance in congestive heart failure (CHF). Renal production of ET-1 increases in CHF and it is a significant independent predictor of sodium excretion. ANP inhibits the ET system through cGMP, a second messenger of ANP. However, in severe CHF, plasma cGMP levels reached a plateau despite the activation of ANP secretion. Thus, ANP does not seem to sufficiently oppose exaggerated ET-1 actions in severe CHF, partially due to the accelerated degradation of cGMP, through phosphodiesterase type 5 (PDE5). We examined the chronic effects of a PDE5 inhibitor, T-1032 (1 mg/kg per day, n=5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270 beats/min). Vehicle dogs were given a placebo (n=5) and normal dogs (n=5) served as normal controls without pacing. In this experimentally produced CHF, plasma levels of ET-1, ANP and cGMP were elevated and renal production of cGMP was increased compared with the normal group, associated with increases in renal expression of preproET-1 mRNA and the number of ET-1-positive cells in glomeruli. In the T-1032 group, systemic and renal production of cGMP were further increased compared with the vehicle group despite no significant difference in plasma ANP levels between the two groups. Subsequently, the agent significantly improved urine flow rate, sodium excretion rate and glomerular filtration rate (GFR) associated with reductions in renal expression of preproET-1 mRNA and the number of ET-1-positive cells compared with the vehicle group. Moreover, there was a significant negative correlation between the number of ET-1-positive cells and GFR (r=-0.802 and P<0.001 respectively). Our results indicate that chronic PDE5 inhibition ameliorates the antagonistic relationship between renal ANP and ET-1 through the cGMP pathway, subsequently preventing renal dysfunction during the progression of CHF.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Depression, Chemical; Dogs; Endothelin-1; Endothelins; Glomerular Filtration Rate; Heart Failure; Isoquinolines; Kidney; Models, Animal; Phosphodiesterase Inhibitors; Protein Precursors; Pyridines; RNA, Messenger; Sodium; Urine

PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.

Topics: Adult; Angiotensin II; Aorta; Atrial Natriuretic Factor; Coronary Vessels; Diastole; Echocardiography; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Myocardium; Natriuretic Peptide, Brain; Norepinephrine; Parathyroid Hormone-Related Protein; Peptide Fragments; Protein Biosynthesis; Proteins; Stroke Volume; Systole; Ventricular Function, Left

We investigated the short-term effects of a phosphodiesterase III inhibitor (Olprinone) on hemodynamics and thoracic duct lymph flow in anesthetized open-chest sheep with heart failure induced by endothelin-1 (cardiogenic shock). Ultrasound transit-time flow probes were attached to the thoracic duct, the ascending aorta and the renal artery. Arterial, pulmonary and central venous pressures were monitored. Endothelin-1 was infused intravenously at a dosage that reduced cardiac output to 50% or more of baseline (n=11). The effects of Olprinone were examined (n=5) by intravenous infusion after endothelin-1 administration. Other sheep (n=6) were used as controls. Olprinone significantly increased cardiac output that had been decreased by endothelin-1 and further increased thoracic duct flow that had been increased by endothelin-1. Increased arterial and pulmonary pressures induced by endothelin-1 administration were rapidly decreased by Olprinone. Renal arterial flow and central venous pressure were, however, unchanged by Olprinone. Overall, Olprinone acutely improved experimental cardiogenic shock (heart failure) induced by endothelin-1, and maintained thoracic duct lymph flow at a high level after endothelin-1 administration.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiac Output; Central Venous Pressure; Cyclic Nucleotide Phosphodiesterases, Type 3; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Female; Heart Failure; Imidazoles; Lung; Male; Models, Cardiovascular; Pyridones; Renal Circulation; Sheep; Shock, Cardiogenic; Thoracic Duct; Time Factors; Treatment Outcome; Vascular Resistance

In a group of 124 patients the authors investigated the importance of assessment of plasma levels of big endothelin and endothelin 1 in patients with chronic heart failure as compared with other currently used non-invasive parameters. A six fold increase of plasma levels of both substances was found in patients in functional class NYHA IV as compared with patients in class NYHA II-III. But even patients in the milder stage of NYHA had twice as high values as compared with the standard of the healthy population. Similarly patients with interstitial pulmonary oedema had a twice as high level of both parameters as compared with patients who had a normal finding on X-ray or merely a redistribution of the pulmonary vascularization. The sensitivity of assessment of plasma levels is such that this examination could become part of the basic diagnosis.

Topics: Biomarkers; Endothelin-1; Endothelins; Female; Heart Failure; Humans; Male; Middle Aged; Protein Precursors; Pulmonary Edema; Sensitivity and Specificity

Topics: Adult; Aged; Angiotensin II; Endothelin-1; Female; Gene Expression Regulation; Heart Failure; Humans; Male; Middle Aged; Monocytes; Norepinephrine; Thromboplastin

Topics: Atrial Natriuretic Factor; Biomarkers; Coronary Artery Disease; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Neurotransmitter Agents; Rest; Supine Position

In fewer than than 15 years since its discovery, endothelin is now recognized as playing a central role in the pathogenesis of chronic heart failure. This review examines the signaling pathways and mechanism of action of endothelin in relation to the studies that have elucidated this role. Early investigations observed that the endothelin system is markedly upregulated in heart failure, whereas others demonstrated that endothelin is the most potent vasoconstrictor. However, it has multiple other actions, including mediating pathologic hypertrophy and fibrosis of both ventricular and vascular tissues, acting as a proarrhythmic, and potentiating the effects of other neurohormones. Endothelin receptor antagonists were developed to investigate the hypothesis that these adverse effects could be prevented and experimental studies showed promise in this regard. Clinical studies to date have not fulfilled this promise. Further analysis of these trials will hopefully provide insight into these disparate findings and guidance for future investigations.

Topics: Animals; Clinical Trials as Topic; Endothelin-1; Heart Failure; Humans; Models, Animal; Receptors, Endothelin; Vasoconstriction

Given the high incidence of sudden death in patients with chronic heart failure (CHF) and the efficacy of implantable cardioverter-defibrillators, an appropriate tool for the prediction of sudden death is desirable. B-type natriuretic peptide (BNP) has prognostic significance in CHF, and the stimuli for its production cause electrophysiological abnormalities. This study tests BNP levels as a predictor of sudden death.. BNP levels, in addition to other neurohormonal, clinical, and hemodynamic variables, were obtained from 452 patients with a left ventricular ejection fraction (LVEF) < or =35%. For prediction of sudden death, only survivors without heart transplantation (HTx) or a mechanical assist device and patients who died suddenly were analyzed. Up to 3 years, 293 patients survived without HTx or a mechanical assist device, 89 patients died, and 65 patients underwent HTx. Mode of death was sudden in 44 patients (49%), whereas 31 patients (35%) had pump failure and 14 patients (16%) died from other causes. Univariate risk factors of sudden death were log BNP (P=0.0006), log N-terminal atrial natriuretic peptide (P=0.003), LVEF (P=0.005), log N-terminal BNP (P=0.006), systolic blood pressure (P=0.01), big endothelin (P=0.03), and NYHA class (P=0.04). In the multivariate model, log BNP level was the only independent predictor of sudden death (P=0.0006). Using a cutoff point of log BNP <2.11 (130 pg/mL), Kaplan-Meier sudden death-free survival rates were significantly higher in patients below (99%) compared with patients above (81%) this cutoff point (P=0.0001).. BNP levels are a strong, independent predictor of sudden death in patients with CHF.

Topics: Adrenergic beta-Antagonists; Alprostadil; Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cardiotonic Agents; Chronic Disease; Comorbidity; Death, Sudden, Cardiac; Endothelin-1; Endothelins; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Factors; Stroke Volume; Survival Analysis; Treatment Outcome

To compare the precursor of atrial and brain natriuretic peptide (N-ANP, N-BNP), brain natriuretic peptide (BNP), big endothelin-1, the 6-min walk test and the Minnesota Living with Heart Failure Questionnaire (LHFQ) with regard to short-term outcome in an ambulatory heart failure population.. Ninety-six individuals (left ventricular ejection fraction of 26+/-10%) were included in the study. Within 1 day blood samples of N-ANP, N-BNP, BNP and big endothelin-1 were obtained, and the 6-min walk test and LHFQ were measured. The predictive power of these variables - including renin-angiotensin system antagonist therapy - in respect of 1-year event-free survival were calculated with a Cox regression analysis. All investigated variables had the power to predict outcome in a univariate analysis. Multivariate analysis revealed that N-ANP (chi-square=58 P<0.0001), BNP (chi-square=8 P<0.01), the LHFQ (chi-square=6 P<0.02) and the renin-angiotensin system antagonist (chi-square=4 P<0.05), are independent predictors.. We conclude that, in an open clinical cohort of patients with large differences in the progression of the disease, N-ANP, BNP and LHFQ are the most reliable predictors of worsening heart failure in the short term. However, the dosage of the ACE inhibitor influenced short-term survival in this population.

Topics: Activities of Daily Living; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Cohort Studies; Endothelin-1; Endothelins; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Protein Precursors; Surveys and Questionnaires; Walking

Intervention with selective endothelin (ET)A receptor antagonists within 24h after myocardial infarction (MI) in rats has been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ET(A)/ET(B) receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention with a mixed ET(A)/ET(B) receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg x kg(-1) SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48h after MI. Treatment with SB 209670 adversely affected the postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4+/-0.5 vs 9.1+/-0.2 mm; LV end-systolic diameter: 8.5+/-0.4 vs 7.2+/-0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention with a potent, mixed ET(A)/ET(B) receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical and that potent ET receptor antagonists may be harmful during the first few days after MI.

Topics: Animals; Cardiomegaly; Collagen; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Extracellular Matrix; Fibrosis; Gene Expression; Heart; Heart Failure; Hemodynamics; Indans; Male; Myocardial Infarction; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Ventricular Function, Left; Ventricular Remodeling

We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI).. Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI.. Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition.. Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Collagen; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Heart Failure; Heart Ventricles; Hemodynamics; Indoles; Male; Matrix Metalloproteinase 2; Models, Animal; Myosin Heavy Chains; Norepinephrine; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Renin; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta

Elevated plasma endothelin-1 (ET-1) levels have been reported in association with hypoxia and congestive heart failure (CHF). Furthermore, Cheyne-Stokes respiration-central sleep apnea (CSR-CSA) has been found to correlate with the degree of pulmonary hypertension and the severity of CHF; however, the association between ET-1 levels and CSR-CSA has not been investigated previously.. Veterans Affairs Medical Center.. We studied 46 consecutive patients with CHF (left ventricular function < or = 40%) who underwent right-heart catheterization and overnight polysomnography. Thirty-nine patients completed the study. Sixteen patients (41%) had CSR-CSA, 5 patients (13%) had obstructive apnea, and 18 patients (46%) had no sleep-disordered breathing. Circulating plasma ET-1 levels were assayed in patients with CSR-CSA and in patients with no sleep-disordered breathing using commercially available enzyme-linked immunosorbent assay kits.. ET-1 levels were significantly elevated in patients with CSR-CSA (mean +/- SD, 5.4 +/- 1.3 pg/mL) compared to those without central apnea (3.9 +/- 1.1 pg/mL; p < 0.01), and correlated with mean pulmonary artery pressure (r = 0.66, p < 0.01), pulmonary capillary wedge pressure (r = 0.56, p < 0.03), and central apnea frequency (r = 0.66, p < 0.01). In multivariate analysis, the severity of CSR-CSA was the only variable independently associated with plasma ET-1.. We conclude that elevated plasma ET-1 levels are linked to the severity of CSR-CSA. Whether ET-1 represents an important pathogenic factor in CSR-CSA or marker of its occurrence requires further evaluation.

Topics: Aged; Cheyne-Stokes Respiration; Endothelin-1; Heart Failure; Hemodynamics; Humans; Male; Sleep Apnea, Central

Heart failure (HF) is characterized by activation of both neurohumoral and sympathetic nervous systems. Specifically, HF is associated with increases in vasopressin (VP) and endothelin (ET) and in arterial baroreflex dysfunction. Hypothesis was that central ET-1 potentiates VP secretion in HF due to impaired pressor response and diminished arterial baroreflex inhibition. Male Sprague-Dawley rats were studied 42 to 54 days after sham or coronary ligation (HF) and 7 days after sinoaortic denervation (SAD). Conscious rats received intracerebroventricular artificial cerebrospinal fluid (CSF), 10 pmol of ET-1, 40 nmol BQ123, or both. Basal mean arterial pressure (MAP) did not differ, but heart rate and left ventricular end-diastolic pressure were significantly higher in HF and HF/SAD. Baseline VP was higher in both HF and HF/SAD: 5.9 +/- 0.4 pg/ml and 5.6 +/- 0.7 pg/ml versus sham 2.8 +/- 0.2 and sham-SAD 1.6 +/- 0.2 (p < 0.001). ET-1 increased MAP in sham rats by 16.0 +/- 1.4 mm Hg, but only by 7.4 +/- 2.2 mm Hg in HF (p < 0.05 versus sham) and 5.8 +/- 2.4 mm Hg in HF/SAD (p < 0.01 versus sham SAD). Tachycardic response was attenuated in HF/SAD compared with HF alone. After ET-1, VP increased by 3.3 +/- 2.7 pg/ml in sham and 13.3 +/- 2.6 pg/ml in HF (p < 0.05), but only by 2.3 +/- 0.7 pg/ml in HF/SAD (p < 0.01 versus HF). BQ123 blocked all responses to exogenous ET-1 but had no effect on baseline values. Thus, ET-evoked a lower pressor response in HF due to an impaired ability to increase heart rate and cardiac output. ET-1-induced VP release in HF was higher than in controls as a result of lower pressor response or impaired arterial baroreflex. In contrast to rats with normal left ventricular function, sinoaortic denervation in HF failed to potentiate either pressor response or VP secretion. These findings suggest that acute, though modest, increases in afterload may increase left atrial pressure more in HF/SAD such that cardiopulmonary reflexes may be activated or natriuretic peptides may be released that further restrain both pressor and VP responses.

Topics: Animals; Endothelin-1; Heart Failure; Male; Pressoreceptors; Rats; Rats, Sprague-Dawley; Vasopressins

The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.. DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.. The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Catecholamines; Collagen; Diastole; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Endothelin-1; Gene Expression; Heart Failure; Heart Function Tests; Hydroxyproline; Myocardium; Myosin Heavy Chains; Organ Size; Rats; Rats, Inbred Dahl; Receptors, Angiotensin; RNA, Messenger; Sodium Chloride, Dietary; Survival Rate; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

Endothelin-1 (ET-1), plays an important role in the pathophysiology of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure.. We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung, the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P<0.001). Run-on assay demonstrated that ET-1 overexpression is regulated at a transcriptional level (P<0.01). In contrast, there was no change in ET-1 mRNA expression in aortae, left ventricular myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ET(B) receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ET(A) receptor mRNA did not differ between groups. The lung and plasma ET-1 peptide levels were respectively 4.2 and 9 fold higher in the rats with decompensated HF than in control rats (P<0.05; P<0.0001). Organoculture experiments showed that the lung ET-1 peptide secretion level in rats with decompensated HF was higher than that in control rats (P<0.01). In contrast, there was no change in ET-1 peptide secretion by the left ventricular myocardium and skeletal muscle. In plasma of rats with decompensated HF, the rate of bigET-1 conversion to ET-1 was 22%. ET-1 peptide was also present in the pleural effusion of decompensated heart failure. Plasma ET-1 concentration was significantly correlated with upstream markers of left ventricular diastolic dysfunction, with the expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 concentration and with the expression ratio of ET-1/ET(B) receptor mRNA.. Taken together, these data suggest that overexpression of ET-1 and down-regulation of ET(B) receptors in the lung are determinants of circulating endothelin in CHF. As a corollary, increased plasma endothelin may provide evidence of pulmonary endothelial dysfunction in CHF.

Topics: Analysis of Variance; Animals; Aorta; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Gene Expression; Heart Failure; Heart Ventricles; Lung; Male; Metalloendopeptidases; Muscle, Skeletal; Organ Culture Techniques; Pleural Effusion; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger

The diastolic dysfunction present at rest in congestive heart failure (CHF) is exacerbated during exercise (Ex). Increases in circulating ANG II and endothelin-1 (ET-1) during Ex may contribute to this response. We assessed the effect of Ex on circulating plasma levels of ANG II and ET-1 and left ventricular (LV) dynamics before and after pacing-induced CHF at rest and during Ex in nine conscious, instrumented dogs. Before CHF, there were modest increases in circulating levels of ANG II (but not ET-1) during Ex. LV diastolic performance was enhanced during Ex with decreases in the time constant of LV relaxation (tau), LV end-systolic volume (V(ES)), and LV minimum pressure with a downward shift of the LV early diastolic portion of the pressure-volume (P-V) loop. This produced an increase in peak LV filling rate without an increase in mean left atrial (LA) pressure. After CHF, the resting values of ANG II and ET-1 were elevated and increased to very high levels during Ex. After CHF, mean LA pressure, tau, and LV minimum pressure were elevated at rest and increased further during Ex. Treatment with L-754,142, a potent ET-1 antagonist, or losartan, an ANG II AT(1)-receptor blocker, decreased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.

Topics: Acetamides; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Atrial Function, Left; Diastole; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Losartan; Nitroprusside; Physical Exertion; Reference Values; Vasodilation; Ventricular Function, Left

Although reduced pulmonary clearance of endothelin-1 (ET-1) has been suggested to contribute to increased circulating levels in congestive heart failure (CHF), the regulation of the pulmonary ET system with CHF remains to be defined. Accordingly, the aim of the present study is to investigate the expression and activity of the ET system with the development of CHF.. Pulmonary tissue samples were collected from pigs with pacing CHF (240 bpm, 3 wks, n = 10) and controls (n = 10). The pulmonary messenger RNA (mRNA) and protein levels of endothelin converting enzyme-1 (ECE-1) subisoforms, ET-1, and ET receptor profiles were determined. The gene expression of ET-1 precursor, ECE-1a, and ET(A) was upregulated 4-, 3-, and 2-fold, respectively, with CHF. Pulmonary tissue ET-1 was increased to 13 +/- 2 fmol/mg protein from control values of 5 +/- 1 fmol/mg protein (P <.05), and ECE-1 activity was augmented from 3,264 +/- 665 fmol/mg protein in control animals to 14,073 +/- 654 fmol/mg protein per hour in CHF animals (P <.05). The ET(B) receptor density decreased, whereas ET(A) receptors were increased in CHF, indicating a shift in the ET(A) to ET(B) ratio.. Both the increased synthesis and the decreased clearance of ET-1 via ET(B) receptors may contribute to the increased systemic and pulmonary ET-1 levels in CHF.

Topics: Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Heart Failure; Lung; Metalloendopeptidases; Models, Animal; Polymerase Chain Reaction; Receptors, Endothelin; RNA, Messenger; Swine

Studies of congestive heart failure (CHF) in man and in experimental CHF have demonstrated elevated circulating levels of endothelin (ET). In order to examine whether there are concomitant ET receptor alterations, the vasomotor effects of endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were examined in endothelium-intact and -denuded isolated mesenteric arteries from rats with CHF. CHF was induced by ligation of the left anterior descending coronary artery. Vasomotor responses were studied using small mesenteric arteries (approx. 250 microm in diameter, determined after normalisation). The antagonists IRL2500 and FR139317 were used in order to characterise the ET-1-induced response. In mesenteric arteries with intact endothelium, ET-1-induced contractions were more potent in CHF as compared to sham (pEC(50) 9.6+/-0.2 and 9.1+/-0.1, respectively, P<0.01). In endothelium-denuded arteries, there was no difference in potency of ET-1 between CHF and sham arteries, or in maximum contraction. In the presence of IRL2500, a selective ET(B)-receptor antagonist, ET-1 was more potent in endothelium-denuded arteries of CHF rats, while this difference was not seen in sham arteries. S6c had no consistent contractile or dilatory effect in CHF and sham rats. The results indicate that the enhanced contractile effects of ET-1 noted in CHF might be due to an attenuated endothelial function and that inhibition of smooth muscle cell ET(B) receptors increase the effects of contractile ET(A) receptors in CHF rats.

Topics: Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Male; Mesenteric Arteries; Myocardial Contraction; Myocardial Infarction; Potassium; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstrictor Agents; Viper Venoms

Endothelin (ET)-1 is a potent vasoconstrictor peptide produced in the myocardium that can exert important effects on cardiac myocyte growth and phenotype; cardiac natriuretic peptides (ANP and BNP) are known to act as physiological antagonists of ET-1. In this study a comparative determination of ET-1 receptors and of the local productions of ET-1 and of ANP and BNP was made in different sites of failing and nonfailing hearts. Tissue from right and left atrium, right and left ventricle and interventricular septum from seven adult heart transplant recipients with end-stage idiopathic dilated cardiomyopathy (functional class III and IV, with ejection fraction < 35%) and from four postmortem subjects without cardiac complications was analyzed. In failing hearts we observed a tendency to increase of density of binding sites, most evident in left ventricle (62.6+/-22.6 fmol/mg protein vs. 29.0+/-3.3, mean +/- SEM, p = ns). A prevalence of ET-A subclass, observed in all samples, resulted more pronounced in failing hearts where this increase, found in all the cardiac regions, was more evident in left ventricle (p = 0.0007 vs nonfailing hearts). The local concentrations of ET-1, ANP and BNP resulted significantly increased in failing hearts with respect to controls in all sides of the heart. In failing hearts we have observed a tendency to increase in endothelin receptor density mainly due to a significant upregulation of ET-A subtype and a parallel increase of the tissue levels of ANP, BNP and ET-1 indicating an activation of these systems in heart failure.

Topics: Adult; Atrial Natriuretic Factor; Endothelin-1; Female; Heart Failure; Humans; Male; Myocardium; Natriuretic Peptide, Brain; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

Topics: Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Receptors, Endothelin

In this study we compared the transcardiac gradient of plasma endothelin-1 in patients with normal ventricular function and in those with congestive heart failure. We documented a significant reduction in the plasma levels of endothelin-1 across the failing human heart, an effect not seen in patients with normal left ventricular function.

Topics: Case-Control Studies; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Myocardium; Ventricular Function, Left

This study was designed to analyze the pathophysiological role of the endogenous endothelin (ET) system and the therapeutic approach to congestive heart failure (CHF) with ET(A)/ET(B) receptor antagonists in a canine CHF model. After 3 weeks of rapid right ventricular pacing (240 beats/min), concentrations of immunoreactive ET-1 in dogs increased approximately 2-fold in plasma and in the left and right ventricles but not in the lung. There were no meaningful changes in the density and affinity of total ET receptors, or in the ratio of ET(A) to ET(B) receptors. To clarify the functional role of endogenous ET, we examined the effects of acute injection of J-104132 (1 and 3 mg/kg i.v.), an ET(A)/ET(B) receptor antagonist, on cardiovascular and renal function in dogs with CHF. Compared with vehicle, J-104132 at both doses significantly decreased pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP), and increased cardiac output (CO) and renal blood flow. J-104132 had no effects on heart rate and cardiac contractility. In addition, we examined whether J-104132 has an additive effect in the presence of enalaprilat. J-104132 (1 mg/kg i.v.) administered after enalaprilat (0.05 mg/kg i.v.) induced further decreases in MAP, PCWP and PAP, and further increases in CO, resulting in further decreases in total peripheral resistance. These results indicate that the endogenous ET system is exaggerated in CHF and has a detrimental effect on cardiac function. Therefore, J-104132 given alone or as combination therapy may play a beneficial role in the treatment of CHF in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Pacing, Artificial; Chronic Disease; Dogs; Echocardiography; Enalaprilat; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Pyridines; Receptors, Endothelin; Tissue Distribution; Ventricular Function

Increased secretion of atrial and brain natriuretic peptide (ANP and BNP) from hearts is known to exhibit favorable effects in patients and animals with heart failure, and inhibition of neutral endopeptidase (NEP), an enzyme that degrades ANP and BNP, may further increase these peptide levels. However, it is still unknown whether such elevation of the ANP and BNP may offer a therapeutic benefit to the progression of chronic heart failure (CHF). We examined the effects of ONO-9902, a novel NEP inhibitor, on changes in hemodynamic parameters, NEP activity and neurohumoral factors in rats with CHF induced by left coronary artery ligation (CAL).. Male Wistar rats (220-240 g) were subjected to induction of acute myocardial infarction by CAL. Rats were orally treated with ONO-9902 (300 mg/kg/day) from the 1st to 6th week after the operation. Hemodynamic and/or biochemical assessments were performed at the 1st and 6th weeks after the operation.. A single administration of ONO-9902 inhibited the plasma and kidney NEP activities and thereby further augmented the elevation of plasma ANP concentration in rats with CAL at the 1st week after the operation. In rats with CAL at the 6th week after the operation, the left ventricular end-diastolic pressure (LVEDP) increased and cardiac output index (COI) decreased as compared with those of sham-operated rats. These changes were accompanied by marked increases in the plasma ANP, BNP and endothelin-1 (ET-1). Chronic treatment with ONO-9902 attenuated the increase in LVEDP and the decrease in COI. These changes were associated with a decrease in plasma ANP, BNP and ET-1 concentrations.. The results suggest that chronic treatment with NEP inhibitor improves depressed cardiac function in rats with CHF. ONO-9902 may offer a new and possible therapeutic approach in patients with CHF.

Topics: Analgesics, Non-Narcotic; Animals; Atrial Natriuretic Factor; Drug Administration Schedule; Endothelin-1; Enkephalins; Enzyme Inhibitors; Heart Failure; Heart Ventricles; Hemodynamics; Male; Natriuretic Peptide, Brain; Neprilysin; Rats; Rats, Wistar

In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental.. In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6- and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3- and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal's survival without additional decreases in systolic pressure.. The pathophysiological roles in the myocardium during the transition to CHF differ qualitatively between Ang II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Disease Progression; Endothelin-1; Endothelins; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hemodynamics; Hypertrophy, Left Ventricular; Male; Organ Size; Peptidyl-Dipeptidase A; Protein Precursors; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Survival Analysis; Thiazepines; Time Factors

Interactions between angiotensin (ANG) II and endothelin (ET)-1 receptor transduction pathways have been unclear in congestive heart failure (CHF). Therefore the objects of this study are, in CHF, whether production of ET-1 is modulated by ANG II and/or whether hemodynamic effects of endogenous ET-1 are modulated by ANG II. Twelve dogs were randomly assigned to two groups: untreated (n = 6) and treated with ANG II type 1 (AT1) receptor antagonist (TCV116, 1.5 mg/kg/d) (n = 6). After rapid ventricular pacing (240 bpm) for 4 weeks, plasma and cardiac ET-1 levels were compared between the two groups. Acute hemodynamic effects of a nonspecific ET(A&B) receptor antagonist, TAK044 (3 mg/kg plus 3 mg/kg/h i.v.) were examined in both groups by a conductance catheter and a micromanometer. After 4 weeks of pacing, plasma and cardiac tissue ET-1 levels were elevated in both groups to a similar degree. In the group treated with TCV116, TAK044 produced an increase in stroke volume and a decrease in total systemic resistance; heart rate was unchanged. The time constant of left ventricular (LV) relaxation was significantly decreased. The slope of LV end-systolic pressure-volume relation (E(ES)) was increased (p < 0.05), indicating an increased LV contractility. Thus endogenous ET-1 produces an arterial vasoconstriction and impairs LV contractility and relaxation in CHF with AT1 receptor antagonism. These hemodynamic responses to TAK044 in CHF treated with TCV116 were similar in untreated CHF. These results suggest that the production of ET-1 and the cardiac effects of endogenous ET-1 in CHF may be unaffected by ANG II acting through AT1 receptors.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Endothelin-1; Heart Failure; Hemodynamics; Male; Random Allocation; Receptors, Angiotensin; Tetrazoles; Ventricular Function, Left

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.

Topics: Adrenomedullin; Antihypertensive Agents; Arteries; Chronic Disease; Dose-Response Relationship, Drug; Endothelin-1; Female; Heart Failure; Humans; In Vitro Techniques; Male; Peptides; Protease Inhibitors; Thiorphan; Vascular Resistance; Vasoconstriction

Human congestive heart failure is characterized by complex neurohumoral activation associated with the up-regulation of vasoconstricting and salt-retaining mediators and the compensatory rise of counter-regulatory hormones. In the present study, we provide the first evidence that relaxin (RLX), known as a pregnancy hormone, represents a potential compensatory mediator in human heart failure: plasma concentrations of RLX and myocardial expression of the two RLX genes (H1 and H2) correlate with the severity of disease and RLX responds to therapy. The failing human heart is a relevant source of circulating RLX peptides, and myocytes as well as interstitial cells produce RLX. Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure. Furthermore, RLX modulates effects of angiotensin II, another crucial mediator. Our data identify RLX as a new player in human heart failure with potential diagnostic and therapeutic relevance.

Topics: Animals; Aspartic Acid Endopeptidases; Cattle; Cells, Cultured; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Immunohistochemistry; Male; Middle Aged; Myocardium; Organ Culture Techniques; Proprotein Convertases; Protein Precursors; Rats; Rats, Wistar; Relaxin; RNA, Messenger; Up-Regulation; Ventricular Pressure

Topics: Acute Disease; Antihypertensive Agents; Bosentan; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Exercise Tolerance; Heart Failure; Hemodynamics; Humans; Phenylpropionates; Pyridines; Pyrimidines; Sulfonamides; Tetrazoles; Treatment Outcome; Vasodilator Agents

Topics: Amlodipine; Antihypertensive Agents; Atenolol; Atrial Natriuretic Factor; Bendroflumethiazide; Cardiomegaly; Endothelin-1; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Perindopril; Procollagen; Randomized Controlled Trials as Topic

To evaluate the effects of endothelin (ET)-converting enzyme (ECE) inhibitor on vascular remodeling in dogs with congestive heart failure (CHF), we chronically administered an ECE inhibitor, FR901533 (FR, iv. 0.3mg/kg/hr, n=6), to dogs with CHF induced by rapid ventricular pacing. Vehicle CHF dogs were given saline (n=7). In the vehicle CHF group after 3 weeks of pacing, the ET system was activated in the plasma and vasculature (3 and 5 times higher than normal, respectively). Inward remodeling occurred in the femoral artery; medial thickness (MT, 225+/-5 vs 193+/-4 microm, P<0.05) and deposition of collagen (DC, 22+/-2 vs 17+/-1%, P<0.01) significantly increased, while lumen diameter (LD, 1173+/-39 vs 1481+/-44 microm, P<0.05) decreased in the femoral artery with CHF compared with the normal femoral artery. There were significant correlations between the number of ET-1 positive cells and MT, DC, LD and systemic vascular resistance. FR significantly suppressed the changes in these vascular parameters compared with the changes in the vehicle CHF group despite the lack of an effect on blood pressure, and moreover FR caused decreases in ET-1 levels in both the plasma and femoral artery (reduced to 43% and 54%, respectively, of the levels in the vehicle CHF group, P<0.05). In conclusion, ET-1 plays a critical role in the structural deterioration of the vasculature during the progression of CHF, and ECE inhibitors can prevent the development of vascular remodeling.

Topics: Animals; Aspartic Acid Endopeptidases; Dogs; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Enzyme Inhibitors; Female; Heart Failure; Hemodynamics; Immunohistochemistry; Male; Metalloendopeptidases; Tetracyclines

To evaluate the effect of age and body weight on several neurohumoral variables that are commonly altered in heart failure in Cavalier King Charles Spaniels.. 17 healthy privately owned Cavalier King Charles Spaniels, 10 males and 7 females, ranging in age from 0.4 to 9.7 years, and ranging in body weight from 6.6 to 12.2 kg.. The clinical condition of the dogs was evaluated by physical examination, thoracic radiography, and echocardiography. Plasma nitrate and nitrite (P-NN), N-terminal atrial natriuretic and brain natriuretic peptides (NT-ANP and BNP, respectively), endothelin (ET-1), urine cyclic guanosine monophosphate (U-cGMP), and urine nitrate and nitrite (U-NN) concentrations were analyzed.. Plasma concentrations of NT-ANP and P-NN increased significantly with age, but plasma NT-ANP and P-NN also correlated significantly, irrespective of age. A modest increase of left atrial size did not explain the increase of NT-ANP and P-NN with age. Concentration of ET-1 correlated positively with heart rate; heart rate did not change with age. Weight had a negative impact on NT-ANP, P-NN, and U-cGMP concentrations and left atrial relative size.. Age-matched controls are essential for evaluation of NT-ANP and P-NN concentrations and left atrial size. Weight may alter reference values of plasma NT-ANP, P-NN, and urine cGMP concentrations. Natriuretic peptides can be used as further evidence that heart failure exists. The increased plasma concentrations of NT-ANP (but not BNP) and P-NN with aging reflect neurohumoral physiologic changes that must be distinguished from pathologic changes in patients with heart failure.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Body Weight; Cardiac Output; Creatinine; Cyclic GMP; Dogs; Echocardiography; Electrocardiography; Endothelin-1; Female; Heart Failure; Heart Rate; Male; Natriuretic Peptide, Brain; Neurotransmitter Agents; Nitrites; Radiography, Thoracic; Regression Analysis

Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Binding, Competitive; Body Weight; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Isoquinolines; Kinetics; Male; Muscles; Myocardial Contraction; Myocardial Infarction; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oligopeptides; Organ Culture Techniques; Organ Size; Papillary Muscles; Peptides, Cyclic; Piperidines; Protein Binding; Quinapril; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrahydroisoquinolines; Time Factors; Vasoconstrictor Agents; Viper Venoms

A range of neurohumoral substances have been suggested as diagnostic markers in heart failure. It is, however, undetermined which marker has the greatest diagnostic potential, and whether additional information is gained by a comprehensive neurohumoral evaluation.. The purpose of the study was to compare the value of epinephrine, norepinephrine, renin activity, aldosterone (ALDO), atrial (ANP) and brain (BNP) natriuretic peptides, arginine-vasopressin and endothelin (ENDO) as markers for left ventricular (LV) dimensions and ejection fraction (LVEF) in patients with systolic heart failure.. Forty-eight patients with symptomatic heart failure were examined with blood samples and magnetic resonance imaging along with 20 age and gender-matched normal controls.. In multiple regression analyses, BNP was the strongest independent marker for LV end-diastolic (r=0.71, P<0.0001), and end-systolic (r=0.75, P<0.0001) volumes, myocardial mass (r=0.69, P<0.0001), and LVEF (r=-0.78, P<0.0001). ANP was a supplementary independent marker for LV end-diastolic (r=0.76, P<0.0001) and end-systolic (r=0.78, P<0.0001) (ANP and BNP combined) volumes, ENDO for myocardial mass [r=0.71, P<0.0001 (ENDO/BNP)], and ALDO for LVEF [r=-0.81, P<0.0001 (ALDO/BNP)].. BNP is the strongest marker for LV dimensions and LVEF in patients with systolic heart failure. However, a comprehensive neurohumoral evaluation may add some information to the diagnosis.

Topics: Aged; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Endothelin-1; Epinephrine; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Norepinephrine; Regression Analysis; Renin; Stroke Volume; Ventricular Dysfunction, Left

Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1.. In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated protein kinase (MAPK) and oxidative stress in cardiac myocytes, as demonstrated by an increase in positive immunostaining for 8-hydroxy-2'-deoxyguanosine. Inhibition of p38 MAPK by cotransfection of a dominant-negative form of MKK6 as well as by administration of a specific inhibitor, SB203580 or FR167653, almost completely blocked the induction of apoptosis by LOX-1 activation. Antioxidant catalase also blocked LOX-1-induced apoptosis as well as activation of p38 MAPK.. These findings demonstrate that LOX-1 expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure and that LOX-1-dependent apoptosis in these cells requires p38 MAPK, a component of oxidant stress-sensitive signaling pathways.

Topics: Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Endothelin-1; Enzyme Activation; Enzyme Inhibitors; Heart Failure; Heart Ventricles; Imidazoles; Immunohistochemistry; In Situ Nick-End Labeling; Intracellular Membranes; Membrane Potentials; Mitochondria; Mitogen-Activated Protein Kinases; Norepinephrine; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Rats; Rats, Inbred Dahl; Receptors, LDL; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Signal Transduction; Transfection

To study the effects of a selective endothelin receptor A (ETA) antagonist FR139317 on rats with congestive heart failure.. A congestive heart failure model was established via left coronary artery ligation in adult male Wistar rats. The rats with congestive heart failure were treated with FR139317 at two doses (1 and 5 mg . kg-1 . d-1 respectively for 6 weeks) or with vehicle. Hemodynamics, plasma level of endothelin-1 (ET-1), and mortality rate of rats were measured.. Both groups treated with FR139317 (high and low dose) have lower mortality rate (25.0 % and 28.6 % vs 50.0 %) and lower plasma level of ET-1 than that of vehicle [(3.6 +/- 1.2) ng/L and (4.9 +/- 1.5) ng/L vs (5.8 +/- 1.3) ng/L]. Comparing to vehicle group, left ventricular end-diastolic pressures of the FR139317-treated groups were improved significantly [(12 +/- 6) mmHg and (14 +/- 7) mmHg vs (22 +/- 9) mmHg]. FR139317 at a higher dose reduced the mean arterial pressure of the rats with congestive heart failure and decreased the plasma concentration of endothelin to a closer level of rats with normal heart function than lower dose.. Selective ETA antagonist FR139317 improved the hemodynamics and reduced the plasma ET-1 level and the mortality of rats with congestive heart failure

Topics: Animals; Azepines; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Indoles; Male; Rats; Rats, Wistar; Receptor, Endothelin A; Survival Rate

Cardiac natriuretic peptides may induce apoptosis in myocytes; however, the relationship between plasma levels of cardiac natriuretic peptides and those of soluble Fas (sFas) and tumor necrosis factor (TNF)-alpha remains unknown in patients with congestive heart failure (CHF).. We measured plasma levels of sFas and TNF-alpha and those of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, and endothelin 1 in 96 patients with CHF (ejection fraction < 45%). The patients were monitored for 3 years. Plasma levels of sFas and TNF-alpha increased with the severity of CHF. There was no significant correlation between sFas plasma levels and those of ANP and BNP. Cox proportional hazard analysis showed that high levels of sFas (P = .009) and BNP (P < .0001) and a low ejection fraction (P = .019) were independent significant prognostic predictors.. There is no significant correlation between cardiac natriuretic peptide and sFas levels in plasma. Plasma sFas is a useful prognostic marker independent of neurohumoral factors, suggesting that immune activation and/or apoptosis play a significant role in the pathogenesis of CHF.

Topics: Age Factors; Aged; Apoptosis; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; fas Receptor; Female; Follow-Up Studies; Heart Failure; Humans; Japan; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Predictive Value of Tests; Prognosis; Severity of Illness Index; Solubility; Stroke Volume; Survival Analysis; Tumor Necrosis Factor-alpha

The results of the Randomized Aldactone Evaluation Study (RALES) and of several experimental studies have indicated that excess aldosterone detrimentally affects cardiovascular morbidity and mortality by acting through both classical and non-classical mineralocorticoid receptors. The effects mediated through classical mineralocorticoid receptors entail enhanced sodium and water reabsorption, potassium loss and hypokalaemia, congestion, increased vascular resistance and hypertension. Those occurring through non-classical mineralocorticoid receptors located on myofibroblasts comprise cardiac hypertrophy and fibrosis, which may be due to a direct effect of aldosterone on collagen synthesis. Data obtained in primary aldosteronism patients demonstrated left ventricular hypertrophy, as well as changes in left ventricular filling that can be accounted for by cardiac fibrosis. Available clinical data indicate that in a considerable proportion of congestive heart failure (CHF) patients treated with angiotensin converting enzyme (ACE) inhibitors, aldosterone secretion can escape from blockade of the renin-angiotensin system, thus suggesting that additional mechanisms, besides angiotensin II, can play an important role in the regulation of aldosterone secretion. Compelling evidence indicates that endothelin (ET)-1 is overtly increased in severe CHF and thus is a likely candidate for the aldosterone 'escape' phenomenon in CHF. Endothelin-1 is expressed in the adrenal cortex, together with its receptor subtypes A (ETA) and B (ETB), and directly stimulates aldosterone secretion in different species, in humans by acting via both ETA and ETB receptor subtypes. Moreover, we have recently found that the novel endothelin peptide ET-1 (1-31), by acting as an ETA agonist, can also be involved in the regulation of growth of the adrenal cortex, as well as in the pathogenesis of Conn's adenoma. In this paper, we review the findings suggesting a relationship between activation of the ET-1 system, enhanced aldosterone secretion and cardiac fibrosis and discuss the implications of endothelin antagonism for cardiovascular disease.

Topics: Adrenal Cortex; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Collagen; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Morbidity; Randomized Controlled Trials as Topic; Receptor, Endothelin A; Receptor, Endothelin B; Renin-Angiotensin System; Spironolactone

A role of the potent and long-acting vasoconstrictor peptide endothelin (ET)- I in the pathophysiology of chronic human heart failure has been postulated, based upon indirect evidence such as elevated plasma ET-1 levels and their relationship to the degree of haemodynamic impairment. Acute heart failure shares many features of chronic heart failure, albeit in an exaggerated fashion. As both the mixed ETA/ETB-receptor antagonist bosentan and the selective ETA receptor antagonist BQ 123 acutely improved the haemodynamics of chronic heart failure patients, there seems to be good reason to believe that ET-1 receptor antagonism may also be of benefit in the setting of acute heart failure. However, appropriate trials will have to be performed to document the clinical benefit of such an approach. Finally, the question remains open as to whether mixed ET-1 receptor antagonists like bosentan will prove better, worse or equal to antagonists that block the ETA, receptor only.

Topics: Acute Disease; Animals; Antihypertensive Agents; Bosentan; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides

Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ET(A) and ET(B), exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ET(A) and ET(B) agonist) and sarafotoxin S6c (a selective ET(B) agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26+/-7% and 51+/-6% peak reduction in vein calibre respectively; P=0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17+/-5% and 17+/-4% peak reduction in vein calibre respectively). Both ET(A) and ET(B) receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ET(A)- and ET(B)-receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET(A) receptor sensitivity, but further studies are required to clarify the functional significance of this observation.

Topics: Aged; Analysis of Variance; Case-Control Studies; Endothelin Receptor Antagonists; Endothelin-1; Hand; Heart Failure; Humans; Infusions, Intravenous; Male; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

Topics: Aspartic Acid Endopeptidases; Benzazepines; Benzhydryl Compounds; Benzofurans; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Inhibitors; Heart Failure; Humans; Metalloendopeptidases; Organophosphonates; Pyrimidines; Vascular Diseases; Vasoconstrictor Agents

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide elaborated by many cell types. Plasma ET-1 levels are significantly augmented in patients and experimental animals with heart failure. Enhanced levels of ET-1 may contribute to myocardial depression and alterations in sympathetic nerve activity in the setting of chronic heart failure. The effects of chronic blockade of endothelin A (ET(A)) receptors on the development and severity of experimental heart failure and sympathoexcitation were evaluated in these experiments using the specific ET(A) antagonist, PD156707.. Four groups of conscious, chronically instrumented mongrel dogs were administered either PD156707 (750 mg orally thrice daily) or a placebo starting 1 day before ventricular pacing or a sham (nonpaced) period. Before pacing or the sham period, baseline hemodynamic and plasma norepinephrine (NE) measurements were made. Hemodynamic and NE measurements were made every 3 to 4 days for the next 28 days. All parameters were relatively stable in nonpaced dogs administered placebo. Paced placebo dogs showed classic hemodynamic and sympathoexcitatory changes indicative of heart failure. Nonpaced dogs administered PD156707 showed a significant decrease in mean arterial pressure and total peripheral resistance beginning 3 days after drug administration. Myocardial function was not affected by PD156707 in nonpaced dogs. In paced dogs, PD156707 also reduced arterial pressure and peripheral resistance. Changes in myocardial function were small and insignificant. Paced dogs administered PD156707 showed an approximately 50% lower increase in plasma NE level from days 10 to 24 compared with paced dogs administered placebo (941.8 +/- 122.8 vs 501.1 +/- 92.6 pg/mL at 17 days; P < .01).. These data suggest that ET-1 contributes to the maintenance of arterial pressure in both sham dogs and dogs paced into heart failure. ET-1 does not appear to have a potent effect on inotropic state, but the data strongly suggest that ET-1 may contribute to the progressive deterioration of circulatory function in heart failure by mediating sympathoexcitation and enhancing plasma NE concentration.

Topics: Animals; Biomarkers; Cardiac Pacing, Artificial; Dioxoles; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Norepinephrine; Potassium; Receptor, Endothelin A; Receptor, Endothelin B; Sodium; Sympathetic Nervous System

To date, the use of beta-blockers in treating patients with chronic heart failure gains support, this since several large clinical trials reported reduced mortality after chronic beta-blockade. Part of these beneficial effects may result from inhibition of deleterious neurohormone activation that accompanies progression of chronic heart failure. The present study evaluates whether this neurohormone inhibition is preserved after chronic beta-blockade.. In a retrospective analysis the neurohormonal profiles of patients with moderate to severe chronic heart failure were studied from three treatment subgroups: (1) Without beta-blockers or ACE-inhibitors (n=15), (2) without beta-blockers, with ACE-inhibitors (n=324), (3) with beta-blockers and ACE-inhibitors (n=31). Patients were on beta-blockers for an average period of 3.8 years. Plasma samples were obtained under controlled conditions.. Despite uneven group sizes, the groups were well matched for clinical characteristics. Plasma renin levels were significantly lower in patients treated adjunctively with beta-blockers. Plasma aldosterone and endothelin-I levels also tended to be lower after chronic beta-blockade, however, this did not reach statistical significance.. Chronic adjunctive beta-blocker treatment shows significantly lower plasma renin levels when compared to single ACE-inhibition. This persistent reduction of plasma neurohormone activation may concomitantly reduce the chance of neurohormones to escape from inhibition.

Topics: Adrenergic beta-Antagonists; Aged; Aldosterone; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Endothelin-1; Female; Heart Failure; Humans; Logistic Models; Male; Neuropeptides; Neurotransmitter Agents; Norepinephrine; Renin; Retrospective Studies

Endothelin (ET) contributes to the increased systemic vascular resistance and elevated cardiac filling pressures seen in congestive heart failure (CHF). We investigated to what extent ET-mediated vasoconstriction in CHF occurs through an endocrine action of elevated plasma ET or by an autocrine/paracrine mechanism related to induction of vascular ET gene expression. Three weeks of pacing (225 beats/min) induced a marked release of ET-1 from the pulmonary circulation with a sixfold elevation of arterial plasma ET in CHF pigs compared with sham-operated pigs. Arterial plasma ET was the strongest and only independent predictor of systemic vascular resistance. In contrast, vascular preproET-1 and ET-receptor mRNA expression were unaltered or decreased in CHF pigs and did not correlate with indexes of vascular tone. However, myocardial preproET-1 mRNA expression increased twofold in CHF pigs. PreproET-2 and preproET-3 mRNAs were not detectable in cardiovascular tissues. In conclusion, plasma ET was markedly increased because of an augmented release from the pulmonary circulation during CHF, and arterial plasma ET correlated with systemic vascular resistance. The absence of ET induction in the peripheral vasculature suggests that ET increases vascular tone during CHF by an endocrine, not an autocrine/paracrine, mechanism.

Topics: Amino Acid Sequence; Animals; Autocrine Communication; Endothelin-1; Endothelin-2; Endothelins; Female; Gene Expression; Heart; Heart Failure; Heart Rate; Lung; Male; Molecular Sequence Data; Myocardium; Pacemaker, Artificial; Paracrine Communication; Protein Precursors; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Swine; Vasoconstriction

Endothelin (ET) induces hypertrophy of cardiomyocytes and increases synthesis of collagen in vitro. Interestingly, these features are hallmarks of the cardiac remodeling taking place in heart failure. The aim of the present study was to examine cardiac ET peptide and preproET-1 mRNA synthesis in human heart failure. Cardiac tissue was obtained from 11 patients with end-stage heart failure undergoing orthothopic heart transplantation (NYHA III-IV). Cardiac tissue from nine organ donors served as controls. The specimens were examined by immunohistochemistry and mRNA slot blot analyses. Significantly stronger ET-1-like immunoreactivity (ET-1-ir) was seen in the left atrial myocardium of failing hearts compared to the left atrial myocardium of donor hearts. Within each heart, the epicardium showed the strongest ET-1-ir. Left ventricular preproET-1 mRNA expression in the entire group of patients did not differ significantly from that of donor hearts. However, hypertrophic obstructive cardiomyopathy may be associated with a twofold increase in left ventricular preproET-1 mRNA. We report an increase in cardiac ET peptide in human heart failure.

Topics: Adolescent; Adult; Biomarkers; Blotting, Northern; Endothelin-1; Endothelins; Heart Atria; Heart Failure; Heart Transplantation; Heart Ventricles; Humans; Immunohistochemistry; Middle Aged; Myocardium; Protein Precursors; RNA, Messenger; Tissue Donors

Activation of neuroendocrine factors plays a major role in the pathophysiology and progression of heart failure. The aim of the present study was 1) to assess the clinical correlates of elevated plasma natriuretic peptides [atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] and Big endothelin-1 in a population of 180 ambulatory patients from the Italian registry of heart failure (Italian Network on Congestive Heart Failure, IN-CHF) in 22 clinical centers, 2) to assess the within-patient variability of plasma BNP concentration, and 3) to evaluate the analytical agreement for BNP determination between a core laboratory and local sites.. ANP and BNP were measured with specific immunoradiometric methods, Big endothelin-1 with an enzyme immunoassay.. Elevated BNP was associated with severe mitral valve regurgitation (odds ratio 8.546, 95% confidence interval 1.879-38.510, p = 0.0052); high circulating concentrations of ANP and BNP were found in older patients, and in patients with higher NYHA functional class or reduced left ventricular ejection fraction. Elevated plasma concentration of Big endothelin-1 was a strong and independent predictor of atrial fibrillation (odds ratio 4.001, 95% confidence interval 1.531-10.454, p = 0.0047). Plasma concentration of BNP was reasonably stable at 3-month interval in patients with mild-to-moderate heart failure (mean between-visit difference -1.5+/-45 pg/ml, n = 96). There was a satisfactory analytical agreement between the central laboratory and sites, over a broad range of concentrations (2-1133 pg/ml, n = 283) with a slope for the best line fitted by linear regression of 1.09 (r2 = 0.96).. BNP assay may become an appropriate tool for routine clinical practice in patients with congestive heart failure.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Disease Progression; Endothelin-1; Endothelins; Female; Heart Failure; Humans; Immunoenzyme Techniques; Incidence; Italy; Male; Natriuretic Peptide, Brain; Observer Variation; Outpatients; Prognosis; Protein Precursors; Registries; Stroke Volume

To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF).. Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest.. The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%.. Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant.. In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.

Topics: Catecholamines; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Phenylpropionates; Pyrimidines

Increased plasma levels of endothelin-1 (ET-1) have been identified in congestive heart failure (CHF), but local myocardial interstitial ET-1 levels and the relation to determinants of ET-1 synthesis remain to be defined. Accordingly, myocardial interstitial ET-1 levels and myocyte endothelin-converting enzyme (ECE)-1 activity and expression with the development of CHF were examined. Pigs were instrumented with a microdialysis system to measure myocardial interstitial ET-1 levels with pacing CHF (240 beats/min, 3 wk; n = 9) and in controls (n = 14). Plasma ET-1 was increased with CHF (15 +/- 1 vs. 9 +/- 1 fmol/ml, P < 0.05) as was total myocardial ET-1 content (90 +/- 15 vs. 35 +/- 5 fmol/g, P < 0.05). Paradoxically, myocardial interstitial ET-1 was decreased in CHF (32 +/- 4 vs. 21 +/- 2 fmol/ml, P < 0.05), which indicated increased ET-1 uptake by the left ventricular (LV) myocardium with CHF. In isolated LV myocyte preparations, ECE-1 activity was increased by twofold with CHF (P < 0.05). In LV myocytes, both ECE-1a and ECE-1c mRNAs were detected, and ECE-1a expression was upregulated fivefold in CHF myocytes (P < 0.05). In conclusion, this study demonstrated compartmentalization of ET-1 in the myocardial interstitium and enhanced ET-1 uptake with CHF. Thus a local ET-1 system exists at the level of the myocyte, and determinants of ET-1 biosynthesis are selectively regulated within this myocardial compartment in CHF.

Topics: Animals; Aspartic Acid Endopeptidases; Cardiac Pacing, Artificial; Endothelin-1; Endothelin-Converting Enzymes; Extracellular Space; Heart Failure; Isoenzymes; Metalloendopeptidases; Myocardium; RNA, Messenger; Swine; Ventricular Function, Left

To elucidate the effect of selective endothelin ET(A)- and mixed ET(A/B)-receptor antagonists on endothelial vasomotor dysfunction in rats with heart failure after myocardial infarction (MI).. Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats 12 weeks after extensive MI (>46% of left ventricle) compared to sham-operated animals. Rats were either treated with the selective ET(A)-receptor antagonist LU 135252 (30 mg/kg/day), the mixed ET(A/B)-receptor antagonist Bosentan (100 mg/kg/day) or placebo.. In MI rats, the concentration-response curve of the endothelium-dependent, nitric oxide-mediated relaxation induced by acetylcholine was significantly shifted to the right and the maximum relaxation was attenuated. Long-term treatment with both ET antagonists significantly improved acetylcholine-induced relaxation in MI rats. LU 135252 was more effective than Bosentan. Endothelium-independent relaxations induced by sodium nitroprusside as well as endothelin- and phenylephrine-induced contractions were similar in all groups of rats. Plasma renin activity and aortic superoxide formation, which were enhanced in rats with heart failure, were normalized by LU 135252, but not by Bosentan treatment.. Long-term treatment with ET-receptor antagonists improves endothelial vasomotor dysfunction in rats with chronic MI. This mechanism may essentially contribute to the beneficial effects of ET receptor blockade in heart failure.

Topics: Acetylcholine; Analysis of Variance; Animals; Aorta; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; In Vitro Techniques; Male; Myocardial Infarction; Nitroprusside; Oxygen; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Renin; Sulfonamides; Superoxide Dismutase; Vasoconstrictor Agents; Vasodilator Agents

Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides.. We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant.. Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery.. The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

Topics: Aged; Calcitonin Gene-Related Peptide; Chronic Disease; Endothelin-1; Femoral Artery; Heart Failure; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Pulmonary Artery; Radioimmunoassay; Vasoactive Intestinal Peptide; Veins

Although isolated diastolic heart failure with preserved left ventricular (LV) systolic function frequently occurs, regulation of local neurohumoral factors in the transition from diastolic dysfunction without signs of heart failure to diastolic failure, a target for therapeutic strategy, remains to be clarified, partly because of a lack of animal models. Our laboratory recently demonstrated that Dahl-Iwai salt-sensitive (Dahl-S) rats fed on a high-salt diet since 7 weeks of age develop hypertension followed by compensated LV hypertrophy at 13 weeks and transition to isolated diastolic heart failure at 19 weeks.. Gene expression of the components of the renin-angiotensin system, endothelin (ET) system and natriuretic peptide system in the left ventricle was investigated in the transition to isolated diastolic heart failure in this model.. The compensated ventricular hypertrophy was associated with slight increases in angiotensin-converting enzyme (ACE) and angiotensin II type-1a (AT1a) receptor mRNA levels. Although preproET-1 (ppET-1) and ET-converting enzyme-1 (ECE-1) mRNA levels were not increased, mRNA levels of ET type-A (ETA) and ET type-B (ETB) receptors were increased. Atrial natriuretic peptide (ANP) mRNA level increased, but not brain natriuretic peptide (BNP) mRNA level. At the decompensated failing stage (at 19 weeks), ACE mRNA level further increased without downregulation of ATla receptor mRNA level. The mRNA levels of ppET-1 and ECE-1 increased with persistent upregulation of mRNA levels of ETA and ETB receptors, and immunohistochemical staining for ET-1 was found at endothelial cells and myocytes. BNP mRNA level increased with a further increase in ANP mRNA level.. The transition to isolated diastolic heart failure in hypertrophied hearts was associated with preserved gene expression of the renin-angiotensin system and 'overdrive' of gene expression of the ET system. BNP gene expression is likely to be activated by the progression of diastolic failure rather than by LV hypertrophy alone.

Topics: Analysis of Variance; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Diastole; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Gene Expression; Heart Failure; Immunohistochemistry; Male; Metalloendopeptidases; Myocardium; Natriuretic Peptide, Brain; Peptidyl-Dipeptidase A; Protein Precursors; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Angiotensin; Receptors, Endothelin; Renin-Angiotensin System; RNA, Messenger

The relative efficacy of endothelin-A (ET(A)) receptor blockade versus combined ET(A)-ET(B) receptor blockade in chronic heart failure (CHF) is still largely unknown.. We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET(A) antagonist ABT-627 (5 mg x kg(-1) x d(-1)), the ET(B) antagonist A-192621 (30 mg x kg(-1) x d(-1)) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET(A) blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET(B) blockade). ET(A) and combined ET(A)-ET(B) blockade reduced systolic blood pressure to the same extent, whereas ET(B) blockade had no effect. In contrast, only combined ET(A)-ET(B) blockade significantly reduced heart rate. Both ET(A) and combined ET(A)-ET(B) blockade, but not ET(B) blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ET(B) blockade) decreased LV collagen accumulation.. The chronic blockade of both ET(A) and ET(B) receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET(A) receptor blockade alone. However, only combined ET(A)-ET(B) receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET(A) or mixed ET(A)-ET(B) antagonists in CHF remains to be determined.

Topics: Animals; Atrasentan; Blood Pressure; Collagen; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Myocardial Infarction; Myocardium; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Function, Left

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ET(A)-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo (n = 24) or LU (50 mg. kg(-1). day(-1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of L-NNA, whereas contraction induced by ET(B) receptor (receptor B) stimulation was increased (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ET(B)-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ET(A) blockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.

Topics: Animals; Cerebral Arteries; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Infarction; Nitroarginine; Nitroprusside; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Vasoconstrictor Agents; Vasodilation; Viper Venoms

We compared the value of plasma neurohormones and cardiopulmonary exercise testing for predicting long-term prognosis in patients with moderate congestive heart failure (CHF). We studied 264 consecutive patients with CHF due to left ventricular systolic dysfunction. Plasma atrial natriuretic peptide (ANP), norepinephrine, and endothelin-1 were measured at rest in all patients, who also underwent a symptom-limited maximal exercise with oxygen consumption (VO(2)) determination. After a median follow-up of 789 days, 52 deaths and 31 heart transplantations occurred, of which 4 were urgent. In an univariate analysis, New York Heart Association functional class, systolic blood pressure at rest, left ventricular end-diastolic diameter, left ventricular ejection fraction, peak VO(2), percent of predicted peak VO(2), plasma ANP, plasma norepinephrine, and plasma endothelin-1 were associated with survival without urgent heart transplantation. In a multivariate stepwise regression analysis, only plasma ANP (p = 0.0001), left ventricular ejection fraction (p = 0.007), and plasma norepinephrine (p = 0.035), but neither peak VO(2) nor percentage of predicted peak VO(2), were independent predictors of death or urgent heart transplantation. Determination of plasma ANP and norepinephrine provides additional independent information for long-term prognostic determination compared with exercise testing alone. Measurement of plasma neurohormones should therefore be considered routinely as a complementary or alternative tool for identifying high-risk patients with moderate CHF.

Topics: Atrial Natriuretic Factor; Chronic Disease; Disease-Free Survival; Endothelin-1; Exercise Test; Female; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Oxygen Consumption; Prognosis; Stroke Volume

Although interest in diastolic heart failure is growing because of its clinical frequency, little is known about this type of heart failure. Our laboratory recently developed a diastolic heart failure model using Dahl salt-sensitive rat. In this model, gene expression of angiotensin-converting enzyme and endothelin (ET) system in the left ventricle was enhanced at heart failure stage without downregulation of angiotensin type 1a receptor mRNA level. However, the roles of these humoral systems in the transition to diastolic failure remain unclear.. Subdepressor doses of angiotensin II type 1 (AT1) receptor and ET type A (ETA) receptor antagonists were administered in this model just after onset of hypertension, and their effects were investigated.. Neither AT1 nor ETA receptor blockade inhibited the early (13 weeks) compensatory left ventricular (LV) hypertrophy. This form of compensatory hypertrophy is associated with subnormal LV end-systolic stress, which was normalized by AT1 receptor blockade but not by ETA receptor blockade. Progression of LV hypertrophy and fibrosis and transition to heart failure (19 weeks) in the untreated rats were prevented by both antagonists, resulting in normalization of LV end-diastolic pressure and lung weight. AT1 receptor blockade, but not ETA receptor blockade, normalized time constant of LV relaxation. Enhanced gene expression for ET system in the left ventricle observed in the untreated rats was suppressed with AT1 receptor antagonist administration. ETA receptor blockade slightly but significantly elevated the AT1a receptor mRNA level as compared with the untreated rats.. RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart diseases, however, neither RAS nor ET system is mandatory for normal compensation for pressure overload. RAS apparently causes such diastolic effects at least partly through the ET system.

Topics: Angiotensin Receptor Antagonists; Animals; Aspartic Acid Endopeptidases; Benzimidazoles; Biphenyl Compounds; Diastole; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Heart Failure; Heart Ventricles; Hypertension; Male; Metalloendopeptidases; Peptidyl-Dipeptidase A; Protein Precursors; Pyrimidines; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptors, Angiotensin; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Tetrazoles

Endothelin-1 (ET-1) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P < 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF.

Topics: Animals; Cardiac Output; Disease Models, Animal; Dogs; Endothelin-1; Endothelins; Gene Expression; Heart Failure; Heart Ventricles; Kidney; Lung; Male; Myocardium; Pacemaker, Artificial; Protein Precursors; Pulmonary Wedge Pressure; RNA, Messenger; Ventricular Remodeling

We investigated plasma endothelin (ET) levels in patients with congestive heart failure (CHF) during treatment for acute decompensation; we also measured imbalances in ET peptides across the pulmonary, coronary, and peripheral circulation. Methods and Results-In patients with severe CHF (n=21; cardiac index [CI], 1.9+/-0.2 L. min(-1). m(-2); pulmonary capillary wedge pressure [PCWP], 31+/-1 mm Hg), vasodilation was achieved with the nitric oxide donor sodium nitroprusside (n=11) or with the alpha(1)-antagonist urapidil (nitric oxide-independent, n=10). ET concentrations were determined from arterial blood and blood from the pulmonary artery, coronary sinus, and antecubital vein. Depending on sites of measurement, baseline big ET and ET-1 levels were, respectively, 12 to 16 times and 5 to 11 times higher than in controls (n=11), and 4 to 6 times and 2 to 3 times higher than in patients with moderate CHF (n=10; CI, 2.7+/-0.3 L. min(-1). m(-2); PCWP, 14+/-2 mm Hg). Patients with severe CHF demonstrated pulmonary net release and coronary and peripheral net consumption of both peptides (ie, arterial levels [big ET, 7.3+/-1.3 pmol/L; ET-1, 1.8+/-0.1 pmol/L] were higher than levels in the pulmonary artery [6.7+/-1.2 pmol/L; 1. 3+/-0.1 pmol/L], coronary sinus [6.4+/-1.0 pmol/L; 1.4+/-0.1 pmol/L], and antecubital vein [6.6+/-1.1 pmol/L; 1.3+/-0.1 pmol/L]). In these patients, sodium nitroprusside (SNP) and urapidil resulted in comparable hemodynamic improvement after 6 hours (CI: SNP, 63+/-2%; urapidil, 72+/-3%; PCWP: SNP, -50+/-2%; urapidil, -47+/-2%) and a maximum decrease in ET peptides by >50%. After 3 hours, pulmonary net release and coronary and peripheral net consumption were no longer detectable.. In patients with severe CHF, the lungs act as a producer and the heart and the periphery act as consumers of elevated circulating ETs. Short-term vasodilator therapy decreases ETs and restores their pulmonary, coronary, and peripheral balance.

Topics: Aged; Coronary Circulation; Endothelin-1; Endothelins; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Nitroprusside; Piperazines; Pulmonary Circulation; Stroke Volume; Vasodilator Agents

The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT(1)) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF).. Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT(1) receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT(1) and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT(1) or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing-induced CHF, remained reduced after AT(1) receptor blockade, increased after ET receptor blockade (compared with rapid pacing-induced CHF values), and returned to within control values after combined blockade.. Combined AT(1) and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Bosentan; Cardiac Pacing, Artificial; Combined Modality Therapy; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Myocardial Contraction; Norepinephrine; Receptor, Endothelin A; Renin; Sulfonamides; Swine; Tetrazoles; Valine; Valsartan; Ventricular Dysfunction, Left

Endothelin-1 (ET-1) and cardiac natriuretic peptide plasma concentrations have prognostic significance in congestive heart failure (CHF). However, their respective prognostic values in this setting have never been directly compared.. We studied the prognostic performances of ET-1, N-terminal proatrial natriuretic factor (N-proANF), and brain natriuretic peptide (BNP) to predict the long-term cardiac mortality in fully treated patients with CHF. Peripheral plasma concentrations of the 3 peptides were measured in 109 patients (left ventricular ejection fraction [LVEF] < 35%) in New York Heart Association (NYHA) functional classes II (n = 65) or III to IV (n = 44). The outcome of the patients was evaluated 3 years after the beginning of the study, and a Cox regression model was used to identify predictors of death. Plasma concentrations of the 3 peptides increased with the severity of heart failure. By univariate analysis, 6 parameters were significantly associated with death during follow-up: ET-1 level, NYHA classes III to IV, N-proANF level, BNP level, LVEF, and age (all P < .01). By multivariate analysis, only ET-1 level and, to a lesser extent, N-proANF level contributed significantly and independently to risk stratification (chi2 = 53.4 and 12.8; P < .0001 and P < .001, respectively).. In a group of patients in whom the vast majority were administered angiotensin-converting enzyme inhibitor therapy, plasma ET-1 and N-proANF concentrations identify better than several clinical markers a very high-risk group, fairly amenable to heart transplantation or new therapies.

Topics: Aged; Atrial Natriuretic Factor; Belgium; Biomarkers; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Protein Precursors; Survival Analysis; Treatment Outcome

To determine the transcardiac gradient of plasma endothelin-1 (ET-1) in patients with congestive heart failure (CHF), we measured plasma levels of ET-1 in both the aortic root and the coronary sinus in 14 normal subjects and 79 consecutive patients with CHF. In normal subjects, plasma ET-1 was significantly higher in the coronary sinus than in the aortic root; these findings were also shown in patients with mild CHF, suggesting that there was ET-1 spillover across the heart. In contrast, plasma ET-1 was significantly lower in the coronary sinus than in the aortic root in patients with severe CHF, suggesting there was ET-1 extraction across the heart in patients with severe CHF. The transcardiac gradient of plasma ET-1 was correlated with the left ventricular end-diastolic volume index (r = 0.501, p <0.0001) and plasma level of procollagen type III amino terminal peptide in the coronary sinus (r = 0.54, p = 0.0008), a marker of myocardial fibrosis. Stepwise multivariate analysis showed that the transcardiac gradient of plasma ET-1 was an independent and significant relation with the left ventricular end-diastolic volume index in patients with CHF (r = 0.665, p <0.0001). These findings suggest that elevated circulating ET-1 is extracted across the failing heart with a significant correlation between the transcardiac gradient of plasma ET-1 and the left ventricular end-diastolic volume index, suggesting that ET receptors are upregulated in the failing ventricle and that the elevated circulating ET-1 might stimulate the process of left ventricular remodeling in patients with severe CHF.

Topics: Angiotensin II; Aorta; Coronary Vessels; Endothelin-1; Heart Failure; Hemodynamics; Humans; Norepinephrine; Peptide Fragments; Procollagen; Reference Values; Ventricular Function, Left

Recent studies have shown that endothelin-1 (ET-1) antagonists increase sodium excretion and improve renal blood flow in experimental heart failure (HF). However, despite a number of investigations that have reported a significant increase in ET-1 plasma levels in patients with HF, it is still not known whether increased renal synthesis and urinary excretion of ET-1 occur. Our aim was to investigate renal ET-1 formation and its relation to sodium excretion in patients with HF.. One hundred forty-seven patients with HF, subdivided according to New York Heart Association (NYHA) functional classes, and 28 healthy controls were studied. ET-1 and big ET-1 were measured in plasma and in 24-hour urine by radioimmunoassay. Atrial and brain natriuretic peptide, arginine vasopressin, plasma renin activity, and hemodynamic variables were also investigated.. Urinary ET-1 excretion was already increased in NYHA class II patients (P <.001 vs controls), whereas plasma ET-1 increased only in NYHA class III and IV patients (P <.001). In the 71 subjects who were not receiving diuretic treatment, urinary ET-1 was selected as the strongest predictor of sodium excretion by multivariate stepwise analysis.. Urinary ET-1 excretion increases in an earlier phase of HF than plasma ET-1 and appears to be closely correlated with sodium excretion, indicating renal ET-1 is a target for ET-1 antagonists in patients with HF.

Topics: Aged; Arginine Vasopressin; Atrial Natriuretic Factor; Biomarkers; Circadian Rhythm; Disease Progression; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Kidney; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Radioimmunoassay; Renin; Severity of Illness Index; Sodium; Survival Rate

We investigated whether impairment of myocardial energy metabolism attenuates cardiac function and increases cardiac endothelin-1 (ET-1) gene expression in rats. Three weeks after commencing administration of cobalt chloride (CoCl2), an inhibitor of mitochondrial function, the peak positive first derivative of left ventricular (LV) pressure, an indicator of myocardial contractility, was significantly decreased in the CoCl2-treated rats. LV end-diastolic pressure and right ventricular systolic pressure were increased in the CoCl2-treated rats. Echocardiography showed that fractional shortening was significantly decreased in the CoCl2-treated rats. Myocardial expressions of acyl-CoA synthase mRNA, an enzyme involved in fatty acid utilization, was markedly decreased in the CoCl2-treated rats. Under such conditions, myocardial expression of preproendothelin-1 mRNA and atrial natriuretic peptide (ANP) mRNA, molecular markers of heart failure, was markedly increased in the CoCl2 rats. In conclusion, the data suggest that impairment of myocardial energy metabolism causes hemodynamic abnormality and increases molecular markers of heart failure (ET-1, ANP mRNA). These data suggest that myocardial energy metabolism is one of the factors involved in the upregulation of ET-1 gene expression in the failing heart.

Topics: Animals; Atrial Natriuretic Factor; Cobalt; Endothelin-1; Endothelins; Energy Metabolism; Heart Failure; Male; Myocardium; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

We previously reported that the spillover of interleukin-6 (IL-6) into the peripheral circulation increases with the severity of congestive heart failure (CHF), and that the increase is mainly associated with activation of the endogenous sympathetic nervous system. However, the role of the sympathetic nervous system in the increase of IL-6 in CHF patients is not yet fully understood. To address this question, we measured plasma IL-6 levels before and after therapeutic administration of dopamine and betablockers in patients with CHF. After more than 24 h (mean, 34 h) of treatment with a low dose of intravenous dopamine (mean, 2.4 microg/kg/min) in 1 patients with dilated cardiomyopathy and deterioration of CHF, the plasma IL-6 level was increased significantly (30.8 vs. 16.6 pg/ml; p = 0.003) despite the improved hemodynamics. After 377 days of beta-blocker therapy in 24 patients with dilated cardiomyopathy, the plasma IL-6 level was decreased significantly (2.04 vs. 3.11 pg/ml; p = 0.01) along with the improvement of symptoms, left ventricular ejection fraction, and neurohumoral factors. Dopamine increases and beta-blockers decrease the plasma IL-6 level in patients with CHF, suggesting that drugs modulating the sympathetic nervous system may alter IL-6 in these patients.

Topics: Adrenergic beta-Antagonists; Atrial Natriuretic Factor; Dopamine; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Interleukin-6; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Prognosis

BACKGROUND--Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist. METHODS AND RESULTS--CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05). CONCLUSIONS--An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Blood Pressure; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Heart; Heart Failure; Hemodynamics; Indoles; Kidney; Male; Neuropeptides; Pulmonary Wedge Pressure; Receptor, Endothelin A; Tetracyclines; Time Factors; Vascular Resistance

This study was done to determine the spillover and extraction of endothelin-1 (ET-1) in the peripheral circulation, and to evaluate the factors that regulate local ET-1 extraction in the peripheral circulation in patients with congestive heart failure (CHF).. The relationship between the spillover and extraction of the ET-1 in the peripheral circulation and systemic vascular resistance (SVR) has not been fully clarified.. We measured plasma levels of ET-1 both in femoral artery (FA) and femoral vein (FV) in 93 patients with CHF.. Plasma ET-1 was significantly higher in FV than in FA in New York Heart Association (NYHA) functional class II patients, but there was no difference of ET-1 between FA and FV in functional class III patients. In patients with functional class IV, plasma ET-1 was significantly lower in FV than in FA, and SVR was significantly higher than in patients with NYHA class II or class III. Moreover, a significant positive correlation existed between plasma ET-1 extraction across the lower leg and SVR in these patients. Among the various neurohumoral factors and hemodynamics, plasma levels of ET-1, angiotensin II in the FA showed an independent and significant relationship with the plasma arteriovenous difference of ET-1 in the lower limb.. Circulating ET-1 is extracted in peripheral circulation in patients with severe CHF, suggesting the possibility of upregulation of ET receptors of vascular beds in the lower limb in these patients. The peripheral extraction of ET-1 correlates with SVR in severe CHF patients and is mainly regulated by the local ET-1 and renin angiotensin systems.

Topics: Adolescent; Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Endothelin-1; Female; Femoral Artery; Femoral Vein; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Pulmonary Wedge Pressure; Severity of Illness Index; Vascular Resistance

Endothelin-1 (ET-1) is a positive inotrope in normal hearts; however, the direct cardiac effects of endogenous ET-1 in congestive heart failure (CHF) are unknown. We evaluated the cardiac responses to endogenous ET-1 using an ETA and ETB receptor blocker (L-754,142) in seven conscious dogs before and after pacing-induced CHF. Before CHF, when the plasma ET-1 was 7.3 +/- 1.7 fmol/ml, L-754,142 caused no significant alterations in heart rate, left ventricular (LV) end-systolic pressure, total systemic resistance, and the time constant of LV relaxation (tau). LV contractile performance, measured by the slopes of LV pressure (P)-volume (V) relation (EES), dP/dtmax-end-diastolic V relation (dE/dtmax), and stroke work-end-diastolic V relation, was also unaffected. After CHF, when the plasma ET-1 was significantly increased to 14.1 +/- 3.0 fmol/ml (p <.05), L-754,142 produced a significant decreases in LV end-systolic pressure (101 +/- 11 versus 93 +/- 8 mm Hg) and total systemic resistance (0.084 +/- 0.022 versus 0.065 +/- 0.15 mm Hg/ml/min). The tau (42 +/- 12 versus 38 +/- 10 ms), mean left atrial P (22 +/- 5 versus 18 +/- 4 mm Hg) (p <.05), and minimum LVP were also significantly decreased. After CHF, the slopes of P-V relations, EES (3.4 +/- 0.4 versus 4.8 +/- 0.8 mm Hg/ml), dE/dtmax (42.4 +/- 7.8 versus 50.0 +/- 7.8 mm Hg/s/ml), and stroke work-end-diastolic V relation (58.1 +/- 3.3 versus 72.4 +/- 5.2 mm Hg) (p <.05) all increased after L-754,142, indicating enhanced contractility. Before CHF, low levels of endogenous ET-1 have little cardiac effect. However, after CHF, elevated endogenous ET-1 produces arterial vasoconstriction, slows LV relaxation, and depresses LV contractile performance. Thus, elevated endogenous ET-1 may contribute to the functional impairment in CHF in this canine model.

Topics: Animals; Dogs; Endothelin-1; Heart Failure; Hemodynamics; Nitroprusside; Receptors, Endothelin; Time Factors; Ventricular Dysfunction, Left

Congestive heart failure (CHF) and heart transplantation (HTX) are characterized by endothelial dysfunction as indicated by elevation of markers of endothelial function, including endothelin and von Willebrand factor (vWF). However, previous studies included both patients with idiopathic dilated cardiomyopathy and ischemic heart disease; the latter condition shows endothelial dysfunction, per se. The 2 endothelial factors have different origin and may provide different information about endothelial dysfunction in CHF and after HTX caused by idiopathic dilated cardiomyopathy.. We investigated plasma endothelin and vWF, the relation between these 2 factors, and determinants of endothelin and vWF plasma levels in 32 healthy controls, 25 patients with CHF, and 22 patients who had HTX; both conditions were caused by idiopathic dilated cardiomyopathy.. Plasma endothelin was elevated in CHF (6.8 +/- 3.4 pg/mL) and after HTX (6.1 +/- 2.1) compared with healthy controls (4.0 +/- 1.0, P <.0001 for both). VWF was also elevated in CHF (1.6 +/- 0.6 U/mL) and after HTX (2.6 +/- 1.0) compared with healthy controls (1.0 +/- 0.5, P <.0001 for both). VWF was increased after HTX compared with CHF (P <.001), in contrast to similar endothelin levels in CHF and after HTX. Plasma endothelin and vWF correlated in both CHF (r = 0.65, P <.001) and HTX (r = 0.66, P <. 001) but not in controls. In CHF, New York Heart Association functional class was an independent determinant of vWF (P <.0001) and furosemide dose of endothelin (P <.0001). In cardiac transplant recipients, plasma albumin was an independent determinant of vWF (P <.01), and plasma sodium and furosemide dose were independent determinants of endothelin (P <.01).. Plasma endothelin and vWF were directly correlated in both CHF and after HTX caused by idiopathic dilated cardiomyopathy. However, the production of the 2 factors appeared to be stimulated by different mechanisms and provided different information about endothelial function, as indicated by the different determinants and different response to heart transplantation.

Topics: Adult; Biomarkers; Cardiomyopathy, Dilated; Diuretics; Endothelin-1; Endothelium, Vascular; Female; Furosemide; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Myocardial Ischemia; Regression Analysis; Serum Albumin; Sodium; von Willebrand Factor

Since 1992, adrenalectomy for pheochromocytoma has been recognized as a safe and efficient technique when performed by a laparoscopic approach. Most of the cases of pheochromocytomas treated as such and published in the literature were not associated with malignant hypertension and acute heart failure. We report the case of a 23-year-old woman who presented with this clinical picture and show that laparoscopic adrenalectomy may be as safe and efficient as conventional adrenalectomy when performed in this situation. The intraoperative changes in the secretion of catecholamines, endothelin-1, angiotensin II, N- and C-terminus of atrial natriuretic factor prohormone were also analyzed. Noradrenaline release during tumor dissection was associated with a stimulation of atrial natriuretic factor.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Endothelin-1; Epinephrine; Female; Heart Failure; Humans; Laparoscopy; Monitoring, Intraoperative; Norepinephrine; Pheochromocytoma; Protein Precursors

The aim of this study was to investigate the contribution of endothelin-1 (ET-1) to the development of secondary pulmonary hypertension (PH) in patients with left heart failure (HF).. The subjects were 40 patients with left HF with (group 1; n = 20) and without (group 2; n = 20) acute exacerbation. Before treatment, the ET-1 level in the pulmonary capillary wedge region was three times greater in patients of group 2 than group 1, although there was no significant difference in mean pulmonary artery pressure (mPAP) or pulmonary vascular resistance index (PVRI) between the two groups. Also, the ET-1 level significantly correlated with mPAP and PVRI for both groups, but with different slopes of the regression lines. After treatment of group 1, the extent of reduction in the ET-1 level significantly correlated with that in mPAP and in PVRI, whereas the ET-1 level itself correlated with mPAP, with the regression lines approximating those of group 2.. Our findings suggest that ET-1 may have differential roles in the development of secondary PH in patients with left HF with or without acute exacerbation.

Topics: Aged; Blood Pressure; Endothelin-1; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Vascular Resistance

Elevated plasma levels of endothelin (ET)-1 have been reported in association with heart diseases, including heart failure. Furthermore, it has been suggested that ET-1 acts as a local autocrine/paracrine factor with biological activities such as vasoconstriction, mitogenesis, and inotropic effects on the heart. This study investigated alterations of ET-1, ET receptor, and endothelin-converting enzyme (ECE) expression in left ventricular myocardium from patients with end-stage heart failure.. mRNA concentrations of ETA and ETB receptors, prepro-ET-1 (ppET-1), and ECE in left ventricles from nonfailing donors hearts (NF) and from patients with end-stage chronic heart failure (NYHA functional class IV) due to dilated cardiomyopathy (DCM) were compared by use of a competitive reverse transcription-polymerase chain reaction technique. There was no significant difference in mRNA expression for ppET-1, ECE-1, and ETA receptors, whereas a significant reduction of ETB-receptor mRNA was observed in DCM hearts. 125I-labeled ET-1 radioligand binding studies demonstrated a significant downregulation of ETB receptors, whereas ETA-receptor density was increased in membranes from DCM hearts. Phosphoramidon-sensitive ECE activity and immunodetectable amounts of ECE protein in left ventricular membrane preparations did not differ between NF and DCM hearts. Finally, immunoreactive ET-1 concentrations were increased in DCM hearts.. The present study demonstrates changes in the ET-receptor expression pattern in favor of the ETA receptor in human end-stage heart failure. Furthermore, activation of the cardiac ET system with increased tissue ET-1 concentrations in the failing myocardium is observed. This is more likely due to decreased clearance than to increased synthesis, because ppET-1 gene expression and ECE activity are unchanged.

Topics: Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; DNA Primers; Down-Regulation; Endothelin-1; Endothelin-Converting Enzymes; Heart Failure; Heart Transplantation; Humans; Metalloendopeptidases; Myocardium; Radioligand Assay; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Adrenergic, beta; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic

We previously reported that chronic endothelin (ET) receptor blockade ameliorated the survival rate and cardiac hemodynamics in rats with chronic heart failure (CHF) due to myocardial infarction. However, it remains unclear whether ET-1 is involved in the pathophysiology of cardiomyopathy, which is one of the major causes of CHF. Accordingly, we investigated the production of ET-1 in the heart and the effect of chronic ETA receptor blockade on survival rate and cardiac function in the Bio 14.6 hamster, which is an idiopathic model of CHF caused by cardiomyopathy.. We used 52-week-old Bio 14.6 cardiomyopathic hamsters and age-matched F1b normal hamsters. The expression of preproET-1 mRNA and the ET-1 level in the hearts were markedly higher in the cardiomyopathic hamsters than in the normal hamsters. The cardiomyopathic hamsters showed severe CHF, illustrated by lower left ventricular (LV) +dP/dt/Pmax and right ventricular (RV) +dP/dt/Pmax and by higher LV end-diastolic pressure (EDP), RVEDP, and central venous pressure compared with the normal hamsters. Long-term (9 weeks) treatment with an ETA antagonist (TA-0201, 1.3 mg. kg-1. d-1) markedly increased survival of cardiomyopathic hamsters (untreated, 16%; TA-0201-treated, 65.2%; P<0.001). After 6 weeks of treatment, LV +dP/dt/Pmax and RV +dP/dt/Pmax were significantly higher and LVEDP and RVEDP were lower in the TA-0201-treated group than in the untreated group, suggesting that chronic TA-0201 treatment effectively prevented deterioration of cardiac dysfunction.. In the cardiomyopathic hamsters with CHF, the production of ET-1 in the heart was markedly increased, and chronic ETA receptor blockade greatly ameliorated survival and cardiac dysfunction. These results suggest that ET-1 plays an important role in the deterioration of CHF caused by cardiomyopathy, and ETA antagonists may exert therapeutic effects in CHF due to cardiomyopathy.

Topics: Animals; Blood Pressure; Cardiomyopathies; Cricetinae; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Heart Rate; Hemodynamics; Male; Myocardium; Pyrimidines; Rats; Receptor, Endothelin A; Sulfonamides; Survival Rate; Ventricular Function, Left; Ventricular Function, Right

Heart transplantation is associated with a reduction of the neurohumoral activation seen in patients with severe congestive heart failure. In this study, we investigated whether pharmacologically induced complex hemodynamic improvement during assessment of reversibility of pulmonary hypertension with a phosphodiesterase inhibitor is able to induce neurohormonal changes of diagnostic importance.. Twenty-one patients with New York Heart Association class III-IV heart failure underwent infusion of 3 mg/kg enoximone over a period of 30 minutes. Before and after drug infusion, we determined the plasma concentrations of atrial natriuretic peptide, endothelin-I, angiotensin-II, aldosterone, norepinephrine, epinephrine, and angiotensin-converting enzyme activity sampled from a peripheral vein and the pulmonary artery. In addition to the expected significant reduction of pulmonary hypertension and enhancement of cardiac output, increased levels of the vasoconstrictors endothelin-I, angiotensin-II, and norepinephrine were observed. Aldosterone fell after enoximone infusion; a higher baseline aldosterone level correlated to the degree of reduction of the pulmonary arteriolar resistance by enoximone. Baseline atrial natriuretic peptide levels correlated with parameters, indicating the severity of heart failure. However, the plasma concentration of this peptide did not change significantly after enoximone infusion.. Acute hemodynamic improvement after enoximone bolus in candidates for heart transplantation is not accompanied by a reduction of the enhanced neurohumoral activity in these patients. The reaction of the investigated hormones cannot predict the individual degree of reversibility of pulmonary hypertension.

Topics: Angiotensin II; Atrial Natriuretic Factor; Biomarkers; Cardiac Catheterization; Catecholamines; Endothelin-1; Enoximone; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Peptidyl-Dipeptidase A; Phosphodiesterase Inhibitors; Prognosis; Pulmonary Artery; Pulmonary Veins; Severity of Illness Index

Topics: Aged; Angiotensin II; Aorta; Biomarkers; Cardiac Catheterization; Coronary Vessels; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain

Topics: Angiotensin II; Biomarkers; Endothelin-1; Female; Heart Failure; Humans; Natriuretic Peptide, Brain

We evaluate the acute hemodynamic and neurohormonal effects of losartan in 15 patients with symptomatic chronic heart failure (CHF), mean age 72+/-8 years, which were classified in two subgroups: (A) Patients with left ventricular ejection fraction (LVEF)< or =0.35 (n = 7); (B) subjects with LVEF>0.35 (n = 8). Sympathetic reactivity (blood pressure, heart rate and plasma norepinephrine) and plasma endothelin-1 (ET-1) were evaluated by a cold pressor test (CPT). Single doses of losartan (50 mg p.o.) lowered delta DBP in both subgroups (A, 8+/-9 to 0+/-5 mm Hg, P<0.05; B, 10+/-6 to 3+/-4 mm Hg, P<0.05) and attenuated the rise of HR in patients with mild (4+/-6 to -1+/-2 bpm, P<0.05) but not with severe (4+/-5 to 2+/-5 bpm, n.s.) impairment of left ventricular function. Losartan blunted the response (delta) of PNE during CPT (A, 142+/-131 to 10+/-74 pg/ml, P<0.05; B, 129+/-72 to 1+/-144 pg/ml, P<0.01). A significant rise in plasma ET-1 was observed during CPT in patients from subgroup B (0.64+/-0.40 to 0.81+/-0.40 fmol/ml, P<0.05) but not in patients with LVEF< or =0.35 (1.79+/-0.44 to 1.51+/-0.66 fmol/ml, n.s.). Losartan attenuated the rise in ET-1 during CPT in patients with LVEF>0.35 (delta ET-1 0.17+/-0.86 to 0.03+/-0.11 fmol/ml, P<0.05), with no significant changes in subgroup A. Acute effects of losartan were characterized by a more favorable hemodynamic and neurohumoral response in patients with chronic heart failure and preserved systolic ventricular function related to subjects with lower ejection fractions.

Topics: Aged; Aged, 80 and over; Angiotensin II; Antihypertensive Agents; Blood Pressure; Chronic Disease; Cold Temperature; Endothelin-1; Exercise Test; Female; Heart Failure; Heart Rate; Humans; Losartan; Male; Middle Aged; Norepinephrine; Sympathetic Nervous System; Vasoconstriction

The objective of this study was to define further the local activation of endothelin-1 (ET-1) and the ETA receptor as well as the functional consequences of activated ET-1 for renal hypoperfusion associated with experimental congestive heart failure (CHF). We studied eight rabbits permanently instrumented with Doppler flow probes around the renal arteries before and after the induction of epinephrine-induced CHF. CHF was characterized by left-ventricular dysfunction (fractional shortening 34+/-2% vs. 46+/-3%; p < or = 0.05) and dilatation (LVEDd 13.6+/-0.3 vs. 11.5+/-0.4 mm; p < or = 0.05), decreased mean arterial pressure (59.4+/-2.9 vs. 74.6+/-3.7 mm Hg; p < or = 0.05), increased heart rate (236+/-11 vs. 216+/-8 beats/min; p < or = 0.05) and renal vasoconstriction (vascular resistance 49.65 +/-8.55 vs. 24.61+/-5.85 U; p < 0.05; blood flow velocity, 1.58+/-0.21 vs. 3.63+/-0.31 kHz; p < 0.05). ET-1 concentrations were significantly increased not only in plasma (7.67+/-0.47 vs. 4.56 +/-0.69 pg/ml; p < 0.05) but also in renal tissue (4.8+/-0.5 vs. 3.5 +/-0.64 pg/mg; p < 0.05). Northern analysis revealed an unchanged expression of ETA receptor messenger RNA (0.79+/-0.05 vs. 0.77+/-0.04 arbitrary units; NS) in renal tissue, whereas expression of prepro-ET-1 was below the range of detection. In CHF, selective ETA-receptor antagonism with BQ-123 (1 mg/ kg bolus, i.v.) significantly increased renal blood flow velocity (3.07+/-0.38 vs. 1.33+/-0.19 kHz; p < 0.05) and reduced renal vascular resistance (29.63+/-6.22 vs. 58.17+/-8.75 U; p < 0.05) without significant effects on mean arterial pressure or heart rate. These studies demonstrate activation of the renal ET system, unaltered gene expression, and functional integrity of the renal ETA receptor in CHF. They indicate a principal functional role for the ETA receptor in renal vasoconstriction and suggest blockade of the renal ETA receptor as an important strategy to attenuate renal hypoperfusion in CHF.

Topics: Animals; Blotting, Northern; Echocardiography; Endothelin-1; Epinephrine; Heart Failure; Hemodynamics; Laser-Doppler Flowmetry; Male; Peptides, Cyclic; Rabbits; Radioimmunoassay; Receptors, Endothelin; Renal Artery; RNA; Sympathomimetics

Since its discovery in 1988, endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET antagonists have favourable effects in experimental models of these conditions and have proved useful in elucidating the role of the ET system. Orally acting ET antagonists appear very promising in clinical trials, particularly in patients with chronic heart failure and hypertension, but more information on the roles of the ET receptor subtypes in health and disease is required so that an informed choice can be made between the use of endothelin-A (ET-A) receptor-selective and nonselective receptor antagonists.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Drugs, Investigational; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hypertension; Receptors, Endothelin

We and other groups have reported that endothelin (ET)-1 expression in the heart is altered in the setting of heart diseases. We have also reported that myocardial ET-1 is involved in the progression of heart failure, and that an ET receptor antagonist improves long-term survival in heart failure (Nature 384: 353-355, 1996). However, the role of myocardial ET-2 in disease states are not known. To characterize the role of ET-2, we used a) the failing hearts of rats with heart failure caused by myocardial infarction, and b) primary cultured cardiomyocytes subjected to hypoxia. In the failing heart in vivo, ET-1 mRNA increased by 390% compared with that in the non-failing heart, while ET-2 mRNA drastically decreased by 88%. Thus, gene expression of ET-1 and ET-2 was reciprocally altered in the failing heart in vivo. In in vitro studies, reciprocal alterations in ET-1 and ET-2 gene expression were also observed in isolated primary cultured cardiomyocytes, subjected to hypoxia. Specifically, acute hypoxic stress induced a significant increase (360% of the basal level) in ET-2 mRNA expression compared with that in normoxic cells, whereas it decreased ET-1 mRNA expression by 62% in primary cultured cardiomyocytes. Although these two crucial conditions, i.e., heart failure in vivo and acute hypoxic stress in vitro, are pathophysiologically distinct from each other, reciprocal alteration of ET-1 and ET-2 gene expression was observed in both cases. To further investigate the regulatory mechanism of the altered gene expression, luciferase analysis was performed using primary cultured cardiomyocytes. ET-2 promoter, which is the 5'-flanking region of preproET-2 gene (5'ET-2), showed a marked increase in luciferase activity during acute hypoxia. In contrast, the luciferase activity of 5'ET-1 (ET-1 promoter) did not change in response to hypoxic stress. The present study suggests that there are transcriptionally distinct regulatory mechanisms for ET-1 and ET-2 expression in cardiomyocytes, and therefore this study may provide a new aspect of cardiac ET system that not only ET-1 but also ET-2 can be participated in the pathophysiological conditions.

Topics: Animals; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Endothelin-1; Endothelin-2; Endothelins; Gene Expression Regulation; Heart Failure; Hemodynamics; Male; Myocardial Ischemia; Myocardium; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

The physiological response to a chronically failing heart is the implementation of compensatory mechanisms intended to support blood pressure. These mechanisms, which are not fully understood, increase peripheral vascular tone, thus increasing the strain on the weakened myocardium. This study investigated the structure and function of small arteries from heart failure patients and controls without heart failure in an attempt to identify abnormalities associated with heart failure which may be related to these mechanisms. Small arteries were dissected from gluteal biopsies and studied using wire myography. Arterial morphological parameters were measured and concentration-response curves constructed for a number of vasoconstrictor and vasodilator agonists. Plasma concentrations of neuroendocrine hormones were also measured. There were no morphological differences between small arteries from control subjects and those from patients with chronic heart failure. In heart failure patients, vasoconstrictor responses to endothelin-1 were significantly reduced, although plasma endothelin-1 levels were increased. Arteries from heart failure patients also showed evidence of an impaired neuronal uptake mechanism, since blockade by cocaine had no effect on noradrenaline-induced vasoconstriction in these vessels. These results suggest that small-artery structure is not altered in chronic heart failure and so cannot account for the heightened vascular resistance in this syndrome. However, abnormal neuronal uptake and impaired vasoconstriction in response to endothelin-1 may be associated with the complex compensatory phenomenon involved in heart failure.

Topics: Acetylcholine; Adult; Aged; Analysis of Variance; Angiotensin II; Arteries; Bradykinin; Case-Control Studies; Dose-Response Relationship, Drug; Endothelin-1; Epoprostenol; Female; Heart Failure; Humans; Male; Middle Aged; Muscle, Skeletal; Myography; Natriuretic Peptide, Brain; Nitroprusside; Norepinephrine; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

The clinical success of neurohumoral manipulation by ACE inhibitors and beta blockers in heart failure has led to new therapeutic approaches. New neurohumoral factors are now viewed as offering the potential for treatment interventions. Not only do we consider blocking the production of deleterious hormones, but also, more recently, consideration has been given to augmenting the actions of factors with potentially beneficial actions. Hopefully such manipulation of ADM and ET-1 can result in further improvement in the well-being of heart failure patients.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptides; Vasoconstriction

Two groups of patients with acute congestive heart failure (CHF), New York Heart Association class III, presenting elevated plasma values of beta-endorphin, norepinephrine, atrial natriuretic factor (ANF) and endothelin-1, underwent the Mental Arithmetic Test (MAT) during placebo (n = 10) and naloxone hydrochloride (n = 10) infusion. The MAT during placebo significantly (p < 0.01) increased blood pressure, heart rate, plasma levels of Met-enkephalin, dynorphin B, beta-endorphin, norepinephrine, ANF and endothelin-1. The increases in norepinephrine, ANF and hemodynamics after the MAT during naloxone infusion were higher (p < 0.01) than those during placebo; thus, the transient upregulation of the endogenous opioid system during stress in CHF patients attenuates the hemodynamic response by reducing norepinephrine release.

Topics: Atrial Natriuretic Factor; beta-Endorphin; Blood Pressure; Endothelin-1; Enkephalin, Methionine; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Intelligence Tests; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Opioid Peptides; Stress, Physiological

We investigated the hemodynamic effects of amrinone and assessed its effects on neurohormonal factors in 15 patients with evolving congestive heart failure with various origins. We serially determined the pulmonary and systemic vascular-resistance indices after amrinone infusion and examined the relation between changes in hemodynamic parameters and changes in concentrations of norepinephrine, atrial natriuretic peptide, angiotensin II, and endothelin-1 in the pulmonary capillary wedge region (PCWR) and in the peripheral veins. Amrinone significantly reduced pulmonary vascular-resistance index (PVRI; Wood x m2) in patients with high PVRI (> or =15) before the infusion, significantly reduced systemic vascular-resistance index (SVRI; Wood x m2) in patients with high SVRI (> or =50) before the infusion, and had little effect on vascular resistances in patients with low PVRI (<15) and low SVRI (<50). The reduction in PVRI was correlated with the reduction in the endothelin-1 level (r = 0.75) in the PCWR, and the reduction in SVRI with norepinephrine level (r = 0.70) in the peripheral veins. The angiotensin II level did not change throughout the study. These findings suggest that amrinone had selective hemodynamic effects on pulmonary and systemic circulations with neurohormonal effects, according to PVRI and SVRI before infusion.

Topics: Aged; Amrinone; Angiotensin II; Biomarkers; Cardiotonic Agents; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Norepinephrine; Statistics as Topic; Vascular Resistance

We 1) evaluated whether interleukin-6 (IL-6) is produced in the peripheral circulation in patients with congestive heart failure (CHF), 2) estimated the factors for increased IL-6, and 3) clarified the prognostic role of high plasma levels of IL-6 in patients with CHF.. Although plasma levels of IL-6 have been reported to increase in patients with CHF, and production of IL-6 in endothelial cells and vascular smooth muscle cells has been postulated from in vitro studies, the origin of the increase of IL-6 in CHF remains unknown. Moreover, the prognostic value of a high plasma level of IL-6, independent of classic neurohumoral factors, remains to be elucidated.. A comparison was made of the plasma levels of IL-6 between the femoral artery and the femoral vein in 13 normal subjects and in 80 patients with CHF. In another study, we measured plasma IL-6 in 100 patients with CHF and follow-up data.. Plasma IL-6 levels increased significantly from the femoral artery to the femoral vein in normal subjects and in patients with CHF. Arteriovenous IL-6 spillover in the leg increased with the severity of CHF. Among the hemodynamic variables and the various neurohumoral factors, the plasma norepinephrine (NE) level showed an independent and significant positive relation with the plasma IL-6 level in patients with CHF. Moreover, treatment with beta-adrenergic blocking agents showed an independent and significant negative relation with plasma IL-6 levels. In 100 patients, plasma IL-6 (p < 0.0001), NE (p = 0.0004) and left ventricular ejection fraction (0.015) were significant independent prognostic predictors by Cox proportional hazards analysis.. Our findings indicate that the IL-6 spillover in the peripheral circulation increases with the severity of CHF and that the increase in plasma IL-6 is mainly associated with the activation of the sympathetic nervous system. High plasma levels of IL-6 can provide prognostic information in patients with CHF, independent of left ventricular ejection fraction and plasma NE, suggesting an important role for IL-6 in the pathophysiology of CHF.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Case-Control Studies; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Femoral Vein; Follow-Up Studies; Forecasting; Heart Failure; Humans; Interleukin-6; Male; Middle Aged; Muscle, Smooth, Vascular; Neurotransmitter Agents; Norepinephrine; Prognosis; Proportional Hazards Models; Stroke Volume; Sympathetic Nervous System; Sympathomimetics; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents; Ventricular Function, Left

Forearm blood flow (ml/min/100 ml) was determined with strain-gauge venous occlusion plethysmography at rest and in response to handgrip exercise in 7 patients with congestive heart failure and in 9 normal subjects before and after regional administration of endothelin-1 in the brachial artery. Administration of endothelin-1 significantly decreased forearm blood flow at rest and during exercise in normal subjects but did not change it at rest or during exercise in patients with congestive heart failure.

Topics: Adult; Brachial Artery; Endothelin-1; Exercise; Exercise Test; Female; Forearm; Hand Strength; Heart Failure; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Regional Blood Flow; Vasodilation

Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ET(A) receptors and ET(B) receptors. We previously reported that an ET(A) receptor antagonist greatly ameliorated pulmonary hypertension due to congestive heart failure (CHF) in rats. In the present study of rats with pulmonary congestion secondary to CHF, we determined not only ET(A) receptor mRNA expression but also ET(B) receptor mRNA expression in the congestive lung because lung ET(B) receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-1 and circulating ET-1 levels. The expression of ET(B) receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ET(A) receptor mRNA did not differ between the two groups. The protein level of ET(B) receptor, determined by Western blot, in the lung was lower in the rats with CHF than in the control rats, while the protein level of ET(A) receptor did not differ between the two groups. The lung ET-1 level and plasma ET-1 level were significantly higher in the rats with CHF than in the controls by 1.4-fold and 5.3-fold, respectively. Thus, in the rats with CHF, ET-1 was increased to a much greater extent in plasma than in the lung. The present findings suggest that selective down-regulation of ET(B) receptor, but not ET(A) receptor, occurs in the congestive lung. Since lung ET(B) receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ET(B) receptors partly contributes to marked increases in circulating ET-1 and that increased ET-1 in the circulating plasma as well as in the lung is involved in the progression of pulmonary hypertension in CHF.

Topics: Animals; Blood Pressure; Disease Models, Animal; Down-Regulation; Endothelin-1; Heart Failure; Lung Diseases; Organ Size; Polymerase Chain Reaction; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET(A) and ET(B), resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ETA antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (n = 6) and a group that received an orally active ET(A) receptor antagonist (A-127722, Abbott Pharmaceuticals, 5 mg/kg PO bid, n = 6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET(A) receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET(A) receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET(A) receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET(A) receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET(A) receptor antagonism in CHF.

Topics: Administration, Oral; Animals; Atrasentan; Atrial Natriuretic Factor; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart; Heart Failure; Hemodynamics; Kidney; Male; Pyrrolidines; Receptor, Endothelin A; Sodium; Vasoconstriction

Pulmonary hypertension (PHT) is associated with increased endothelin-1 (ET-1) levels that correlate with the severity of the disease. The pulmonary circulation is an important site for ET-1 metabolism and may modulate plasma ET-1 through an increase in production, a reduction in removal, or a combination of both. We measured and compared pulmonary metabolism of circulating ET-1 in controls and in patients with PHT.. The indicator-dilution technique was combined with measurements of ET-1 levels to quantify pulmonary metabolism of ET-1 in controls (n = 13) and in patients with PHT (n = 17). ET-1 levels doubled in PHT (p < 0.05) and, although there was no difference between aortic and pulmonary artery levels in controls (0.68+/-0.09 and 0.61+/-0.08 pg/ml, respectively, p = 0.22), they tended to be higher in PHT (1.23+/-0.26 vs 1.07+/-0.19 pg/ml, p = 0.08). Pulmonary extraction of tracer iodine-125-ET-1 was reduced from 47%+/-2.0% in the controls to 34%+/-3.6% in PHT (p = 0.005) and inversely correlated with the severity of pulmonary hypertension (r = -0.524, p = 0.03). Consequently, circulating ET-1 clearance was reduced by PHT from 1424+/-77 ml/min to 892+/-119 ml/min (p < 0.001). Pulmonary production of circulating ET-1 (in picograms per minute) was not different but the quantity of ET-1 that survives passage through the lungs was increased by PHT (1860+/-359 pg/min vs 992+/-152 pg/min, p = 0.037).. PHT is associated with a reduced pulmonary clearance of ET-1 that contributes to the increase in circulating levels.

Topics: Aorta, Thoracic; Biomarkers; Blood Pressure; Cardiac Catheterization; Echocardiography; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Iodine Radioisotopes; Middle Aged; Mitral Valve Stenosis; Pulmonary Artery; Pulmonary Wedge Pressure; Severity of Illness Index; Spectrophotometry; Vascular Resistance

Fluid retention is a major characteristic of symptomatic, progressive heart failure when a main factor implicated in the pathogenesis of renal dysfunction is renal hypoperfusion. This may be a consequence of forward cardiac failure, resulting in a low cardiac output integrating poor left ventricular function secondary to myocardial impairment and increased resistance in the regional renal vasculature secondary to locally released vasoconstrictors, e.g. endothelin. So far, the role of the pulmonary circulation in perpetuating renal dysfunction in heart failure is unclear.. We investigated the relationship of hemodynamic variables obtained during right heart catheterization and plasma big endothelin levels to renal function variables in 18 male patients aged 52 +/- 3 years, with heart failure in the NYHA function class III-IV, based on idiopathic causes in 8 and ischemic causes in 10 patients. Renal plasma flow (RPF) was established by paraaminohippurate (PAH) clearance and the glomerular filtration rate (GFR) was measured by iothalamate clearance.. Plasma big endothelin (ET) levels were increased above the upper normal range (1.8 fmol/ml) in 16 out of 18 patients, averaging 5.0 +/- 0.8 fmol/ml (1.7-11.9 fmol/ml). Positive correlations to big ET plasma levels were detected with mean pulmonary pressure (r = 0.73, p < 0.001) pulmonary capillary wedge pressure (r = 0.56, p < 0.05) and pulmonary vascular resistance index (r = 0.69, p < 0.01). Glomerular filtration rate (70 +/- 7 ml/min) and renal plasma flow (358 +/- 36 ml/min) were considerably reduced and exhibited a tendency to correlate inversely with big ET levels (r = -0.46, p = 0.056 and r = -0.44, p = 0.069, respectively). Contrary to expectations, RPF did not correlate significantly with cardiac index, systemic vascular resistance index or arterial blood pressure. In contrast, significant correlations were detected of RPF with pulmonary capillary wedge pressure (r = -0.69, p < 0.01), mean pulmonary artery pressure (r = -0.65, p < 0.01), right atrial pressure (r = -0.47, p < 0.05) and right ventricular ejection fraction (r = 0.49, p < 0.05).. The findings suggest a role for endothelin in renal vasoconstriction and accord well with the concept that in severe heart failure renal hypoperfusion--by volume retention--as well as increased endothelin synthesis--by pulmonary vasoconstriction--play a part in the increased pulmonary filling pressures.

Topics: Endothelin-1; Endothelins; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Humans; Ischemia; Kidney; Male; Middle Aged; Protein Precursors; Pulmonary Circulation; Pulmonary Wedge Pressure; Renal Insufficiency; Vascular Resistance; Ventricular Function, Left; Ventricular Function, Right; Water-Electrolyte Balance

Congestive heart failure(CHF) is associated with a marked decrease in cortical blood flow and preservation of medullary blood flow. In the present study we tested the hypothesis that changes in the endothelin (ET) and nitric oxide (NO) systems in the kidney may contribute to the altered intrarenal hemodynamics in rats with aortocaval fistula, an experimental model of CHF. Cortical and medullary blood flow were measured simultaneously by laser-Doppler flowmetry in controls and rats with compensated and decompensated CHF. As previously reported [K. Gurbanov, I. Rubinstein, A. Hoffman, Z. Abassi, O. S. Better, and J. Winaver. Am. J Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F1166-F1172, 1996], administration of ET-1 in control rats produced a sustained cortical vasoconstriction and a transient medullary vasodilatory response. In rats with decompensated CHF, cortical vasoconstriction was severely blunted, whereas ET-1-induced medullary vasodilation was significantly prolonged. This prolonged response was mimicked by IRL-1620, a specific ETB agonist, and partially abolished by NO synthase (NOS) blockade. In line with these findings, expression of ET-1, ETA and ETB receptors, and endothelial NOS (eNOS), assessed by RT-PCR, and eNOS immunoreactivity, assessed by Western blotting, was significantly higher in the medulla than in the cortex. Moreover, expression of ET-1 mRNA in the cortex and eNOS mRNA in the cortex and the medulla increased in proportion to the severity of heart failure. These findings indicate that CHF is associated with altered regulation of intrarenal blood flow, which reflects alterations in expression and activity of the ET and NO systems. It is further suggested that exaggerated NO activity in the medulla contributes to preservation of medullary blood flow in the face of cortical vasoconstriction in CHF.

Topics: Animals; Endothelin-1; Endothelins; Endothelium, Vascular; Heart Failure; Kidney Cortex; Kidney Medulla; Male; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Polymerase Chain Reaction; Rats; Rats, Wistar; Receptors, Endothelin; Regional Blood Flow; Renal Circulation; RNA, Messenger; Transcription, Genetic

Plasma atrial natriuretic peptide (ANP), mainly from the atrium, brain natriuretic peptide (BNP), mainly from the ventricle, norepinephrine (NE), and endothelin-1 (ET-1) levels are increased with the severity of congestive heart failure (CHF). Although a close correlation between the left ventricular end-diastolic pressure (LVEDP) and plasma ANP in patients with left ventricular dysfunction has been reported, it is not yet known which cardiac natriuretic peptide is a better predictor of high LVEDP in patients with CHF.. To investigate the biochemical predictors of the high LVEDP in patients with left ventricular dysfunction, we measured plasma ANP, BNP, NE, and ET-1 levels and the hemodynamic parameters in 72 patients with symptomatic left ventricular dysfunction. Stepwise multivariate regression analyses were also used to determine whether the plasma levels of ANP, BNP, NE, and ET-1 could predict high LVEDP.. Although significant positive correlations were found among the plasma levels of ANP, BNP, ET-1, and NE and the LVEDP, only BNP (p = 0.0001) was an independent and significant predictor of high LVEDP in patients with CHF. In all eight patients with severe CHF measured for hemodynamics before and after the treatments, the plasma BNP levels decreased in association with the decrease of LVEDP, whereas other factors increased in some patients despite the decrease of LVEDP.. These findings suggest that plasma BNP is superior to ANP as a predictor of high LVEDP in patients with symptomatic left ventricular dysfunction.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Brain; Cardiac Catheterization; Diastole; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Norepinephrine; Prognosis; Regression Analysis; Ventricular Dysfunction, Left; Ventricular Function, Left

The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are increased in the circulation of patients with chronic heart failure. However, their correlation with left ventricular dysfunction has not yet been thoroughly evaluated, and their interrelation with other neurohumoral systems, such as the adrenergic system and endothelin, is unclear. Therefore TNF-alpha, its soluble receptor II, IL-6, big endothelin, and noradrenaline levels were simultaneously measured in venous blood from 65 patients with heart failure in New York Heart Association (NYHA) class II to IV during therapy with digitalis, furosemide, and enalapril. TNF-alpha plasma levels were 3.2+/-0.2 SEM pg/ml in 38 patients in NYHA function class II, 4.0+/-0.3 SEM pg/ml in 16 patients in NYHA function class III, and 5.3+/-0.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.001 vs NYHA function class II). IL-6 plasma levels were 3.1+/-0.6 SEM pg/ml in 38 patients in NYHA function class II, 5.2+/-0.8 SEM pg/ml in 16 patients in NYHA function class III, and 13.3+/-3.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.0001 vs NYHA function class II andp < 0.0001 vs NYHA class III). Thus both cytokines increased with increasing severity of heart failure, but only IL-6 plasma levels were different in patients in the more severe function classes. TNF-alpha correlated closely with TNF soluble receptor II (r = 0.8, p < 0.0001) and modestly with serum creatinine (r = 0.6, p < 0.0001), whereas IL-6 plasma levels were not statistically related to kidney function. Significant modest correlations were also found among TNF-alpha and IL-6 (r = 0.3, p < 0.01), big endothelin (r = 0.3, p < 0.01), and noradrenaline levels (r = 0.4, <0.001). This study supports the hypothesis that in heart failure both cytokines, TNF-alpha, and IL-6, as well as neurohumoral factors, play a role in the clinical progression of the disease. Thereby levels of TNF-alpha but not IL-6 seem to be related to concomitant kidney dysfunction.

Topics: Adrenergic Agonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiotonic Agents; Chronic Disease; Creatinine; Digitalis Glycosides; Disease Progression; Diuretics; Enalapril; Endothelin-1; Endothelins; Female; Furosemide; Heart Failure; Humans; Interleukin-6; Kidney; Linear Models; Male; Middle Aged; Multivariate Analysis; Neurotransmitter Agents; Norepinephrine; Protein Precursors; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Endothelin (ET)-1 increases in plasma during congestive heart failure (CHF). Some ET antagonists improve hemodynamics, suggesting its potential benefits in the treatment of CHF. We examined the acute and chronic effects of a new ET receptor antagonist, T-0201 (Tanabe Seiyaku Co. Ltd., Japan), in CHF. To confirm the in vivo effects of T-0201, we observed the inhibitory effects of T-0201 (1-100 micrograms/kg) on the response of blood pressure to exogenously administered ET-1 (0.75 nmol/kg) in conscious normal dogs. Pretreatment with T-0201 significantly inhibited the ET-1-induced initial hypotension that is mediated by ETB receptors, and attenuated the subsequent hypertension, which is primarily mediated by ETA receptors. Thus, T-0201 at a dose of 100 micrograms/kg not only works as a potent ETA antagonist but also shows antagonist activity for ETB receptors in dogs. To evaluate the chronic therapeutic effects of T-0201, we administered T-0201 (0.3 mg/kg/day; n = 5) orally to dogs with CHF induced by rapid right ventricular pacing (22 days, 270 beats/min) for 15 days, beginning 8 days after pacing. T-0201 significantly prevented the deterioration of cardiorenal function during the development of CHF, expressed as a decrease in cardiac pressure and an increase in cardiac and urine output. These results suggest that chronic antagonism of both ET receptors prevents the progressive exacerbation of CHF.

Topics: Animals; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Chronic Disease; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Pulmonary Wedge Pressure; Urodynamics

The potent vascular, cardiac, and renal actions of endothelin-1 (ET-1) suggest a role for this vasoconstrictor peptide in the pathophysiology of heart failure (HF). Recent studies have shown increased levels of ET-1 peptide accompanied by increased ETB receptor binding in the left ventricle during experimental HF. However, much less is known about the regulation of mRNA expression of these genes in HF. We compared the levels of mRNA expression for ET-1 and ET receptors (ETA and ETB) in the left ventricle of rats with HF induced by coronary artery ligation (n = 6) vs. sham-operated animals (n = 6). Levels of mRNA for ET-1 were determined by ribonuclease protection assay (RPA) using beta-actin as the internal control, whereas ET receptors were quantified by quantitative-competitive RT-PCR. Compared with sham animals, ET-1, ETA, and ETB receptor mRNA levels were markedly upregulated in the left ventricle by 6.6 +/- 1.8-fold (p < 0.01), 3.2 +/- 0.6-fold (p < 0.05), and 3.5 +/- 1.0-fold (p < 0.05), respectively. ET-1 mRNA levels were measured in two additional groups of rats (HF and sham; n = 6 each) treated for 4 weeks with the selective ETA receptor antagonist LU135252. This treatment had no significant effect on ET-1 mRNA expression in sham animals but reduced the upregulation of ET-1 expression in the HF group by 41 +/- 19% (p < 0.05). This study confirms the potential importance of ET-1 in HF and suggests that increased expression of ET-1 and ET receptors in the failing ventricle may contribute to alteration in basal cardiac contractility and myocardial remodeling.

Topics: Animals; Endothelin-1; Endothelins; Heart; Heart Failure; Male; Polymerase Chain Reaction; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Ribonucleases; RNA, Messenger; Up-Regulation

Accumulating evidence suggests that endogenous endothelin-1 (ET-1) may contribute to the development of heart failure. In this study we determined sites of ET-1 synthesis and production in the failing human myocardium by immunohistochemistry and in situ hybridization for ET-1 and endothelin-converting enzyme-1 (ECE-1). Myocardial tissues were obtained from 19 patients with heart failure and from four noncardiac patients as controls. In both failing and nonfailing hearts, apparent immunoreactivity for ET-1 and ECE-1 was consistently seen in cardiac myocytes. Endothelial cells of intramyocardial coronary arteries and veins had only weak or focal ET-1 and apparent ECE-1 immunoreactivities. On the other hand, in situ hybridization showed strong signals for ET-1 and ECE-1 mRNAs in vascular endothelial cells but a lesser intensity of signals in cardiac myocytes. Apparent immunoreactivity and strong hybridization signals for both ET-1 and ECE-1 were seen in macrophages, which were abundant in infarcted regions of ischemic cardiomyopathy and in myocardium of septic patients but were rare in healthy hearts. These results suggest that, in failing human heart, vascular endothelial cells and macrophages rather than cardiac myocytes appear to be the principal ET-1 synthetic sites, although ET-1 peptides are abundantly present in cardiac myocytes of both failing and nonfailing hearts. Endogenous ET-1 may play a pathophysiologic role in human heart failure.

Topics: Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Heart Failure; Humans; Immunohistochemistry; In Situ Hybridization; Metalloendopeptidases; Muscle Proteins; Myocardium; RNA, Messenger

The canine model of pacing-induced heart failure (HF) simulates human dilated cardiomyopathy and is characterized by severe hemodynamic perturbations. We have previously demonstrated increased plasma endothelin-1 (ET-1) and left ventricular (LV) tissue peptide levels in this model. However, the gene expression of ET-1 has not been studied. Accordingly, we compared preproET-1 mRNA in the lungs and LV in control normal dogs, dogs with severe HF after 3 weeks of rapid pacing (pHF), and pHF dogs chronically treated with an ETA antagonist, LU135252 (pHF-LU). PreproET-1 mRNA expression was determined by ribonuclease protection assay and quantified by densitometry. In paced dogs, mean pulmonary artery pressure (PA) and LV end-diastolic pressure (LVEDP) increased markedly from 16 +/- 4 and 8 +/- 3 mm Hg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mm Hg, respectively, at 3 weeks (both p < 0.001). Treatment with LU135252 attenuated the increase in PA and LVEDP by 30% and 19%, respectively (p < 0.05 for both). Compared to controls, preproET-1 mRNA expression in the LV and lungs was markedly increased in pHF. This was not changed in the LV but was reduced in the lungs by treatment with the ETA antagonist. Increased pulmonary and LV expression of preproET-1 suggests that ET-1 plays a role in mediating the pulmonary hypertension and LV dysfunction characteristic of this model.

Topics: Animals; Cardiac Pacing, Artificial; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Gene Expression; Heart Failure; Humans; Lung; Male; Myocardium; Phenylpropionates; Protein Precursors; Pyrimidines; Receptor, Endothelin A; Ribonucleases; RNA, Messenger

We have previously reported that production of endothelin (ET)-1 is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET-1 in the left ventricle (LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore, we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-1 production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.

Topics: Angiotensinogen; Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Induction; Heart Failure; Hemodynamics; Male; Metalloendopeptidases; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

1. Endothelium-dependent vasodilatation via nitric oxide in response to muscarinic stimulation is decreased in chronic heart failure while basal release of nitric oxide may be increased. As production of the endothelium-derived vasoconstrictor endothelin-1 is increased in chronic heart failure, endothelin-1 may act in an autocrine manner to modulate these effects. 2. To test this, we determined whether prolonged endothelin infusion in normal subjects would reproduce the alterations in basal and stimulated nitric oxide release observed in patients with chronic heart failure. Basal nitric oxide production was determined by measurement of forearm blood flow using strain gauge venous occlusion plethysmography before and after brachial artery infusion of a nitric oxide synthase inhibitor (NG-monomethyl-L-arginine). Stimulated nitric oxide production was determined by brachial artery infusion of acetylcholine. As metabolic vasodilatation is thought to be mediated in part via nitric oxide and is decreased in chronic heart failure, forearm blood flow during peak reactive hyperaemia was also measured. Studies were then repeated during brachial artery infusion of endothelin-1 and a non-specific vasoconstrictor, noradrenaline. 3. Neither basal nor stimulated nitric oxide production was altered by endothelin-1 and noradrenaline infusion. However, absolute forearm blood flow responses to peak reactive hyperaemia were decreased during infusion of endothelin-1 in comparison to noradrenaline. These data suggest that increased endothelin-1 may not contribute greatly to altered basal and stimulated nitric oxide production in patients with chronic heart failure but may contribute to impaired metabolic vasodilatation, by mechanisms presumably unrelated to altered nitric oxide production.

Topics: Acetylcholine; Adult; Endothelin-1; Endothelium, Vascular; Female; Forearm; Heart Failure; Humans; Hyperemia; Male; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; omega-N-Methylarginine; Regional Blood Flow; Stimulation, Chemical; Vasoconstriction; Vasoconstrictor Agents

Endothelin is a very potent vasoconstrictor peptide produced by the vascular endothelium. Several studies have shown that the endothelin system is activated in various cardiovascular conditions, including myocardial infarction, heart failure and pulmonary hypertension. The known actions of the endothelin-1 isoform suggest that it may be an important mediator in several of the pathophysiological manifestations of heart failure. Data on the potential value of endothelin antagonists in heart failure are reviewed.

Topics: Endothelin-1; Endothelins; Endothelium, Vascular; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

To investigate whether endogenous ET-1 participates in an adaptive process of left ventricular hypertrophy (LVH) or a maladaptive process from LVH to congestive heart failure (CHF), we used a Dahl salt-sensitive (DS) rat model, in which systemic hypertension caused compensated concentric LVH at the age of 11 weeks followed by marked LV dilatation and global hypokinesis at the age of 17 weeks.. By specific sandwich enzyme immunoassay, serum and myocardial ET-1 levels at the LVH stage were not elevated compared with age-matched Dahl salt-resistant (DR) rats, despite the marked increase of LV/body weight ratio (LV/BW). However, at the CHF stage, serum and LV ET-1 levels increased by 3. 8-fold and 5.4-fold, respectively. LV ET-1 contents had close relationships with the fractional shortening (r=0.763) and the systolic wall stress (r=0.858) measured by in vivo transthoracic echocardiography. Immunohistochemistry demonstrated that the remarkably increased ET-1 in LV is located mainly in cardiomyocytes. By competitive reverse transcriptase-polymerase chain reaction, LV prepro-ET-1 mRNA levels increased by 4.1-fold in CHF rats. We randomized 11-week-old LVH rats to chronic treatment with the endothelin receptor antagonist bosentan (Bos, 100 mg. kg-1. d-1, n=14), the alpha1-receptor antagonist doxazosin (Dox, 1 mg. kg-1. d-1, n=12), or vehicle (Cont, n=14). Bos treatment did not alter the LV geometry and function at 15 weeks; however, it attenuated the decrease of LV fractional shortening by 51% (P<0.01) without reducing the LV/BW at 17 weeks. Conversely, Dox, which decreased the blood pressure to the same extent as Bos, did not affect the progression of LV dysfunction. Bos (93%; P<0.0001 versus Cont) but not Dox (42%; P=0.8465 versus Cont) ameliorated the survival rate at 17 weeks (Cont; 36%).. The accelerated myocardial synthesis of ET-1 contributes directly to LV contractile dysfunction during the transition from LVH to CHF. Unelevated levels of LV ET-1 at the established LVH stage and lack of effects on LV mass by chronic bosentan treatment suggest that myocardial growth is mediated through alternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in humans.

Topics: Adaptation, Physiological; Animals; Blood Pressure; Cardiomegaly; Echocardiography; Endothelin-1; Endothelins; Heart Failure; Immunohistochemistry; Male; Myocardium; Organ Size; Protein Precursors; Rats; Rats, Inbred Dahl; RNA, Messenger; Survival Analysis; Systole; Ventricular Dysfunction, Left

Inhibition by endothelin antagonist is a potential therapy in heart failure. However, the effect of endothelin inhibition during the development of heart failure has not been evaluated. The goal of our study was to examine the acute hemodynamic effects of the mixed endothelin receptor antagonist bosentan in the control state and at different stages of heart failure induced by right ventricular pacing (250 bpm) in conscious dogs.. Nine dogs were chronically instrumented for the measurements of left ventricular pressure and its first derivative (dP/dt), cardiac output, left ventricular regional wall thickness and aortic pressure. Bosentan (3 mg/kg, i.v. bolus) and placebo were given at control, at 1 week of pacing (stage of left ventricular dysfunction with perserved cardiac output) and at 3 weeks of pacing (phase of heart failure with low cardiac output).. With the development of heart failure, baseline plasma endothelin level increased progressively. Placebo did not induce hemodynamic and plasma endothelin changes during the 30 min recording at any stage. At control, bosentan did not change hemodynamics. At 1 and 3 weeks of pacing, bosentan did not modify left ventricular myocardial function indices but reduced mean arterial pressure (by 7 +/- 2 and 8 +/- 1 mm Hg respectively, p < 0.005). Bosentan increased stroke volume at 3 weeks of pacing only.. Endothelin inhibition by endothelin antagonist bosentan, decreases aortic pressure in both early left ventricular dysfunction and in heart failure in contrast with the control state. In the phase of heart failure with low cardiac output, bosentan increases stroke volume. In the early left ventricular dysfunction, bosentan, by reducing arterial pressure, may limit the deterioration of cardiac function through a reduction of the workload imposed on the heart.

Topics: Animals; Bosentan; Cardiac Output; Cardiac Pacing, Artificial; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Heart Failure; Hemodynamics; Male; Protein Precursors; Stroke Volume; Sulfonamides; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Pressure

The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF).. We measured the plasma levels of ET-1 and compared the effects of ET-1 (10(-10)-10(-8) M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF.. With CHF, the plasma levels of ET-1 (19.7 +/- 6.3 vs. 4.1 +/- 0.5 fmol/ml, p < 0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8-16%) and the peak velocity of shortening (dL/dtmax, 20-35%; p < 0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9-13%) and in the velocity of relengthening, dR/dtmax (10-14%; p < 0.05). The myocytes' dR/dtmax also decreased by 8-10% (p < 0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20-23%, p < 0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine).. ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amiloride; Animals; Anti-Arrhythmia Agents; Calcium; Cardiotonic Agents; Cell Size; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Heart Failure; Hemodynamics; Isoproterenol; Male; Myocardial Contraction; Myocardium; Peptides, Cyclic; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Sodium-Hydrogen Exchangers; Staurosporine

Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling.. Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density.. In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.

Topics: Animals; Blood Pressure; Cardiac Output; Collagen; Coronary Vessels; Dose-Response Relationship, Drug; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Heart Rate; Hemodynamics; Ligation; Male; Myocardium; Organ Size; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Vasoconstrictor Agents; Ventricular Remodeling; Viper Venoms

Plasma endothelin-1 (ET-1) increases in congestive heart failure (CHF). The pulmonary vascular bed could contribute to this increase through a reduced clearance. We evaluated the effect of tachycardia-induced CHF on pulmonary ET-1 kinetics. To discern between changes due to variations in pulmonary hemodynamics from true alterations of endothelial cell functions, we quantified ET-1 kinetics in isolated rat lungs under variable pressure and flow-rate conditions.. Indicator-dilution studies were performed in anesthetized dogs (n = 14) before and 3 weeks after rapid ventricular pacing and in isolated lungs from healthy rats (n = 4). In isolated lungs, graded increases in perfusion rate from 5-25 ml/min caused gradual reductions in ET-1 extraction from 60 +/- 1.5% to 17 +/- 4.9% (mean +/- S.D.). The capacity to clear ET-1 from the circulation, as computed from the permeability-surface area product (PS), however did not vary over this range of flows. CHF increased plasma ET-1 (11.2 +/- 11.4 vs. 5.2 +/- 1.6 fmol/ml, p < 0.01), did not affect pulmonary ET-1 extraction (29.4 +/- 12.5% vs. 29.9 +/- 12.9%), but decreased the PS (8.3 +/- 5.4 cm3/s vs. 14.4 +/- 9.9 cm3/s, p = 0.038). Contrary to the invariability of the PS in normal isolated rat lungs, CHF was associated with a positive relationship between the PS and pulmonary plasma flow (r = 0.65, p < 0.01). ET-1 binding studies in lung tissues showed no significant variations in ETA and ETB receptors densities but revealed a threefold decrease in binding affinity (p < 0.01) that may explain the reduced clearance.. CHF causes a reduction of pulmonary ET-1 clearance that likely contributes to the increased circulating ET-1 levels and reflects pulmonary metabolic dysfunction associated with this condition.

Topics: Analysis of Variance; Animals; Blood Flow Velocity; Cardiac Pacing, Artificial; Dogs; Endothelin-1; Heart Failure; Hemodynamics; In Vitro Techniques; Indicator Dilution Techniques; Lung; Male; Perfusion; Protein Binding; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Statistics, Nonparametric

Both the selective endothelin (ET) ETA receptor and mixed ETA/ETB receptor antagonists improve haemodynamics in patients and experimental models with congestive heart failure (CHF) and reduce the mortality in CHF rats. However, it remains unclear which of these antagonists is superior in the treatment of CHF. In addition, there is little information as to whether these ET receptor antagonists contribute to the neuroendocrine regulation and body fluid balance. We therefore investigated the cardiorenal and neurohumoral benefits of selective ETA receptor and mixed ETA/ETB receptor antagonists in CHF.. We administered acutely either the selective ETA receptor antagonist FR139317 (FR, n = 6, 1 and 10 mg/kg) or the mixed ETA/ETB receptor antagonist TAK-044 (TAK, n = 6, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days.. Both FR and TAK decreased the cardiac pressures and the plasma atrial natriuretic peptide level and increased the cardiac output and urinary sodium excretion. FR increased the urine flow rate in association with an increased glomerular filtration rate and renal plasma flow, while TAK reduced the plasma aldosterone level. Neither antagonist increased the plasma renin activity or norepinephrine levels.. These ETA/ETB antagonist. However, the long-term administration of a mixed ETA/ETB receptor antagonist would improve not only the haemodynamics but also prevent fluid retention by suppressing secretion of aldosterone during the treatment of chronic CHF.

Topics: Aldosterone; Analysis of Variance; Animals; Atrial Natriuretic Factor; Azepines; Cardiac Pacing, Artificial; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Female; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Indoles; Kidney; Male; Peptides, Cyclic; Receptor, Endothelin A; Renal Plasma Flow; Sodium

We examined the effects of chronic type A endothelin receptor (ETA) blockade in a dog model of pacing-induced cardiomyopathy.. Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg orally daily) and nine dogs received a matching placebo starting at day three of pacing and continued for the remainder of the three weeks of pacing.. In the placebo group, the mean pulmonary artery pressure and left ventricular end diastolic pressure increased from 16 +/- 3 and 8 +/- 2 mmHg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mmHg, respectively, at two weeks (both p < 0.001 versus baseline). Cardiac output declined from 3.5 +/- 0.7 to 1.9 +/- 0.6 l/min (p < 0.001). In the treatment group, LU 135252 attenuated the increase in mean pulmonary artery and left ventricular end diastolic pressure (16 +/- 3 and 9 +/- 1 mmHg at baseline to 29 +/- 3 and 27 +/- 3 mmHg, respectively, at two weeks (p < 0.001), and the decline in cardiac output (3.2 +/- 0.3 to 2.6 +/- 0.8 l/min, p < 0.01; p < 0.05 versus placebo for the three parameters). Systemic and pulmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. However, LU 135252 attenuated the increase in plasma norepinephrine level (placebo, 1.2 +/- 0.5 to 3.7 +/- 1.9 pmol/l; treatment, 0.8 +/- 0.3 to 2.4 +/- 0.6 pmol/l; both p < 0.001 versus baseline; p < 0.05 versus placebo).. Our results suggest that endothelin-1 plays a role in the hemodynamic perturbations in canine pacing-induced cardiomyopathy. The favourable hemodynamic effects without concomitant aggravation of neurohormonal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure.

Topics: Administration, Oral; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Dogs; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Male; Norepinephrine; Phenylpropionates; Pyrimidines; Random Allocation; Receptor, Endothelin A; Vascular Resistance; Ventricular Remodeling

Recent reports indicate that endothelin (ET) plays an important pathophysiological role in congestive heart failure (CHF). However, existing data on local cardiopulmonary ET production are few. No studies have hitherto examined the specific anatomic localization of cardiopulmonary ET synthesis in CHF. Thus, the aims of the present study were to examine whether cardiopulmonary preproET-1 mRNA synthesis is upregulated in CHF and to determine the anatomic localization of preproET-1 mRNA and the mature peptide.. CHF was induced in rats by occluding the left coronary artery. Only animals with a left ventricular end-diastolic pressure above 15 mmHg after one week were included (n = 28). Sham-operated animals served as controls (n = 24). Hearts and lungs were examined by mRNA slot blot analyses, in situ hybridization (ISH) and immunohistochemistry (IHC).. In CHF-rats, slot blot analyses revealed a 3.5 +/- 1.1-fold and a 6.4 +/- 0.8-fold upregulation of preproET-1 mRNA in the noninfarcted and the infarcted area of the left ventricles, respectively (p < 0.05 for both). ISH revealed that the preproET-1 mRNA was localized predominantly over the granulation tissue in the infarcted region. The ET peptide was predominantly localized to inflammatory cells and remaining cardiomyocytes in the infarcted region as determined by IHC. Lungs from CHF-rats showed a 1.5 +/- 0.1-fold upregulation of preproET-1 mRNA (p = 0.01). The most abundant preproET-1 mRNA and ET-1-like-immunoreactivity (ET-1-ir) was seen over inflammatory cells and over airway epithelial cells. Some ET-1-ir was also located to bronchial and vascular smooth muscle cells.. Increased cardiopulmonary ET synthesis strongly suggest a pathophysiological role for ET in CHF.

Topics: Animals; Autoradiography; Coronary Vessels; Endothelin-1; Endothelins; Gene Expression; Heart Failure; Immunoblotting; Immunohistochemistry; In Situ Hybridization; Ligation; Lung; Male; Myocardium; Protein Precursors; Random Allocation; Rats; Rats, Wistar; RNA, Messenger

The use of cardiac peptide measurements as possible diagnostic tools in congestive heart failure has been extensively discussed in the recent literature. Therefore, the aim of this study was to establish a model of experimental chronic heart failure, and thereby perform a comparative study of secretion and circulating levels of the cardiac peptides atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (N-terminal proANP) and brain natriuretic peptide (BNP) during evolving heart failure. Chronic heart failure was induced in seven pigs by rapid left atrial pacing for three weeks. The effects of failure induction were documented 24 h after pacemaker deactivation. Hemodynamic indices of cardiac preload, like pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP), were all considerably increased compared to sham operated controls. Likewise, plasma endothelin-L, noradrenaline, renin activity, aldosterone and angiotensin II were all markedly increased. Heart failure was accompanied by significant increases in both estimated cardiac secretory rate and plasma concentrations of all three cardiac peptides, significantly correlated to the PCWP. The directional changes during evolving heart failure were similar, although the percentage increase in plasma BNP was much larger than for ANP and N-terminal proANP. In absolute molar terms, however, the BNP concentration changes were minor compared to those of the other two peptides. The larger percentage increase of BNP might indicate its superiority as a marker of heart failure development, provided a functional assay suitable for clinical use can be designed for a peptide circulating in this low concentration range.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Epinephrine; Female; Heart Failure; Male; Myocardium; Natriuretic Peptide, Brain; Norepinephrine; Pacemaker, Artificial; Protein Precursors; Renin; Swine

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Heart; Heart Failure; Humans; Myocardium; Peptides; Prognosis

Endothelin-1 is a potent vasoconstrictive and multifunctional peptide. Elevated concentrations have been reported in congestive heart failure. We hypothesized that the level of endothelin-1 in plasma is a prognostic marker in congestive heart failure.. Plasma levels of endothelin-1 were measured by radioimmunoassay in 120 congestive heart failure patients with ischaemic or non-ischaemic cardiomyopathy (mean ejection fraction 28 +/- 11%, in New York Heart Association (NYHA) functional class I:21, class II 35, class III: 61, class IV: 3). During a median follow-up of 361 +/- 338 days, 14 cardiac deaths occurred. In the univariate Cox model, endothelin-1 was the most powerful prognostic marker among the variables tested (P = 0.0001). A multivariate model, including plasma atrial natriuretic peptide and noradrenaline, NYHA class, age, and echocardiographic left ventricular end-diastolic diameter index was highly predictive of mortality (P = 0.00008), but only endothelin-1 remained significantly associated with outcome (P = 0.02). Patients with plasma endothelin-1 > or = 5 pg. ml-1 had a higher mortality rate than those with endothelin-1 < 5 pg. ml-1 (21% vs 4%, P = 0.001).. Our results suggest that elevated endothelin-1 plasma levels are associated with a poor prognosis and routine plasma endothelin-1 determination provides important prognostic information in mild to moderate heart failure.

Topics: Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Death; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Norepinephrine; Prognosis; Radioimmunoassay; Survival Rate

The results of early acute haemodynamic studies with anti-endothelin agents are promising. Much still needs to be done, however, before endothelin antagonism is established as a therapeutic strategy in heart failure. We need to know, for example, whether the haemodynamic effects of anti-endothelin drugs are sustained. We need to ensure that there is no reflex activation of other neuroendocrine systems and, preferably, to demonstrate neuroendocrine suppression. Characterisation of the renal actions of endothelin receptor antagonists will also be important. Perhaps the most pressing issue in the development of these agents is elucidation of the role of the endothelial ETB receptor in heart failure. It is now clearly shown that vascular smooth muscle ETB receptors can mediate vasoconstriction in human blood vessels and that these receptors may be particularly important in heart failure. The effect of selective ETB receptor blockade in humans in vivo is not currently known, however, and whether endothelial ETB receptors might tonically offset ETA and ETB receptor mediated smooth muscle contraction remains conjectural. This question is directly relevant to whether selective ETA or non-selective ETA and ETB receptor antagonism might be the better therapeutic strategy in heart failure. ECE inhibition may become another therapeutic option in due course, but at present no specific and selective inhibitors of the enzyme have been developed. The recent demonstration that the selective ETA receptor antagonist BQ-123 improves long term survival in rats with heart failure induced by myocardial infarction suggests that anti-endothelin strategies may hold great therapeutic promise in heart failure.

Topics: Aspartic Acid Endopeptidases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Heart Failure; Humans; Metalloendopeptidases; Peptides, Cyclic; Protease Inhibitors

Topics: Aging; Angiotensin II; Animals; Bosentan; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Mice; Mice, Transgenic; Rabbits; Receptors, Endothelin; Sulfonamides

Plasma levels of endothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present project tested the hypothesis that chronic blockade of the ETA receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF.. Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400 bpm, 3 weeks), RVP and concomitant administration of the selective ETA receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17 +/- 5 versus 42 +/- 3%) and end-diastolic dimension increased (2.36 +/- 0.44 versus 1.24 +/- 0.18 cm) compared with controls (P < .05). With RVP plus ETA blockade, LV fractional shortening was increased (33 +/- 6%) and end-diastolic dimension decreased (2.02 +/- 0.30 cm) compared with RVP-only values (P < .05). Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ETA blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42 +/- 13 versus 72 +/- 10 microns/s, P < .05) compared with controls but was normalized with RVP plus ETA blockade (77 +/- 16 microns/s). Myocyte inotropic response to extracellular Ca2+, beta-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ETA receptor blockade.. The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ETA receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ETA receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.

Topics: Animals; Cardiac Pacing, Artificial; Cells, Cultured; Dioxoles; Disease Progression; Drug Evaluation, Preclinical; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Myocardial Contraction; Myocardium; Norepinephrine; Rabbits; Receptor, Endothelin A; Renin; Ventricular Function, Left

We studied the effect of congestive heart failure (CHF) on the tissue levels of endothelin 1 (ET-1) and of the mRNA of prepro-ET-1 in the rat. Congestive heart failure was produced by ligation of the left coronary artery. The rats were killed 3 weeks after the ligation. Congestive heart failure was determined by elevated plasma atrial natriuretic peptide and by a myocardial infarction scar covering more than 30% of the left ventricular circumference. Both ET-1 and prepro-ET-1 mRNA were measured in cardiac ventricles and lungs by radioimmunoassay and quantitative polymerase chain reaction. The rats with CHF had an increased heart weight/body weight ratio and elevated plasma atrial natriuretic peptide levels. In rats with CHF, as compared to controls, the concentration of ET-1 was elevated 3.6-fold in pulmonary tissue and 1.4-fold in the right ventricle, respectively, but not in the left ventricle. The concentration of mRNA showed a similar pattern, but due to methodological limitations this was assumed to represent a rough estimate only. The enhanced production of ET-1 in the right ventricle and in the pulmonary tissue may be of pathophysiological importance for the development of high pulmonary vascular resistance in CHF.

Topics: Animals; Endothelin-1; Endothelins; Heart Failure; Lung; Male; Myocardium; Protein Precursors; Rats; Rats, Wistar; Ventricular Function, Right

Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.. Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.. Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiac Volume; Chronic Disease; Collagen; Consciousness; Coronary Vessels; Cyclic GMP; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Heart Ventricles; Male; Myocardial Infarction; Myocardium; Norepinephrine; Pressure; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Survival Analysis; Ventricular Function, Left

Increased myocardial expression of preproendothelin-1 (ppET-1) mRNA has been associated with congestive heart failure (CHF) in rats. However, the time course and isoform pattern of ppET mRNA induction and the cellular localization of ET in failing hearts are unknown. Thus our aim was to investigate myocardial ppET mRNA expression in CHF rats during the first 6 wk after induction of myocardial infarction. Furthermore, performing immunohistochemical analysis, we also investigated the origin and localization of immunoreactive endothelin (ET) in different regions of the failing heart. Ribonuclease protection assays revealed a marked increase in ppET-1 mRNA levels in rat myocardial tissues during CHF. The induction of ppET-1 mRNA was isopeptide specific and transient. The most substantial upregulation was observed in the infarcted area, where maximal expression of ppET-1 mRNA was observed after 7 days (25-fold increase, P < 0.05). However, a marked and statistically significant induction of ppET-1 mRNA was also observed in the nonischemic myocardium. Immunohistochemical analysis revealed ET-1-like immunoreactivity in cardiomyocytes, vascular endothelial cells, macrophages, and proliferating fibroblasts. Thus immunohistochemistry revealed the structural basis for the dramatic upregulation of the myocardial ET system in the infarcted region, suggesting a role for ET in the healing process after myocardial infarction. However, the global upregulation of ppET-1 mRNA in the heart also suggests an autocrine/paracrine regulatory mechanism in the nonischemic myocardium during CHF.

Topics: Animals; Endothelin-1; Endothelins; Heart Failure; Hemodynamics; Immunohistochemistry; Isomerism; Male; Myocardium; Protein Precursors; Rats; Rats, Wistar; RNA, Messenger; Time Factors

This study sought to test the hypothesis that big endothelin-1 plasma levels in advanced heart failure are related to survival.. In heart failure, production of the potent vasoconstrictor endothelin-1 is increased. Because elevation of immunoreactive endothelin-1 in severe heart failure is primarily related to the precursor "big" endothelin-1, increased big endothelin-1 levels may be associated with a poor prognosis.. Plasma big endothelin-1 concentrations, in addition to 16 clinical, hemodynamic and neurohumoral variables, were obtained from 113 patients (mean age -=/[SEM] 53 +/- 1 years) with left ventricular ejection fraction <20% and were related to 1-year mortality by a stepwise Cox regression multivariate analysis.. Plasma big endothelin-1 concentrations were significantly higher in patients with moderate and severe heart failure than in those with mild heart failure (4.5 +/- 0.4 and 6.0 +/- 0.1 vs. 2.7 +/- 0.1 fmol/ml, p = 0.0001, respectively) and lower in 58 one-year survivors than in 29 nonsurvivors (2.6 +/- 0.1 vs. 5.9 +/- .04 fmol/ml, p = 0.0001) and 26 heart transplant recipients. By univariate analysis, big endothelin-1 plasma concentrations (p < 0.0001), functional class, daily furosemide dose, left ventricular ejection fraction, most hemodynamic variables and plasma atrial natriuretic peptide, sodium renin activity and aldosterone levels were all related to mortality, but only functional class provided additional prognostic information when big endothelin-1 plasma levels were entered into the multivariate model.. In advanced heart failure, plasma big endothelin-1 is strongly related to survival and appears to predict 1-year mortality better than hemodynamic variables and levels of atrial natriuretic peptide, an established neurohumoral prognostic marker in chronic heart failure.

Topics: Adult; Aged; Atrial Natriuretic Factor; Endothelin-1; Endothelins; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Protein Precursors; Severity of Illness Index; Survival Analysis

Although it was demonstrated that circulating endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelin(A) (ETA) receptor antagonist, on both heart and myocardial contractility in rats with CHF.. We used the left coronary artery-ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression prepro-ET-1 mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500+/-41 versus 102+/-10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243+/-20 versus 155+/-17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg x kg(-1) x min(-1) for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP x dt(max) (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats.. In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor-mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.

Topics: Animals; Endothelin-1; Endothelins; Heart; Heart Failure; Hemodynamics; Male; Peptides, Cyclic; Protein Precursors; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

In congestive heart failure, in addition to a compensatory increase in neurohumoral activation, there is an increase in the endothelial-derived vasoconstrictive and positive inotropic substance, endothelin. Whether downregulation of the cardiac inotropic effects of this endothelial-derived substance occurs, as has been shown to occur with neurohumoral beta- and alpha-adrenergic agonists, remains unknown. In this study we investigated the effects of endothelin-1 [dose-response curve (10(-11) to 10(-7) M)] on the contractile characteristics of isolated papillary muscles from normal dogs and from dogs with heart failure induced by pacing overdrive, with or without removing endocardial endothelium from the papillary muscles. Endothelin-1 caused a similar absolute increase in myocardial contractile indices in all four groups, except for shortening, which increased more in muscles with heart failure without endocardial endothelium. However, in muscles with an intact endocardial endothelium, the relative increase was greater in muscles from pacing overdrive dogs (failing) as compared with normal dogs (tension increase of 110% vs. 53%, p < 0.01 and shortening increase of 127% vs. 24%, p < 0.01). Also, failing muscles with intact endocardial endothelium began responding to endothelin-1 at lower endothelin-1 concentrations (10(-10) vs. 10(-9) M) than normal muscles with intact endocardial endothelium. Endocardial endothelial removal increased the contractile effects of endothelin-1, whether this was done in normal or failing myocardium. This study thus indicates that, in contrast to other positive inotropic substances, in this model of heart failure there is an increase in sensitivity and relative response to endothelin-1. It also indicates that although endocardial endothelial removal increases the relative effects of endothelin-1 in both normal and failing myocardium, the increased responsiveness of failing myocardium is not endocardial endothelial dependent.

Topics: Animals; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Down-Regulation; Endocardium; Endothelin-1; Endothelium; Heart Failure; In Vitro Techniques; Myocardial Contraction; Papillary Muscles

Neuropeptide Y (NPY) has been shown to potentiate the effects of various vasoactive agents in both in vitro and in vivo experiments. The present study was designed to investigate the potentiation effects of NPY on various vasoconstrictive agents and the influence of NPY on the dilatation effects of endothelin-1 in rats with congestive heart failure (CHF). CHF was induced by left coronary artery ligation. Sham-operated rats subjected to thoracotomy served as normal controls. Experiments in conscious rats were performed 4-6 weeks after coronary artery ligation or sham operation. The pressor responses of intravenous phenylephrine (12.5 nmol/kg), endothelin-1 (400 pmol/kg) and angiotensin II (10 ng) but not tyramine (40 micrograms) were significantly decreased in CHF rats compared with sham-operated rats (p < 0.01). In sham-operated rats, subthreshold dose of NPY (0.1 microgram/kg/min) potentiated the pressor responses of all the agonists (p < 0.05). In CHF rats, significant enhancement of mean arterial pressure (MAP) by subthreshold dose of NPY was observed with angiotensin II (p < 0.05). The MAP was enhanced by 45.4% in CHF and 40.6% in sham-operated rats respectively. NPY did not enhance the pressor responses induced by phenylephrine, endothelin-1 or tyramine in CHF rats. The initial decrease of MAP after bolus injection of endothelin-1 was observed in both CHF and sham-operated control rats, and magnitude of this response was similar in both groups. Subthreshold dose of NPY significantly reduced the vasodilatation effect of endothelin-1 in CHF (p < 0.05) but not in normal control rats. We conclude that NPY potentiates pressor effects of angiotensin II and reduces vasodilatation effects of endothelin-1 in rats with CHF. These effects of NPY may contribute to the increased vascular tone in CHF.

Topics: Animals; Blood Pressure; Cardiovascular System; Drug Synergism; Endothelin-1; Heart Failure; Heart Rate; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vasodilator Agents

The purpose of this study was to investigate whether 1) endothelin-1, a potent vasoconstrictor peptide, is involved in progression of pulmonary hypertension caused by congestive heart failure (CHF); and 2) whether long-term treatment with BQ-123, an endothelin receptor antagonist, ameliorates pulmonary hypertension caused by CHF.. Congestive heart failure accompanies pulmonary hypertension, and the severity of pulmonary hypertension is an important determinant of prognosis. Although we reported that production of endothelin-1 is increased in the failing heart in rats with CHF, it is not known whether production of endothelin-1 in the lung is altered by CHF.. Congestive heart failure was induced by coronary artery ligation in rats. Expression of preproendothelin-1 messenger ribonucleic acid (mRNA) in the lung and kidney was determined. Endothelin-1 staining (immunoreactivity) in the lung was studied by immunohistochemical analysis. Effects of long-term BQ-123 treatment on the rats were studied.. Two weeks postoperatively, CHF accompanied by pulmonary hypertension developed in the rats (CHF rats). Expression of preproendothelin-1 mRNA in the lung was markedly higher in the CHF rats than in the sham-operated rats, whereas that in the kidney did not differ between the two groups. Endothelin-1 staining on the pulmonary vascular endothelial cells was more intense in the CHF rats. BQ-123 treatment over a 2-week period in the CHF rats greatly reduced right ventricular systolic pressure and central venous pressure, but it did not affect blood pressure or left ventricular contractility (peak positive first derivative of left ventricular pressure) in these rats.. Long-term BQ-123 treatment greatly ameliorated pulmonary hypertension in the CHF rats. The present study suggests that endothelin-1 plays an important role in the progression of pulmonary hypertension caused by CHF and that an endothelin receptor antagonist may be a new therapeutic agent for CHF-induced pulmonary hypertension.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Kidney; Lung; Peptides, Cyclic; Protein Precursors; Rats; RNA, Messenger

Atrial natriuretic peptide (ANP) has been shown to counteract the response of endothelin-1 (ET-1), but whether endogenous ANP actually inhibits the systemic release of ET-1 in vivo has not yet been determined. We administered HS-142-1 (HS), a specific antagonist of the guanylate cyclase-coupled ANP receptor, to conscious dogs with severe congestive heart failure (CHF) produced by rapid right ventricular pacing (n = 5, for 22 days) at doses of 0.3, 1.0, and 3.0 mg/kg at 30-minutes intervals. In the present study, plasma ANP and ET-1 levels were significantly elevated in CHF(348 +/-58 and 4.54 +/- 0.60 pg/ml, respectively compared with those in control dogs (65 +/- 4, P < 0.01, 1.30 +/- 0.17 pg/ml, P < 0.001). HS inhibited plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels, a biological market of endogenous ANP activity, in a dose-dependent manner from 21.8 +/- 2.2 to 7.2 +/- 1.4 pmol/ml (P < 0.001), with concomitant significant increases in plasma ET-1 levels from 4.54 +/- 0.60 to 6.60 +/- 0.72 pg/ml (P < 0.05). There was a significant negative correlation between the decrease in plasma cGMP and the increment in plasma ET-1 (r = -0.64, P < 0.01). Despite these responses, mean arterial pressure and pulmonary arterial pressure did not change significantly. Plasma angiotensin II and arginine vasopressin levels, both of which have been reported to stimulate ET-1 secretion in vitro, also showed no significant changes. These results strongly suggest that endogenous ANP directly inhibits endogenous ET-1 secretion through a cGMP-mediated pathway in chronic severe CHF.

Topics: Animals; Atrial Natriuretic Factor; Dogs; Endocrine Glands; Endothelin-1; Heart Failure; Hemodynamics; Hormones; Polysaccharides

To ascertain the pathophysiological roles of the renin-angiotensin system and endothelin in heart failure and cardiac hypertrophy, we assessed changes in cardiac angiotensin converting enzyme (ACE) and endothelin-1 (ET-1) receptor using rats in which myocardial infarction was induced by left coronary ligation. The animals were decapitated 1 or 8 months after the operation. Cardiac ACE and ET-1 receptor were quantified by computerized in vitro autoradiography using 125I-MK351A (a lisinopril derivative) and 125I-ET-1. One month after myocardial infarction, cardiac weight and plasma atrial natriuretic peptide had increased in rats with infarction, compared to sham-operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium and plasma renin activity were unchanged. Cardiac ACE increased markedly in the infarcted area and moderately in hypertrophied myocardium without any change in affinity compared to sham-operated rats. On the other hand, there was no change in cardiac ET-1 receptors in infarcted rats. The same results were found even at 8 months after myocardial infarction. The present study indicates that cardiac ACE may participate in tissue repair at the site of myocardial infarction and may also play a role in the pathophysiology of cardiac hypertrophy in rats with chronic heart failure. However, the present results do not reveal whether ET-1 receptor participates in the pathophysiology of cardiac hypertrophy in this model.

Topics: Angiotensin II; Animals; Autoradiography; Cardiomegaly; Chronic Disease; Endothelin-1; Female; Heart Failure; Image Processing, Computer-Assisted; Iodine Radioisotopes; Ligation; Myocardial Infarction; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptors, Endothelin; Renin; Ventricular Function, Left

In vitro binding of (3-[125I]Tyr)-endothelin-1 ([125I]ET-1) and (3-[125I]Tyr)-big ET-1(1-38) ([125I]big ET-1) to plasma proteins of healthy humans, cardiac patients and normotensive and hypertensive rats was investigated by equilibrium dialysis. Binding of both tracers was similar in plasma from healthy humans, patients with congestive heart failure, and following myocardial infarction (approximately 60%), and marginally higher in rat plasmas (approximately 70%). Binding of [125I]ET-1 to human plasma could be explained by binding to human serum albumin. Endogenous plasma ET-1 levels were approximately 9 pg/ml in healthy humans, and approximately 12-16 pg/ml in cardiac patients; big ET-1 concentrations were approximately two- to threefold higher. ET-1 bound to plasma protein was partly lost in column extraction. In rat isolated perfused hearts, the coronary dilator and constrictor potency of exogenous free and albumin-bound ET-1 was similar, whereas the kinetics of endogenous ET-1 was impeded by tight binding to ET receptors. The data indicate that binding of ET-1 to plasma proteins is without effect on peptide vasoactivity, but binding to tissue receptors greatly impedes its tissue kinetics.

Topics: Animals; Blood Proteins; Endothelin-1; Endothelins; Female; Heart Failure; Humans; In Vitro Techniques; Iodine Radioisotopes; Kinetics; Male; Myocardial Contraction; Myocardial Infarction; Protein Binding; Protein Precursors; Rats; Reference Values; Serum Albumin; Serum Albumin, Bovine; Sex Characteristics; Vasoconstrictor Agents; Vasodilator Agents

The present study was designed to evaluate the effects of big endothelin (ET) on renal hemodynamics and excretory functions in rats with experimental congestive heart failure (CHF) produced by aortocaval fistula. Clearance studies were performed in control and in chronic (7 day) CHF rats. Administration of bit ET (1 and 3 nmol/kg, i.v.) to control rats caused an increase (29%) in mean arterial pressure (MAP) associated with a decrease (38%) in renal blood flow (RBF) and a marked increase (130%) in renal vascular resistance (RVR). These changes were accompanied by a decrease in glomerular filtration rate (GFR) and a significant increase in sodium excretion. In contrast, the effects of big ET on MAP and renal hemodynamics were blunted in CHF rats, and sodium excretion increased only minimally in response to big ET despite a significant increase in GFR. The data suggest that rats with CHF have reduced sensitivity to the vascular and renal action of ET.

Topics: Animals; Endothelin-1; Endothelins; Glomerular Filtration Rate; Heart Failure; Kidney; Male; Protein Precursors; Rats; Rats, Wistar; Renal Circulation

Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction.. The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts.. The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Topics: Chromatography, Gel; Endothelin-1; Endothelins; Female; Heart Failure; Humans; Immunohistochemistry; Male; Middle Aged; Myocardium; Protein Precursors; Radioimmunoassay; Ventricular Function, Left