endothelin-1 and Ventricular-Dysfunction--Left

Pulmonary hypertension (PH) is a frequent complication of left heart disease arising from a wide range of cardiac disorders. In the clinical classification, PH associated with left heart disease is classified as Group 2, which includes left heart systolic dysfunction, left heart diastolic dysfunction and left heart valvular disease. In the past, rheumatic mitral valve disease was the most common cause of PH in left heart disease; however, today it is more likely to be associated with hypertensive and/or ischaemic heart disease. As the incidence of these conditions is increasing, the number of patients presenting with PH is also increasing and, today, left heart disease represents the most frequent cause of PH. The development of PH in patients with left heart disease is associated with poor prognosis. However, despite the increasingly large number of patients affected and the impact of PH on outcome, there are currently no specific treatment options for these patients. This review gives an overview of the pathophysiology and epidemiology of PH associated with left heart disease, and discusses the challenges associated with its management and treatment.

Topics: Antihypertensive Agents; Bosentan; Echocardiography, Doppler; Electrocardiography; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Exercise Test; Heart Valve Prosthesis; Humans; Hypertension, Pulmonary; Mitral Valve; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Wedge Pressure; Radiography, Thoracic; Stroke Volume; Sulfonamides; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Left; Weight Loss

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

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

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

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

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

The aim of our research was to assess the role of vasoactive factors of endothelium (NO and endothelin-1) during diastolic dysfunction of the left ventricle and to determine the effects of nebivolol in the early treatment period of endothelial dysfunction. In the investigation were included 36 male patients (mean age 49+/-6 years) with LVDD due to CAD (22 patients) and essential hypertension (14 patients) as well as in 18 male patients (control group, 12 patients with CAD and 6 with hypertension) without LVDD of matched age, who underwent 2 week treatment with 5 mg nebivolol (Nebilet, Berlin-Chime) . The endothelial dysfunction was assessed by (a) a noninvasive method, brachial artery ultrasound during reactive hyperemia, measured by flow-mediated vasodilatation (FMD), which indirectly reflects the amount of NO and (b) measurement of the amount of ET-1 in the plasma by method of an enzyme-linked immunoassay (ELISA). According to the results of our studies FMD (%) was increased by 73% among the patients with DD of LV whereas among the patients without DD was increased by 66% (p<0,05). Furthermore, statistically none significant decrease of endothelin-1 levels were observed and no difference was found among the groups of patients. Importantly, statistically significant increase of early ventricular filling was found: E/A ratio with Doppler echocardiography at the end of 2 week period treatment reached 1,10+/-0,04 vs. 0,92+/-0,01 before the treatment (p<0,05). Positive correlation was found between FMD (%) and the relaxation capability of the left ventricle (r=0,38, p<0,05). Based on these results we can conclude that endothelial dysfunction might be indicator of LVDD, and by treating the former we can prevent the diastolic dysfunction.

Topics: Benzopyrans; Endothelin-1; Endothelium, Vascular; Ethanolamines; Female; Humans; Male; Middle Aged; Nebivolol; Nitric Oxide; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left

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

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

Plasma levels of immunoreactive endothelin-1 (ET-1) are elevated in chronic heart failure (CHF) and have been reported to correlate closely with pulmonary hemodynamic measurements. We investigated the effects of exogenous ET-1 on the pulmonary vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. ET-1 was infused at 1, 5, and 15 pmol/min into a distal pulmonary artery of 10 patients with LVD. Hemodynamics were measured by a thermodilution catheter and arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. Systemic hemodynamic changes occurred with ET-1 infusion in a dose-dependent fashion. Mean arterial pressure (100 +/- 8-107 +/- 11 mm Hg; p < 0.01) and systemic vascular resistance (1,699 +/- 375-2,033 +/- 427 dynes/s/cm-5; p < 0.001) rose, whereas the cardiac index fell from 2.43 +/- 0.53 to 2.20 +/- 0.491/min/m2 (p < 0.002). However, mean pulmonary artery pressure (21 +/- 7 mm Hg) and pulmonary vascular resistance (151 +/- 43-147 +/- 43 dynes/s/cm-5) did not change. Exogenous ET-1, when infused into patients with LVD, causes systemic but not pulmonary vasoconstriction.

Topics: Aged; Angiography; Endothelin-1; Hemodynamics; Humans; Male; Middle Aged; Nitroprusside; Pulmonary Circulation; Ventricular Dysfunction, 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

Although considerable research highlights the interactions between obstructive sleep apnea-hypopnea syndrome (OSAHS) and cardiovascular diseases, the effect of mandibular advancement device (MAD) treatment on cardiovascular complications in OSAHS patients remains unclear. We evaluated the effect of OSAHS treatment with MADs on the myocardium. All methods in this study were in accordance with relevant guidelines and regulations of the medical ethics committee in Hospital of Stomatology, Hebei Medical University approved the work. Thirty New Zealand rabbits were randomized into three groups: the control group, Group OSAHS, and Group MAD. Hydrophilic polyacrylamide gel was injected into the soft palate of the rabbits to induce OSAHS. In Group MAD, a MAD was positioned after OSAHS induction. All animals were induced to sleep in a supine position for 4-6 h/day for 8 weeks. Echocardiography was used to determine the structure and function of the heart. The histological changes were detected by optical microscopy and transmission electron microscopy (TEM). The levels of ET-1(endothelin-1) and Ang II (Angiotensin II) in the plasma were measured by an enzyme-linked immunosorbent assay (ELISA). The expression of ET-1 mRNA in heart tissue was detected by RT-PCR. Histological abnormalities, left ventricular hypertrophy, and left ventricular dysfunctions were demonstrated in Group OSAHS, and the abnormities were rescued with MAD treatment. Higher levels of plasma ET-1 and Ang II and elevated expression of ET-1 mRNA in cardiac tissue were detected in Group OSAHS compared with Group MAD and the control group. The blood oxygen saturation was negatively correlated with the levels of ET-1 and Ang II. OSAHS-induced elevated levels of ET-1 and Ang II may be attributed to myocardial structural abnormalities and dysfunction. Early treatment of MADs may play an important role in preventing myocardial damage in OSAHS rabbit model.

Topics: Acrylic Resins; Angiotensin II; Animals; Cytokines; Echocardiography; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Heart; Male; Myocardium; Occlusal Splints; Polysomnography; Rabbits; RNA, Messenger; Sleep Apnea, Obstructive; Ventricular Dysfunction, Left

In chronic kidney disease (CKD), endothelin-1 (ET-1) always increases and there are changes in cardiac ultrasonography. In the present study, we aimed at investigating the role of serum ET-1 in predicting cardiac complications in patients with CKD.. The level of serum ET-1 was measured by enzyme-linked immunosorbent assay (ELISA) and cardiac ultrasonography was performed in enrolled patients. Indexes of heart failure, such as left ventricular mass index, interventricular septum thickness and left ventricular end diastolic diameter, were measured in patients with CKD.. In the present study, we found that the level of serum ET-1 was significantly correlated with left ventricular mass index, interventricular septum thickness and left ventricular end diastolic diameter (p < .001) in non-dialysis patients with CKD.. The results of the present study indicated that the level of serum ET-1 is closely related to the cardiac complications of CKD and is a useful predictor of cardiac complication.

Topics: Adult; Echocardiography; Endothelin-1; Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Insufficiency, Chronic; Ventricular Dysfunction, Left; Ventricular Remodeling; Ventricular Septum

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

Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho-kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho-kinase inhibitors could ameliorate PVR, little is known about the role of Rho-kinase in left ventricular dysfunction-induced PH. We utilized the ascending aortic-banded rat and assessed the effect of Rho-kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho-kinase II, Rho-kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho-kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho-kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arterioles; Cyclic GMP; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Kinase Inhibitors; Pulmonary Artery; Rats; Rats, Wistar; rho-Associated Kinases; Treatment Outcome; Ventricular Dysfunction, Left

Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET(A) receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1  nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt(max)) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET(B) receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET(A) receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET(B) receptors to exert its related beneficial actions.

Topics: Animals; Aspartic Acid Endopeptidases; Atrasentan; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Male; Metalloendopeptidases; Myocardial Reperfusion Injury; Norepinephrine; Pyrrolidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Sulfonylurea Compounds; Ventricular Dysfunction, Left

Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.

Topics: Allopurinol; Analysis of Variance; Animals; Antioxidants; Atrasentan; Biomarkers; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gout Suppressants; Hypertrophy, Left Ventricular; Hyperuricemia; Isoprostanes; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Superoxides; Time Factors; Up-Regulation; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Xanthine Oxidase

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

To determine whether a tendency to angry rumination predicts anger recall (AR) stress-provoked increase in endothelin (ET)-1 among patients with coronary heart disease (CHD).. Patients with chronic stable CHD (n = 105) completed a five-item measure of tendency to angry rumination (DAB-VR) and underwent a laboratory AR stress protocol (15-minute resting baseline [BL], 8-minute AR). Blood samples drawn at end of BL and AR were assayed for ET-1. Change in ET-1 from BL to AR (increase versus decrease/no change) was treated dichotomously in multivariate logistic regression models, including DAB-VR score and potential confounders, to evaluate the contribution of DAB-VR to the prediction of change in ET-1.. In the multivariate model, DAB-VR score significantly predicted ET-1 increase (odds ratio, 1.34; 95% confidence interval, 1.10-1.1.63; p = .004), controlling for age, history of diabetes, hypercholesterolemia, rate pressure product, use of beta blockers, and statins.. A tendency to angry rumination independently predicted AR stress-provoked ET-1 increase among patients with CHD. Given the involvement of ET-1 in plaque rupture, anger rumination tendency may identify vulnerability to anger-triggered acute coronary syndrome through prolongation of initial anger mobilization. The contribution of ruminative thinking to sustained poststress ET-1 elevation and the synergistic relationship of ET-1 during emotional stress with norepinephrine and nitric oxide remain to be explored.

Topics: Aged; Anger; Coronary Disease; Data Collection; Electrocardiography; Endothelin-1; Female; Health Status; Humans; Male; Mental Recall; Middle Aged; Norepinephrine; Risk Assessment; Risk Factors; Stress, Psychological; Thinking; Ventricular Dysfunction, Left

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

Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged tau and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

Topics: Animals; Apoptosis; Collagen; Diastole; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Male; Monocrotaline; Myocardial Contraction; Myocardium; Myosin Heavy Chains; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Systole; Tenascin; Time Factors; Ventricular Dysfunction, Left; Ventricular Pressure

The treatment of end-stage heart failure can include heart transplantation. During this procedure, cardiac lymphatics are disrupted, which has been demonstrated in animal models to alter left ventricular function, and this compromise itself can cause an increase in endothelin-1 and angiotensin II. We undertook a study in rabbits to assess the effect of cardiac lymphatic obstruction on left ventricular function and plasma levels of endothelin-1 and angiotensin II. Sixty-three New Zealand white rabbits were divided into study (n = 41) and control (n = 22) groups. Plasma levels of endothelin and angiotensin II were measured before, and at 3, 7, 14, 30, 90 and 180 days following the obstruction of cardiac lymphatic vessels. Left ventricular function was assessed by echocardiography. Six months following the surgery, 18 study and 6 control animals survived. In the study group, a significant decrease was seen in left ventricular ejection fraction within the first three months following the lymphatic obstruction (0.76 +/- 0.04 vs 0.72 +/- 0.01, p < 0.01). Levels of plasma endothelin-1 and angiotensin II were elevated following ligation of cardiac lymphatic vessels with a peak between 3-7 days following lymphatic obstruction (all p < 0.05). Plasma endothelin-1 and angiotensin II began to decline 14 days after lymphatic obstruction and returned to almost baseline levels in 6 months. The left ventricular ejection fraction, plasma endothelin-1 and angiotensin in the control group remained unchanged (all p > 0.05). We conclude that cardiac lymphatic obstruction reduces left ventricular function in the first three months following obstruction. Cardiac lymphatic obstruction also increases plasma levels of endothelin-1 and angiotensin II. The clinical significance of these transitory changes requires further investigation.

Topics: Angiotensin II; Animals; Endothelin-1; Female; Heart Diseases; Lymphatic Diseases; Male; Rabbits; Stroke Volume; Ventricular Dysfunction, Left

Endothelin-1 (ET-1) exhibits potent proinflammatory and profibrotic properties. Moreover, inflammation is a potent stimulus for inducible NO synthase (iNOS), which has been shown to contribute to cardiac injury. We thus hypothesized that ET-1-induced cardiac injury is attenuated by concomitant lack of iNOS. We established crossbred animals of ET-1 transgenic mice (ET+/+) and iNOS knockout mice (iNOS-/-). At 13 months of age, mice were allocated according to their genotype to one of 4 study groups: wild type (WT) controls (n=8); ET-1 transgenic (ET+/+) mice (n=10); iNOS knockout (iNOS-/-) mice (n=7); and crossbred (ET+/+ iNOS-/-) mice (n=15). Left ventricular function was determined in vivo by using a tip catheter. Animals were subsequently euthanized and hearts were harvested for weight assessment and histologic evaluation. No cardiac hypertrophy was present, as evidenced by similar mean cardiac weight and myocyte diameter in all groups. Cardiac perivascular fibrosis was significantly increased in ET+/+ and iNOS-/- groups versus WT, whereas ET+/+ iNOS-/- mice did not differ from WT. Regarding left ventricular function, plasma B-type natriuretic peptide was elevated in ET+/+ and iNOS-/- mice, but again in crossbred animals this effect was blunted. Heart catheterization revealed a significantly increased stiffness constant in both ET-overexpressing groups versus WT, but this increase was significantly attenuated in the ET+/+iNOS-/- group versus the ET+/+ group. Parameters indicating systolic heart failure (EF, cardiac output), however, were not different between all study groups. Our study demonstrates that ET transgenic mice develop left ventricular stiffening with subsequent diastolic dysfunction in a slow, age-dependent manner. Additional knock out of iNOS significantly attenuates cardiac injury. We thus conclude that ET-1-induced cardiac injury is at least partially mediated by iNOS.

Topics: Aging; Animals; Diastole; Endothelin-1; Mice; Mice, Knockout; Mice, Transgenic; Myocardium; Natriuretic Peptide, Brain; Nitric Oxide Synthase Type II; Ventricular Dysfunction, Left

Cardiac inflammation and generation of oxidative stress are known to contribute to doxorubicin (Dox)-induced cardiomyopathy. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signalling, we investigated whether or not TLR4 is involved in Dox-induced cardiotoxicity.. Five days after a single injection of Dox (20 mg/kg; i.p.), left ventricular pressure-volume loops were measured in wild-type and TLR4-deficient mice (TLR4-/-) Dox-treated and control mice. Analyses of possible pathophysiological mechanisms were performed in left ventricular tissue and isolated myocytes, respectively. Dox injection resulted in an impairment of left ventricular function and neurohumoral activation, indexed by increased ET-1 expression. This was further associated with an increase in cardiac oxidative stress, inflammation and apoptosis, as indicated by an up-regulation of cardiac lipid peroxidation, TNF-alpha expression and enhanced content of TUNEL-positive cells. In contrast, TLR4-/- Dox mice showed improved left ventricular function with reduced oxidative and inflammatory stress response including reduced cardiac apoptosis. These results were found to be associated with an increase of GATA-4 expression.. TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in Dox-induced cardiomyopathy.

Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Endothelin-1; GATA4 Transcription Factor; In Situ Nick-End Labeling; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Mice, Knockout; Toll-Like Receptor 4; Tyrosine; Ventricular Dysfunction, Left

It has been reported that high intramyocardial peroxisome proliferator-activated receptor alpha (PPARalpha) stimulation or overexpression altered cardiac contractile function in mouse models of cardiac hypertrophy and heart failure. Nevertheless, it has never been demonstrated that clinically relevant doses of drugs stimulating PPARalpha activity such as fenofibrate increase the risk to develop heart failure in humans. To determine if fenofibrate accelerates the development of heart failure in large mammals, we have tested its effects on the progression of left ventricular dysfunction in pacing-induced heart failure in pigs. Fenofibrate treatment blunted reduction in left ventricular ejection fraction, reduced cardiac hypertrophy, and attenuated clinical signs of heart failure. Fenofibrate impeded the increase in atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 plasma levels. The expression of PPARalpha, fatty acyl-CoA-oxidase, and carnitine palmitoyltransferase-Ibeta was reduced at mRNA levels in the left ventricle from untreated heart failure pigs but maintained near normal values with fenofibrate. Fenofibrate prevented heart failure-induced overexpression of TNFalpha mRNA and enhanced catalase activity in left ventricle compared to placebo. These data suggest that a clinically relevant dose of fenofibrate does not accelerate but slows down heart failure development in the model of pacing-induced heart failure in large mammals.

Topics: Acyl-CoA Oxidase; Animals; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Cardiomyopathies; Carnitine O-Palmitoyltransferase; Endothelin-1; Female; Fenofibrate; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; PPAR alpha; RNA, Messenger; Swine; Tachycardia; Thiobarbituric Acid Reactive Substances; Ventricular Dysfunction, Left

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg.kg(-1).day(-1)). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ET(A) and ET(B) receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.

Topics: Animals; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Male; Rats; Up-Regulation; Ventricular Dysfunction, Left; Ventricular Remodeling

Pressure overload in the left ventricle of the heart follows a chronic and progressive course, resulting in eventual left heart failure and pulmonary hypertension (PH). The purpose of this research was to determine whether a differential pulmonary gene change of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) occurred in adult rats with left ventricular overload. Eight groups of eight rats each were used (four rats with banding and four rats with sham operations). The rats underwent ascending aortic banding for 1 day, 2 weeks, 4 weeks, and 12 weeks before sacrifice. Significant medial hypertrophy of the pulmonary arterioles developed in two groups (4 and 12 weeks). Increased pulmonary arterial pressures were noted in three groups (1 day, 4 weeks, and 12 weeks). The aortic banding led to significant increases in pulmonary preproET-1 messenger RNA (mRNA) at 1 day and 12 weeks, and in pulmonary eNOS mRNA at 1 day and 12 weeks. In addition, there was increased pulmonary eNOS content at 1 day and 12 weeks in the banded rats, and increased lung cGMP levels were observed at 1 day. Increased lung ET-1 levels were also noted at 1 day (banded, 310 +/- 12 ng/g protein; sham, 201 +/- 12 ng/g protein; P < 0.01), 4 weeks (banded, 232 +/- 12 ng/g protein; sham, 201 +/- 12 ng/g protein; P < 0.01) and 12 weeks (banded, 242 +/- 12 ng/g protein; sham, 202 +/- 12 ng/g protein; P < 0.01). This indicates that the upregulated expression of ET-1 developed at least 4 weeks before eNOS expression in the course of PH, and, thus, medication against ET-1 could play a crucial role in treating PH with cardiac dysfunction secondary to aortic banding.

Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Lung; Male; Nitric Oxide Synthase Type III; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Ventricular Dysfunction, Left

Pulmonary hypertension (PH) usually develops secondary to left ventricular (LV) dysfunction; therefore, it is also called retrograde PH. To investigate our hypothesis that PH is at least partially reversible, as in some congenital heart diseases, in a rat model we investigated whether release of constriction could attenuate pulmonary vascular remodeling and change the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). We used rats with LV dysfunction produced by an ascending aortic banding. In this study, there were four groups enrolled: 4-weeks banded (AOB(1-28); n = 7), 7-weeks banded (AOB(1-49); n = 7), debanded groups (AOB(1-28)/DeB(29-49); n = 7), and rats receiving a sham operation (n = 7). Subsequently, there was significant attenuation of medial hypertrophy in pulmonary arterioles and reversal of PH in the AOB(1-28)/DeB(29-49) group (sham, 19 +/- 1.3 mm Hg; AOB(1-28), 31 +/- 2.7 mm Hg; AOB(1-49), 32 +/- 2.7 mm Hg; and AOB(1-28)/DeB(29-49), 20 +/- 1.3 mm Hg). PreproET-1 mRNA and eNOS mRNA were measured by competitive reverse transcriptase (RT) polymerase chain reaction (PCR), and eNOS was measured by Western blotting. Compared with the banded groups, debanding significantly decreased pulmonary preproET-1 mRNA, pulmonary ET-1 (sham, 210 +/- 12 pg/g protein; AOB(1-28), 242 +/- 12 pg/g protein; AOB(1-49), 370 +/- 49 pg/g protein; and AOB(1-28)/DeB(29-49), 206 +/- 1.9 pg/g protein), and plasma ET-1 levels (sham, 10.1 +/- 1.5 pg/ml; AOB(1-28), 13.4 +/- 2.0 pg/ml; AOB(1-49), 15.4 +/- 2.0 pg/ml; and AOB(1-28)/DeB(29-49), 10.3 +/- 0.9 pg/ml protein). Debanding could not, however, alter pulmonary eNOS, eNOS mRNA, or cGMP. These findings suggest that pulmonary vascular remodeling, increased pulmonary arterial pressure, and upregulation of ET-1 gene expression are all reversible. We infer that it is the upregulated gene expression of ET-1, not eNOS, that is closely related to the development of the PH secondary to 4 weeks of aortic banding.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Ventricular Dysfunction, Left

The bioactive peptide endothelin modulates left ventricular function by changing afterload, coronary vascular tone, and myocardial contractility. However, whether increased plasma endothelin levels observed in patients during and after coronary revascularization and cardiopulmonary bypass reflect actual myocardial interstitial levels are unknown.. A microdialysis probe (outer diameter: 0.77 mm; length: 4 mm) was placed in the left ventricular apical midmyocardium in 20 patients and myocardial interstitial fluid was collected (2.5 microL/min) at baseline and up to 30 minutes after cardiopulmonary bypass. Myocardial interstitial and systemic arterial endothelin were measured by radioimmunoassay.. Baseline myocardial interstitial endothelin was over 6-fold higher than plasma (20.11 +/- 2.07 vs 3.19 +/- 0.25 fmol/mL, P < .05). Plasma endothelin increased by 23% +/- 12% at 60 minutes of cardiopulmonary bypass whereas myocardial interstitial endothelin increased by 105% +/- 24%, P < .05), and this change was higher than in the plasma ( P < .05). Although no further change in plasma endothelin occurred during cardiopulmonary bypass, myocardial interstitial levels increased further after crossclamp removal (400% +/- 75%) and remained significantly higher than plasma at separation from cardiopulmonary bypass.. The unique findings of this study were 2-fold: First, significant compartmentalization of endothelin exists within the human myocardium. Second, a significantly higher and temporally disparate change in myocardial interstitial endothelin occurs during and after cardiopulmonary bypass when compared with systemic levels. These dynamic changes in myocardial endothelin likely influence coronary vascular tone and contractility.

Topics: Aged; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Endothelin-1; Female; Humans; Male; Microdialysis; Middle Aged; Myocardial Contraction; Myocardium; Postoperative Period; Ventricular Dysfunction, Left

Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350-400 g) were anesthetised using Nembutal (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1 (bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation.

Topics: Animals; Endothelin-1; Enzyme Activation; Hemodynamics; Male; Mitogen-Activated Protein Kinases; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Phosphorylation; Rats; Rats, Sprague-Dawley; Sepsis; tau Proteins; Ventricular Dysfunction, Left

We examined the role of endothelial dysfunction in the development and progression of cardiorenal syndrome in 93 patients with type 1 diabetes mellitus.. According to the stage of renal insufficiency all patients were divided into equal groups: those with normal albumin excretion rate, with microalbuminuria, with proteinuria, and with chronic renal failure. We analyzed endothelial flow-mediated dilation of the brachial artery, levels of endothelin-1, von Willerbrand factor, C-reactive protein, renal:albumin and protein excretion rates, glomerular filtration rate (GFR), and cardiovascular (ECG, echocardiography, blood pressure monitoring) functions.. There were negative correlations between the GFR, BP level and endothelial dysfunction markers. At the same time GFR correlated positively with the coefficient of sensitivity of endothelium to shear stress. There were also positive correlations between BP, permeability of glomerular filter and endothelial dysfunction markers and negative correlation with the coefficient of sensitivity of endothelium to shear stress and GFR. Left ventricle mass correlated with markers of endothelial dysfunction and stage of renal disease. Patients with chronic renal failure had negative correlations between LVM and GFR, ILVM and GFR and a positive correlation between ejection fraction and GFR.. There is a close relationship between endothelial dysfunction and development and progression of renal and cardiovascular pathology in patients with type 1 diabetes mellitus.

Topics: Adolescent; Adult; Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Echocardiography; Endothelin-1; Endothelium, Vascular; Female; Glomerular Filtration Rate; Heart Diseases; Humans; Male; Middle Aged; Ventricular Dysfunction, Left; Ventricular Function, Left

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

Rapid hemodynamic deterioration is caused by induction of brain death, but the exact mechanism is still uncertain. The aim of this study was to investigate the contribution of endothelin-1 by using endothelin-1 receptor antagonist (TAK-044) in a canine brain-death model.. Dogs were divided into 2 groups: (1) the TAK group, in which TAK-044 was intravenously injected 30 minutes before brain-death induction at a dose of 3 mg/kg; and (2) the control group. Brain death was induced by rapid inflation of a sub-durally placed balloon catheter. Left ventricular function and coronary flow reserve was compared between the 2 groups.. Brain death caused a transient hyperdynamic response followed by hemodynamic deterioration after 60 minutes in both groups. Left ventricular function, evaluated by the slope of the end-systolic pressure-volume relation was significantly decreased from 7.7 +/- 0.6 to 3.7 +/- 0.3 mm Hg/ml (p < 0.01) in the control group, but was not decreased in the TAK group (7.7 +/- 0.8 to 7.3 +/- 0.9 mm Hg/ml, p = 0.75). Coronary flow reserve, measured by direct injection of acetylcholine (3 microg) into the coronary artery, was significantly reduced at 60 minutes after brain death in the control group (264.8% to 176.6%, p < 0.01), but not in the TAK group (291.2% to 301.3%, p = 0.84). Exactly the same results were obtained when sodium nitroprusside (SNP; 100 microg) was administered.. TAK-044 can prevent the deterioration of left ventricular function and coronary flow reserve that follows induction of brain death, suggesting that endothelin-1 could play an important role in hemodynamic deterioration by impairment of coronary microcirculation after brain death.

Topics: Animals; Brain Death; Cardiovascular Agents; Coronary Circulation; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Epinephrine; Hemodynamics; Norepinephrine; Peptides, Cyclic; Ventricular Dysfunction, Left; Ventricular Function, Left

1. Peroxisome proliferator activated receptor gamma (PPARgamma) has been implicated in several cellular pathways assumed to beneficially affect heart failure progression. In contrast, population-based studies demonstrate an increased incidence of heart failure in patients treated with PPARgamma agonists. Therefore, we examined the effect of pioglitazone, a PPARgamma agonist, on chronic left ventricular remodeling after experimental myocardial infarction (MI) in mice. 2. Mice were treated with placebo or pioglitazone (20 mg x kg(-1) by gavage) from week 1 to week 6 after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at weeks 1, 3, and 6. 3. Over 6 weeks, there was no difference in mortality (placebo 12%, pioglitazone 10%). Echocardiography showed significant left ventricular dilatation in animals with MI (week 6, end-systolic area, placebo sham 9.6+/-1.3 vs placebo MI 14.4+/-2.5 mm(2)). However, there was no difference between the placebo and pioglitazone groups (week 6, end-systolic area, pioglitazone MI 14.8+/-2.9 mm(2), P=NS vs placebo). 4. Moreover, there were no changes in metabolic parameters, inflammation, and collagen deposition. Endothelial function in the aorta was not changed by PPARgamma activation. 5. In conclusion, PPARgamma activation did not adversely affect left ventricular remodeling and survival in mice with chronic MI. However, we were also not able to identify a protective effect of pioglitazone.

Topics: Animals; Aorta; Blood Glucose; Body Weight; Chronic Disease; Collagen; Coronary Vessels; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Echocardiography; Endothelin-1; Endothelium, Vascular; Inflammation Mediators; Intubation, Gastrointestinal; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Organ Size; Phenylephrine; Pioglitazone; Thiazolidinediones; Triglycerides; Vasoconstriction; Ventricular Dysfunction, Left; Ventricular Remodeling

Cardiac dysfunction has been reported in a substantial part of patients infected with the human immunodeficiency virus (HIV). However, most studies are from a time before the introduction of highly active antiretroviral treatment (HAART), which has significantly reduced HIV-associated morbidity and mortality rates. Accordingly, the prevalence of HIV-associated cardiac dysfunction may also have changed. The aim of the study was to establish the prevalence of right- and left-sided cardiac dysfunction in a Danish HIV population, most of whom were undergoing HAART, with radionuclide ventriculography.. Ninety-five consecutive patients with HIV infection were included. Mean HIV duration was 104 months, and 84% of the patients received HAART. All patients underwent radionuclide ventriculography, and plasma levels of atrial natriuetic peptide (ANP), brain natriuetic peptide (BNP), and endothelin-1 (ET-1) were measured. Thirty age- and sex-matched healthy volunteer subjects were included to establish reference values of radionuclide measurements of left and right ventricular ejection fraction and of left ventricular volume.. Of 95 patients with HIV, 1 (1%) had a reduced left ventricular ejection fraction and 6 (7%) had a reduced right ventricle ejection fraction (0.35-0.42) compared with reference values from the age- and sex-matched reference population. Patients with HIV and reduced cardiac function did not differ in the duration of HIV, CD4 count, CD4 nadir, or HIV RNA load. No correlations were found between reduced cardiac function and levels of the 3 peptides measured.. No major dysfunction of the left ventricle is present in a developed world HIV population. However, a small but significant part of this population has modestly reduced right-sided systolic function.

Topics: Adult; Antiretroviral Therapy, Highly Active; Atrial Natriuretic Factor; Denmark; Developed Countries; Endothelin-1; Female; HIV Infections; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Radionuclide Ventriculography; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right

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

We hypothesized that sepsis during hyperglycemia would activate left ventricular (LV) mitogen activated protein kinase (MAPK) signaling mechanisms and modulate generation of endothelin-1 (ET-1) and nitric oxide (NO) that can contribute to the progression of LV dysfunction. A single injection of streptozotocin (STZ, 60 mg/kg, via tail vein) was used to produce type 2 diabetes in male SD rats. Polymicrobial sepsis and sham-sepsis were induced using single i.p. injection of cecal inoculum and sterile 5% dextrose water, respectively, on the 13th and 27th day following STZ injection. Both 2-week (2-wk) and 4-wk diabetes groups were associated with hyperglycemia and weight loss. LV end diastolic pressure (LVEDP) was significantly increased in 4-wk diabetes but not in 2-wk diabetes group. Plasma concentration of tumor necrosis factor-alpha (TNF-alpha) was significantly increased in 4-wk diabetes+sepsis group as compared to sham, 2-wk diabetes+sepsis and sepsis groups. Elevated plasma and LV ET-1 and NO byproducts (NOx) along with LV preproET-1 and inducible nitric oxide synthase (iNOS) protein expression were observed in 4-wk but not in 2-wk diabetes group. Sepsis further elevated LV iNOS and preproET-1 in 4-wk diabetes group. Up-regulated phosphorylation of LV p38-MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein-27 (Hsp27) was observed in 4-wk diabetes group. Sepsis caused a factorial increase in LV p38-MAPK and Hsp27 phosphorylation and iNOS up-regulation but not ERK1/2 following progression from 2-wk to 4-wk diabetes. The study provides evidence that sepsis up-regulated LV iNOS, p38-MAPK phosphorylation and elevated LVEDP during 4-wk diabetes. We concluded that sepsis contributes in the development of LVEDP dysfunction and alteration in signaling mechanisms depending upon the progression from 2-wk to 4-wk diabetes in the rat.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Endothelin-1; Hyperglycemia; Male; Mitogen-Activated Protein Kinases; Myocardium; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Precursors; Rats; Rats, Sprague-Dawley; Sepsis; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Hypertension is associated with changes in concentrations of vasoactive peptides and procollagen propeptides, but their relationships with left ventricular hypertrophy and cardiac function are unclear.. We measured plasma levels of atrial natriuretic peptide (ANP), its amino terminal propeptide (NT-proANP), B-type natriuretic peptide (BNP), endothelin-1 (ET-1), and serum levels of the aminoterminal propeptide of type I procollagen (PINP) and the aminoterminal propeptide of type III procollagen (PIIINP) and echocardiographic parameters in 97 patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial.. Median values (reference values) of the peptides were: ANP 11.2 (6.9-14.9) pmol/l, NT-proANP 351 (143-311) pmol/l, BNP 1.1 (0.4-7.2) pmol/l, ET-1 8.7 (1.2-5.0) pmol/l, PIIINP 2.8 (1.7-4.2) microg/l and PINP 29 (19-84) microg/l. Plasma BNP levels in patients with left ventricular hypertrophy (1.2 pmol/l) and patients with echocardiographic signs of diastolic dysfunction (1.5 pmol/l) were greater than those in patients without hypertrophy (0.7 pmol/l) and normal diastolic parameters (0.9 pmol/l) (p<0.05). BNP was the only biochemical parameter that independently predicted interventricular septal diastolic diameter (p<0.05), left ventricular mass index (p<0.01) and ratio of the velocity-time integrals of the E and A waves of the mitral inflow in a stepwise logistic regression analysis (p<0.05).. The results show that BNP reflects the remodelling process in hypertension.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Diastole; Endothelin-1; Humans; Hypertension; Hypertrophy, Left Ventricular; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Procollagen; Protein Precursors; Ultrasonography; Ventricular Dysfunction, Left

Endothelin (ET) and natriuretic peptides have prognostic significance in chronic heart failure (CHF). Because stimuli for forming these neurohormones differ, this study investigates whether their prognostic power depends on clinical stage and on length of the observation period.. Plasma big ET, B-type natriuretic peptide (BNP), N-terminal BNP (N-BNP), and N-terminal atrial natriuretic peptide (N-ANP), in addition to 11 clinical and hemodynamic variables, were obtained from 452 patients with left ventricular ejection fraction (LVEF)

Topics: Biomarkers; Cardiac Output, Low; Chronic Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptides; Prognosis; Risk Factors; Ventricular Dysfunction, Left

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

Topics: Animals; Endothelin-1; Hypertension, Pulmonary; Nitric Oxide; Serotonin; Ventricular Dysfunction, Left

1. Using an in vivo model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction (LVD), the pulmonary arterial response to the nitric oxide synthase (NOS) blocker L-NAME (30 micromol.min(-1) i.v.) and the subsequent responses to cumulatively administered endothelin-1 (ET-1) (0.001 -- 4 nmol.kg(-1) i.v.) or big ET-1 (0.1 -- 2.0 nmol.kg(-1) i.v.) were studied. Additionally, the effect of the non-selective ET-1 receptor antagonist, SB209670, was investigated. 2. Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy. 3. Blockade of NOS caused a greater increase in basal PAP (increased by 7.7 +/- 1.1 mmHg c.f. 3.8 +/- 1.0 mmHg in controls, P<0.05) and uncovered a greater pulmonary pressor response to exogenous ET-1 in rabbits with PHT (increased by 10.2 +/- 2.3 mmHg c.f. 4.9 +/- 1.0 mmHg in controls, P<0.05). 4. Big ET-1 evoked a pulmonary pressor effect, in both groups of rabbits, that was increased following blockade of NOS and was more potent in rabbits with PHT. 5. The non-selective ET-1 receptor antagonist, SB209670, reduced basal PAP (from 16.9 mmHg to 15.9 mmHg, P < 0.05) in rabbits with PHT and blocked the response to ET-1 in the presence of L-NAME. 6. In conclusion, the results demonstrate that basal NO activity masks a pulmonary pressor response to exogenously administered ET-1. An increased responsiveness to ET-1 was shown in the pulmonary arterial bed of rabbits with PHT secondary to LVD, implicating a pathophysiological role for ET-1 in this model.

Topics: Animals; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Enzyme Inhibitors; Hemodynamics; Hypertension, Pulmonary; Indans; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Protein Precursors; Pulmonary Artery; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Ultrasonography; Ventricular Dysfunction, Left

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.

Topics: Animals; Brain; Cardiovascular Diseases; Cells, Cultured; Endothelin-1; Enzyme Inhibitors; Gene Expression Regulation; Humans; Luciferases; Myocardium; Natriuretic Peptide, Brain; Phosphatidic Acids; Phospholipases A; Promoter Regions, Genetic; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transfection; Ventricular Dysfunction, Left

The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation. Methods and Results-- Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (tau) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*P<0.05 versus controls: 139+/-4* versus 123+/-4 mm Hg), week 5 (174+/-7* versus 124+/-4 mm Hg), and week 12 (181+/-12* versus 124+/-4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. tau was increased in HTN-5wk (50+/-3* ms) and HTN-12wk (62+/-10* ms) dogs compared with sham (41+/-2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls.. Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.

Topics: Angiotensin II; Animals; Catecholamines; Diastole; Disease Models, Animal; Dogs; Endothelin-1; Heart Ventricles; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Kidney; Natriuretic Peptide, Brain; Propranolol; Renin; Systole; Ventricular Dysfunction, Left

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

Clinical heart failure, often the result of myocardial infarction, may be preceded by a period of compensated left ventricular impairment. There is substantial need for an experimental model that reflects this human condition. In sheep, coronary artery ligation produced consistent left ventricular anteroapical myocardial infarctions resulting in chronic (5 wk), stable hemodynamic changes compared with sham controls, including reductions in ejection fraction (51 +/- 2 vs. 30 +/- 5%, P < 0.001), cardiac output (6.3 +/- 0.2 vs. 5.1 +/- 0.2 l/min, P < 0.01), and arterial pressure (93 +/- 2 vs. 79 +/- 3 mmHg, P < 0.001), and increases in cardiac preload (left atrial pressure, 3.3 +/- 0.1 vs. 8.3 +/- 1.3 mmHg, P < 0.001). These changes were associated with acute and sustained increases in plasma concentrations of atrial natriuretic peptide (ANP; 5 wk, 11 +/- 2 vs. 27 +/- 5 pmol/l, P < 0.001), brain natriuretic peptide (BNP; 3 +/- 0.2 vs. 11 +/- 2 pmol/l, P < 0.001), and amino-terminal pro-brain natriuretic peptide (NT-BNP; 17 +/- 3 vs. 42 +/- 12 pmol/l, P < 0.001). Significant correlations were observed between plasma levels of the natriuretic peptides (ANP, day 7 to week 5 samples; BNP and NT-BNP, day 1 to week 5 samples) and changes in left ventricular volumes and ejection fraction. In contrast, renin activity, aldosterone, catecholamines, and endothelin were not chronically elevated postinfarction and were not related to indexes of ventricular function. Coronary artery ligation in sheep produces the pathological, hemodynamic, and neurohormonal characteristics of compensated left ventricular impairment secondary to myocardial infarction. Plasma concentrations of the cardiac natriuretic peptides are sensitive markers of left ventricular dysfunction. This is a reproducible model that reflects the clinical condition and should prove suitable for investigating the pathophysiology of, and experimental therapies in, early left ventricular dysfunction.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Coronary Vessels; Disease Models, Animal; Endothelin-1; Epinephrine; Female; Hemodynamics; Ligation; Myocardial Infarction; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Neuropeptides; Norepinephrine; Peptide Fragments; Renin; Sheep; Ventricular Dysfunction, Left

The objective was to determine the independent association between atrial fibrillation (A-Fib) and activation of natriuretic peptides.. The association of A-Fib with activation of N-terminal atrial and brain natriuretic peptides (N-ANPs and BNPs, respectively) is uncertain but of great importance for the diagnostic utilization of natriuretic peptides. This uncertainty is related to the lack of appropriate controls, with left ventricular (LV) and atrial overload similar to A-Fib.. We prospectively measured N-terminal atrial and BNPs and endothelin-1 levels in 100 patients and 14 age- and gender-matched control subjects. The 32 patients with A-Fib were compared with 68 patients in sinus rhythm and similar LV and atrial overload (due to mitral regurgitation or LV dysfunction) measured simultaneously with hormonal levels with comprehensive Doppler echocardiography.. Patients with A-Fib compared with those in sinus rhythm had similar symptoms, comorbid conditions, cardioactive medications, pulmonary pressure, left atrial volume, and LV ejection fraction and filling characteristics but demonstrated higher N-ANP levels (2,613 +/- 1,681 vs. 1,654 +/- 1,323 pg/ml, p = 0.007) even after adjustment for the underlying cardiac disease (p < 0.0001). Conversely, BNP levels were similar in both groups (165 +/- 163 vs. 160 +/- 269 pg/ml, p = 0.9). In multivariate analysis, a higher N-ANP level was associated with A-Fib (p = 0.0003), symptom class (p < 0.0001) and endothelin-1 level (p = 0.032) independently of left atrial volume and LV ejection fraction. Conversely, BNP showed no independent association with and was most strongly associated with LV ejection fraction (p < 0.0001).. Atrial fibrillation is an independent determinant of higher N-ANP levels and blurs its association with LV dysfunction. Conversely, the BNP is not independently associated with A-Fib and is strongly determined by LV dysfunction, for which it is an independent marker.

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Chronic Disease; Echocardiography, Doppler; Endothelin-1; Female; Humans; Male; Multivariate Analysis; Natriuretic Peptide, Brain; Prospective Studies; Protein Precursors; Reproducibility of Results; Severity of Illness Index; Stroke Volume; Ventricular Dysfunction, Left

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) 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

This study was designed to assess the functional importance of endothelin (ET)B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET(A) and ET(B) agonist, with ET-3, a selective ET(B) receptor agonist.. Knowledge of the functional importance of ET(B) receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET(A) and ET(B) receptors are required to fully prevent vasoconstriction to endogenously produced ET-1.. We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line.. Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dyn/s/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m , p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group.. Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET(B) receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.

Topics: Aged; Chronic Disease; Endothelin-1; Endothelin-3; Female; Hemodynamics; Humans; Male; Middle Aged; Receptor, Endothelin B; Receptors, Endothelin; Systole; Vasoconstriction; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Cardiovascular Diseases; Endothelin-1; Endothelin-3; Hemodynamics; Humans; Receptor, Endothelin B; Receptors, Endothelin; Systole; Vasoconstriction; Ventricular Dysfunction, Left; Ventricular Function, Left

We measured plasma concentrations of vasoactive peptides in 32 patients with acute myocardial infarction and evaluated their value as markers of left ventricular dysfunction. Plasma levels of atrial natriuretic peptide (ANP), the N-terminal fragment of proANP (NT-proANP), B-type natriuretic peptide (BNP) and endothelin-1 were measured serially by radioimmunoassays. The infarct size was estimated from the creatine kinase MB release curve. Coronary angiography and left ventricular cineangiography were performed in all patients during hospitalization and 6 months later in 15 patients. Myocardial infarction caused an increase in vasoactive peptides, the highest values for ANP (36.5+/-6.79 pmol/l), NT-proANP (1130+/-170 pmol/l) and endothelin-1 (9.72+/-0.68 pmol/l) being found on admission and those for BNP (56.0+/-7.13 pmol/l) on Day 2. Plasma levels of natriuretic peptides were dependent on infarct size, its location and degree of myocardial dysfunction and that of BNP also on infarct artery patency. Plasma endothelin-1 level was higher in patients with TIMI 3 than TIMI 0-2 flow. Plasma vasoactive peptides remained elevated during the 6-month follow-up period and they were dependent on the degree of myocardial dysfunction. BNP measured on any day of hospitalization showed the best correlation with ejection fraction measured during the acute phase of infarction or at 6 months. The results show that BNP is the best indicator of left ventricular dysfunction after myocardial infarction and its reliability is not dependent on the time point of measurement.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Creatine Kinase; Endothelin-1; Female; Humans; Isoenzymes; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Regression Analysis; Time Factors; Ventricular Dysfunction, Left

The current study addresses the functional status and role of the endothelin ET(A) receptor for renal vascular function in rabbits with and without heart failure (epinephrine-induced cardiomyopathy). Under baseline conditions, the ET(A) receptor antagonist BQ-123 did not change basal renal hemodynamics, but completely prevented endothelin-1 (ET-1)-induced renal vasoconstriction. In heart failure, in the presence of elevated plasma ET-1 concentrations (P < .05), renal vasoconstriction in response to exogenous ET-1 was intact. Unlike under baseline conditions, ET(A) receptor antagonism markedly increased renal blood flow (P <.05) and decreased renal vascular resistance (P < .05) in heart failure. The current study provides new insight into the pathophysiology of renal vasoconstriction associated with heart failure and the specific role of the renal ET(A) receptor in this pathophysiologic adaptation.

Topics: Adrenergic Agonists; Animals; Cardiac Output, Low; Chinchilla; Endothelin Receptor Antagonists; Endothelin-1; Epinephrine; Hemodynamics; Male; Neurotransmitter Agents; Peptides, Cyclic; Rabbits; Receptor, Endothelin A; Receptors, Endothelin; Renal Circulation; Vasoconstriction; Ventricular Dysfunction, Left

To evaluate the level of plasma brain natriuretic peptide as a predictor of morbidity and mortality in patients with asymptomatic or minimally symptomatic left ventricular dysfunction.. We measured plasma levels of atrial natriuretic peptide, brain natriuretic peptide, norepinephrine, angiotensin II, and endothelin-1 and monitored haemodynamic parameters in 290 consecutive patients with asymptomatic or minimally and newly symptomatic left ventricular dysfunction (functional classes I-II, mean left ventricular ejection fraction=37%). All patients were followed up for a median period of 812 days. The Cox proportional hazards model was used to assess the association of variables with mortality and morbidity.. At the end of the follow-up, 24 patients had suffered cardiac death and 25 had been hospitalized for worsening heart failure during the follow-up period. Among 21 variables such as clinical characteristics, treatment, haemodynamics, and neurohumoral factors, high levels of plasma brain natriuretic peptide (P<0.0001), norepinephrine (P=0.042), left ventricular end-diastolic volume index (P=0.0035), and left ventricular end-diastolic pressure (P=0.033) were shown to be independent predictors of mortality and morbidity by stepwise multivariate analysis. Moreover, only a high level of plasma brain natriuretic peptide (P<0.0001) was shown to be an independent predictor of mortality in these patients.. These results indicate that a high plasma brain natriuretic peptide level provides information about mortality and morbidity in patients with asymptomatic or minimally symptomatic left ventricular dysfunction.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin II; Biomarkers; Endothelin-1; Female; Humans; Incidence; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Proportional Hazards Models; Radioimmunoassay; Retrospective Studies; Severity of Illness Index; Stroke Volume; Survival Rate; Ventricular Dysfunction, Left; Ventricular Pressure

Increased pressure in pulmonary artery is connected among other things with increased endothelin plasma concentration. The aim of the study was to assess plasma endothelin concentration in patients with pulmonary hypertension. The analysis comprised 22 patients with increased pressure in pulmonary artery in the course of pulmonary thromboembolism or chronic exacerbated left ventricular failure and 10 patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration was measured in pulmonary artery and capillary wedge pressure were evaluated with Swan-Ganz catheter and also peripheral and pulmonary vascular resistance were calculated. Endothelin plasma concentration in peripheral vein was compared between patients and healthy volunteers. Plasma endothelin concentration in pulmonary artery, peripheral artery and vein was higher in patients with pulmonary hypertension than in patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration in patients with chronic exacerbated left ventricular failure without pulmonary hypertension was higher in pulmonary artery than in peripheral artery and vein. At these patients plasma endothelin concentration in the peripheral vein didn't differ significantly from the healthy volunteers.

Topics: Adult; Aged; Chronic Disease; Endothelin-1; Endothelin-2; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Ventricular Dysfunction, Left

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

To determine whether pulmonary hypertension developed in a coronary artery-ligated rabbit model of left ventricular dysfunction (LVD) and to examine the effects of i.v. 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) on pulmonary arterial pressure (PAP).. Eight weeks after experimental coronary artery ligation or sham operation, ejection fractions were assessed by echocardiography. The rabbits were later anaesthetised and pulmonary arterial pressure was measured via a catheter inserted into the pulmonary artery via the right external jugular vein. 5-HT (1-400 micrograms/kg) and ET-1 (0.001-4 nmol/kg) were administered i.v.. Ejection fraction was significantly decreased from 76.6 +/- 1.4% in sham-operated to 42.2 +/- 1.3% in coronary artery-ligated rabbits (n = 9 in each group; P < 0.001), consistent with LVD. Baseline mean pulmonary arterial pressure was significantly increased in the coronary artery-ligated group compared to the shams, (16.5 +/- 0.5 vs. 11.5 +/- 0.8 mmHg; P < 0.001). A significant degree of right ventricular hypertrophy was found in the coronary artery-ligated rabbits (0.70 +/- 0.04 g/kg final body weight (f.b.wt.), n = 8 cf. 0.48 +/- 0.02 g/kg f.b.wt. in sham-operated controls, n = 8; P < 0.001). There was a significant increase in the percentage of muscularised pulmonary vessels adjacent to alveolar ducts and alveoli < 60 microns i.d. in the LVD rabbits compared with their sham-operated controls (8.5 +/- 0.4 cf. 20 +/- 0.5%; P < 0.0005). 5-HT produced a greater response in the coronary artery-ligated rabbits (a maximum increase of 8.7 +/- 1.0 mmHg in mean pulmonary artery pressure vs. 4.6 +/- 1.5 mmHg for sham-operated controls; P < 0.05). ET-1 did not have any effect on pulmonary arterial pressure in either group.. In the rabbit, LVD secondary to coronary artery ligation, causes right ventricular hypertrophy, pulmonary vascular remodelling, and an increased PAP consistent with the onset of pulmonary hypertension (PHT). The greater PAP response to i.v. 5-HT in the PHT group supports the hypothesis that this substance could be involved in the development of PHT. A role for ET-1 cannot be excluded, despite its lack of effect on PAP when intravenously administered in either group.

Topics: Animals; Echocardiography; Endothelin-1; Hypertension, Pulmonary; Male; Rabbits; Regression Analysis; Serotonin; Ventricular Dysfunction, Left

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

Plasma levels of immunoreactive endothelin-1 (ET-1) are raised in chronic heart failure. Whether plasma ET-1 contributes to the haemodynamic derangement found in chronic heart failure is not known. We investigated the effects of exogenous ET-1 on the pulmonary and systemic vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure.. ET-1 was infused at 1, 5 and 15 pmol/min into a distal pulmonary artery of ten patients with LVD to achieve plasma concentrations of ET-1 similar to those found in patients with heart failure and pulmonary hypertension. Haemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients.. Systemic haemodynamic changes occurred with ET-1 infusion: mean arterial pressure (100 +/- 3 [standard error of the mean]) to 107 +/- 3 mmHg; p < 0.01) and systemic vascular resistance (1699 +/- 118 to 2033 +/- 135 dynes s/cm5; p < 0.001) rose, while the cardiac index fell from 2.43 +/- 0.17 to 2.20 +/- 0.16 l/min/m2 (p < 0.002). Mean pulmonary artery pressure (21 +/- 2 mmHg) and pulmonary vascular resistance (151 +/- 14 to 147 +/- 14 dynes s/cm5) did not change however.. Exogenous ET-1, when infused to achieve plasma concentrations similar to those in severe heart failure and pulmonary hypertension, causes systemic but not pulmonary vasoconstriction.

Topics: Aged; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Nitroprusside; Pulmonary Artery; Radiography; Regional Blood Flow; Ultrasonography, Interventional; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; 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

There is little information available regarding local vasomotor regulating processes in chronic heart failure. In this study, we tested the hypothesis that chronic heart failure impaired the endothelial function, and long term captopril treatment might reverse endothelial activity through tissue endothelin (ET) pathway.. Forty Sprague-Dawley rats were divided into 4 groups including 15 rats in each of the sham-operated with or without captopril-treated groups and 5 rats in each of large infarcted with or without captopril-treated groups.. Concentration-response curves obtained in aortic rings without endothelium revealed no difference in nitroprusside-induced relaxation. With endothelium, rightward shifting was noted only in the untreated large infarct group during acetylcholine-induced relaxation. As compared to the non-treated group, plasma ET-1 concentrations were lower in the captopril-treated with or without large infarct groups. However, endothelin-like immunoreactivity in endothelial cells and cytoplasma of smooth muscle cells of the media of the aorta were lower only in the non-treated large infarct group.. Endothelial function was impaired in the chronic heart failure model. Coverting enzyme inhibitor might improve endothelial function through the Local endothelin pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Endothelin-1; Hemodynamics; Male; Myocardial Infarction; Random Allocation; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left

We evaluated 30 consecutive patients and 48 age- and sex-matched controls to explore the possibility of a pathogenic contribution by plasma endothelin-1 in the cardiac expression of systemic sclerosis. Venous plasma endothelin-1 was measured by radio-immunoassay and left ventricular function by echocardiography. The patient group had elevated plasma endothelin-1 (2.6 +/- 0.2 vs. 1.8 +/- 0.1 pmol/1, P < 0.001), but endothelin-1 was not related to age, heart rate, blood pressure, total peripheral resistance, disease duration or systemic sclerosis score. Endothelin-1 was related to left ventricular hypertrophy in terms of septal thickness (r = 0.33, P < 0.01) and left ventricular mass index (r = 0.32, P < 0.01). Plasma endothelin-1 was further related to measures indicating reduced left ventricular filling; left atrial emptying index (r = -0.50, P < 0.0005), the first third filling fraction (r = -0.31, P < 0.05) and the time velocity integral of Doppler early/late filling velocity (r = -0.40, P < 0.001). Furthermore, circulating endothelin-1 was related to impaired left ventricular contractility as estimated by pre-ejection period/left ventricular ejection time (r = 0.32, P < 0.01) and end-systolic wall stress/volume index (r = -0.30, P < 0.05). We conclude that plasma endothelin-1 is elevated in relation to the degree of left ventricular hypertrophy, diastolic dysfunction and impaired contractility in systemic sclerosis. It may be of pathogenic importance to the cardiac involvement in systemic sclerosis which is not mediated via an increase in systemic blood pressure. It is not yet clear whether our findings are exclusive to systemic sclerosis patients or represent a generalized phenomenon in patients with impaired left ventricular function.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathies; Case-Control Studies; Echocardiography; Endothelin-1; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Multivariate Analysis; Scleroderma, Systemic; Ventricular Dysfunction, Left

Hypertension and central obesity are two conditions closely linked, but the mechanisms responsible for obesity-associated hypertension are still unclear. In the last few years, several studies addressed the role of endothelin-1 (ET-1) in the development and maintenance of hypertension. This study was designed to evaluate plasma ET-1 in normotensive and hypertensive central obese subjects compared with a lean healthy group. Our final goal was to analyze the relationship between plasma ET-1, blood pressure, and left ventricular structure and function in central obese subjects (both normotensives and hypertensives). ET-levels have been assessed by the radioimmunoassay method in 20 lean normotensives and in 57 central obese subjects; 30 of them were hypertensives and 27 of them were normotensives. Twenty-four-hour mean blood pressure (MBP/24 h) by noninvasive ambulatory blood pressure monitoring, left ventricular mass/ height (LVM/H), and left ventricular ejection fraction (LVEF) by echocardiography and peak filling rate (PFR) by radionuclide study were also measured. ET levels were significantly (P < .05) higher in obese hypertensives and obese normotensives than in lean normotensives. In addition, ET levels were significantly (P < .05) higher in obese hypertensives than in obese normotensives. ET were directly related to LVM/ H (r = 0.86; P < .001) and MBP/24 h (r = 0.48; P < .009) but only in obese hypertensives. Multiple regression analysis indicated that ET-1 plasma levels remain an independent predictor of MBP/ 24 h and LVM/H also when age was included in the analysis. These data suggest that obesity-associated hypertension is characterized by an endothelial dysfunction that may contribute to the higher cardiovascular risk detectable in these patients.

Topics: Adult; Blood Pressure Monitoring, Ambulatory; Body Constitution; Body Height; Body Mass Index; Echocardiography; Endothelin-1; Female; Heart Rate; Humans; Hypertension; Male; Obesity, Morbid; Radioimmunoassay; Radionuclide Angiography; Regression Analysis; Stroke Volume; Ventricular Dysfunction, Left