adrenomedullin and Heart-Failure

Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.

Topics: Adrenomedullin; Cardiovascular Diseases; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets.. We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using. Forty-four of ninety proteins were positively associated with risk of incident HF (. We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

Topics: Adrenomedullin; Genome-Wide Association Study; Heart Failure; Humans; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Proteomics

Congestion is a cardinal sign of heart failure (HF). In the past, it was seen as a homogeneous epiphenomenon that identified patients with advanced HF. However, current evidence shows that congestion in HF varies in quantity and distribution. This updated view advocates for a congestive-driven classification of HF according to onset (acute vs. chronic), regional distribution (systemic vs. pulmonary), compartment of distribution (intravascular vs. extravascular), and clinical vs. subclinical. Thus, this review will focus on the utility of circulating biomarkers for assessing and managing the different fluid overload phenotypes. This discussion focused on the clinical utility of the natriuretic peptides, carbohydrate antigen 125 (also called mucin 16), bio-adrenomedullin and mid-regional pro-adrenomedullin, ST2 (also known as interleukin-1 receptor-like 1), cluster of differentiation 146, troponin, C-terminal pro-endothelin-1, and parameters of haemoconcentration. The utility of circulation biomarkers on top of clinical evaluation, haemodynamics, and imaging needs to be better determined by dedicated studies. Some multiparametric frameworks in which these tools contribute to management are proposed.

Topics: Adrenomedullin; Biomarkers; Cardiology; Heart Failure; Humans; Prognosis

Topics: Adrenomedullin; Biomarkers; Cystatins; Galectin 2; Glycopeptides; Heart Failure; Humans; Lipocalin-2; Troponin I

Adrenomedullin (AM), a peptide isolated from an extract of human pheochromocytoma, comprises 52 amino acids with an intramolecular disulfide bond and amidation at the carboxy-terminus. AM is present in various tissues and organs in rodents and humans, including the heart. The peptide concentration increases with cardiac hypertrophy, acute myocardial infarction, and overt heart failure in the plasma and the myocardium. The principal function of AM in the cardiovascular system is the regulation of the vascular tone by vasodilation and natriuresis via cyclic adenosine monophosphate-dependent or -independent mechanism. In addition, AM may possess unique properties that inhibit aldosterone secretion, oxidative stress, apoptosis, and stimulation of angiogenesis, resulting in the protection of the structure and function of the heart. The AM receptor comprises a complex between calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 2 or 3, and the AM-CLR/RAMP2 system is essential for heart development during embryogenesis. Small-scale clinical trials have proven the efficacy and safety of recombinant AM peptide therapy for heart failure. Gene delivery and a modified AM peptide that prolongs the half-life of the native peptide could be an innovative method to improve the efficacy and benefit of AM in clinical settings. In this review, we focus on the pathophysiological roles of AM and its receptor system in the heart and describe the advances in AM and proAM-derived peptides as diagnostic biomarkers as well as the therapeutic application of AM and modified AM for cardioprotection.

Topics: Adrenomedullin; Animals; Calcitonin Receptor-Like Protein; Cardiomegaly; Heart Failure; Humans; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3

Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin-angiotensin-aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio-ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio-ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non-neutralizing ADM-binding antibody with a half-life of 15 days. Adrecizumab binds at the N-terminal epitope of ADM, leaving the C-terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM-binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

Topics: Adrenomedullin; Animals; Biomarkers; Cardiotonic Agents; Heart Failure; Humans; Molecular Targeted Therapy; Stroke Volume

Adrenomedullin (AM) is a vasodilatory peptide originally discovered in human pheochromocytoma tissue. Although AM is highly expressed in the adrenal glands, heart, lungs, and kidneys, vascular endothelium and smooth muscle are thought to be the main source of plasma AM. The AM precursor is processed to AM-glycine, which is then converted to AM-mature through C-terminal amidation. In this process, mid-regional pro-adrenomedullin (MR-proAM) is also produced. Plasma AM, AM-mature, AM-glycine, and MR-proAM levels are all higher in patients with heart failure than healthy subjects in proportional to the disease severity. All molecular forms of AM are prognostic markers for heart failure.

Topics: Adrenomedullin; Biomarkers; Heart Failure; Humans

Acute dyspnea is a common chief complaint among patients who visit an emergency room and presents diagnostic challenges for clinicians in both identifying the etiology and determining the clinical severity. The study of biomarkers in the prognostication and risk stratification of these patients has been increasing, including the investigation of the prognostic value for mid-regional pro-adrenomedullin (MR-proADM). Areas covered: In this review, the authors cover what is known about MR-proADM testing in patients presenting with acute dyspnea and the supporting evidence of its prognostic value in common conditions in medical patients with acute dyspnea, including acute heart failure, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, and acute pulmonary embolism. Expert commentary: Numerous studies have proposed MR-proADM as a more accurate, prognostic tool in the evaluation of acute dyspnea than other biomarkers and consensus risk scores such as Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA). The authors review recent prospective studies, systematic reviews, and meta-analyses that demonstrate its prognostic value and role in risk stratification, including its use in biomarker-based triage algorithms as part of the diagnostic evaluation of the acutely dyspneic patient.

Topics: Adrenomedullin; Biomarkers; Community-Acquired Infections; Dyspnea; Heart Failure; Humans; Pneumonia; Prognosis; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism

Heart failure has a high prevalence in developed countries. It is a frequent cause of hospital admission and has an important impact on morbidity, mortality and healthcare costs. Biomarkers have been widely studied in heart failure, as they improve diagnosis and prognostic assessment. Natriuretic peptides are already a part of daily clinical practice but several other biomarkers are being studied. This review focuses on mid-regional pro-adrenomedullin (MR-proADM) and ST2. Neither of these biomarkers is useful in the diagnosis of acute heart failure. However, both have considerable short- and long-term prognostic value in patients with acute and with stable chronic heart failure. The utility of these two biomarkers in guiding heart failure treatment is yet to be established. ST2 appears to have some advantages compared to MR-proADM, because it is more closely associated with ventricular remodeling and fibrosis.

Topics: Acute Disease; Adrenomedullin; Biomarkers; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Prognosis

Biomarkers are increaingly being used in the management of heart failure not only for the purpose of screening, diagnosis, and risk stratification, but also as a guide to evaluate the response to treatment in the individual patient and as an entry criterion and/or a surrogate marker of efficacy in clinical trials testing novel drugs. In this chapter, we review the role of established biomarkers for heart failure management, according to the main classification of HF phenotypes, based on the measurement of left ventricular ejection fraction, including heart failure with reduced (<40%), preserved (≥50%), and, as recently proposed, mid-range (40-49%) ejection fraction.

Topics: Adrenomedullin; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; beta-N-Acetyl-Galactosaminidase; Biomarkers; C-Reactive Protein; Cardio-Renal Syndrome; Catecholamines; Chromogranin A; Creatinine; Galectin 3; Glycopeptides; Growth Differentiation Factor 15; Heart Failure; Hepatitis A Virus Cellular Receptor 1; Humans; Interleukin-1; Interleukin-1 Receptor-Like 1 Protein; Interleukin-18; Interleukin-6; Lipocalin-2; MicroRNAs; Natriuretic Peptide, Brain; Peptide Fragments; Renin; Renin-Angiotensin System; Stroke Volume; Troponin; Troponin T; Tumor Necrosis Factor-alpha

Heart failure (HF) is a complex clinical condition. The newer guidelines have phased out the designations of systolic and diastolic HF and replaced them with the more physiologically applicable classifications of HF with reduced or preserved ejection fraction (EF). Although the numbers of new patients within these two groups are similar, patient characteristics and risk factors often differ. There also are differences in the incidence of HF among racial and ethnic groups, with blacks having the highest incidence. Although survival has improved over time among patients with reduced EF, no significant change in survival has been observed among those with preserved EF. Many models have been proposed to explain the underlying pathophysiology of HF, including the hemodynamic, neurohumoral, and cardiorenal models. The evaluation of a patient with signs and symptoms of and risk factors for HF includes a detailed history and physical examination, laboratory tests, chest x-ray, electrocardiography, and echocardiography. Serum natriuretic peptide levels are already in use, and other novel biomarkers reflecting the different pathophysiologic pathways are being investigated. The Seattle Heart Failure Model is a tool available for clinicians to use in estimating patient mortality risk.

Topics: Adrenomedullin; Biomarkers; Echocardiography; Electrocardiography; Galectin 3; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Physical Examination; Radiography, Thoracic; Risk Factors; Stroke Volume; Troponin I; Troponin T

We undertook this systematic review to determine the prognostic significance of adrenomedullin (ADM) in patients with heart failure and acute myocardial infarction (AMI). Given the difficulty in measuring mature ADM, its surrogate, midregional proadrenomedullin (MRproADM) has been used in most studies. Systematic search of original published studies through MEDLINE and the Cochrane Collaboration databases restricted to reports in English from January 1, 1993, to June 30, 2014, in humans was undertaken. Heterogeneity of studies prohibited a meta-analysis. In patients with heart failure, the area under the curve for prediction of mortality by MRproADM ranged from 0.68 to 0.81 (95% confidence intervals [CI] 0.63 to 0.91) across studies. One nmol/l increase in MRproADM was associated with hazard ratios (HRs) ranging from 1.77 to 2.79 (95% CI 1.29 to 5.95) for death in patients with heart failure. In patients with AMI, the area under the curve for MRproADM predicting MACE ranged from 0.64 to 0.80 (CI 0.51 to 0.87) across studies and death 0.79 to 0.84 (CI 0.73 to 0.90). One nmol/l increase in MRproADM was associated with HR for MACE ranging from 1.78 to 4.10 (CI 1.20 to 10.12), whereas log10 of MRproADM had HRs of 3.63 to 9.75 (CI 1.48 to 26.16) for MACE and 4.86 to 16.68 (CI 4.56 to 60.99) for death across studies in patients with AMI. In conclusion, adrenomedullin is an independent predictor of death in patients with heart failure and of MACE and death in patients who have suffered an AMI. Quantification of this peptide might contribute to improved risk stratification in settings of heart failure and myocardial infarction.

Topics: Adrenomedullin; Biomarkers; Electrocardiography; Global Health; Heart Failure; Humans; Myocardial Infarction; Predictive Value of Tests; Prognosis; Survival Rate

The care of patients with acutely decompensated heart failure is being reshaped by the availability and understanding of several novel and emerging heart failure biomarkers. The gold standard biomarkers in heart failure are B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide, which play an important role in the diagnosis, prognosis, and management of acute decompensated heart failure. Novel biomarkers that are increasingly involved in the processes of myocardial injury, neurohormonal activation, and ventricular remodeling are showing promise in improving diagnosis and prognosis among patients with acute decompensated heart failure. These include midregional proatrial natriuretic peptide, soluble ST2, galectin-3, highly-sensitive troponin, and midregional proadrenomedullin. There has also been an emergence of biomarkers for evaluation of acute decompensated heart failure that assist in the differential diagnosis of dyspnea, such as procalcitonin (for identification of acute pneumonia), as well as markers that predict complications of acute decompensated heart failure, such as renal injury markers. In this article, we will review the pathophysiology and usefulness of established and emerging biomarkers for the clinical diagnosis, prognosis, and management of acute decompensated heart failure.

Topics: Acute Disease; Acute Kidney Injury; Adrenomedullin; Biomarkers; Calcitonin; Galectin 3; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Natriuretic Peptides; Protein Precursors; Receptors, Cell Surface; Troponin

Patients presenting with heart failure symptoms are categorized into heart failure (HF) with reduced and preserved ejection fraction.. Aim is to investigate the additional use of candidate biomarkers to characterize patients with either sub-type of HF.. Literature search was conducted in the electronic databases MEDLINE and Cochrane Central Register of Controlled Trials from inception through November 2014.. The results of 47 diseased and general population cohorts were included.. Current studies could outline the additional use of candidate biomarkers especially GDF-15, MR-proADM and high-sensitive determined troponin, although major outcome studies are still missing.

Topics: Adrenomedullin; Biomarkers; Growth Differentiation Factor 15; Heart Failure; Humans; Peptide Fragments; Prognosis; Protein Precursors; Sensitivity and Specificity; Stroke Volume

First isolated from human pheochromocytoma cells, adrenomedullin (ADM) is a peptide hormone with natriuretic, vasodilatory, and hypotensive effects mediated by cyclic adenosine monophosphate (cAMP), nitric oxide, and renal prostaglandin systems. ADM expression occurs in many tissues and organ systems, including cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues where it acts as a circulating hormone and a local autocrine and paracrine hormone. ADM plasma concentrations are increased in hypertension, chronic renal disease, and heart failure. As ADM is unstable in vitro, it is necessary to measure its mid-regional pro-hormone fragment, the levels of which correspond to ADM concentration (MR-proADM). The prognostic potential of MR-proADM was recently demonstrated in the Biomarkers in Acute Heart Failure (BACH) trial. In this trial of 568 acute heart failure patients, MR-proADM was superior to both brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days. MR-proADM also provided significant additive incremental predictive value for 90-day mortality when added to BNP and NT-proBNP.

Topics: Adrenomedullin; Biomarkers; Heart Failure; Humans; Peptide Fragments; Prognosis

Heart failure is a major burden to the health care system in terms of not only cost, but also morbidity and mortality. Appropriate use of biomarkers is critically important to allow rapid identification and optimal risk stratification and management of patients with both acute and chronic heart failure. This review will discuss the biomarkers that have the most diagnostic, prognostic, and therapeutic value in patients with heart failure. We will discuss established biomarkers such as natriuretic peptides as well as emerging biomarkers reflective of myocyte stress, myocyte injury, extracellular matrix injury, and both neurohormonal and cardio-renal physiology.

Topics: Adrenomedullin; Biomarkers; Cost-Benefit Analysis; Cystatin C; Disease Progression; Early Diagnosis; Extracellular Matrix; Female; Galectin 3; Glycopeptides; Heart Failure; Hepatitis A Virus Cellular Receptor 1; Humans; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins; Male; Membrane Glycoproteins; Muscle Cells; Natriuretic Peptides; Neurotransmitter Agents; Peptide Fragments; Predictive Value of Tests; Prognosis; Protein Precursors; Receptors, Cell Surface; Receptors, Virus; Renal Insufficiency

Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Blood Pressure Monitoring, Ambulatory; Cardiotonic Agents; Clinical Trials as Topic; Diet, Sodium-Restricted; Diuretics; Dopamine; Dose-Response Relationship, Drug; Dyspnea; Glycopeptides; Heart Failure; Hemofiltration; Hospitalization; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Nitroglycerin; Peptide Fragments; Prognosis; Protein Precursors; Quality of Health Care; Relaxin; Risk Assessment; Saline Solution, Hypertonic; Urea; Vasodilator Agents; Xanthines

Many neurohumoral factors play important roles in the regulation of the cardiovascular system and in the pathophysiology of cardiovascular disease. Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in the acid extract of human pheochromocytoma tissue but now known to exert a variety of effects within the cardiovascular system. AM expression is widely distributed throughout the cardiovascular system and has been identified in the heart, lungs, blood vessels and kidneys. In addition, the co-localization of AM and its receptor components suggest AM acts as an autocrine and/or paracrine factor to play a key role in the regulation of cardiovascular function. Evidence also strongly suggests that cardiovascular disease is associated with elevated levels of AM in plasma and tissue. In this review, we describe the pathophysiological changes in plasma and local AM associated with myocardial infarction, heart failure and pulmonary hypertension. We also describe the clinical application of AM in cardiovascular disease from the viewpoints of diagnosis and treatment.

Topics: Adrenomedullin; Animals; Biomarkers; Cardiovascular Diseases; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

Topics: Adrenomedullin; Chronic Disease; Endothelins; Heart Failure; Hemodynamics; Humans; Natriuretic Peptides; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

Circulating biomarkers have become increasingly important in diagnosing and risk-stratifying patients with heart failure (HF). While the natriuretic peptides have received much focus in the past decade, there is increasing interest in the role of other circulating biomarkers such as mid-regional proadrenomedullin (MR-proADM), a stable peptide of the precursor of adrenomedullin (ADM), responsible for volume regulation and electrolyte homeostasis. Increased levels of MR-proADM are associated with an increased risk of mortality and morbidity in patients with HF, independent of natriuretic peptides. MR-proADM outperforms all other established markers in the identification of patients at highest risk of death, particularly death within 30 days. The prognostic superiority has consistently been shown for various cardiovascular disease states, including acute heart failure. In this article, we discuss the potential role of MR-proADM in the syndrome of acute heart failure and its implication on prognosis and risk stratification.

Topics: Acute Coronary Syndrome; Acute Disease; Adrenomedullin; Biomarkers; Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Vasodilation

Heart failure goes beyond mechanical dysfunction and involves an interplay of multiple pathophysiologic mechanisms, including inflammation, tissue remodeling, neurohormonal and endocrine signaling, and interactions with the renal and nervous systems. This article highlights some novel biomarkers that may aid in diagnosis, treatment, and prognosis of acute heart failure, specifically focusing on ST2, endoglin, galectin-3, cystatin C, neutrophil gelatinase-associated lipocalin, midregional pro-adrenomedullin, chromogranin A, adiponectin, resistin, and leptin and their emerging clinical roles.

Topics: Acute Disease; Acute-Phase Proteins; Adiponectin; Adrenomedullin; Antigens, CD; Biomarkers; Chromogranin A; Cystatin C; Endoglin; Galectin 3; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Leptin; Lipocalin-2; Lipocalins; Proto-Oncogene Proteins; Receptors, Cell Surface; Resistin

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

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

Topics: Adrenomedullin; Animals; Heart Failure; Humans; Rats

Adrenomedullin (AM) is a vasodilator peptide that originally isolated from pheochromocytoma tissue. However, the mRNA is expressed in the normal adrenal gland, heart, kidney and blood vessels. The human AM gene is located in the short arm of chromosome 11 and is composed of 4 exons. There are 2 single nucleotide polymorphisms in introns 1 and 3, and the 3'-end of the AM gene is flanked by a microsatellite marker of cytosine-adenine repeats that is associated with an increased risk of developing hypertension and diabetic nephropathy. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of the renin-angiotensin and sympathetic nervous systems. The AM gene promoter region possessed binding site for several transcription factors, including nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2). Further, plasma AM levels are increased in patients with various cardiovascular diseases, including hypertension, heart failure and renal failure. These findings suggest that AM plays a role in the development of or response to cardiovascular disease. Indeed, experimental and clinical studies have demonstrated that systemic infusion of AM may have a therapeutic effect on myocardial infarction, heart failure and renal failure. Further, vasopeptidase inhibitors which augment the bioactivity of endogenous AM may benefit patients with hypertension and arteriosclerosis. Finally, the angiogenic and cytoprotective properties of AM may have utility in revascularization and infarcted myocardium and ischemic limbs. Because of the potential clinical benefits of AM, indications for use and optimal dosing strategies should be established.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Carcinogens; Cardiovascular Diseases; Cell Transplantation; Genetic Therapy; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Molecular Sequence Data; Myocardial Infarction; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Renal Insufficiency; Renin-Angiotensin System; Signal Transduction

Topics: Adrenomedullin; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Disease Models, Animal; Endothelin-Converting Enzymes; Endothelins; Heart Failure; Intracellular Signaling Peptides and Proteins; Metalloendopeptidases; Natriuretic Peptide, Brain; Nitric Oxide; Oxidative Stress; Peptides; Protein Serine-Threonine Kinases; Rats; Rats, Inbred Dahl; Renin-Angiotensin System; rho-Associated Kinases

Topics: Adrenomedullin; Animals; Blood Pressure; Diuresis; Endothelins; Heart Failure; Humans; Natriuretic Peptides; Peptides; Vasoconstriction; Ventricular Remodeling

Co-localization of adrenomedullin (AM) and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in peripheral tissues, including the heart, kidney, and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, we previously reported that AM gene expression and / or immunoreactivity are increased in the ventricles of cardiac hypertrophy and heart failure. Recently, we also found that not only levels of AM peptide and AM gene expression, but also mRNA levels of CRLR, RAMP2 and RAMP3 are increased in cardiac hypertrophy and failing heart. Cardiac myocytes and fibroblast produce and secrete two molecular forms of AM and express CRLR, RAMP2 and RAMP3, and AM is known to have inhibitory effect of collagen synthesis and antiproliferative effect in cardiac fibroblasts. Stimulation by IL-1beta significantly increased gene expression of AM and its receptor components in cardiac fibroblasts. Preincubated IL-1beta elevated the intracellular cAMP response to exogenous administered AM. AM antisense oligodeoxynucleotide treatment significantly lowered AM levels in cultured medium. IL-1beta significantly increased (3)H-proline incorporation and AM antisense oligodeoxynucleotide treatment further increased (3)H-proline incorporation. Collectively, these results support a protective role for increased AM in the cardiac hypertrophy and heart failure. Then, we tested the effects of acute administration of AM in experimental and human heart failure, because AM has hemodynamic effects including vasodilation, increases in cardiac contractility, cardiac output, diuresis, and natriuresis. We observed profound and sustained cardiovascular, hormonal and renal effects. These effects may incorporate many of the therapeutic goals of heart failure management.

Topics: Adrenomedullin; Animals; Calcitonin Receptor-Like Protein; Cardiomegaly; Heart Failure; Humans; Peptides; Protein Processing, Post-Translational; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide

Topics: Adrenomedullin; Arteriosclerosis; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Kidney Failure, Chronic; Peptides; Radioimmunoassay; Reference Values; Shock, Septic; Specimen Handling; Systemic Inflammatory Response Syndrome

Adrenomedullin (AM), inducing a potent and powerful hypotensive activity caused by dilatation of resistance vessels, has elicited interest for its cardiovascular actions. AM is secreted from various cell type, including vascular endothelial and smooth muscle cell. AM plasma levels are increased in various cardiovascular diseases as heart failure and hypertension and may be involved in pathophysiological changes in cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Chronic Disease; Glomerulonephritis; Heart Failure; Homeostasis; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Infarction; Peptides; Rats; Shock, Septic

Adrenomedullin, a 52-amino acid residue peptide, has numerous biological actions which are of potential importance to cardiovascular homeostasis, growth and development of cardiovascular tissues and bone, prevention of infection, and regulation of body fluid and electrolyte balance. Studies in man using intravenous infusion of the peptide have demonstrated that, at plasma levels detected after myocardial infarction or in heart failure, adrenomedullin reduces arterial pressure, increases heart rate and cardiac output, and activates the sympathetic and renin-angiotensin systems but suppresses aldosterone. The thresholds for these responses differ, being lower under some experimental circumstances for arterial pressure than for the other biological effects. Adrenomedullin administration inhibits the pressor and aldosterone-stimulating action of angiotensin II in man. By contrast, the pressor effect of norepinephrine is little altered by concomitant adrenomedullin administration. Although in the absence of a safe, specific antagonist of the actions of endogenous adrenomedullin it is difficult to be certain about the physiological and pathophysiological importance of this peptide in man, current evidence suggests that it serves to protect against cardiovascular overload and injury. Hope has been expressed that adrenomedullin or an agonist specific for adrenomedullin receptors might find a place in the treatment of cardiovascular disorders.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiotonic Agents; Endothelins; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypertension; Hypopituitarism; Peptides

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

Topics: Adrenomedullin; Animals; Autocrine Communication; Biomarkers; Cell Division; Heart Failure; Hemodynamics; Humans; Myoblasts, Cardiac; Myocytes, Cardiac; Paracrine Communication; Peptides; Severity of Illness Index

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Antioxidants; Clinical Trials as Topic; Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Genetic Therapy; Heart Failure; Humans; Hypertension, Pulmonary; Natriuretic Agents; Neprilysin; Peptides; Pyridines; Thiazepines; Vasodilator Agents

Many neurohumoral factors participate in the pathophysiology of heart failure, and adrenomedullin (AM) may be involved in their derangement. This work reviews the accumulating evidence in support of a compensatory role of AM in heart failure, and describes the possible mechanisms of this role. It has been established that plasma AM levels are increased in patients with heart failure in proportion to the severity of the disease. Furthermore, recent studies suggest that plasma AM level is an independent prognostic indicator of heart failure. Thus, AM may be not only a biochemical marker for evaluating the severity of heart failure, but also a prognostic indicator of this syndrome. In patients with heart failure, AM production is increased not only in the plasma, but also in the heart. AM secretion from the failing human heart is also increased, but this increase is small and responds slowly to the stimulus. This phenomenon may be explained by the fact that AM is secreted via a constitutive pathway and that AM is an autocrine and/or a paracrine factor in the heart. An experiment using cultured myocytes suggested that cytokines and mechanical stress are important stimuli for AM production in the heart. Regarding the action of AM in the heart, recent studies have suggested that AM exerts an inotropic action both in vitro and in vivo. AM also attenuates cardiac hypertrophy in myocytes and inhibits proliferation and collagen production in cardiac fibroblasts. These results suggest that AM may be an antifibrotic, antihypertrophic, and positive inotropic factor in the failing and hypertrophied heart. Because AM has many cardiorenal actions, AM administration may be useful for the treatment of heart failure. Indeed, acute administration of AM has been shown to improve the hemodynamics, renal function, and hormonal parameters in patients with heart failure. Moreover, recent studies have shown that AM gene therapy or long-term AM infusion significantly improved cardiac hypertrophy and fibrosis, and prolonged the survival time in an animal model of hypertension and heart failure. In conclusion, these findings suggest that AM plays a compensatory role in the pathophysiology of heart failure and that administration of AM may be a new and promising approach for the treatment of patients with this syndrome.

Topics: Adrenomedullin; Animals; Cardiotonic Agents; Heart Failure; Humans; Peptides

Patients with heart failure have frequently been reported to show elevated levels of plasma adrenomedullin. These levels generally correlate with severity of hemodynamic dysfunction and also with neurohormonal indices which are activated according to the severity of heart failure. Furthermore, adrenomedullin gene expression in the heart and kidney is increased in experimental and clinical heart failure. A small number of studies have examined the responses to infusion of adrenomedullin in experimental and clinical heart failure. These studies have generally shown that infusion of adrenomedullin has beneficial hemodynamic effects and promotes maintenance or improvement in renal function, although most of these trials were of short duration. The available data suggest that adrenomedullin in the heart, kidney and plasma is increased in heart failure, possibly to counter the activation or actions of vasoconstricting and sodium-retaining hormone systems. An improved understanding of the role of adrenomedullin in heart failure might lead to the development of therapeutic agents acting through adrenomedullin receptors.

Topics: Adrenomedullin; Animals; Cardiotonic Agents; Heart Failure; Humans; Peptides

The studies concerning the structure and variations of the human adrenomedullin (AM) gene are reviewed, and their relations to the gene function and genetic predisposition to cardiovascular diseases are discussed. The genomic human AM gene is composed of four exons, and the whole nucleotide sequence corresponding to mature AM resides in the fourth exon. In chromosomal sublocalization, the AM gene is located in the distal portion of the short arm of chromosome 11 (11p15.1-3). Analysis of the promoter region of the AM gene has revealed that two transcription factors, nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2), participate in the regulation of AM gene expression. It is surmised that NF-IL6 mediates inflammatory stimuli and AP-2 mediates signals of phospholipase C and protein kinase C activation. In addition to these factors, hypoxia induces AM gene expression via the hypoxia inducible factor-1 (HIF-1) binding site. The 3'-end of the AM gene is flanked by a microsatellite marker of cytosine adenine (CA) repeats. In Japanese, there are four types of alleles with different CA-repeat numbers: 11, 13, 14 and 19. It is suggested that existence of the 19-repeat allele is associated with genetic predispositions to develop essential hypertension and diabetic nephropathy.

Topics: Adrenomedullin; Diabetic Nephropathies; Heart Failure; Humans; Hypertension, Renal; Peptides; Polymorphism, Genetic

Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenomedullin (AM) is hypotensive as a result of dramatic reductions in peripheral resistance. Furthermore, it does not appear to increase aldosterone secretion in spite of often vigorous activation of circulating renin. Hence, we postulate that AM may act as a functional antagonist to angiotensin II both in the vasculature and the adrenal glomerulosa. In the series of studies performed in sheep and human (normal and circulatory disorders) reviewed here, we report significant hemodynamic and hormonal actions of AM. These actions include consistent reduction of arterial pressure associated with rises in cardiac output and hence a dramatic reduction in calculated total peripheral resistance (CTPR). AM also consistently attenuates the pressor effects of angiotensin II (but not norepinephrine). Furthermore, AM consistently increases plasma renin activity (PRA) and induces either a reduction in plasma aldosterone, dissociation between aldosterone/PRA ratio, or attenuation of angiotensin II-induced aldosterone secretion. Thus, these results clearly point to a role for AM in pressure and volume homeostasis acting, at least in part, by interaction with the renin-angiotensin-aldosterone system (RAAS).

Topics: Adrenomedullin; Angiotensin II; Animals; Heart Failure; Hemodynamics; Humans; Nitroprusside; Norepinephrine; Peptides; Renin-Angiotensin System

Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. Circulating concentrations of AM are elevated in cardiovascular disease in proportion to the severity of cardiac and hemodynamic impairment. Raised plasma AM levels following acute cardiac injury and in heart failure provide prognostic information on adverse outcomes. In heart failure, elevated circulating AM also identifies patients likely to receive long-term benefit from inclusion of additional anti-failure therapy (carvedilol). Administration of AM in experimental and human heart failure induces reductions in arterial pressure and cardiac filling pressures, and improves cardiac output, in association with inhibition of plasma aldosterone (despite increased renin release) and sustained (or augmented) renal glomerular filtration and sodium excretion. Furthermore, AM in combination with other therapies (angiotensin-converting enzyme inhibition and augmentation of the natriuretic peptides) results in hemodynamic and renal benefits greater than those achieved by the agents separately. Manipulation of the AM system holds promise as a therapeutic strategy in cardiac disease.

Topics: Adrenomedullin; Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Heart Failure; Humans; Molecular Sequence Data; Natriuretic Peptide, Brain; Peptides; Sequence Alignment; Sheep

Adrenomedullin is a 52-amino acid peptide that circulates in human plasma. The plasma concentrations of the peptide are increased in cardiovascular disease in proportion to the degree of hemodynamic impairment. Plasma adrenomedullin levels in heart failure, and in subjects with acute myocardial infarction, have been shown to convey independent prognostic information. Adrenomedullin has multiple biologic effects, but characteristically causes vasodilatation. The actions of adrenomedullin and the activation of this peptide in cardiovascular disease suggest it may have an important pathophysiologic role in heart failure. Manipulation of adrenomedullin or its receptor may have therapeutic potential.

Topics: Adrenomedullin; Heart Failure; Humans; Peptides; Vasodilator Agents

Adrenomedullin (AM) is a novel 52-aminoacid-peptide hormone, originally isolated from human phaeocromocytoma. Adrenomedullin acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood lowering properties, but its exact role is still uncertain. Adrenomedullin is considered to play an important endocrine role in various tissues maintaining the electrolyte and fluid homeostasis. Its normal plasma concentration is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases parallel to the seriousness of the disease. It is assumed that this peptide may be important under pathologic conditions compensating the effects of the vasoconstrictor molecules. Till now, investigations have proved that in diabetic angiopathies the levels and the production of vasoconstrictor factors and adrenomedullin were increased, while, those of other relaxing substances including nitrogenoxid were decreased. It is still uncertain whether increased release of adrenomedullin in diabetes is a compensatory mechanism or a coincidental event. Although, the precise role of adrenomedullin in the pathogenesis of diabetic complications is still to be elucidated, the elevated concentration of adrenomedullin in diabetes--which influences the vascular functions--let us speculate that there might be a certain interaction between adrenomedullin induction and vascular functions in diabetes. Thus, the induction of vascular adrenomedullin could be a new target of a therapeutic approach to the diabetic complications.

Topics: Adrenomedullin; Antihypertensive Agents; Calcitonin Gene-Related Peptide; Diabetes Mellitus; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Peptides; Tissue Distribution; Vasodilator Agents

Although the biological effects of adrenomedullin (AM) and PAMP have been reported extensively in animal studies and from in-vitro experiments, relatively little information is available on responses to the hormone administered to man. This review summarizes data from the few studies carried out in man. In healthy volunteers, i.v. infusion of AM reduces arterial pressure, probably at a lower rate of administration than is required to elicit other responses. AM stimulates heart rate, cardiac output, plasma levels of cAMP, prolactin, norepinephrine and renin whilst inhibiting any concomitant response in plasma aldosterone. Little or no increase in urine volume or sodium excretion has been observed. Patients with essential hypertension differ only in showing a greater fall in arterial pressure and in the development of facial flushing and headache. In patients with heart failure or chronic renal failure, i.v. AM has similar effects to those seen in normal subjects but also induces a diuresis and natriuresis, depending on the dose administered. Infusion of AM into the brachial artery results in a dose-related increase in forearm and skin blood flow, more prominent and more dependent on endogenous nitric oxide in healthy volunteers than in patients with cardiac failure. When infused into a dorsal hand vein, AM partially reversed the venoconstrictor action of norepinephrine. Although much more information is required to clarify the role of AM under physiological and pathophysiological circumstances, it is clear that it has prominent hemodynamic and neurohormonal effects, though generally lesser urinary effects when administered short-term in doses sufficient to raise its levels in plasma to those seen in a number of clinical disorders. The only study of PAMP in man showed that its skeletal muscle vasodilator potency, when infused into the brachial artery of healthy volunteers, was less than one hundredth that of AM, and it was without effect on skin blood flow.

Topics: Adrenomedullin; Cardiovascular Diseases; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Kidney Failure, Chronic; Peptide Fragments; Peptides; Proteins; Veins

Topics: Adrenomedullin; Atrial Natriuretic Factor; Autoantibodies; Biomarkers; Bone Diseases, Metabolic; Diabetes Mellitus; Heart Failure; Humans; Immunoglobulins, Thyroid-Stimulating; Molecular Diagnostic Techniques; Multiple Endocrine Neoplasia; Peptides; Receptors, Thyrotropin; Thyroid Diseases; Thyroxine; Triiodothyronine

Topics: Adrenomedullin; Animals; Brain; Disease Models, Animal; Heart Failure; Humans; Injections, Intraventricular; Male; Myocardial Infarction; Peptides; Radioimmunoassay; Sheep; Vasodilator Agents

Topics: Adrenomedullin; Cardiovascular Physiological Phenomena; Heart Failure; Humans; Hypertension; Peptides; Vasodilator Agents

Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment.. Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status.. MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure.. PROVE-HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588.

Topics: Adrenomedullin; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Microcirculation; Neprilysin; Stroke Volume; Tetrazoles; Valsartan

Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection.. Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events.. A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively).. plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.

Topics: Adrenal Gland Neoplasms; Adrenergic Antagonists; Adrenomedullin; Adult; Aged; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Female; Follow-Up Studies; Heart Failure; Humans; Intraoperative Complications; Male; Middle Aged; Natriuretic Peptide, Brain; Pheochromocytoma; Prognosis; Risk Assessment; Treatment Outcome

The TIM-HF2 study showed less days lost due to unplanned cardiovascular hospitalization or all-cause death and improved survival in patients randomly assigned to remote patient management (RPM) instead of standard of care.. This substudy explored whether the biomarkers mid-regional pro-adrenomedullin (MR-proADM) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) could be used to identify low-risk patients unlikely to benefit from RPM, thereby allowing more efficient allocation of the intervention. For 1538 patients of the trial (median age 73 years, interquartile range 64-78 years, 30% female), baseline biomarkers were used to select subpopulations recommended for RPM with various safety endpoints (100%, 98%, 95% sensitivity), and efficacy of RPM was assessed. Both biomarkers were strongly associated with events. The primary endpoint of lost days increased from 1.0% (1.4%) in the lowest to 17.3% (17.6%) in the highest quintile of NT-proBNP (MR-proADM). After combining biomarkers to identify patients recommended for RPM with 95% sensitivity, in the most efficient scenario (excluding 27% of patients; NT-proBNP < 413.7 pg/mL and MR-proADM < 0.75 nmol/L), the effect of RPM on patients was highly similar to the original trial (ratio of lost days: 0.78, hazard ratio for all-cause death: 0.68). Number needed to treat for all-cause death was lowered from 28 to 21. Rates of emergencies and telemedical efforts were significantly lower among patients not recommended for RPM. Biomarker guidance would have saved about 150 h effort/year per 100 patients of the eligible population.. The combined use of MR-proADM and NT-proBNP may allow safe, more precise, effective and cost-saving allocation of patients with heart failure to RPM and warrants further prospective studies.

Topics: Adrenomedullin; Aged; Biomarkers; Cause of Death; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Precision Medicine; Protein Precursors; Risk Assessment; Survival Rate; Telerehabilitation

Midregional proadrenomedullin (MR-proADM) has demonstrated prognostic potential after myocardial infarction (MI). Yet, the prognostic value of MR-proADM at admission has not been examined in patients with ST-segment-elevation MI (STEMI).. The aim of this substudy, DANAMI-3 (The Danish Study of Optimal Acute Treatment of Patients with ST-segment-elevation myocardial infarction), was to examine the associations of admission concentrations of MR-proADM with short- and long-term mortality and hospital admission for heart failure in patients with ST-segment-elevation myocardial infarction. Outcomes were assessed using Cox proportional hazard models and area under the curve using receiver operating characteristics. In total, 1122 patients were included. The median concentration of MR-proADM was 0.64 nmol/L (25th-75th percentiles, 0.53-0.79). Within 30 days 23 patients (2.0%) died and during a 3-year follow-up 80 (7.1%) died and 38 (3.4%) were admitted for heart failure. A doubling of MR-proADM was, in adjusted models, associated with an increased risk of 30-day mortality (hazard ratio, 2.67; 95% confidence interval, 1.01-7.11;. Elevation of admission MR-proADM was associated with long-term mortality and heart failure, whereas the association with short-term mortality was borderline significant. MR-proADM may be a marker of prognosis after ST-segment-elevation myocardial infarction but does not seem to add substantial prognostic information to established clinical models.. URL: http:/www.ClinicalTrials.gov/. Unique identifiers: NCT01435408 and NCT01960933.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Denmark; Female; Heart Failure; Humans; Male; Middle Aged; Peptide Fragments; Percutaneous Coronary Intervention; Predictive Value of Tests; Protein Precursors; Risk Assessment; Risk Factors; ST Elevation Myocardial Infarction; Time Factors; Treatment Outcome; Up-Regulation

Heart failure can be associated with inflammation but it is unclear if inflammation is directly related to hemodynamic worsening or is an independent pathway. Our aim was to investigate inflammation and mechanical stress using serial measurements of biomarkers in acute and chronic heart failure with reduced ejection fraction (AHF and CHF).. The following biomarkers were measured on admission, at discharge and one month after discharge: B-type natriuretic peptide (BNP), high-sensitivity C-Reactive protein (hsCRP), Tumour Necrosis Factor alpha (TNFα), interleukin 6 (IL6), myeloperoxidase (MPO), suppression of tumorigenicity 2 (ST2), mid-regional pro-adrenomedullin (MR-proADM), galectin 3 (Gal3), Growth differentiating factor 15 (GDF15) and procalcitonin (PCT).. In control CHF group (n=20, 69±11y, NYHA 1-2), most biomarker levels were low and stable over time. In AHF (n=55, 71±14y), BNP, ST2 and GDF15 levels were highly increased on admission and then decreased rapidly with clinical improvement; BNP, ST2 and GDF15 levels were statistically correlated (r=0.64, 0.46 and 0.39; p<0.001 for both). Both hsCRP, MPO, TNFα and Gal3 levels were increased in most AHF patients (70, 56, 83 and 98% respectively) with poor change over time. HsCRP, MPO and TNFα levels were correlated. IL6, MR-proADM and PCT levels were slightly increased, without change over time. Highest quartiles of BNP and ST2 were associated with death or readmission at one year (HR 2.33 [95CI 1.13-4.80] and 2.42 [1.27-4.60]).. AHF is associated with systemic inflammation. This inflammatory response continued up to one month after discharge despite normalisation of mechanical stress-related markers.

Topics: Adrenomedullin; Aged; Biomarkers; C-Reactive Protein; Female; Follow-Up Studies; Heart Failure; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged; Natriuretic Peptide, Brain; Stroke Volume

Mid-regional pro-adrenomedullin (MR-proADM) is a surrogate marker for adrenomedullin; a hormone that attenuates myocardial remodeling. Accordingly, we hypothesized that MR-proADM could provide diagnostic and prognostic information in patients with acute dyspnea.. We measured MR-proADM by a commercial ELISA on hospital admission in 311 patients with acute dyspnea and compared the utility of MR-proADM with N-terminal pro-B-type natriuretic peptide (NT-proBNP). Blood samples were also available after 24h (n=232) and before discharge (n=94). The principal diagnosis of the index hospitalization was determined by an adjudication committee. MR-proADM concentrations on hospital admission were higher in patients with acute heart failure (HF; n=143) vs. patients hospitalized with non-HF-related dyspnea (n=168): 1.31 (Q1-3 0.97-1.89) vs. 0.85 (0.59-1.15) nmol/L; p<0.001. The receiver-operating characteristics area under the curve (ROC-AUC) for MR-proADM to diagnose HF was 0.77 (95% CI 0.72-0.82) and 0.86 (0.82-0.90) for NT-proBNP. During a median follow-up of 816days, 66/143 patients (46%) with acute HF and 35/84 patients (42%) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) died; p=0.58 between groups. In multivariate Cox regression analyses, admission MR-proADM concentrations were associated with mortality in patients with acute HF (HR 5.90 [3.43-10.13], p<0.001), but not in patients with AECOPD. Admission MR-proADM concentrations also improved risk stratification in acute HF as assessed by the net reclassification index. MR-proADM concentrations decreased from admission to later time points.. Admission MR-proADM concentrations provide strong prognostic information in patients with acute HF, but modest diagnostic information in patients with acute dyspnea.

Topics: Acute Disease; Adrenomedullin; Aged; Biomarkers; Dyspnea; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Hospitalization; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Protein Precursors

Chest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR-proADM) in prediction of mortality and major adverse cardiac events (MACE).. This was a subanalysis of the CHOPIN study, a 16-center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6-month all-cause mortality and the secondary endpoint was 30-day and 6-month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure.. MR-proADM performed similarly to troponin (cTnI; c-statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR-proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6-month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR-proADM, history of coronary artery disease (CAD), and hypertension were predictors of short-term MACE, while history of CAD, hypertension, cTnI, and MR-proADM were predictors of long-term MACE.. In patients with chest pain, MR-proADM predicts mortality and MACE in all-comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses-generating and future prospective studies to identify its utility in risk stratification should be considered.

Topics: Acute Disease; Adrenomedullin; Aged; Biomarkers; Chest Pain; Emergency Service, Hospital; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pravastatin; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Severity of Illness Index

Biomarkers may contribute to risk stratification in coronary heart disease (CHD). We examined whether plasma midregional proadrenomedullin (MR-proADM) concentration at baseline and its change over one year predicts long-term outcomes in stable CHD patients.. The LIPID study randomised patients 3-36 months after an acute coronary syndrome with total cholesterol 4.0-7.0 mmol/L (155-271 mg/dL), to placebo or pravastatin 40 mg. Follow-up was 6.0 years. MR-proADM plasma concentrations at baseline and one year later were determined in 7863 and 6658 patients, respectively. These were categorised into quartiles to perform Cox regression analysis, adjusting for baseline parameters.. Baseline MR-proADM concentrations predicted major CHD events (non-fatal myocardial infarction or CHD death; hazard ratio (HR) 1.52, 1.26-1.84 for Q4-Q1), CHD death (HR 2.21, 1.67-2.92), heart failure (HR 2.30, 1.78-2.97) and all-cause mortality (HR 1.82, 1.49-2.23). Associations were still significant after adjustment for baseline B-type natriuretic peptide (BNP) concentration. Increase in MR-proADM after one year was associated with increased risk of subsequent CHD events (HR 1.34, 1.08-1.66), non-fatal myocardial infarction (HR 1.50, 1.12-2.03), heart failure (HR 1.78, 1.37-2.30) and all-cause mortality (HR 1.31, 1.04-1.64). Associations with heart failure and all-cause mortality remained significant after adjusting for baseline and change in BNP concentration. Change in MR-proADM moderately improved risk reclassification for major CHD events (net reclassification improvement (NRI) 3.48%) but strongly improved risk reclassification for heart failure (NRI 5.60%).. Baseline and change in MR-proADM concentrations over one year are associated with risk of major clinical events, even after adjustment for BNP concentrations.

Topics: Adrenomedullin; Adult; Aged; Biomarkers; Coronary Disease; Female; Follow-Up Studies; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Natriuretic Peptide, Brain; Pravastatin; Predictive Value of Tests; Prognosis; Protein Precursors; Recurrence; Risk Assessment

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

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

To assess the cardiovascular prognostic value of mid-regional pro-adrenomedullin (MR-proADM) and compare this with B-type natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), on death or a composite end point in patients who developed heart failure after an acute myocardial infarction (AMI).. From a subset of 214 patients from the OPTIMAAL study, blood samples were obtained at a median of 3 days after AMI when patients had developed signs and/or symptoms of heart failure (HF) or a left ventricular ejection fraction <0.35%. End points were all-cause mortality and a composite end point, including death, myocardial reinfarction, stroke and/or resuscitated cardiac arrest.. Mean age of the patients was 68±10 years and mean follow-up was 918±311 days. During follow-up 31 patients died and 61 reached the composite end point. In multivariable Cox proportional hazard models adjusted for BNP, NT-proBNP and other covariates, a doubling of MR-proADM showed a 3.02 (95% CI 1.66 to 5.49) times increased risk of mortality (p<0.001) and a 1.77 (95% CI 1.13 to 2.78) times increased risk of reaching the composite end point (p=0.013). Receiver operating characteristic curves indicated that MR-proADM (area under the curve (AUC)=0.81) was a stronger predictor of mortality than BNP (AUC=0.66; p=0.0034 vs MR-proADM) and NT-proBNP (AUC=0.67; p<0.001 vs MR-proADM). Furthermore, MR-proADM enhanced significantly risk classification and integrated discrimination improvement in comparison with BNP and NT-proBNP. Finally, changes in MR-proADM over time significantly added prognostic information to the baseline value.. MR-proADM is a promising biomarker and has strong prognostic value for mortality and morbidity in patients with HF after an AMI. In this study, MR-proADM had stronger predictive value than BNP and NT-proBNP.

Topics: Adrenomedullin; Aged; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis

Though various neurohormonal systems are concurrently activated during heart failure (HF), their biological effectors are not always easy to measure due to their short life in vivo, instability in biological samples, or very low concentrations. We measured the plasma concentrations of four stable precursor fragments of neurohormonal systems in patients with chronic HF and evaluated their relationship with outcome.. This study was performed in 1237 patients with chronic and stable HF enrolled in the GISSI-heart failure trial (GISSI-HF). The following four precursor fragments, mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1) and C-terminal pro-vasopressin (CT-proAVP or copeptin), were measured at randomization and after 3 months. Baseline concentrations were independent predictors of clinical outcome (median follow-up 3.9 years). The addition of MR-proANP improved net reclassification for mortality when added to multivariable models based on clinical risk factors alone [net reclassification improvement (NRI) = 0.12, P = 0.0007] or together with NT-proBNP (NRI = 0.06, P = 0.01). Changes in MR-proANP concentrations were related to mortality [HR (95% CI) 1.38 (0.99-1.93), P = 0.0614 and 1.58 (1.13-2.21), P = 0.0078 in the middle and highest vs. lowest tertiles], while changes in the other markers were not.. In patients with chronic and stable HF enrolled in a multicentre, randomized, clinical trial, measurement of stable precursor fragments of vasoactive peptides provided prognostic information independent of natriuretic peptides which are currently the best biomarkers for risk stratification.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Confidence Intervals; Double-Blind Method; Female; Heart Failure; Humans; Italy; Kaplan-Meier Estimate; Linear Models; Male; Peptide Fragments; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Factors; ROC Curve

Increase in adrenomedullin (ADM) plasma levels in congestive heart failure (HF) patients is due to many cardiac and systemic factors, particularly to greater fluid retention and to activation of sympathetic nervous system. Aim of this study was to assess the role of plasma ADM levels in HF patients treated by cardiac resynchronization therapy (CRT).. 50 patients, mean age 70 years, 34 male, New York Heart Association (NYHA) Class III-IV HF, left ventricular ejection fraction (LVEF) < 35%, underwent CRT. All patients were in sinus rhythm and with complete left bundle branch block (QRS duration 138 +/- 6 msec). A complete echoDoppler exam, blood samples for brain natriuretic peptide (BNP), and ADM were obtained from 2 to 7 days before implantation.. At 16 +/- 6 months follow-up, >or=1 NYHA Class improvement was observed in 38 patients. However, a >10% reduction in end-systolic dimensions (ESD) was reported in 21 patients (Group I): -16.6 +/- 1.8%; in the remaining 29 patients ESD change was almost negligible: -2.0 +/- 1.03% (Group II), P < 0.0001. The two groups were comparable for age, sex, cause of LV dysfunction, therapy, QRS duration at baseline, preimplantation ESD, LVEF%, and BNP. Significantly higher pre implantation ADM levels were present in Group I than in Group II (27.2 +/- 1.8 pmol/l vs 17.9 +/- 1.4, P = 0.0003).. Significantly higher ADM levels indicate a subgroup of patients in whom reverse remodeling can be observed after CRT. Patients with lower ADM basal values before CRT could represent a group in whom the dysfunction is so advanced that no improvement can be expected.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiac Pacing, Artificial; Female; Heart Failure; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Our purpose was to assess the diagnostic utility of mid-regional pro-atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF.. There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient.. The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory.. MR-proANP (> or =120 pmol/l) proved noninferior to BNP (> or =100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p < 0.001). In adjusted multivariable Cox regression, MR-proADM, but not BNP, carried independent prognostic value (p < 0.001). Results were consistent using NT-proBNP instead of BNP (p < 0.001). None of the biomarkers was able to predict rehospitalization or visits to the emergency department with clinical relevance.. MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Dyspnea; Female; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Reproducibility of Results

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

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

We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo.. Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported.. Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months.. Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4 [1.3-4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value.. In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.

Topics: Adrenergic beta-Antagonists; Adrenomedullin; Biomarkers; Carbazoles; Carvedilol; Chronic Disease; Heart Failure; Humans; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Peptides; Prognosis; Propanolamines; Risk Factors; Ventricular Dysfunction, Left

Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown.. Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo.. Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

Topics: Adrenomedullin; Cardiotonic Agents; Female; Heart Failure; Hemodynamics; Hormones; Humans; Injections, Intravenous; Kidney; Male; Middle Aged; Peptides

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Calcitonin Gene-Related Peptide; Cardiac Output; Cardiotonic Agents; Central Venous Pressure; Double-Blind Method; Female; Heart Failure; Humans; Injections, Intravenous; Male; Middle Aged; Peptides; Radioimmunoassay; Treatment Outcome

Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings.. The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure.. In all, 98 patients [65 men and 33 women, aged 58.2 +/- 11.0 years, mean +/- standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 +/- 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification.. Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one-fifth to one-seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration.. Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiac Catheterization; Cardiomyopathies; Epinephrine; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peptides; Prognosis; Proteins; Radioimmunoassay; Vasodilator Agents

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

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

Adrenomedullin is a potent vasodilator peptide and occurs in circulating blood of human beings and experimental animals. Because it is produced in intact aorta of rats and in cultured vascular endothelial cells, adrenomedullin seems to participate in regulation of local vascular tone. To determine the pathophysiological roles of adrenomedullin, we investigated its plasma concentrations in 49 patients with heart failure. Plasma adrenomedullin levels increased significantly with advancing severity of the disease (New York Heart Association functional class I, 4.1 +/- 1.0; II, 5.6 +/- 1.6; III, 6.4 +/- 0.8; IV, 13.2 +/- 6.8 (fmol/l). Plasma adrenomedullin was correlated with pulmonary artery pressure (r = 0.44, p = 0.0114) and pulmonary capillary wedge pressure (r = 0.53, p = 0.0002). These findings indicate that adrenomedullin may play some important role in the pathophysiologic makeup of heart failure by its vasodilating effects against the concomitant exaggeration of humor pressor agents such as catecholamine and the renin-angiotensin system. Hemodynamic changes in pulmonary circulation may have some influence on the increased synthesis and secretion of plasma adrenomedullin in chronic congestive heart failure.

Topics: Adrenomedullin; Adult; Aged; Cardiac Catheterization; Cardiac Output; Chronic Disease; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Peptides; Severity of Illness Index

Heart failure (HF) is a frequent condition in the elderly, further complicated by associated pulmonary hypertension (PH), with impact on morbidity and mortality. Plasma proteins associated with cardiovascular disease, related to inflammation, neurohormonal changes, and myocyte stress, pathways recognized in the pathophysiology of HF, may provide information on disease severity and prognosis. We aimed to investigate such cardiovascular proteins and their relationship to haemodynamics before and 1 year after heart transplantation (HT), as well as their prognostic value in advanced HF with PH.. Elevated plasma levels of ADM may be a marker of pressure/volume overload in HF patients with PH, as well as long-term prognosis after HT. In line with previous studies, our findings additionally confirm that ADM may be a marker of venous congestion in HF. Further studies are encouraged to establish a deeper understanding of the properties of ADM and its relationship with HF and PH, in order to potentially facilitate clinical management of HF and associated PH.

Topics: Adrenomedullin; Aged; Biomarkers; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Prognosis

We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS).. N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses.. Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker.. MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Aortic Valve Stenosis; Atrial Natriuretic Factor; Biomarkers; Female; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Stroke Volume; Ventricular Function, Left

Background and Objectives: the cardiovascular adverse events including mortality and heart failure, persist significantly during the first months after the acute phase of ST-segment elevation myocardial infarction (STEMI). The increased level of midregional proadrenomedullin (MR-proADM), at hospital presentation in STEMI patients is considered an independent predictor of short-term and long-term mortality and heart failure. This study aimed to measure MR-proADM levels during the acute and recovery phases of STEMI and corroborate whether MR-proADM level was associated with the adverse cardiac events after recovering from STEMI. Materials and Methods: this prospective study enrolled subjects with acute phase STEMI admitted to the intensive cardiac care unit. After recovering and discharged from hospitalization, subjects were followed-up for 90 days. For MR-proADM measurement, the blood samples during acute phase were withdrawn on hospital admission (MR-proADM-0) and during recovery at the day-30 follow up (MR-proADM-30). Adverse cardiac events were evaluated at 30-day and 90-day follow up, namely a composite of death, chronic heart failure, and hospital readmission of any cardiac causes. Results: 83 subjects were enrolled. The median MR-proADM-0 was 3313.33 pg/mL and MR-proADM-30 was significantly reduced at 292.50 pg/mL, p < 0.001. Nineteen subjects (22.9%) experienced adverse cardiac events at 30-day follow up. The MR-proADM-0 level was independently associated with 30-day adverse cardiac events (adjustedOR 1.002, 95%CI: 1.001−1.003, p = 0.040), after adjustment with other variables. In this case, 25 subjects (32.5%) experienced adverse cardiac events at 90-day follow-up. The MR-proADM-0 level was independently associated with 90-day adverse cardiac events (adjustedOR 1.002, 95%CI: 1.001−1.003, p = 0.049). The higher changes of MR-proADM-0 to MR-proADM-30 also associated with adverse cardiac events at 90 days. Conclusions: The MR-proADM was significantly increased during the acute phase of STEMI and declined during recovery phase. The higher MR-proADM level during the acute phase of STEMI and its change intensity were predictors of adverse cardiac events within the 90-day follow up.

Topics: Adrenomedullin; Biomarkers; Follow-Up Studies; Heart Failure; Humans; Prognosis; Prospective Studies; Protein Precursors; ST Elevation Myocardial Infarction

Bioactive adrenomedullin (bio-ADM) is a vascular-derived peptide hormone that has emerged as a promising biomarker for assessment of congestion in decompensated heart failure (HF). We aimed to evaluate diagnostic and prognostic performance of bio-ADM for HF in comparison to amino-terminal pro-B-type natriuretic peptide (NT-proBNP), with decision thresholds derived from invasive haemodynamic and population-based studies.. Normal reference ranges for bio-ADM were derived from a community-based cohort (n = 5060). Correlations with haemodynamic data were explored in a cohort of HF patients undergoing right heart catheterization (n = 346). Mortality and decision cutoffs for bio-ADM was explored in a cohort of patients presenting in the ER with acute dyspnoea (n = 1534), including patients with decompensated HF (n = 570). The normal reference range was 8-39 pg/mL. The area under the receiver operating characteristic curve (AUROC) for discrimination of elevated mean right atrial pressure (mRAP) and pulmonary arterial wedge pressure (PAWP) was 0.74 (95% CI = 0.67-0.79) and 0.70 (95% CI = 0.64-0.75), respectively, with optimal bio-ADM decision cutoff of 39 pg/mL, concordant with cubic spline analyses. NT-proBNP discriminated PAWP slightly better than mRAP (AUROC 0.73 [95% CI = 0.68-0.79] and 0.68 [95% CI = 0.61-0.75]). Bio-ADM correlated with (mRAP, r = 0.55) while NT-proBNP correlated with PAWP. Finally, a bio-ADM decision cutoff of 39 pg/mL associated with 30 and 90 day mortality and conferred a two-fold increased odds of HF diagnosis, independently from NT-proBNP.. Bio-ADM tracks with mRAP and associates with measures of systemic congestion and with mortality in decompensated HF independently from NT-proBNP. Our findings support utility of bio-ADM as a biomarker of systemic venous congestion in HF and nominate a decision threshold.

Topics: Adrenomedullin; Biomarkers; Heart Failure; Humans; Hyperemia; Prognosis

Background and Objectives: The aim of this paper is to evaluate the impact of humoral substance mid-regional pro-adrenomedullin (MR-proADM) on the two-year survival of patients with chronic heart failure and relate it to the dosage of furosemide. Materials and Methods: The data is taken from the stable systolic heart failure (EF < 50%) FAR NHL registry (FARmacology and NeuroHumoraL activation). The primary endpoint at two-year follow-up was death, heart transplantation, or LVAD implantation. Results: A total of 1088 patients were enrolled in the FAR NHL registry; MR-proADM levels were available for 569 of them. The mean age was 65 years, and 81% were male. The aetiology of HF was ischemic heart disease in 53% and dilated cardiomyopathy in 41% of patients. The mean EF was 31 ± 9%. Statistically significant differences (p < 0.001) were obtained in several parameters: patients with higher MR-proADM levels were older, rated higher in NYHA class, suffered more often from lower limb oedema, and had more comorbidities such as hypertension, atrial fibrillation, diabetes, and renal impairment. MR-proADM level was related to furosemide dose. Patients taking higher doses of diuretics had higher MR-proADM levels. The mean MR-proADM level without furosemide (n = 122) was 0.62 (±0.55) nmol/L, with low dose (n = 113) 1−39 mg/day was 0.67 (±0.30) nmol/L, with mid dose (n = 202) 40−79 mg/day was 0.72 (±0.34) nmol/L, with high dose (n = 58) 80−119 mg/day was 0.85 (±0.40) nmol/L, and with maximum dose (n = 74) ≥120 mg/day was 1.07 (±0.76) nmol/L, p < 0.001. Patients with higher MR-proADM levels were more likely to achieve the primary endpoint at a two-year follow-up (p < 0.001) according to multivariant analysis. Conclusions: Elevated plasma MR-proADM levels in patients with chronic heart failure are associated with an increased risk of death and hospitalization. Higher MR-proADM levels in combination with increased use of loop diuretics reflect residual congestion and are associated with a higher risk of severe disease progression.

Topics: Adrenomedullin; Aged; Biomarkers; Diuretics; Female; Follow-Up Studies; Furosemide; Heart Failure; Humans; Male; Peptide Fragments; Prognosis; Protein Precursors; Registries; Risk Assessment; Sodium Potassium Chloride Symporter Inhibitors

Adrenomedullin, a peptide with vasodilatory, natriuretic, and diuretic effects, may be a novel agent for treating heart failure. Heart failure is associated with an increased risk of atrial fibrillation (AF), but the effects of adrenomedullin on atrial arrhythmogenesis remain unclear. This study investigated whether adrenomedullin modulates the electrophysiology of the atria (AF substrate) or pulmonary vein (PV; AF trigger) arrhythmogenesis. Conventional microelectrode or whole-cell patch clamps were used to study the effects of adrenomedullin (10, 30, and 100 pg/mL) on the electrical activity, mechanical response, and ionic currents of isolated rabbit PV and sinoatrial node tissue preparations and single PV cardiomyocytes. At 30 and 100 pg/mL, adrenomedullin significantly reduced the spontaneous beating rate of the PVs from 2.0 ± 0.4 to 1.3 ± 0.5 and 1.1 ± 0.5 Hz (reductions of 32.9% ± 7.1% and 44.9 ± 8.4%), respectively, and reduced PV diastolic tension by 12.8% ± 4.1% and 14.5% ± 4.1%, respectively. By contrast, adrenomedullin did not affect sinoatrial node beating. In the presence of L-NAME (a nitric oxide synthesis inhibitor, 100 μM), adrenomedullin (30 pg/mL) did not affect the spontaneous beating rate or diastolic tension of the PVs. In the single-cell experiments, adrenomedullin (30 pg/mL) significantly reduced the L-type calcium current (I

Topics: Adrenomedullin; Animals; Atrial Fibrillation; Heart Atria; Heart Failure; Pulmonary Veins; Rabbits

The aim of this study is to evaluate the use of on-admission plasma levels of BNP, MR-proADM, and cTnI in diagnosing the clinical severity and progression of heart failure (HF) in children with CHD. Also, to correlate the levels of these biomarkers with the HF outcome (survival versus in-hospital mortality).. A prospective cohort study conducted in period from January 2017 to March 2018. All children presenting with HF had a Ross score assessment, echocardiography, and on-admission plasma level assay of BNP, MR-proADM, and cTnI. Patients were followed clinically throughout their hospital stay. The discriminatory power of on-admission measurement of each biomarker was determined using the receiver-operating characteristic (ROC). The results showed a significantly high on-admission plasma level of the 3 biomarkers among CHD cohort children than healthy controls (p < 0.001). Linear correlation was noted between the 3 biomarkers with Ross score, ejection fraction, and duration of hospital stay. Furthermore, significant association between on-admission level of the 3 biomarkers (BNP, MR-proADM, and cTnI) with patient's in-hospital mortality (p = 0.0003, Beta coefficient = 0.842; p = 0.0495, Beta coefficient = 0.183; and p < 0.001, Beta coefficient = 0.635, respectively), with on-admission BNP (cut of point 507.13) predicting in-hospital mortality, with 95.5% sensitivity, 88% specificity.. There is a high diagnostic value of measuring the on-admission levels of BNP, MR-proADM, and cTnI regarding the clinical severity and disease progression in the setting of pediatric heart failure, but the BNP level was more superior in prediction of the patients' outcome.

Topics: Adrenomedullin; Biomarkers; Child; Heart Failure; Humans; Natriuretic Peptide, Brain; Prognosis; Prospective Studies; Troponin I

Acute dyspnea with underlying congestion is a leading cause of emergency department (ED) visits with high rates of hospitalization. Adrenomedullin is a vasoactive neuropeptide hormone secreted by the endothelium that mediates vasodilation and maintains vascular integrity. Plasma levels of biologically active adrenomedullin (bio-ADM) predict septic shock and vasopressor need in critically ill patients and are associated with congestion in patients with acute heart failure (HF) but the prognostic value in unselected dyspneic patients at the ED is unknown. The purpose of this study is to test if bio-ADM predicts adverse outcomes when sampled in patients with acute dyspnea at presentation to the ED. In this single-center prospective observational study, we included 1402 patients from the ADYS (Acute DYSpnea at the Emergency Department) cohort in Malmö, Sweden. We fitted logistic regression models adjusted for sex, age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and C-reactive protein (CRP) to associate bio-ADM plasma levels to mortality, hospitalization, intravenous (IV) diuretic treatment and HF diagnosis. Using receiver operating characteristic (ROC) curve analysis we evaluated bio-ADM discrimination for these outcomes compared to a reference model (sex, age, NT-proBNP, creatinine, and CRP). Model performance was compared by performing a likelihood ratio test on the deviances of the models. Bio-ADM (per interquartile range from median) predicts both 90-day mortality [odds ratio (OR): 1.5, 95% confidence interval (CI) 1.2-2.0, p < 0.002] and hospitalization (OR: 1.5, 95% CI 1.2-1.8, p < 0.001) independently of sex, age, NT-proBNP, creatinine, and CRP. Bio-ADM statistically significantly improves the reference model in predicting mortality (added χ

Topics: Adrenomedullin; Biomarkers; Creatinine; Diuretics; Dyspnea; Emergency Service, Hospital; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis

Quantifying the activity of the adrenomedullin system might help to monitor and guide treatment in acute heart failure (AHF) patients. The aims were to (1) identify AHF patients with marked benefit or harm from specific treatments at hospital discharge and (2) predict mortality by quantifying the adrenomedullin system activity.. This was a prospective multicentre study. AHF diagnosis and phenotype were centrally adjudicated by two independent cardiologists among patients presenting to the emergency department with acute dyspnoea. Adrenomedullin system activity was quantified using the biologically active component, bioactive adrenomedullin (bio-ADM), and a prohormone fragment, midregional proadrenomedullin (MR-proADM). Bio-ADM and MR-proADM concentrations were measured in a blinded fashion at presentation and at discharge. Interaction with specific treatments at discharge and the utility of these biomarkers on predicting outcomes during 365-day follow-up were assessed.. Among 1886 patients with adjudicated AHF, 514 patients (27.3%) died during 365-day follow-up. After adjusting for age, creatinine, and treatment at discharge, patients with bio-ADM plasma concentrations above the median (> 44.6 pg/mL) derived disproportional benefit if treated with diuretics (interaction p values < 0.001). These findings were confirmed when quantifying adrenomedullin system activity using MR-proADM (n = 764) (interaction p values < 0.001). Patients with bio-ADM plasma concentrations above the median were at increased risk of death (hazard ratio 1.87, 95% CI 1.57-2.24; p < 0.001). For predicting 365-day all-cause mortality, both biomarkers performed well, with MR-proADM presenting an even higher predictive accuracy compared to bio-ADM (p < 0.001).. Quantifying the adrenomedullin's system activity may help to personalise post-discharge diuretic treatment and enable accurate risk-prediction in AHF.

Topics: Adrenomedullin; Aftercare; Biomarkers; Diuretics; Heart Failure; Humans; Patient Discharge; Prognosis; Prospective Studies

Topics: Adrenomedullin; Heart Failure; Humans; Natriuretic Peptide, Brain

The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi.. Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up.. Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition.. The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.

Topics: Adrenomedullin; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Biomarkers; Heart Failure; Heart Failure, Systolic; Humans; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Receptors, Angiotensin; Stroke Volume

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

Recently, bio-adrenomedullin (bio-ADM) was proposed as a congestion marker in heart failure (HF). In the present study, we aimed to study whether bio-ADM levels at discharge from a hospital admission for worsening HF could provide additional information on (residual) congestion status, diuretic dose titration and clinical outcomes.. Plasma bio-ADM was measured in 1236 acute HF patients in the PROTECT trial at day 7 or discharge. Median discharge bio-ADM was 33.7 [21.5-61.5] pg/mL. Patients with higher discharge bio-ADM levels were hospitalised longer, had higher brain natriuretic peptide levels, and poorer diuretic response (all P < 0.001). Bio-ADM was the strongest predictor of discharge residual congestion (clinical congestion score > 3) (odds ratio 4.35, 95% confidence interval 3.37-5.62; P < 0.001). Oedema at discharge was one of the strongest predictors of discharge bio-ADM (β = 0.218; P < 0.001). Higher discharge loop diuretic doses were associated with a poorer diuretic response during hospitalisation (β = 0.187; P < 0.001) and higher bio-ADM levels (β = 0.084; P = 0.020). High discharge bio-ADM levels combined with higher use of loop diuretics were independently associated with a greater risk of 60-day HF rehospitalisation (hazard ratio 4.02, 95% confidence interval 2.23-7.26; P < 0.001).. In hospitalised HF patients, elevated pre-discharge bio-ADM levels were associated with higher discharge loop diuretic doses and reflected residual congestion. Patients with combined higher bio-ADM levels and higher loop diuretic use at discharge had an increased risk of rehospitalisation. Assessment of discharge bio-ADM levels may be a readily applicable marker to identify patients with residual congestion at higher risk of early hospital readmission.

Topics: Adrenomedullin; Heart Failure; Humans; Patient Discharge; Patient Readmission; Sodium Potassium Chloride Symporter Inhibitors

The performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in diagnosing acute decompensated heart failure (ADHF) among patients presenting with breathlessness is markedly impaired in the presence of atrial fibrillation (AF). We evaluated the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin T as possible alternative markers for discrimination of ADHF in this setting.. Breathless patients (n = 1107) were prospectively and contemporaneously recruited in emergency departments in Singapore and New Zealand. The diagnoses of ADHF and presence of AF were adjudicated by two clinician specialists, blinded to MR-proADM, NT-proBNP and high-sensitivity cardiac troponin T (hs-cTnT) results. MR-proADM exhibited strong discrimination of ADHF with little change in performance irrespective of the presence of AF (area under the curve 0.83 in non-AF vs. 0.76 in AF) compared to NT-proBNP (0.91 vs. 0.71) and hs-cTnT (0.83 vs. 0.62), respectively. The accuracy of MR-proADM (73.3%) for diagnosing ADHF among patients with AF was superior to both NT-proBNP (61.6%) and hs-cTnT (64.6%). The superior performance of MR-proADM remained apparent when data from Singapore and New Zealand were analysed separately.. In the presence of AF, MR-proADM showed greater discrimination and accuracy, and less impairment in performance compared to that in non-AF cases, for the diagnosis of ADHF, compared to the guideline-endorsed NT-proBNP.

Topics: Adrenomedullin; Atrial Fibrillation; Biomarkers; Heart Failure; Humans; Natriuretic Peptide, Brain; New Zealand; Peptide Fragments; Protein Precursors; Singapore

Topics: Adrenomedullin; Heart Failure; Humans; Inflammation; Sepsis; Shock, Septic

Topics: Adrenomedullin; Heart Failure; Humans; Inflammation; Sepsis; Shock, Septic

Following the SEPSIS-3 consensus, detection of organ failure as assessed by the SOFA (Sequential Organ Failure Assessment) score, is mandatory to detect sepsis. Calculating SOFA outside of the Intensive Care Unit (ICU) is challenging. The alternative in this scenario, the quick SOFA, is very specific but less sensible. Biomarkers could help to detect the presence of organ failure secondary to infection either in ICU and non-ICU settings.. We evaluated the ability of four biomarkers (C-Reactive protein (CRP), lactate, mid-regional proadrenomedullin (MR-proADM) and procalcitonin (PCT)) to detect each kind of organ failure considered in the SOFA in 213 patients with infection, sepsis or septic shock, by using multivariate regression analysis and calculation of the area under the receiver operating curve (AUROC).. In the multivariate analysis, MR-proADM was an independent predictor of five different failures (respiratory, coagulation, cardiovascular, neurological and renal). In turn, lactate predicted three (coagulation, cardiovascular and neurological) and PCT two (cardiovascular and renal). CRP did not predict any of the individual components of SOFA. The highest AUROCs were those of MR-proADM and PCT to detect cardiovascular (AUROC, CI95%): MR-proADM (0.82 [0.76-0.88]), PCT (0.81 [0.75-0.87] (P < .05) and renal failure: MR-proADM (0.87 [0.82-0.92]), PCT (0.81 [0.75-0.86]), (P < .05). None of the biomarkers tested was able to detect hepatic failure.. In patients with infection, MR-proADM was the biomarker detecting the largest number of SOFA score components, with the exception of hepatic failure.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Area Under Curve; Blood Coagulation Disorders; C-Reactive Protein; Cardiovascular Diseases; Female; Heart Failure; Humans; Infections; Intensive Care Units; Lactic Acid; Liver Failure; Male; Middle Aged; Multivariate Analysis; Nervous System Diseases; Organ Dysfunction Scores; Peptide Fragments; Procalcitonin; Protein Precursors; Renal Insufficiency; Respiratory Insufficiency; ROC Curve; Sepsis; Shock, Septic

Pro-atrial natriuretic peptide (proANP) and pro-adrenomedullin (proADM) levels increase in acute heart failure and sepsis. After cardiac surgery, children may require increased support in the intensive care unit and may develop complications. The aim of this study was to evaluate the utility of proANP and proADM values, determined prior to cardiac surgery, for predicting the need for increased respiratory or inotropic support during the post-operative period.. This was a prospective study in children. Biomarkers were analyzed before surgery using a single blood test. The primary endpoints were the need for greater respiratory and/or inotropic support during the post-operative period. Secondary endpoints were the relationship between these biomarkers and complications after surgery.. One hundred thirteen patients were included. ProANP and proADM were higher in children who required greater respiratory and inotropic support, especially proANP; for increased respiratory support, 578.9 vs. 106.6 pmol/L (p = 0.004), and for increased inotropic support, 1938 vs. 110.4 pmol/L (p = 0.002). ProANP had a greater AUC than proADM for predicting increased respiratory support after surgery: 0.791 vs. 0.724. A possible cut-off point for proANP could be ≥ 325 pmol/L (sensitivity = 66.7% and specificity = 88.8%). In the multivariate analysis, the logarithmic transformation of proANP was independently associated with the need for increased respiratory support (OR = 3.575). Patients who presented a poor outcome after cardiac surgery also had higher biomarker values (proADM, p = 0.013; proANP, p = 0.001).. Elevated proANP before cardiac surgery may identify which children will need more respiratory and inotropic support during the post-operative period.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Cardiac Surgical Procedures; Child; Child, Preschool; Female; Heart; Heart Failure; Humans; Infant; Infant, Newborn; Male; Pediatrics; Thoracic Surgery

Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D.. We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP.. A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]).. Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Denmark; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Assessment; Risk Factors; Stroke Volume; Up-Regulation; Ventricular Function, Left

BACKGROUND Chinese hawthorn (Crataegus pinnatifida) fruit is a traditional Chinese medicine for treatment of digestive system and cardiovascular diseases. The fruit contains polyphenol compounds, such as epicatechin, that have anti-inflammatory activity. This study aimed to investigate the effects of an alcohol extract of hawthorn fruit (HAE) on inflammation and oxidative stress in rats with doxorubicin-induced chronic heart failure (CHF). MATERIAL AND METHODS Rats were intraperitoneally injected with doxorubicin to induce CHF and subsequently treated with HAE intragastrically once daily for 6 weeks. At the end of the experiment, echocardiographic and hemodynamic parameters were assessed, and enzyme-linked immunoassays were used to detect the levels of cardiac injury markers (brain natriuretic peptide, creatine kinase-MB, aspartate aminotransferase, lactate dehydrogenase, copeptin, and adrenomedullin), oxidative stress markers (glutathione peroxidase and malondialdehyde), and inflammatory cytokines (interleukin [IL]-6, IL-8, IL-1ß, and tumor necrosis factor-a). The IL-1ß, IL-6, glutathione peroxidase-1, and catalase mRNA levels were also measured by quantitative real-time polymerase chain reaction. RESULTS Our findings indicated that HAE exerts a cardioprotective effect, as shown by improved echocardiographic and hemodynamic parameters, decreased activity of serum myocardial enzymes, reduced serum levels of CHF markers, and inhibited inflammatory response in cardiac tissue. In addition, HAE treatment downregulated the mRNA expression of IL-1ß and tumor necrosis factor-alpha and upregulated the mRNA expression of glutathione peroxidase-1 and catalase compared with untreated doxorubicin-induced CHF rats. CONCLUSIONS HAE shows promise for the prevention and treatment of CHF. The cardioprotective effect of HAE appears to be related to inhibition of both the inflammatory response and oxidative stress in vivo.

Topics: Adrenomedullin; Animals; Antioxidants; Aspartate Aminotransferases; Chromatography, High Pressure Liquid; Chronic Disease; Crataegus; Creatine Kinase; Cytokines; Doxorubicin; Electrocardiography; Ethanol; Fruit; Glutathione Peroxidase; Glycopeptides; Heart Failure; Heart Function Tests; Inflammation; L-Lactate Dehydrogenase; Male; Malondialdehyde; Natriuretic Peptide, Brain; Oxidative Stress; Plant Extracts; Polyphenols; Rats, Wistar; RNA, Messenger

Topics: Adrenomedullin; Connexin 43; Edema, Cardiac; Heart Failure; Humans; Lymphangiogenesis; Myocardial Infarction

To assess the value added to the National Early Warning Score (NEWS) by mid-regional pro-adrenomedullin (MR-proADM) blood level in predicting deterioration in mild to moderately ill people.. Prospective observational study.. The Medical Admissions Suite of the Royal Victoria Infirmary, Newcastle.. 300 adults with NEWS between 2 and 5 on admission. Exclusion criteria included receiving palliative care, or admitted for social reasons or self-harming. Patients were enrolled between September and December 2015, and followed up for 30 days after discharge.. The primary outcome measure was the proportion of patients who, within 72 hours, had an. NEWS and MR-proADM together predicted. MR-proADM is potentially a clinically useful biomarker for deterioration in patients admitted to hospital with a mild to moderately severe acute illness, that is, with NEWS between 2 and 5. As a growing number of National Health Service hospitals are routinely recording the NEWS on their clinical information systems, further research should assess the practicality and use of developing a decision aid based on admission NEWS, MR-proADM level, and possibly other clinical data and other biomarkers that could further improve prognostic accuracy.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; Female; Heart Failure; Hospitalization; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Secretion of adrenomedullin (ADM) is stimulated by volume overload to maintain endothelial barrier function, and higher levels of biologically active (bio-) ADM in heart failure (HF) are a counteracting response to vascular leakage and tissue oedema. This study aimed to establish the value of plasma bio-ADM as a marker of congestion in patients with worsening HF.. Plasma bio-ADM in patients with new-onset and worsening HF is associated with more severe HF and more oedema, orthopnoea, hepatomegaly and jugular venous pressure. We therefore postulate bio-ADM as a congestion marker, which might become useful to guide decongestive therapy.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Disease Progression; Female; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Stroke Volume

Topics: Adrenomedullin; Biomarkers; Heart Failure; Humans

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

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

Previous studies of the authors have indicated that the transplantation of mesenchymal stem cells (MSCs) can attenuate cardiac fibrosis through the secretion of antifibrotic factors, such as adrenomedullin (ADM). Therefore, the authors addressed the hypothesis that ADM overexpression could enhance the antifibrotic effect of MSCs transplantation in a rat model of heart failure. The results of the present study demonstrated that, compared with the group that received the GFP‑MSCs, the transplantation of ADM‑MSCs significantly improved heart function and decreased the percentage of fibrotic area and the expression of matrix metalloproteinase 2. In addition, fluorescence microscopy indicated that the survival of transplanted MSCs also increased significantly in the ADM‑MSCs‑treated group. Furthermore, the expression of fibrosis‑related genes, such as ADM and hepatocyte growth factor, were significantly influenced in the ADM‑MSCs‑treated group. Based on these findings, it may be concluded that, compared with MSCs, MSCs overexpressing ADM can further improve heart function in rats experiencing heart failure through enhanced antifibrotic activity.

Topics: Adrenomedullin; Animals; Cell Survival; Cells, Cultured; Fibrillar Collagens; Fibrosis; Gene Expression; Heart Failure; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardium; Paracrine Communication; Rats, Wistar; Stroke Volume; Transduction, Genetic

We evaluated the utility of preoperative midregional (MR) pro-adrenomedullin (proADM) and cardiac troponin T (TnT) for improved detection of patients at high risk for perioperative cardiac events and mortality after major noncardiac surgery.. This prospective, single-center, observational study enrolled 79 patients undergoing major noncardiac surgery. After initial clinical assessment (clinical history, physical examination, echocardiogram, blood tests, and chest X-ray), MR-proADM and high-sensitivity TnT (hsTnT) were measured within 48 h prior to surgery by immunoluminometric and electrochemiluminescence immunoassay. Patients were followed by the consulting physician until discharge or up to 14 days in the hospital after surgery. Perioperative cardiac events included myocardial infarction and development or aggravation of congestive heart failure. Data were compared between patients who developed target events and event-free patients.. Within 14 days of monitoring, 14 patients (17.72%) developed target events: 9 (11.39%) died and 5 (6.33%) developed cardiovascular events. The average age of the patients was 71.29 ± 6.62 years (range: 55-87). Sex, age, and hsTnT did not significantly differ between groups. MR- proADM concentration was higher in deceased patients (p = 0.01). The upper quartile of MR-proADM was associated with a fatal outcome (66.7 vs. 20.0%, p < 0.01) and with cardiovascular events (64.3 vs. 16.9%, p < 0.01). MR-proADM above the cutoff value (≥0.85) was associated with a fatal outcome (88.9 vs. 20.0%, p < 0.01) and cardiovascular events (71.4 vs. 28.6%, p < 0.01); this association was not observed for hsTnT.. Preoperative measurement of MR-proADM provides useful information for perioperative cardiac events in high-risk patients scheduled for noncardiac surgery.

Topics: Adrenomedullin; Adult; Biomarkers; Female; Heart Failure; Humans; Male; Middle Aged; Preoperative Care; Prospective Studies; Risk Factors; Surgical Procedures, Operative; Troponin T

Topics: Adrenomedullin; Aged; Biomarkers; Female; Heart Failure; Humans; Male; Prognosis; Severity of Illness Index

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes.. Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation.. We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (. MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

Topics: Adrenomedullin; Aged; Biomarkers; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neuropeptides; Peptide Fragments; Prognosis; Prospective Studies

Whereas guidelines recommend the routine use of natriuretic peptides (NPs) in heart failure (HF) care, the clinical relevance and prognostic potential of midregional pro-adrenomedullin (MR-proADM) is less well established. We aimed to compare the prognostic potential of MR-proADM after acute decompensation for systolic HF with that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and midregional pro-atrial NP (MR-proANP), to investigate the significance of high/rising MR-proADM, and to evaluate the incremental prognostic yield of repeat measurements.. The Interdisciplinary Network Heart Failure (INH) programme enrolled patients hospitalized for acute systolic HF and followed them for 18 months (100% complete). Of 1022 INH participants, 917 (68 ± 12 years, 28% female) who had biomaterials available were enrolled. High MR-proADM was associated with more impaired left ventricular function, higher comorbidity burden, lower doses of HF medications, and lower likelihood of left ventricular reverse remodelling. Compared with NPs, MR-proADM had superior prognostic significance (concordance index 0.72 for all-cause mortality), improved Cox regression models including NPs (P < 0.001), and was the only biomarker also predicting non-cardiac death (hazard ratio 1.8 vs. 1.0). In the setting of low NPs, patients with high MR-proADM experienced non-cardiac death more often. Six month MR-proADM enhanced models including baseline MR-proADM (P < 0.001) for prediction of all-cause death (net reclassification index: 0.48, 95% confidence interval 0.19-0.78).. MR-proADM was found to correlate with the global disease burden in HF and proved a potent prognostic indicator, capturing the risk for both cardiac and non-cardiac death. Serial MR-proADM measurements further enhanced risk assessment, thus facilitating substantial reclassification.

Topics: Adrenomedullin; Aged; Biomarkers; Female; Follow-Up Studies; Germany; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Risk Assessment; Statistics as Topic; Ventricular Function, Left

Adrenomedullin (ADM) correlates with adverse cardiovascular outcomes in patients with acute myocardial infarction (AMI) and in patients with heart failure. Measurement of human mature ADM (mADM) has been difficult, and recent studies have used its surrogate - the mid-regional pro-ADM (MRproADM). Our objective was to determine whether mADM measured by a novel sandwich immunoassay, using the anti-C-terminal and an anti-mid-regional monoclonal antibody, was prognostic of 30-day, 90-day, 1-year, and 2-year major adverse cardiovascular events (MACEs) in 1111 consecutive patients who have suffered an AMI. We also compared it with the effect of MRproADM in the same patient population. A total of 311 (27.0%) patients experienced the primary endpoint at 2 years follow-up. The median (inter-quartile range) of mADM was significantly higher in patients who experienced a 2-year MACE [60.90 (44.00-86.97)] pg/ml, compared to event-free survivors [49.59 (36.20-68.15)] pg/ml (P < 0.001). mADM, taken as 1 SD of the continuous variable, was predictive of MACEs in multivariate analysis, with hazard ratios [95% confidence intervals (CIs)] at 90 days [1.28 (1.01-1.62)], 1 year [1.31 (1.08-1.59)], and 2 years [1.42 (1.07-1.64)]. It was also independently predictive of death at 1-year [1.52 (1.12-2.05)] and 2-year [1.42 (1.07-1.89)] follow-up. mADM was a better predictor of these outcomes than MRproADM, apart from death at 90 days, and combined death and heart failure hospitalization at 1 and 2 years, respectively. Human mADM can be reliably measured and predicts MACE events at medium-term follow-up, and confirms the paradigm of risk stratification using MRproADM - a surrogate for the active hormone. The relationship between mADM and MACE appears to be a continuum.

Topics: Adrenomedullin; Aged; Biomarkers; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Prognosis; Proportional Hazards Models; Risk Factors; Survival Rate; Time Factors

Obesity is a risk factor for heart failure (HF) and identification of symptomatic, and obese HF patients are challenging, because obesity can mimic HF symptoms. We aimed to evaluate novel biomarkers for HF in obese subjects of the general population.. Midregional proadrenomedullin (MR-proADM), growth differentiation factor-15 (GDF-15), midregional pro-atrial natriuretic peptide (MR-proANP), and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS), including 1204 obese individuals (BMI ≥ 30 kg/m. NT-proBNP and MR-proANP were lower in obese vs. non-obese HF individuals (p = 0.013 and p = 0.01, respectively), whereas GDF-15 was similar and MR-proADM was higher in obese vs. non-obese HF individuals. All biomarkers increased the odds ratio (OR) for prevalent HF. For NT-proBNP and MR-proANP, this increase was lower in obese vs. non-obese individuals, whereas it was comparable for MR-proADM and GDF-15. All biomarkers were associated with increased all-cause mortality (median follow-up 7.3 years, 211 events). Results were validated in 8373 individuals (n = 1734 with BMI ≥ 30 kg/m. All biomarkers were associated with HF and higher risk for all-cause mortality in the general population. In contrast to the natriuretic peptides NT-proBNP and MR-proANP, the novel biomarkers MR-proADM and GDF-15 were not lower in obese HF individuals, indicating their potential to facilitate HF diagnosis and prognosis in an increasingly obese HF population.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Cohort Studies; Female; Follow-Up Studies; Growth Differentiation Factor 15; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Prognosis; Prospective Studies; Protein Precursors; Risk Factors

BACKGROUND Myocardial fibrosis is the result of persistent anoxia and ischemic myocardial fibers caused by coronary atherosclerotic stenosis, which lead to heart failure, threatening the patient's life. This study aimed to explore the regulatory role of intermedin 1-53 (IMD1-53) in cardiac fibrosis using neonatal rat cardiac fibroblasts and a myocardial infarction (MI) rat model both in vitro and in vivo. MATERIAL AND METHODS The Western blot method was used to detect the protein expression of collagen I and collagen III in myocardial fibroblasts. The SYBR Green I real-time quantitative polymerase chain reaction (PCR) assay was used to detect the mRNA expression of collagen type I and III, IMD1-53 calcitonin receptor-like receptor (CRLR), transforming growth factor-β (TGF-β), and matrix metalloproteinase-2 (MMP-2). Masson staining was used to detect the area changes of myocardial fibrosis in MI rats. RESULTS Results in vivo showed that IMD1-53 reduced the scar area on the heart of MI rats and inhibited the expression of collagen type I and III both in mRNA and protein. Results of an in vitro study showed that IMD1-53 inhibited the transformation of cardiomyocytes into myofibroblasts caused by angiotensin II (Ang II). The further mechanism study showed that IMD1-53 inhibited the expression of TGF-β and the phosphorylation of smad3, which further up-regulated the expression of MMP-2. CONCLUSIONS IMD1-53 is an effective anti-fibrosis hormone that inhibits cardiac fibrosis formation after MI by down-regulating the expression of TGF-β and the phosphorylation of smad3, blocking fibrous signal pathways, and up-regulating the expression of MMP-2, thereby demonstrating its role in regression of myocardial fibrosis.

Topics: Adrenomedullin; Animals; Cardiomyopathies; Collagen; Down-Regulation; Fibroblasts; Fibrosis; Heart Failure; Male; Myocardial Infarction; Myocardium; Neuropeptides; Rats; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta1

Cardiac resynchronization therapy (CRT) induces reverse cardiac remodelling in heart failure (HF), but many patients receiving CRT remain non-responders. This study assessed the role of amino-terminal-pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide (MR-proANP), and mid-regional-pro-adrenomedullin (MR-proADM) at the time of device implantation to predict favourable clinical course (CRT response and/or risk of MACE) in HF patients receiving CRT.. A total of 137 HF patients were prospectively included. Blood was drawn from the coronary sinus (CS) at CRT implantation, and from a peripheral vein (PV) simultaneously and after 6 months. Clinical CRT response at 6 months and major adverse cardiovascular events (MACE) at 2 years were assessed. Baseline PV-levels of MR-proANP (202 vs. 318 pmol/L, P = 0.009) and MR-proADM (843 vs. 1112 pmol/L, P = 0.02) were lower in CRT responders compared with non-responders. At 6 months, CRT responders showed a decrease in MR-proANP levels, compared with an increase in non-responders (-32 vs. +7 pmol/L, P = 0.02). During the same period, NT-proBNP decreased by a similar way in responders and non-responders, while MR-proADM was unchanged in both groups. High baseline MR-proANP, either in PV (OR 0.41, 95% CI 0.24-0.71, P = 0.002) or CS (OR 0.32, 95% CI 0.15-0.70, P = 0.005) was associated with reduced likelihood of CRT response. Furthermore, PV and CS levels of NT-proBNP, MR-proANP, and MR-proADM were all associated with increased risk of 2-year MACE (all P < 0.01).. Mid-regional-pro-atrial natriuretic peptide may assist prediction of clinical course in HF patients undergoing CRT implantation. Low circulating MR-proANP at the time of device implantation is associated with CRT response and more favourable outcome.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiac Resynchronization Therapy; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Odds Ratio; Peptide Fragments; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Protein Precursors; Recovery of Function; Time Factors; Treatment Outcome; Ventricular Remodeling

Risk stratification of elderly patients presenting with heart failure (HF) to an emergency department (ED) is an unmet challenge. We prospectively investigated the prognostic performance of different biomarkers in unselected older patients in the ED.. We consecutively enrolled 302 non-surgical patients ⩾70 years presenting to the ED with a wide range of cardiovascular and non-cardiovascular comorbid conditions. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), ultrasensitive C-terminal pro-arginine-vasopressin (Copeptin-us) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of HF after reviewing all available baseline data using circulating NT-proBNP levels. A final diagnosis of HF was found in 120 (40%) of the 302 patients. All patients were followed up for cardiovascular death within the following 12 months. In order to test the prognostic performance of the investigated biomarkers we used boosting models with age and sex as mandatory covariates. Boosting is a statistical learning technique with built-in variable selection developed to obtain sparse and interpretable prediction models.. Follow-up was 100% complete. During a median follow-up time of 225 days (interquartile range (IQR) 156-319 days), 30 (9.9%) of 302 patients (aged 81±6 years) had cardiovascular deaths. Of these 30 patients, 21 had HF and nine had no HF diagnosed prior to admission. The boosting model selected MR-proADM and hs-cTNT as predictors of cardiovascular deaths. The median values of MR-proADM and hs-cTnT at presentation were significantly higher in patients with cardiovascular deaths compared to surviving patients during follow-up (2.56 nmol/L (IQR 1.62-4.48) vs. 1.11 nmol/L (IQR 0.83-1.80), P<0.001 and 81 ng/L (IQR 38-340) vs. 17 ng/L (IQR 0.9-38), P=0.004). One unit increase in the log-transformed MR-proADM levels was associated with a 1.99-fold risk of death (95% confidence interval (CI) 1.61-2.45, P<0.001). The second marker, hs-cTnT, showed an increased predicted risk but was not significantly correlated to event-free survival (hazard ratio 3.22, 95% CI 0.97-10.68, P=0.056).. Within different biomarkers, MR-proADM was the only predictor of cardiovascular deaths in unselected older patients presenting to the ED.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Emergency Service, Hospital; Female; Heart Failure; Humans; Male; Models, Statistical; Peptide Fragments; Prognosis; Protein Precursors; Risk Assessment

The objective was to evaluate the prognostic performance of a new biomarker, plasma bioactive adrenomedullin (bio-ADM), for short-term clinical outcomes in acute heart failure.. A multicenter prospective cohort study of adult emergency department (ED) patients suspected of having acute heart failure was conducted to evaluate the association between plasma bio-ADM concentration and clinical outcomes. The primary outcome was a composite of the following within 30 days: death, cardiac arrest with resuscitation, respiratory failure, emergency dialysis, acute coronary syndrome, hospitalization >5 days, and repeat ED visit or hospitalization. Prognostic accuracy was evaluated with a nonparametric receiver operating characteristic curve. In addition, a multivariable logistic regression model was constructed to assess the additive prognostic performance of bio-ADM while adjusting for other biomarkers routinely used clinically, including B-type natriuretic peptide, cardiac troponin I, creatinine, and sodium concentration.. Two hundred forty-six patients were enrolled, including 85 (34.6%) patients with the primary outcome. Plasma bio-ADM concentrations were higher among patients who experienced the primary outcome (median, 80.5 pg/mL; interquartile range [IQR], 53.7-151.5 pg/mL) compared with those who did not (median, 54.4 pg/mL; IQR, 43.4-78.4 pg/mL) (P < .01). Area under the receiver operating characteristic curve was 0.70 (95% confidence interval, 0.63-0.75). After adjusting for the other biomarkers, plasma bio-ADM remained a strong predictor of the primary outcome (adjusted odds ratio per IQR change, 2.68; 95% confidence interval, 1.60-4.51).. Bioactive adrenomedullin concentrations at the time of ED evaluation for acute heart failure were predictive of clinically important 30-day outcomes, suggesting that bio-ADM is a promising prognostic marker for further study.

Topics: Adrenomedullin; Aged; Biomarkers; Emergency Service, Hospital; Female; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies

The evaluation of the role of novel biomarkers in the management of cardiac and pulmonary conditions has received particular attention in recent years. A further particular perspective is the use of biomarker panels in the evaluation of patients presenting with acute dyspnea.. We prospectively evaluated three biomarkers (MR-proANP, PCT, and MR-proADM) in consecutive patients presenting with acute dyspnea in a medical emergency unit during a 4-week period. Patients received a final diagnosis. Biomarkers were tested for their potential to predict diagnoses and survival. No intervention was done.. Overall, n = 172 patients were included. Of these, 32.6 % had acute heart failure, 16.9 % pneumonia, and 5.8 % died. MR-proANP was the highest in patients with acute heart failure and lung embolism. Dyspnea scores and levels of MR-pro-ANP correlated positively. MR-proANP achieved an AUC of 0.83 for the diagnosis of acute heart failure. Using a cut-off of 120 pmol/l, sensitivity was 91.1 % and specificity 50 %. PPV was 46.8 % and NPV 92.1 %. In patients with MR-proANP >300 pmol/l, PPV raised to 67.3 %. MR-proADM had an AUC of 0.84 for the prediction of death. PPV was 16 % and NPV 98.4 %. The AUC of PCT was 0.74 for the diagnosis of pneumonia. Using a cut-off of 0.25 ng/ml, PCT had a sensitivity of 44.8 % and a specificity of 85.3 %. PPV was 38.2 and NPV 88.4 %. Using a lower cut-off of <0.1 ng/ml, NPV reached 92.9 %.. A panel of three biomarkers (MR-proANP, PCT, and MR-proADM) in patients presenting to the emergency unit with acute dyspnea provides information about the probability of acute heart failure, nonsurvival, and pneumonia. These biomarkers achieve low to moderate positive predictive values (PPV) and high negative predictive values (NPV).

Topics: Acute Disease; Adrenomedullin; Aged; Aged, 80 and over; Area Under Curve; Atrial Natriuretic Factor; Biomarkers; Calcitonin; Dyspnea; Emergency Service, Hospital; Female; Heart Failure; Humans; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Reproducibility of Results; Risk Factors; ROC Curve; Time Factors

Doxorubicin (DOX) is one of the best known anticancer drugs, and is used in the treatment of lymphoma, lung cancer, stomach cancer, and a number of other cancers. However, DOX has some serious side effects, the worst being lethal heart failure. Occasionally, its side effects result in the cessation of the anticancer treatment, thus having a serious adverse influence on prognosis. Agents that can be administered as alternative prophylactics or to ameliorate the side effects of DOX will be useful in increasing the safety and efficacy of anticancer therapy. Adrenomedullin (AM) is a peptide hormone secreted by many organs, including the heart; it has an organ-protective effect, including antiapoptotic, anti-inflammatory, and antioxidative stress. Blood AM levels increase with heart failure; endogenic AM has been suggested in order to protect the heart. Furthermore, exogenous AM administration has shown therapeutic effects for heart failure in patients. However, it is unclear whether AM can protect the heart against drug-induced cardiac injury in vivo. The present study was performed in order to investigate the effects of AM on DOX-induced cardiac damage. Male BALB/c mice were treated with DOX and/or AM. Exogenous AM improved the survival ratio of DOX-treated mice. In addition, AM reduced serum lactate dehydrogenase (LDH) levels following DOX treatment. On pathological examination, AM was shown to inhibit DOX-induced cardiac tissue damage, mitochondrial abnormality, and cell death. These findings suggest that AM has a protective effect against DOX-induced cardiac damage.

Topics: Adrenomedullin; Animals; Antineoplastic Agents; Cardiotonic Agents; Cell Death; Doxorubicin; Gene Expression; Heart; Heart Failure; Male; Mice, Inbred BALB C; Mitochondria, Heart; Myocardium; NADPH Oxidases

In recent years there has been an increase in the number of biomarkers in heart failure (HF). The clinical role for these novel biomarkers in combination is not clear.. The following novel biomarkers were measured from 628 patients recently hospitalized with decompensated HF; mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin, high-sensitivity cardiac troponin T (hs-cTnT), ST2, galectin-3, cystatin C, combined free light chains (cFLC) and high sensitivity C-reactive protein (hsCRP). The incremental prognostic value of these novel biomarkers was evaluated within an extensive model containing established predictors of mortality. During a mean (SD) follow-up of 3.2 (1.5) years, 290 (46%) patients died. Elevated concentrations of all novel biomarkers were associated with an increased unadjusted risk of mortality but only two-thirds were independent predictors following multivariable analysis. Using dichotomized cut-points from receiver operating characteristic analysis, MR-proADM, hs-cTnT, cFLC, hsCRP, and ST2 remained independent predictors of mortality. Further dichotomization into low (0-2 elevated biomarkers) or high (at least three of the five biomarkers elevated) risk groups provided greatest incremental prognostic value (hazard ratio 2.20, 95% confidence interval 1.37-3.54; P = 0.001) and improved the performance of the model (C-statistic 0.730 from 0.721, net reclassification index 32.5%).. The novel biomarkers included in this study added little, if any, incremental prognostic value on their own to a model containing established predictors of mortality. However, following dichotomization, five of the novel biomarkers provided incremental prognostic value. There was a clear gradient in the risk of death with increasing numbers of elevated novel biomarkers, with the presence of at least three identifying patients at greatest risk of mortality.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; C-Reactive Protein; Cystatin C; Female; Follow-Up Studies; Galectin 3; Glycopeptides; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Mortality; Multivariate Analysis; Peptide Fragments; Prognosis; Proportional Hazards Models; Protein Precursors; ROC Curve; Stroke Volume; Troponin T

Several biomarkers have individually been shown to be useful for risk stratification in patients with acute myocardial infarction (MI). The optimal multimarker strategy remains undefined.. Biomarkers representing different pathobiological axes were studied, including myocardial stress/structural changes (NT-pro B-type natriuretic peptide [NT-proBNP], midregional proatrial natriuretic peptide [MR-proANP], suppression of tumorigenicity 2 [ST2], galectin-3, midregional proadrenomedullin [MR-proADM], and copeptin), myonecrosis (troponin T), and inflammation (myeloperoxidase [MPO], high sensitivity C-reactive protein [hsCRP], pregnancy-associated plasma protein A [PAPP-A], and growth-differentiation factor-15 [GDF-15]), in up to 1258 patients from Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28), a randomized trial of clopidogrel in ST-elevation MI (STEMI). Patients were followed for 30 days. Biomarker analyses were adjusted for traditional clinical variables. Forward step-wise selection was used to assess a multimarker strategy. After adjustment for clinical variables and using a dichotomous cutpoint, 7 biomarkers were each significantly associated with a higher odds of cardiovascular death or heart failure (HF) through 30 days, including NT-proBNP (adjusted odds ratio [ORadj], 2.54; 95% CI, 1.47-4.37), MR-proANP (2.18; 1.27-3.76), ST2 (2.88; 1.72-4.81), troponin T (4.13; 1.85-9.20), MPO (2.75; 1.20-6.27), hsCRP (1.96, 1.17-3.30), and PAPP-A (3.04; 1.17-7.88). In a multimarker model, 3 biomarkers emerged as significant and complementary predictors of cardiovascular death or HF: ST2 (ORadj, 2.87; 1.61-5.12), troponin T (2.34; 1.09-5.01 and 4.13, 1.85-9.20, respectively for intermediate and high levels), and MPO (2.49; 1.04-5.96). When added to the TIMI STEMI Risk Score alone, the multimarker risk score significantly improved the C-statistic (area under the curve, 0.75 [95% CI, 0.69-0.81] to 0.82 [0.78-0.87]; P=0.001), net reclassification index (0.93; P<0.001), and integrated discrimination index (0.09; P<0.001).. In patients with STEMI, a multimarker strategy that combines biomarkers across pathobiological axes of myocardial stress, myocyte necrosis, and inflammation provides incremental prognostic information for prediction of cardiovascular death or HF.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Proteins; C-Reactive Protein; Cardiovascular Diseases; Female; Galectin 3; Galectins; Glycopeptides; Growth Differentiation Factor 15; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Peptide Fragments; Peroxidase; Pregnancy-Associated Plasma Protein-A; Prognosis; Protein Precursors; Risk Assessment; ST Elevation Myocardial Infarction; Troponin T

Biomarkers play a pivotal role in heart failure (HF) management. Reference values and insights from studies in adults cannot be extrapolated to the paediatric population due to important differences in pathophysiology and compensatory reserve. We assessed the diagnostic utility of four novel biomarkers in paediatric HF.. Midregional (MR) pro-atrial natriuretic peptide (proANP), soluble ST2 (sST2), growth differentiation factor-15 (GDF-15), MR-pro-adrenomedullin (proADM) and N-terminal pro-B natriuretic peptide (NT-proBNP) were measured in 114 patients and 89 controls. HF was defined as the presence of HF symptoms and/or abnormal systolic ventricular function. Receiver-operating characteristics were plotted, and the area under the curve (AUC) was measured. This was repeated for subgroups with cardiomyopathy and congenital heart disease (CHD). Ventricular systolic function was measured by magnetic resonance or echocardiography. Reference values were calculated according to the current guidelines.. The AUC for diagnosing HF was 0.76 for MR-proANP (CI 0.70 to 0.84) and 0.82 for NT-proBNP (CI 0.75 to 0.88). These parameters performed similarly in the subgroups with CHD and cardiomyopathy. By contrast, MR-proADM, GDF-15 and sST2 performed poorly. When used in conjunction with NT-proBNP, no parameter added significantly to its diagnostic accuracy. NT-proBNP, MR-proANP, GDF-15 and sST2 could accurately discriminate between patients with preserved and patients with poor functional status. In a subset of patients with dilated cardiomyopathy, NT-proBNP, MR-proANP, MR-proADM and GDF-15 were associated with poor LV function.. MR-proANP could accurately detect HF in children and adolescents. Its diagnostic performance was comparable with that of NT-proBNP, regardless of the underlying condition. Reference values are presented.

Topics: Adolescent; Adrenomedullin; Age Factors; Area Under Curve; Atrial Natriuretic Factor; Austria; Biomarkers; Case-Control Studies; Child; Child, Preschool; Echocardiography; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Growth Differentiation Factor 15; Heart Failure; Humans; Infant; Infant, Newborn; Interleukin-1 Receptor-Like 1 Protein; Magnetic Resonance Imaging; Male; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Protein Precursors; Reference Values; Reproducibility of Results; ROC Curve; United Kingdom; Young Adult

Neurohormones play a key role in regulating hemodynamics in heart failure (HF) both at rest and during exercise. In contrast, little is known about the importance of neurohormonal regulation for exercise capacity in continuous-flow left ventricular assist device (CF-LVAD) patients. The aim of this study was to assess the relation between neurohormonal activation patterns in CF-LVAD patients and exercise capacity.. Plasma concentrations of the C-terminal portion of pro-arginine vasopressin precursor (copeptin), pro-adrenomedullin (proADM), pro-B-type (proBNP) and pro-atrial (proANP) natriuretic peptides were measured in 25 CF-LVAD patients (HeartMate II) in the morning prior to maximal cardiopulmonary exercise testing determining peak oxygen uptake (peak VO2). Quality of life (QOL) was determined by questionnaires.. Peak VO2 was severely reduced averaging 13.0±5.3ml/kg/min and exhibited strong negative correlations with copeptin, r=-0.61 (p=0.001) and proADM, r=-0.56 (p=0.005). Additionally comparing patients with peak VO2<14 vs≥14ml/kg/min demonstrated significant differences in copeptin and proADM concentrations, 2.8±0.8 vs 2.1±0.7pmol/l (p=0.03) and 1.0±0.5 vs 0.7±0.2nmol/l (p=0.01), respectively. In contrast natriuretic peptides were not associated with maximal exercise capacity. Lower QOL correlated with increasing proBNP.. Resting plasma levels of proADM and copeptin are significantly correlated with peak VO2 in CF-LVAD patients. Future studies should address if interventions to lower the levels of these markers are associated with restoration of exercise tolerance.

Topics: Adrenomedullin; Adult; Biomarkers; Exercise Test; Exercise Tolerance; Female; Glycopeptides; Heart Failure; Heart-Assist Devices; Hemodynamics; Humans; Male; Middle Aged; Neuropeptides; Peptide Fragments; Quality of Life; Statistics as Topic; Ventricular Function, Left

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

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

Diabetes mellitus (DM) is associated with an adverse outcome in heart failure (HF). Increased concentrations of midregional proadrenomedullin (MR-proADM) have been associated with DM and are predictors of mortality in HF patients. The aim of this study was to elucidate the impact of DM on MR-proADM concentrations and the prognostic value regarding all-cause mortality and hospitalization among HF patients.. We included 366 patients from an HF clinic; 69 (19%) had a history of DM and 40 (11%) had newly diagnosed DM (HbA1c ≥48 mmol/mol). The median MR-proADM concentration was unaffected by DM status (P = .20) but increased in HF patients with impaired renal function (P < .001). During a median follow-up of 55 months, 189 died, and 292 either died or were hospitalized. After adjustment for clinically relevant parameters, MR-proADM was associated with all-cause mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1-1.4; P = .01) and the combined end point of death and hospitalization (HR 1.2, 95% CI 1.1-1.4; P = .02) per 1 SD increment of ln-transformed variable. No interaction between DM and MR-proADM was found regarding mortality or hospitalization.. Diabetes status had no impact on MR-proADM concentrations or in the predictive ability of MR-proADM in HF patients.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Ambulatory Care; Biomarkers; Cohort Studies; Diabetes Mellitus; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Protein Precursors

Natriuretic peptide receptor 3 (NPR3) is the clearance receptor for the cardiac natriuretic peptides (NPs). By modulating the level of NPs, NPR3 plays an important role in cardiovascular homeostasis. Although the physiological functions of NPR3 have been explored, little is known about its regulation in health or disease. MicroRNAs play an essential role in the post-transcriptional expression of many genes. Our aim was to investigate potential microRNA-based regulation of NPR3 in multiple models. Hypoxic challenge elevated levels of NPPB and ADM mRNA, as well as NT-proBNP and MR-proADM in human left ventricle derived cardiac cells (HCMa), and in the corresponding conditioned medium, as revealed by qRT-PCR and ELISA. NPR3 was decreased while NPR1 was increased by hypoxia at mRNA and protein levels in HCMa. Down-regulation of NPR3 mRNA was also observed in infarct and peri-infarct cardiac tissue from rats undergoing myocardial infarction. From microRNA microarray analyses and microRNA target predictive databases, miR-100 was selected as a candidate regulator of NPR3 expression. Further analyses confirmed up-regulation of miR-100 in hypoxic cells and associated conditioned media. Antagomir-based silencing of miR-100 enhanced NPR3 expression in HCMa. Furthermore, miR-100 levels were markedly up-regulated in rat hearts and in peripheral blood after myocardial infarction and in the blood from heart failure patients. Results from this study point to a role for miR-100 in the regulation of NPR3 expression, and suggest a possible therapeutic target for modulation of NP bioactivity in heart disease.

Topics: 3' Untranslated Regions; Adrenomedullin; Aged; Animals; Base Sequence; Binding Sites; Case-Control Studies; Culture Media, Conditioned; Disease Models, Animal; Down-Regulation; Female; Gene Expression Profiling; Gene Expression Regulation; Heart Failure; Humans; Hypoxia; Male; MicroRNAs; Middle Aged; Myocardial Infarction; Myocytes, Cardiac; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Rats; Receptors, Atrial Natriuretic Factor; RNA Interference; RNA, Messenger; Time Factors

BCL-2-associated athanogene 3 (BAG3) is a protein implicated in the cardiomyocyte stress response and genesis of cardiomyopathy. Extracellular BAG3 is measurable in patients with heart failure (HF), but the relationship of BAG3 with HF prognosis is unclear.. BAG3 plasma concentrations were measured in 39 acutely decompensated HF patients; the primary endpoint was death at 1 year. Baseline characteristics were compared by vital status and median BAG3 concentration. Correlation of BAG3 with left ventricular ejection fraction (LVEF) and other biomarkers was performed. Prognostic value was assessed using Cox proportional hazards regression and Kaplan-Meier analysis.. At baseline, median BAG3 was significantly higher in decedents (N=11) than survivors (N=28; 1489 ng/mL versus 50 ng/mL; P=0.04); decedents also had worse renal function and higher median natriuretic peptide (NP) and sST2. BAG3 was not significantly correlated with NPs, mid-regional pro-adrenomedullin, sST2, or eGFR, however. Mortality was increased in patients with supra-median BAG3 (>336 ng/mL; 42.1% versus 15.0%, P=0.06). In age and LVEF-adjusted Cox proportional hazards, BAG3 remained a significant mortality predictor (HR=3.20; 95% CI=1.34-7.65; P=0.02); those with supra-median BAG3 had significantly shorter time-to-death (P=0.04).. The stress response protein BAG3 is measurable in patients with ADHF and may be prognostic for death.

Topics: Acute Disease; Adaptor Proteins, Signal Transducing; Adrenomedullin; Aged; Aged, 80 and over; Apoptosis Regulatory Proteins; Atrial Natriuretic Factor; Biomarkers; ErbB Receptors; Female; Gene Expression; Heart Failure; Heart Ventricles; Humans; Interleukin-1 Receptor-Like 1 Protein; Kidney Function Tests; Male; Prognosis; Receptors, Cell Surface; Stroke Volume; Survival Analysis

In heart failure (HF), activation of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and adrenomedullin (ADM) is adaptive. The activation of these peptides in relation to different HF phenotypes such as HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF) and after left ventricular assist device (LVAD) and heart transplantation (HTx) remains poorly characterized.. We measured and compared N-terminal (NT)-proBNP, mid-regional (MR)-proANP and mid-regional (MR)-proADM in 86 patients with HFpEF, 49 patients with HFrEF, 13 patients one year post-LVAD and 22 patients one year post-HTx. We assessed their prognostic impact using Kaplan-Meier analysis and multivariable Cox regression.. In HFpEF, HFrEF, LVAD and HTx, NT-proBNP, median (inter-quartile range), was 1000 (465-2335), 3145 (1475-5190), 1430 (986-2570), and 208 (127-353) pmol/L, p < 0.001. MR-proANP was 313 (192-381), 449 (325-596), 276 (216-305), and 118 (96-163) pmol/L, p < 0.001. MR-proADM was 1.2 (0.9-1.6), 1.3 (0.9-2.0), 0.9 (0.7-1.4), and 0.7 (0.6-0.9) nmol/L, p < 0.001 overall and p = 0.212 HFpEF versus HFrEF. In both HFpEF and HFrEF, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and eGFR, whereas MR-proADM did not.. Patterns of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF, HFpEF may represent milder disease and LVAD and HTx may represent progressive resolution of HF severity. NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF. In contrast, MR-proADM did not distinguish between HFpEF and HFrEF, did not predict prognosis in either, and may be more non-specific in HF.

Topics: Adaptation, Physiological; Adrenomedullin; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Cohort Studies; Cross-Sectional Studies; Disease Progression; Female; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Kaplan-Meier Estimate; Male; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Phenotype; Prognosis; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Stroke Volume; Survival Analysis

Intermedin is a proopiomelanocortin-derived peptide before opioid promoting cortical hormone, its main function embodies in mononuclear macrophages and neutrophilic granulocytes to inhibit the proinflammatory cytokines. The aim of this study is to determine intermedin attenuates myocardial infarction and its related mechanisms in a rat model of ischemic heart failure. After rat model of ischemic heart failure was set up, myocardial infarction, blood levels of activities of creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) were effectively reduced by treatment with intermedin. Tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) in a rat model of ischemic heart failure were recovered by pretreatment with intermedin. Administrate of intermedin availably promoted cAMP contents and suppressed caspase-3 protein in ischemic heart failure rat. ERK1/2 and LC3 protein expression were significantly activated and autophagy was significantly promoted by intermedin in a rat model of ischemic heart failure. These results indicate that intermedin protected rat heart, attenuates myocardial infarction from ischemic heart failure in the rat model. The underlying mechanisms may include upregulation of cAMP, ERK1/2 and LC3 protein expression and activating of autophagy.

Topics: Adrenomedullin; Animals; Autophagy; Blotting, Western; Cyclic AMP; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Heart Failure; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Myocardial Infarction; Neuropeptides; Rats; Rats, Sprague-Dawley

To examine whether midregional pro-adrenomedullin (MR-proADM) plasma concentrations predict incident cardiovascular outcomes in the general population. Natriuretic peptides (N-terminal pro-brain natriuretic peptide (NT-proBNP), B-type natriuretic peptide (BNP), and midregional pro-atrial natriuretic peptide (MR-proANP)) were analyzed for comparison.. MR-proADM plasma concentrations and those of the natriuretic peptides were determined in 8444 individuals of the FINRISK 1997 cohort. Patients were followed for 14 years (median). Cox regression analyses, discrimination, and reclassification analyses adjusting for Framingham risk factors were performed to evaluate the additional benefit from MR-proADM.. MR-proADM concentrations significantly predicted all-cause death (hazard ratio highest quintile versus lowest 1.18, 95% confidence interval 1.08-1.28), stroke (1.20, 1.05-1.38), major adverse cardiac events (MACE) (1.27, 1.17-1.37), and heart failure (1.67, 1.49-1.87). MR-proADM remained associated with MACE, death, and heart failure even after additional adjustment for NT-proBNP and C-reactive protein. Adding MR-proADM to the Framingham risk factors significantly improved discrimination (P < 0.001 for C-statistics and integrated discrimination improvement) and risk reclassification for heart failure (net reclassification improvement 12.12%, P < 0.001).. In a healthy general population sample of the FINRISK 1997 cohort MR-proADM significantly predicted all-cause death, MACE, and especially heart failure even beyond NT- proBNP. It also improved risk reclassification for heart failure.

Topics: Adrenomedullin; Adult; Aged; C-Reactive Protein; Female; Finland; Heart Failure; Humans; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptides; Predictive Value of Tests; Protein Precursors

Adrenomedullin (ADM) is a vasodilatory peptide expressed in many tissues. Its levels are elevated in various diseases including chronic heart failure (CHF) and it has been suggested that the up-regulation of ADM in cardiac disease represents a protective mechanism. Similarly, intermedin (IMD), a novel member of the calcitonin/calcitonin gene-related peptide family, is considered a potential endogenous protector of the heart. Previous studies demonstrated that in CHF patients, elevated plasma concentrations of ADM and IMD reflect the patient's disease severity and prognosis, while the behavior of mRNA expression is not known. The aim of this study was to evaluate ADM/IDM transcriptomic profiling in human leukocytes of CHF patients as a function of clinical severity, assessing possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and from CHF patients (NYHA I-II n=10; NYHA III-IV n=14) with PAXgene Blood RNA Kit. Significantly higher levels of ADM and IMD mRNA were found in CHF as a function of clinical severity (ADM: C=0.03 ± 0.013, NYHA I-II=0.11 ± 0.084, NYHA III-IV=11.46 ± 4.72, p=0.037 C vs NYHA III-IV, p=0.028 NYHA I-II vs NYHA III-IV; IMD: C=0.158 ± 0.041, NYHA I-II=0.93 ± 0.40, NYHA III-IV=2.6 ± 0.67, p=0.014 C vs NYHA III-IV, p=0.014 NYHA I-II vs NYHA III-IV). This study highlights, for the first time, the possibility of evaluating ADM and IMD mRNA expression in human whole blood samples by Real-Time PCR study providing further relevant information and providing a more complete interpretation of the pathophysiology of the disease.

Topics: Adrenomedullin; Chronic Disease; Female; Heart Failure; Humans; Leukocytes; Male; Middle Aged; Peptide Hormones; RNA, Messenger; Transcription, Genetic

Mid-regional pro-atrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) demonstrated usefulness for management of emergency department patients with dyspnea.. To evaluate in patients with dyspnea, the prognostic value for 30 and 90 days mortality and readmission of PCT, MR-proADM, and MR-proANP, a multicenter prospective study was performed evaluating biomarkers at admission, 24 and 72 hours after admission. Based on final diagnosis, patients were divided into acute heart failure (AHF), primary lung diseases, or both (AHF + NO AHF).. Five hundred one patients were enrolled. Procalcitonin and MR-proADM values at admission and at 72 hours were significantly (P < .001) predictive for 30-day mortality: baseline PCT with an area under the curve (AUC) of 0.70 and PCT at 72 hours with an AUC of 0.61; baseline MR-proADM with an AUC of 0.62 and MR-proADM at 72 hours with an AUC of 0.68. As for 90-day mortality, both PCT and MR-proADM baseline and 72 hours values showed a significant (P < .0001) predictive ability: baseline PCT with an AUC of 0.73 and 72 hours PCT with an AUC of 0.64; baseline MR-proADM with an AUC of 0.66 and 72 hours MR-proADM with an AUC of 0.71. In AHF, group biomarkers predicted rehospitalization and mortality at 90 days, whereas in AHF + NO AHF group, they predict mortality at 30 and 90 days.. In patients admitted for dyspnea, assessment of PCT plus MR-proADM improves risk stratification and management. Combined use of biomarkers is able to predict in the total cohort both rehospitalization and death at 30 and 90 days.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Dyspnea; Emergency Service, Hospital; Female; Heart Failure; Hospital Mortality; Humans; Italy; Lung Diseases; Male; Patient Admission; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin. It has a wide distribution in the central nervous system (CNS) especially in hypothalamic paraventricular nucleus (PVN). Cardiac sympathetic afferent reflex (CSAR) is enhanced in chronic heart failure (CHF) rats. The aim of this study is to determine the effect of IMD in the PVN on CSAR and its related mechanisms in CHF rats.. Rats were subjected to left descending coronary artery ligation to induce CHF or sham-operation (Sham). Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Acute experiments were carried out 8 weeks after coronary ligation or sham surgery under anesthesia. IMD and angiotensin II (Ang II) levels in the PVN were up-regulated in CHF rats. Bilateral PVN microinjection of IMD caused greater decreases in CSAR and the baseline RSNA and MAP in CHF rats than those in Sham rats. The decrease of CSAR caused by IMD was prevented by pretreatment with AM receptor antagonist AM22-52, but not CGRP receptor antagonist CGRP8-37. Ang II in the PVN significantly enhanced CSAR and superoxide anions level, which was inhibited by PVN pretreatment with IMD or tempol (a superoxide anions scavenger) in Sham and CHF rats.. IMD in the PVN inhibits CSAR via AM receptor, and attenuates the effects of Ang II on CSAR and superoxide anions level in CHF rats. PVN superoxide anions involve in the effect of IMD on attenuating Ang II-induced CSAR response.

Topics: Adrenomedullin; Afferent Pathways; Angiotensin II; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Chronic Disease; Heart Failure; Heart Rate; Hemodynamics; Kidney; Male; Neuropeptides; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Sprague-Dawley; Superoxides; Sympathetic Nervous System

In patients after the Fontan procedure, assessment of a failing Fontan circuit is difficult. Natriuretic peptides failed to be reliable markers of functional status or systemic ventricular function in this patient cohort. The aim of the study was to assess the clinical utility of mid-regional pro-adrenomedullin (MR-proADM) in patients after the Fontan procedure.. Plasma MR-proADM levels were measured in 53 patients after the Fontan procedure and compared with clinical status, echocardiographic, and laboratory parameters including NT-proBNP. Median MR-proADM levels were 0.668 nmol/L in patients with a failing Fontan circuit as compared with 0.357 nmol/L in those without Fontan failure (P = 0.001). Levels of MR-proADM were significantly related to the presence of Fontan failure (r = 0.444, P = 0.001), NYHA class (r = 0.434, P < 0.001), and γ-glutamyltransferase levels (r = 0.554, P < 0.001). According to receiver operating characteristic (ROC) curve analysis, Fontan failure was best predicted by MR-proADM [area under the curve (AUC) 0.985, P = 0.001], NT-proBNP (AUC 0.947, P = 0.003), NYHA class (AUC 0.962, P = 0.002), and the inspiratory/expiratory ratio of the inferior vena cava diameter (AUC 0.973, P = 0.007). The optimal cut-off of MR-proADM for the prediction of Fontan failure was 0.520 nmol/L with a sensitivity of 100%, specificity of 93.9%, positive predictive value of 57.1%, negative predictive value of 100%, and overall accuracy of 94.3%. However, the data should also be validated in a larger cohort of patients.. Serial measurements of MR-proADM levels may help identify patients at risk for a failing Fontan circulation especially when exceeding 0.520 nmol/L. In these patients, intensified medical care should be considered to prevent further clinical deterioration.

Topics: Adolescent; Adrenomedullin; Area Under Curve; Biomarkers; Child; Female; Fontan Procedure; Heart Failure; Heart Ventricles; Humans; Male; Peptide Fragments; Postoperative Complications; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Assessment; Ventricular Function

The aim of this study was to evaluate the long-term prognostic utility of mid-region prohormone adrenomedullin (MR-proADM) in stable outpatients with heart failure (HF).. Echocardiogram and serum for MR-proADM and BNP levels were obtained in 724 stable outpatients. These patients were followed for up to 6 years for the primary endpoint of all-cause mortality. There were 198 stage A patients, 328 stage B patients, and 200 stage C/D patients, with an average age of 68 ± 12 years. There were 195 deaths during the 6-year follow-up period. MR-proADM was predictive of mortality in the overall patient population. The predictive value of MR-proADM for long-term mortality was independent of BNP, echocardiographic indices of structural heart disease, clinical predictors of mortality, and the Framingham risk score. Patients with elevated MR-proADM had significantly increased risk for mortality in stage A and stage C/D HF, with hazard ratio (HR) 3.780, P < 0.001 and HR 2.744, P < 0.001, respectively. There was a trend toward increased mortality in patients with elevated MR-proADM and stage B HF (HR 1.579, P = 0.05005). MR-proADM added incremental predictive value to clinical predictors and the Framingham risk score.. MR-proADM was a potent independent predictor of long-term all-cause mortality in stable outpatients with stage A-D HF, especially in patients in stage A and stage C/D HF. MR-proADM added incremental predictive value to clinical predictors and the Framingham risk score.

Topics: Adrenomedullin; Aged; Biomarkers; Echocardiography; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Natriuretic Peptide, Brain; Patient Acuity; Peptide Fragments; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Assessment; United States

Use of new biomarkers in the handling of heart failure patients has been advocated in the literature, but most often in hospital-based populations. Therefore, we wanted to evaluate whether plasma measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-A-type natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM), individually or combined, gives prognostic information regarding cardiovascular and all-cause mortality that could motivate use in elderly patients presenting with symptoms suggestive of heart failure in primary health care.. The study included 470 elderly patients (mean age 73 years) with symptoms of heart failure in primary health care. All participants underwent clinical examination, 2-dimenstional echocardiography, and plasma measurement of the 3 propeptides and were followed for 13 years. All mortality was registered during the follow-up period. The 4th quartiles of the biomarkers were applied as cutoff values. NT-proBNP exhibited the strongest prognostic information with >4-fold increased risk for cardiovascular mortality within 5 years. For all-cause mortality MR-proADM exhibited almost 2-fold and NT-proBNP 3-fold increased risk within 5 years. In the 5-13-year perspective, NT-proBNP and MR-proANP showed significant and independent cardiovascular prognostic information. NT-proBNP and MR-proADM showed significant prognostic information regarding all-cause mortality during the same time. In those with ejection fraction (EF) <40%, MR-proADM exhibited almost 5-fold increased risk of cardiovascular mortality with 5 years, whereas in those with EF >50% NT-proBNP exhibited >3-fold increased risk if analyzed as the only biomarker in the model. If instead the biomarkers were all below the cutoff value, the patients had a highly reduced mortality risk, which also could influence the handling of patients.. The 3 biomarkers could be integrated in a multimarker strategy for use in primary health care.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Natriuretic Peptide, Brain; Normal Distribution; Peptide Fragments; Primary Health Care; Proportional Hazards Models; Protein Precursors; Risk Assessment; Sensitivity and Specificity; Survival Analysis; Sweden; Time Factors

The purpose of this study was to compare the diagnostic utility of pleural fluid N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregion pro-atrial natriuretic peptide (MR-proANP) and midregion pro-adrenomedullin (MR-proADM) for discriminating heart failure (HF)-associated effusions.. NT-proBNP, MR-proANP and MR-proADM were measured by commercially available methodologies in the pleural fluid of a retrospective cohort of 185 consecutive patients with pleural effusions, of whom 95 had acute decompensated HF. Receiver-operating characteristic and area under the curve (AUC) analyses allowed comparisons of the discriminative properties of these biomarkers to be made at their optimal cut-off points.. The diagnostic accuracy of NT-proBNP and MR-proANP for HF as quantified by the AUC was 0.935 and 0.918, respectively, whereas MR-proADM was of limited value (AUC = 0.62). A pleural fluid MR-proANP >260 pmol/L or NT-proBNP >1700 pg/mL argues for HF (likelihood ratio (LR) positive >5), while levels below these cut-off values significantly decrease the probability of having the disease (respective LR negative 0.19 and 0.10). The optimal cut-off points for natriuretic peptides were influenced by age, renal function and body mass index. Finally, both NT-proBNP and the albumin gradient correctly identified more than 80% of those cardiac effusions misclassified as exudates by standard criteria.. MR-proANP is as valuable a diagnostic tool as NT-proBNP for diagnosing or excluding HF as the cause of pleural effusion.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Diagnosis, Differential; Disease Progression; Female; Follow-Up Studies; Heart Failure; Humans; Immunoassay; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pleural Effusion; Protein Precursors; Reproducibility of Results; Retrospective Studies; Severity of Illness Index

AM5 (adrenomedullin 5), a newly described member of the CGRP (calcitonin gene-related peptide) family, is reported to play a role in normal cardiovascular physiology. The effects of AM5 in HF (heart failure), however, have not been investigated. In the present study, we intravenously infused two incremental doses of AM5 (10 and 100 ng/min per kg of body weight each for 90 min) into eight sheep with pacing-induced HF. Compared with time-matched vehicle control infusions, AM5 produced progressive and dose-dependent increases in left ventricular dP/dt(max) [LD (low dose), +56 mmHg/s and HD (high dose), +152 mmHg/s] and cardiac output (+0.83 l/min and +1.81 l/min), together with decrements in calculated total peripheral resistance (-9.4 mmHg/min per litre and -14.7 mmHg/min per litre), mean arterial pressure (-2.8 mmHg and -8.4 mmHg) and LAP (left atrial pressure; -2.6 mmHg and -5.6 mmHg) (all P<0.001). HD AM5 significantly raised PRA (plasma renin activity) (3.5-fold increment, P<0.001), whereas plasma aldosterone levels were unchanged over the intra-infusion period and actually fell in the post-infusion period (70% decrement, P<0.01), resulting in a marked decrease in the aldosterone/PRA ratio (P<0.01). Despite falls in LAP, plasma atrial natriuretic peptide and B-type natriuretic peptide concentrations were maintained relative to controls. AM5 infusion also induced significant increases in urine volume (HD 2-fold increment, P<0.05) and urine sodium (2.7-fold increment, P<0.01), potassium (1.7-fold increment, P<0.05) and creatinine (1.4-fold increment, P<0.05) excretion and creatinine clearance (60% increment, P<0.05). In conclusion, AM5 has significant haemodynamic, endocrine and renal actions in experimental HF likely to be protective and compensatory in this setting. These results suggest that AM5 may have potential as a therapeutic agent in human HF.

Topics: Adrenomedullin; Aldosterone; Animals; Atrial Natriuretic Factor; Cyclic AMP; Disease Models, Animal; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Natriuretic Peptide, Brain; Renin; Renin-Angiotensin System; Second Messenger Systems; Sheep, Domestic

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

Topics: Acute Disease; Adrenomedullin; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Clinical Trials as Topic; Diabetes Mellitus; Dyspnea; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; Prognosis; Protein Precursors; ROC Curve

The aim of this study was to assess diagnostic and prognostic value of mid-regional pro-atrial natriuretic peptide (MR-proANP) and adrenomedullin (MR-proADM) for the evaluation of patients presenting to the emergency department with acute dyspnoea.. A total of 560 patients from the pro-B type natriuretic peptide Investigation of Dyspnoea in the Emergency Department were evaluated; 180 had acutely decompensated heart failure (ADHF). Concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP), MR-proADM, and MR-proANP were measured, and patients were followed to 4 years for survival. Logistic regression evaluated utility of MR-proANP in ADHF diagnosis. Area under the curve (AUC), multivariate Cox regression, net reclassification improvement, and Kaplan-Meier survival analyses were used for mortality analyses. Mid-regional pro-atrial natriuretic peptide was higher in patients with ADHF (median 329 vs. 58 pmol/L; P < 0.001), and remained an independent predictor of HF diagnosis even when NT-proBNP was included as a covariate (odds ratio = 4.34, 95% CI = 2.11-8.92; P < 0.001). In time-dependent analyses, MR-proADM had the highest AUC for death during the first year; after 1 year, MR-proANP and NT-proBNP had a higher AUC. Both mid-regional peptides were independently prognostic and reclassified risk at 1 year [MR-proANP, hazard ratio (HR) = 2.99, MR-proADM, HR = 2.70; both P < 0.001] and at 4 years (MR-proANP, HR = 3.12, P < 0.001; MR-proADM, HR = 1.51, P = 0.03) and in Kaplan-Meier curves both mid-regional peptides were associated with death out to 4 years, individually or in a multimarker strategy.. Among patients with acute dyspnoea, MR-proANP is accurate for diagnosis of ADHF, while both MR-proANP and MR-proADM are independently prognostic to 4 years of the follow-up.

Topics: Acute Disease; Adrenomedullin; Area Under Curve; Atrial Natriuretic Factor; Dyspnea; Heart Failure; Humans; Kaplan-Meier Estimate; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors

The aim of this study was to evaluate the diagnostic and the prognostic value of a laboratory panel consisting of mid-regional pro-atrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) for patients presenting to the emergency department (ED) with acute dyspnea.. We prospectively enrolled ED patients who presented with a chief complaint of dyspnea and who had an uncertain diagnosis after physician evaluation. Final primary diagnosis of the cause of shortness of breath was confirmed through additional testing per physician discretion. We recorded inpatient admission and 30-day mortality rates.. One hundred fifty-four patients were enrolled in the study. Congestive heart failure exacerbation was the final primary diagnosis in 42.2% of patients, while infectious etiology was diagnosed in 33.1% of patients. For the diagnosis of congestive heart failure exacerbation, MR-proANP had a sensitivity of 92.7% and specificity of 36.8%, with a negative likelihood ratio (LR-) of 0.16 and a positive likelihood ratio (LR+) of 1.44 (cut-off value: 120 pmol/L). For the diagnosis of an infectious etiology, PCT had a 96.5% specificity and 48.8% sensitivity (LR-: 0.58, LR+: 13.8, cutoff value: 0.25 ng/mL). As a prognostic indicator, MR-proADM demonstrated similar values: odds ratio for 30-day mortality was 8.5 (95% CI, 2.5-28.5, cutoff value: 1.5 nmol/L) and the area under the receiver operating characteristic curve in predicting mortality was 0.81 (95% CI, 0.71-0.91).. The good negative LR- of MR-proANP and the good positive LR+ of PCT may suggest a role for these markers in the early diagnosis of ED patients with dyspnea. Furthermore, MR-proADM may assist in risk stratification and prognosis in these patients..

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Dyspnea; Emergency Service, Hospital; Female; Heart Failure; Humans; Male; Peptide Fragments; Prospective Studies; Protein Precursors; Risk Assessment; Sensitivity and Specificity

Topics: Adrenomedullin; Atrial Natriuretic Factor; Dyspnea; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Female; Glycopeptides; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Stroke Volume

The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath.. The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure.. The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission.. Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p < 0.0001). Furthermore, MR-proADM added significantly to all clinical variables (all adjusted hazard ratios: >3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p < 0.0001). Within the model, MR-proADM was the biggest contributor to the predictive performance, with a net reclassification improvement of 8.9%. Serial evaluation of MR-proADM performed in patients admitted provided a significant added value compared with a model with admission values only (p = 0.0005). More than one-third of patients originally at high risk could be identified by the biomarker evaluation at discharge as low-risk patients.. MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Dyspnea; Heart Failure; Humans; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors

Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED).. The Biomarkers in ACute Heart failure (BACH) trial was a prospective, 15-center, international study of patients presenting to the ED with nontraumatic dyspnea. Clinicians were blinded to all investigational markers, except troponin and natriuretic peptides, which used the local hospital reference range. For this secondary analysis, a core lab was used for all markers except troponin. This study evaluated patients diagnosed with AHF by the on-site emergency physician (EP).. In the 1,641 BACH patients, 466 (28.4%) had an ED diagnosis of AHF, of whom 411 (88.2%) had a final diagnosis of AHF. In the ED-diagnosed HF patients, 59% were male, 69% had a HF history, and 19 (4.1%) died within 14 days of their ED visit. The area under the curve (AUC) for the 14-day mortality receiver operating characteristic (ROC) curve was 0.484 for brain natriuretic peptide (BNP), 0.586 for N-terminal pro-B-type natriuretic peptide (NT-proBNP), 0.755 for troponin (I or T), 0.742 for adrenomedullin (MR-proADM), and 0.803 for copeptin. In combination, MR-proADM and copeptin had the best 14-day mortality prediction (AUC = 0.818), versus all other markers.. MR-proADM and copeptin, alone or in combination, may provide superior short-term mortality prediction compared to natriuretic peptides and troponin. Presented results are explorative due to the limited number of events, but validation in larger trials seems promising.

Topics: Acute Disease; Adrenomedullin; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Dyspnea; Emergency Service, Hospital; Female; Glycopeptides; Heart Failure; Humans; Length of Stay; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Risk; ROC Curve; Time Factors

Cardiac biomarkers play a major role in the identification of patients at risk of early death in AL amyloidosis, and a staging system based on amino-terminal pro-natriuretic peptide type-B (NT-proBNP) and troponins (cTn) is used for prognostic stratification. Adrenomedullin is produced by several tissues including the heart, and portends a poor prognosis in heart diseases. We investigated the ability of midregional proadrenomedullin (MR-proADM) to predict early death in AL amyloidosis.. One-hundred and thirty consecutive patients with newly-diagnosed AL amyloidosis were prospectively enrolled. The impact on survival of NT-proBNP, cTnI and MR-proADM was evaluated.. The concentration of MR-proADM correlated with systolic and diastolic function, but did not reflect the amount of amyloid deposited in the heart. Moreover, MR-proADM was associated with non-cardiac markers of advanced disease. The staging system based on NT-proBNP and cTnI identified high-risk subjects, but could not discriminate good-risk and intermediate-risk patients. Conversely, a staging system based on MR-proADM and cTnI identified 3 groups with significantly different survivals.. Midregional-proADM is a powerful prognostic marker in AL amyloidosis, which may not only reflect cardiac dysfunction but also widespread systemic disease, and can be combined with cTn for detecting patients at risk of early death.

Topics: Adrenomedullin; Aged; Amyloid; Amyloidosis; Biomarkers; Female; Heart Failure; Heart Ventricles; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Protein Precursors; Troponin I; Ultrasonography

Adrenomedullin (AM) is a potent vasorelaxing peptide with natriuretic, diuretic, and growth inhibitory properties. Plasma concentrations and myocardial AM expression are increased in heart failure (HF). Since AM and AM binding sites are abundantly expressed in the lungs, we investigated to what extent pulmonary AM and AM receptor subtypes [CRLR/RAMP2 (AM1) and CRLR/RAMP3 (AM2)] are changed in HF and whether the lungs contribute to the increased plasma concentrations of AM reported in HF. Pulmonary AM mRNA and protein expression were increased by 2.8- and 2.6-fold, respectively, whereas mRNA expression of RAMP2 and CRLR was decreased in rats with HF 7 days after induction of MI compared to sham-operated rats (P < 0.05). Pulmonary AM receptor density was substantially decreased in HF rats compared to sham (3.7 +/-0.6 vs. 29.9 +/- 1.1 fmol/mg membrane protein; P < 0.05). Immunoreactivities against AM and the AM receptor components CRLR, RAMP2, and RAMP3 in the pulmonary tissue were seen in vascular smooth muscle cells, vascular endothelial cells, and in alveolar macrophages. AM mRNA expression in alveolar macrophages obtained from HF rats by bronchoalveolar lavage was 2.9-fold higher than in sham-operated rats (P < 0.05). An even more substantial increase of AM mRNA expression was found in alveolar macrophages from patients with HF (10-fold, P < 0.05), and this increase displayed a negative correlation to left ventricular systolic function (P < 0.05). Furthermore, a net release of AM from the lungs into the circulation was only found in HF patients with the most severe left ventricular systolic dysfunction. Thus, our data demonstrate increased expression and decreased receptor binding of AM in the lungs in severe HF. Furthermore, our data indicate that alveolar macrophages are an important source of pulmonary AM in both experimental and clinical HF. Finally, a net release of AM from the lungs into the circulation was only found in patients with severe systolic dysfunction.

Topics: Adrenomedullin; Animals; Binding Sites; Blood Pressure; Calcitonin Receptor-Like Protein; Gene Expression; Heart Failure; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Lung; Macrophages, Alveolar; Male; Membrane Proteins; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Wistar; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide; RNA, Messenger; Systole; Ventricular Function, Left

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

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

Adrenomedullin (ADM) is a vasodilatory peptide. Its plasma levels or its precursors have not been evaluated in large populations of patients with chronic heart failure (CHF). We sought to explore mid-regional proADM (MR-proADM).. We assessed MR-proADM in 501 CHF patients [age 63 +/- 11 years, New York Heart Association (NYHA) class I/II/III/IV 9/44/39/8%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 878 pg/mL (interquartile range-IQR 348-2480 pg/mL), median left ventricular ejection fraction (LVEF) 31% (IQR 25-37%)]. Mid-regional pro-adrenomedullin levels (median 0.64 nmol/L, IQR 0.49-0.87 nmol/L) increased with NYHA class (P < 0.0001). During 1-year follow-up, 70 patients (14%) died. Increasing MR-proADM was a predictor of poor survival at 12 months (hazard ratio 1.82, 95% confidence interval 1.24-2.66, P = 0.002) after multivariable adjustment. In receiver-operating characteristic curve analysis of 12-month survival, the area under the curve for MR-proADM and NT-proBNP was similar (P = 0.3). Comparison of Cox proportional hazard models using the likelihood ratio chi(2) statistic showed that both NT-proBNP and MR-proADM added prognostic value to a base model of LVEF, age, creatinine, and NYHA class. Adding MR-proADM to the base model had stronger prognostic power than adding NT-proBNP (both P < 0.01).. Mid-regional pro-adrenomedullin is an independent predictor of mortality in CHF patients, which adds prognostic information to NT-proBNP.

Topics: Adrenomedullin; Cardiovascular Diseases; Confidence Intervals; Europe; Female; Heart Failure; Humans; Immunoassay; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; ROC Curve; Statistics as Topic; Statistics, Nonparametric; Survival Analysis; Treatment Outcome; Vasodilation

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

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Heart Failure; Humans; Predictive Value of Tests; Prognosis; Reproducibility of Results

The purpose of this study was to assess the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non-ST-elevation myocardial infarction (MI) and identify values to aid clinical decision making. N-terminal pro-B-type natriuretic peptide and GRACE (Global Registry of Acute Coronary Events) score were used as comparators.. sAM is a stable precursor of adrenomedullin.. We measured plasma sAM on admission and discharge in 745 non-ST-elevation MI patients (514 men, median age 70.0 +/- 12.7 years). The primary end point was a composite of death, heart failure, hospitalization, and recurrent acute MI over mean follow-up of 760 days (range 150 to 2,837 days), with each event assessed individually as secondary end points.. During follow-up, 120 (16.1%) patients died, and there were 65 (8.7%) hospitalizations for heart failure and 77 (10.3%) recurrent acute MIs. Both admission and discharge levels were increased (median 0.81 nmol/l [range 0.06 to 5.75 nmol/l] and 0.76 nmol/l [range 0.25 to 6.95 nmol/l], respectively) compared with established normal ranges. Multivariate adjusted Cox regression models revealed that both were associated with the primary end point (hazard ratio: 9.75 on admission and 7.54 on discharge; both p < 0.001). Admission sAM was particularly associated with early (<30 days) mortality (c-statistic = 0.90, p < 0.001), and when compared with N-terminal pro-B-type natriuretic peptide and GRACE score, it was the only independent predictor of this end point. Admission sAM >1.11 nmol/l identified those at highest risk of death (p < 0.001). Patients with above-median admission sAM may benefit from revascularization.. sAM level is prognostic for death or heart failure. Admission levels are a strong predictor of early mortality and, when >1.11 nmol/l, complements the GRACE score to improve risk stratification.

Topics: Adrenomedullin; Aged; Electrocardiography; Female; Follow-Up Studies; Heart Failure; Humans; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Patient Admission; Patient Discharge; Peptide Fragments; Prognosis; Protein Precursors

The cardiac resynchronization therapy (CRT), based on correction of electro-mechanical dyssynchrony by biventricular pacing in patients with severe chronic HF unresponsive to optimal medical treatment and left ventricular conduction disturbances, has been developed. The determination of plasma adrenomedullin (ADM) levels before implantation could provide important additional information to reduce the high percentage (30%) of patients not responding to treatment despite the use of increasingly sophisticated methods for selecting candidates. The case described illustrates the importance of basal ADM plasma levels in predicting the clinical and functional improvement after treatment with CRT.

Topics: Adrenomedullin; Aged; Cardiac Resynchronization Therapy; Female; Heart Failure; Humans; Prognosis

The interplay between the heart and the kidneys has received widespread attention in recent years. A novel five-class definition of cardiorenal syndromes has been proposed. The ability of two markers of cardiac dysfunction to predict progression of primary kidney disease, described by Dieplinger and his co-workers, highlights the prognostic importance of the chronic cardiorenal (types 2 and 4) syndromes.

Topics: Adrenomedullin; Age Factors; Atrial Natriuretic Factor; Biomarkers; Creatinine; Disease Progression; Glomerular Filtration Rate; Heart; Heart Failure; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Proteinuria; Sex Factors

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

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

Our previous study showed elevation of plasma adrenomedullin (ADM) during static handgrip in patients with heart failure (HF). It is hypothesized that ADM increases with left ventricle dysfunction during handgrip and thus plays a compensatory role. In the present study pre-ejection period (PEP) and left ventricular ejection time (LVET) were used to assess cardiac performance in 24 male HF patients (II/III class NYHA) during two 3-min bouts of handgrip at 30% of maximal voluntary contraction (MVC) performed alternately with each hand without any break between the bouts. Plasma ADM, noradrenaline (NA), adrenaline (A), heart rate (HR), blood pressure (BP) and stroke volume (SV) were determined. During handgrip plasma ADM, NA, A, HR, BP, PEP/LVET increased, PEP was prolonged and LVET shortened. The increases in plasma ADM correlated with changes in: PEP (r = -0.881), LVET (r = 0.713), PEP/LVET (r = -0.769), SV (r = 0.836), diastolic BP (r = 0.700), total peripheral resistance (TPR) (r = 0.718) and noradrenaline (r = 0.756). The study demonstrated that in HF patients changes in plasma ADM during handgrip are related to cardiac performance.

Topics: Adrenomedullin; Blood Pressure; Epinephrine; Exercise Test; Hand Strength; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Norepinephrine; Radioimmunoassay; Severity of Illness Index; Stroke Volume; Systole; Time Factors; 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

It was reported previously that 30 min administration of adrenomedullin (AM) improves hemodynamics in chronic stable heart failure patients. The present study was designed to examine whether long-term AM + human atrial natriuretic peptide (hANP) administration can be used as a therapeutic drug in patients with acute decompensated heart failure (ADHF) in clinical setting.. Seven acute heart failure patients (74 +/- 5 years) with dyspnea and pulmonary congestion were studied. AM (0.02 microg x kg(-1) x min(-1)) + hANP (0.05 microg x kg(-1) x min(-1)) was infused for 12 h and then hANP (0.05 microg x kg(-1) x min(-1)) was infused for 12 h. Hemodynamic, renal, hormonal and oxidative stress responses were evaluated. AM + hANP significantly reduced mean arterial pressure, pulmonary arterial pressure and systemic and pulmonary vascular resistance without changing heart rate, and increased cardiac output for most time-points compared with those at baseline. In addition, AM + hANP reduced aldosterone, brain natriuretic peptide and free-radical metabolites compared with those at baseline (all P<0.05). AM + hANP increased urine volume and U(Na)V compared with baseline data.. In this small, pilot trial, AM + hANP therapy had beneficial hemodynamic and hormonal effects in ADHF. Intravenous infusion of AM with hANP could be used as a therapeutic drug in ADHF. These data are preliminary and require confirmation in a larger clinical study.

Topics: Acute Disease; Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Male; Oxidative Stress; Pilot Projects; Time Factors; Treatment Outcome; Urodynamics

The purposes of this study were to determine the tissue distribution of canine adrenomedullin (AM) and to determine whether increased canine AM mRNA expression is associated with congestive heart failure (CHF) due to mitral regurgitation (MR). Canine AM mRNA expression was detectable in various normal tissues, including cardiovascular tissues. In addition, the AM mRNA expression in the left atrium of dogs with MR was significantly higher than that in normal subjects. In conclusion, AM is a potential neurohumoral factor in dogs with CHF due to MR.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Dog Diseases; Dogs; Gene Expression; Heart Failure; Mitral Valve Insufficiency; Myocardium; Natriuretic Peptide, Brain; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric

ST2 is the receptor for interleukin-33, a cytokine with antihypertrophic and antifibrotic effects on the myocardium. Serum levels of the soluble form of ST2 serve as a biomarker for ventricular biomechanical strain and provide prognostic information in patients who have symptomatic heart failure. Adrenomedullin is a vasoactive peptide whose actions run counter to the physiologic derangements of clinical heart failure. It appears that measurements of serum adrenomedullin levels can be used to identify those patients who have advanced heart failure and who are at increased risk for heart failure-related death.

Topics: Adrenomedullin; Biomarkers; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Receptors, Cell Surface; Receptors, Interleukin-1

We aimed to investigate the mechanism mediating the antifibrotic effects of mesenchymal stem cells (MSCs) via in vitro and in vivo study.. In vitro, cardiac fibroblasts (CFs) from passage 2 were cultured and incubated with DMEM/F12 supplemented with 10% fetal bovine serum (DM-10), DM-10 containing angiotensin II (Ang II, 1 x 10(-6) M) or a combination of MSC-conditioned medium (MSC-CM) and Ang II (1 x 10(-6) M) for 48 h. CFs proliferation and gene expression of collagen I and III were analyzed by MTT and reverse transcription-polymerase chain reaction (RT-PCR). In vivo, global heart failure was induced in Wistar rats by isoproterenol (ISO) injection. Four weeks later, MSCs or culture medium were transplanted by intramyocardial injection. Four weeks after transplantation, heart function was assessed, and histological analysis conducted. In addition, the expression of adrenomedullin (ADM), an antifibrotic factor, in MSCs and myocardium were also examined.. In vitro, MSCs expressed ADM. MSC-CM obviously inhibited CFs proliferation and expression of collagen I and III mRNA. In vivo, compared with medium transplantation, MSC transplantation significantly improved heart function, decreased collagen volume fraction and increased expression of ADM in myocardium.. MSC transplantation can inhibit function of CFs by secreting antifibrotic factors such as ADM, resulting in decrease of myocardial fibrosis.

Topics: Adrenomedullin; Animals; Apoptosis; Cell Shape; Cells, Cultured; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Heart Failure; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Paracrine Communication; Rats; Rats, Wistar

Adrenomedullin 2/intermedin (AM2/IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. To investigate the pathophysiological role of AM2/IMD in heart failure, we examined the expression of AM2/IMD, adrenomedullin (AM) and receptor complex components (calcitonin receptor-like receptor, three types of receptor activity-modifying proteins) by quantitative RT-PCR and immunohistochemistry in the hearts and kidneys of rats with congestive heart failure (CHF). Significantly increased levels of AM2/IMD mRNA were found in the atrium, right ventricle, non-infarcted part of the left ventricle and the infarcted part of the left ventricle of CHF rats, compared with sham operated rats (about 2.8-fold, 1.7-fold, 1.7-fold and 2.5-fold, respectively). Expression levels of mRNA encoding AM and the receptor complex components were also increased in the hearts of CHF rats. In a separate experiment, AM2/IMD mRNA levels in the heart did not differ between Wistar-Kyoto and spontaneously hypertensive rats. In both sham operated and CHF rats, the myocardium was diffusely immunostained with AM2/IMD. The fibrotic infarcted layer was not immunostained with AM2/IMD but was surrounded by positively immunostained myocardial layers. These findings suggest that the expression of AM2/IMD is enhanced in the failing heart, and AM2/IMD has a certain pathophysiological role in heart failure.

Topics: Adrenomedullin; Analysis of Variance; Animals; Gene Expression; Heart Failure; Immunoenzyme Techniques; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The aim of the present study was to evaluate the capability B-type natriuretic peptide (BNP) as a prognostic marker in patients with acute destabilized heart failure in comparison with mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and the C-terminal part of the arginine vasopressin prohormone (Copeptin).. BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were obtained in 137 patients with acute destabilized heart failure attending a tertiary care hospital. The end point was defined as all-cause mortality, and the study participants were followed for 365 days. Of the 137 patients enrolled, 41 died and 96 survived during follow-up. ROC curve analysis showed that the areas under curve for the prediction of 1-year mortality were similar for BNP (0.716; 95% CI 0.633-0.790), MR-proANP (0.725; 95% CI 0.642-0.798), MR-proADM (0.708; 95% CI 0.624-0.782), and Copeptin (0.688; 95% CI 0.603-0.764). Using tercile approaches, Kaplan-Meier curve analyses demonstrated that the predictive value of all four analytes for survival probability was comparable (log-rank test for trend, P < .001 for each). In multivariable Cox proportional-hazards regression analyses, increased BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were the strongest predictors of mortality.. BNP is considered an established prognostic marker for heart failure patients. The present study provides evidence that MR-proANP, MR-proADM, and Copeptin measurements might have similar predictive properties compared with BNP determinations for one-year all-cause mortality in acute destabilized heart failure.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Female; Glycopeptides; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Predictive Value of Tests; Protein Precursors; Proteins; ROC Curve

The aim of this study was to evaluate the plasma levels of the adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in adult and pediatric patients with congestive heart failure (CHF) of various etiologies and to investigate their relations with haemodynamic variables e.g. echocardiographic left ventricular ejection fraction (LVEF) and fractional shortening (FS).. The study was made in 38 adult and 21 pediatric patients with CHF of various etiologies and compared with 15 adult and 10 pediatric normal healthy controls. Patients with CHF were classified according to the New York Heart Association (NYHA) functional classification into grades II to IV in adult patients and into grade IV in all pediatric patients. ADM and ANP plasma levels were determined prior to the treatment with enzyme immunoassay.. A statistically significant difference in the plasma levels of ADM and ANP were found between pediatrics and adult patients and corresponding healthy controls. Their levels were progressively increased with severity of NYHA class in adult patients. We found a significant positive correlation between plasma levels of each of ADM and ANP and pulse rate, systolic and diastolic blood pressure; and a significant negative correlation between their plasma levels and echocardiographic LVEF and FS. A significant positive correlation between plasma levels of ADM and ANP in both pediatrics and adult patients were also found.. Plasma levels of ADM and ANP increased in adult and pediatric patients with CHF irrespective of the cause. They were positively correlated with each other and negatively correlated with LVEF and FS. These findings might have important clinical implications in that a noninvasive blood test may be used to identify high-risk subjects for HF for more invasive procedures.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Child; Child, Preschool; Female; Heart Failure; Humans; Infant; Male; Middle Aged; Pulse; Ventricular Dysfunction, Left; Ventricular Function, Left

1. The present study was designed to examine the cardiovascular effects of intravenously administered pcDNA3.1AM, a recombinant non-virus vector carrying a rat adrenomedullin (AM) gene translation fragment, in rats with chronic cardiac dysfunction induced by ligation of the left descending coronary artery. 2. Haemodynamic parameters were recorded by intraventricular catheterization. In situ hybridization and polymerase chain reaction (PCR) were performed to identify the distribution of the introduced vector. The concentration of AM was determined by radioimmunoassay. 3. Progressive cardiac dysfunction was observed following coronary artery ligation, as indicated by a significant reduction in mean arterial pressure (MAP) and increases in both central venous pressure (CVP) and end-diastolic pressure of the left ventricle (LVEDP; P < 0.01). Administration of pcDNA3.1AM significantly attenuated the progressive cardiac dysfunction and lowered the elevated CVP and LVEDP. The introduced vector was widely distributed in different organs, including the lungs, kidney, heart, liver, spleen and brain. However, intense staining of pcDNA3.1 AM was observed in the lungs and kidneys. The introduced vector was localized mainly in the endothelial cells of blood vessels. Radioimmunoassay showed elevated levels of AM in the plasma and lung and heart after surgery, but there was no significant further increase in the concentration of AM after pcDNA3.1AM delivery. 4. The present study has provided some novel findings on the potential beneficial effects of AM gene delivery on chronic cardiac function in rats. Expression of AM by a non-virus vector may also have therapeutic value against cardiac dysfunction in vivo.

Topics: Adrenomedullin; Animals; Blood Pressure; Central Venous Pressure; Chronic Disease; Coronary Vessels; Disease Models, Animal; Endothelial Cells; Genetic Therapy; Genetic Vectors; Heart Failure; Kidney; Ligation; Lung; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Time Factors; Ventricular Function, Left; Ventricular Pressure

Increased circulating adrenomedullin (AM) concentration has been reported in congestive heart failure (HF) and considered as a possible marker of cardiac dysfunction.. The study was undertaken to assess the relationship between circulating AM concentration and left ventricular (LV) functional state, estimated by echo-Doppler techniques in patients with mild to moderate HF and different degrees of LV dysfunction.. Plasma AM, B-type natriuretic peptide (BNP), and N-terminal (NT) proBNP levels were measured in 55 patients with HF (New York Heart Association [NYHA] I n = 8, II n = 26, III n = 21) and in 20 controls; dP/dt was calculated by the Doppler tracing of the mitral regurgitation jet.. The study was completed in 51 patients. Adrenomedullin levels were higher than in controls (19.2 +/- 1.4 vs. 13.3 +/- 0.7, p < 0.005) and elevated in proportion to NYHA functional class. B-type natriuretic peptide and NT-proBNP were 344 +/- 67 vs. 12 +/- 2 pg/ml and 2196 +/- 623 vs. 52 +/- 4 pg/ml, respectively (p < 0.0001); dP/dt was better related to AM (r = 0.582, p < 0.001) than to the other peptides. Adrenomedullin was significantly (p < 0.001) different between patients grouped according to the dP/dt cut-off predictive of event-free survival.. The combination of depressed contractility and increased AM may provide a clue for further characterization of the severity of LV dysfunction in HF, independent of baseline LV ejection fraction.

Topics: Adrenomedullin; Aged; Biomarkers; Case-Control Studies; Echocardiography, Doppler; Echocardiography, Transesophageal; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peptides; Predictive Value of Tests; Probability; Prognosis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Survival Analysis; Ventricular Dysfunction, Left

Our previous study showed that static handgrip caused increases in the plasma adrenomedullin (ADM) both in patients with heart failure (HF) and healthy subjects. The present study was designed to determine the role of the sympathetic nervous system in mediating plasma ADM changes during handgrip in patients with HF. Twelve male HF patients (II class NYHA) treated with carvedilol, a non-selective adrenergic blocker (TC) and 12 patients untreated with carvedilol (UC) performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand. At the end of both exercise bouts and in 5 min of the recovery period, plasma ADM and catecholamines were determined. In addition, heart rate, blood pressure and stroke volume (SV) were measured. The baseline plasma ADM, noradrenaline (NA) and adrenaline (A) levels were similar in the two groups of patients, while SV was higher (P<0.05) in TC than in UC. During exercise plasma ADM concentrations were lower (P<0.05) in TC than in UC, but the handgrip-induced increases in plasma ADM did not differ between the groups. Plasma ADM correlated with NA concentrations (r = 0.764) and with SV (r = -0.435) and increases in plasma ADM expressed as percentage of baseline values correlated with those of plasma NA (r = 0.499), diastolic BP (r = 0.550) and total peripheral resistance (r = 0.435). The study suggests that the sympathetic nervous system may be involved in the stimulation of ADM secretion during static exercise either directly or by changes in the haemodynamic response.

Topics: Adrenergic beta-Antagonists; Adrenomedullin; Aged; Analysis of Variance; Biomarkers; Blood Pressure; Carbazoles; Cardiac Output; Carvedilol; Chronic Disease; Coronary Artery Disease; Epinephrine; Exercise Test; Heart Failure; Heart Rate; Humans; Linear Models; Male; Middle Aged; Norepinephrine; Propanolamines; Sympathetic Nervous System; Treatment Outcome; Vascular Resistance

Adrenomedullin (AM) is a potent vasorelaxing peptide with natriuretic and diuretic actions. Recent data indicate that AM may function as an endogenous regulator of cardiac function. We investigated to what extent AM, the AM receptor subtypes, and AM receptor-associated proteins were regulated in cardiomyocytes and non-cardiomyocytes of rats with congestive heart failure (CHF), and whether such regulation was paralleled by corresponding alterations of functional responses to AM. Cardiomyocytes and non-cardiomyocytes were isolated from myocardial tissue of rats 7 days after induction of myocardial infarction or sham operation. AM immunoreactivity was found in cardiomyocytes, endothelial cells, and fibroblasts. Robust increase of AM mRNA levels was observed both in the cardiomyocytes and in the non-cardiomyocytes of CHF rats compared to that of sham-operated rats (2.7-fold and 3.7-fold, respectively, P <0.05). Fairly high mRNA levels and immunoreactivity against the AM receptor chaperone receptor activity-modifying protein-2 (RAMP2) were also detected in the cardiomyocytes and non-cardiomyocytes. However, induction of RAMP2 mRNA expression was restricted to cardiomyocytes (1.8-fold increase in cardiomyocytes from CHF rats vs. sham rats; P <0.05). In contrast, very low levels of RAMP3 mRNA were observed. RAMP3 mRNA levels, however, were elevated in both cardiomyocytes and non-cardiomyocytes from CHF rats (6.5-fold and 2.4-fold increase vs. sham rats, respectively; P <0.05). Parallel increases of specific AM receptor binding sites and of AM-stimulated adenylyl cyclase activities were observed in failing cardiomyocytes compared to cardiomyocytes from sham rats (fivefold and sixfold increase, respectively; P <0.05). Thus, this study demonstrates that AM mRNA levels, AM receptor binding sites, and AM-stimulated adenylyl cyclase activities are increased in cardiomyocytes from failing rat hearts. Furthermore, our data suggest that induction of RAMP2 and RAMP3 contributes to the increased responsiveness to AM in failing cardiomyocytes.

Topics: Adrenomedullin; Animals; Gene Expression Regulation; Heart; Heart Failure; Hemodynamics; Intracellular Signaling Peptides and Proteins; Lung; Male; Membrane Proteins; Myocardium; Organ Size; Peptides; Rats; Rats, Wistar; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger; Signal Transduction

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

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

Adrenomedullin (AM) is expressed in cardiac tissue, and plasma AM levels increase in patients with acute myocardial infarction (MI). This study was performed to determine whether AM administration immediately after acute MI inhibits progression of heart failure in rats.. Rats were infused with 1.0 microg/h IP AM or saline over 7 days immediately after MI inducted by left coronary ligation and were examined 9 weeks after MI. Compared with the saline infusion, AM infusion significantly improved survival (59% versus 81%; P<0.05) and body weight gain (32%; P<0.01) and reduced heart weight (-28%; P<0.01), lung weight (-26%; P<0.01), left ventricular (LV) end-diastolic pressure (11.4+/-2.0 versus 4.0+/-0.6 mm Hg, mean+/- SEM; P<0.01), collagen volume fraction of noninfarcted LV (-39%; P<0.05), and plasma levels of endogenous rat AM (-38%; P<0.05) without affecting infarct size. To investigate the mechanism of AM actions, another series of MI rats infused with AM were killed on day 7. AM infusion had no effect on organ weights and hemodynamic parameters on day 7 of MI but significantly reduced urinary excretion of isoprostane (-61%; P<0.01) and noninfarcted LV mRNA levels of ACE (-31%; P<0.05) and p22-phox (-30%; P<0.05).. AM administration during the early period of MI improved the survival and ameliorated progression of LV remodeling and heart failure. This beneficial effect was accompanied by reductions in oxidative stress and ACE mRNA expression in noninfarcted LV in the AM infusion period.

Topics: Adrenomedullin; Aldosterone; Animals; Body Weight; Dinoprost; Disease Progression; Drug Evaluation, Preclinical; Heart Failure; Hemodynamics; Ligation; Lung; Male; Membrane Transport Proteins; Models, Animal; Myocardial Infarction; Myocardium; NADPH Dehydrogenase; NADPH Oxidases; Organ Size; Peptides; Peptidyl-Dipeptidase A; Phosphoproteins; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Ventricular Remodeling

In the final step of production of adrenomedullin (AM), an inactive intermediate form of glycine-extended AM (AM-glycine) is converted to the active mature form of adrenomedullin (AM-mature) by enzymatic amidation. Recent studies have revealed that AM-mature and AM-glycine circulate in human plasma. In this study, we investigated the differences of the concentrations of cardiac AM between pressure-overloaded (PO) heart failure (HF) and volume-overloaded (VO)-HF in humans.. We measured AM-mature and AM-glycine by immunoradiometric assays in pericardial fluid and plasma in 38 patients who underwent valve replacement surgery (PO-HF: aortic stenosis, n=14; VO-HF: aortic or mitral regurgitation, n=24). Stable coronary artery disease with normal left ventricular function served as the control (n=24). Plasma AM-mature (VO-HF: +59%, PO-HF: +65%, P<.05) and AM-glycine (VO-HF: +43%, PO-HF: +50%, P<0.05) were similarly higher in the 2 HF groups than in the control group. Interestingly, pericardial fluid AM-mature was markedly higher than that in plasma (control: +789%, VO-HF: +1050%, PO-HF: +1745%, all P<.001). Pericardial fluid AM-mature was higher in VO-HF (+106%, P<.01) than in controls and they were further increased in PO-HF (+243%, P<.05). Pericardial fluid molecular forms of AM correlated with left ventricular systolic pressure, but not with left ventricular end-diastolic volume index in PO-HF. In contrast, they correlated with left ventricular end-diastolic volume index, but not with left ventricular systolic pressure in VO-HF.. These results suggest that cardiac AM is differently regulated from plasma AM and that cardiac AM production is upregulated in both types of HF in response to each different stimulus.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Aortic Valve; Biomarkers; Blood Pressure; Female; Heart Failure; Humans; Male; Middle Aged; Molecular Structure; Myocardial Contraction; Myocardium; Peptides; Pericardium; Statistics as Topic; Stroke Volume; Ventricular Pressure

We investigated whether adrenomedullin (AM) participates in the pathophysiology during the transition from left ventricular hypertrophy (LVH) to heart failure (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18 weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH stage were significantly elevated compared with those in controls, and they were further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM-total ratio was higher only in the HF group than in controls and LVH. The LV tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close relations with the LV weight/body weight (r=0.72, r=0.79, and r=0.70, respectively; all P<0.001). AM gene expression was significantly increased at the LVH stage and was further increased at the HF stage. Furthermore, gene expression of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modified protein 2 (RAMP2), and RAMP3 were significantly increased at the stage of LVH and HF. Regarding other neurohumoral factors, plasma renin and aldosterone levels were not increased at the LVH stage but were increased at the HF stage, whereas atrial natriuretic peptide was increased in both the plasma and myocardium at the LVH stage and was further increased at the HF stage. These results suggest that induction of the cardiac AM system, including the ligand, receptor, and amidating activity, may modulate pathophysiology during the transition from LVH to HF in this model.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Calcitonin Receptor-Like Protein; Disease Progression; Heart Failure; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Peptides; Rats; Rats, Inbred Dahl; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Transcription, Genetic

Acute administration of adrenomedullin (AM) exerts beneficial hemodynamic, renal, and neurohormonal effects in heart failure (HF). However, chronic effects of AM administration on HF remain unknown. This study sought to examine the effect of chronic infusion of AM on progression of HF in rat. Human recombinant AM was administered by osmotic minipump for 7 weeks in the HF model of Dahl salt-sensitive rats. The effect was compared with vehicle and diuretic treatment group. Chronic AM infusion significantly decreased left ventricular end-diastolic pressure, right ventricular systolic pressure, right atrial pressure, and left ventricular weight/body weight (P<0.01 for all). AM significantly attenuated the increase in circulating renin-aldosterone, endogenous rat AM, and atrial natriuretic peptide levels (P<0.01 for all). AM also inhibited the myocardial tissue levels of angiotensin II and atrial and brain natriuretic peptide (P<0.01 for all). These changes were associated with the improvement of cardiac output and systemic vascular resistance (both P<0.05). Furthermore, AM improved left ventricular end-systolic elastance (P<0.01). These improvements were greater in the AM than in the diuretic group, although both drugs similarly decreased systolic blood pressure and increased urinary sodium excretion. Kaplan-Meier survival analysis showed that AM significantly prolonged survival time compared with diuretic (P<0.05) and vehicle (P<0.01) treatment groups. These results suggest that endogenous AM plays a compensatory role in HF and that chronic AM infusion attenuates progression of left ventricular dysfunction and improves survival, at least in part, through inhibition of circulating and myocardial neurohormonal activation.

Topics: Adrenomedullin; Animals; Blood Pressure; Cardiac Output; Disease Progression; Diuretics; Heart Failure; Hemodynamics; Hypertrophy, Left Ventricular; Male; Myocardium; Neurotransmitter Agents; Peptides; Rats; Rats, Inbred Dahl; Survival Rate; Time Factors; Vascular Resistance; Ventricular Pressure

To investigate the changes in plasma levels of adrenomedullin (ADM) and cyclic adenosine monophosphate (cAMP) in patients with chronic heart failure (CHF) in an attempt to understand the role of ADM in the occurrence and development of CHF.. The plasma levels of cAMP and ADM were measured by radioimmunoassay in 45 patients with CHF (including 10 of NYHA classII, 15 of class III, and 20 of class IV) and 20 healthy controls respectively.. Plasma ADM and cAMP levels significantly increased in patients of NYHA class II, III, and IV as compared with the healthy controls (P<0.05), with those of class III patients being the highest. Positive correlation between ADM and cAMP was noted in CHF patients(r=0.735, P<0.01).. Plasma levels of ADM and cAMP were in close correlation with the degree of heart failure, varying dynamically with the development of heart failure. There was mutual accommodation between ADM and cAMP, and increased cAMP level partly results from elevated ADM level in CHF patients.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Chronic Disease; Cyclic AMP; Female; Heart Failure; Humans; Male; Middle Aged; Radioimmunoassay

To study the changes in plasma adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) concentrations and their clinical significance in the pathological process of congestive heart failure (CHF).. Plasma ADM and PAMP concentrations in 45 patients with CHF (according to the functional classification of New York Heart Association, NYHA) and 20 control subjects were measured by specific radioimmunoassay.. Plasma ADM concentrations were 51.464+/-.52 pg/ml and 70.39+/-3.22 pg/ml respectively in patients of NYHA class II and class III, which were significantly higher than those in control subjects (24.12+/-1.59 pg/ml, P<0.05 for both comparisons), while significant differences in plasma PAMP concentrations were not identified in the 2 groups of patients (6.24+/-1.71 pg/ml and 7.38+/-1.28 pg/ml, respectively) in comparison with the control level(8.56+/-2.44 pg/ml, P>0.05 for both comparisons). Patients of NYHA class IV, when compared with the 2 groups of patients mentioned above, had significantly decreased plasma ADM and PAMP concentrations (36.33+/-2.17 pg/ml and 2.79+/-0.89 pg/ml respectively, P<0.05 in both cases), but had higher plasma ADM and lower PAMP concentrations when compared with the control subjects, (P<0.05 respectively).. The changes of plasma ADM and PAMP concentrations at different stages of CHF indicate intramolecular regulation disturbances of vasodilator peptides of proadrenomedullin, and ADM may play a more important role in the development of CHF.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Female; Heart Failure; Humans; Male; Middle Aged; Peptide Fragments; Peptides; Protein Precursors; Proteins

Short-term administration of adrenomedullin, a recently discovered peptide with potent vasodilator, natriuretic, and aldosterone-inhibitory actions, has beneficial effects in experimental and clinical heart failure. The effects of prolonged adrenomedullin administration have not previously been assessed in this setting. Consequently, in 16 sheep with pacing-induced heart failure, we infused either adrenomedullin (10 ng/kg per minute; n=8) or a vehicle control (Hemaccel; n=8) for 4 days. Compared with control data, infusion of adrenomedullin persistently increased circulating levels of the peptide (by approximately 9.5 pmol/L; P<0.001), in association with prompt (15 minutes) and sustained (4 days) increases in cardiac output (day 4, 27%), and reductions in peripheral resistance (30%), mean arterial pressure (13%), and left atrial pressure (24%; all, P<0.001). Adrenomedullin also significantly enhanced urinary sodium excretion (day 4, 3-fold; P<0.05), creatinine excretion (1.2-fold; P<0.001), and creatinine clearance (1.4-fold; P<0.001) over the 4 days of treatment, whereas urine volume and cAMP excretion tended to be elevated (both, 0.1>P>0.05). Plasma renin activity was increased (P<0.05), whereas aldosterone levels were reduced in a sustained fashion (P<0.01). Plasma endothelin rose transiently (hours 1 to 6) after initiation of treatment (P<0.05). Despite substantial cardiac unloading, plasma concentrations of the natriuretic peptides were not significantly different from control. In conclusion, long-term administration of adrenomedullin induces pronounced and sustained cardiovascular and renal effects in experimental heart failure, including reductions in cardiac preload and afterload, as well as augmentation of cardiac output, sodium excretion, and glomerular filtration. These findings support the concept of adrenomedullin as a protective hormone during hemodynamic compromise with therapeutic potential in heart failure.

Topics: Adrenomedullin; Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Cyclic AMP; Disease Models, Animal; Endothelins; Female; Heart Failure; Hemodynamics; Hydrocortisone; Infusions, Intravenous; Kidney; Natriuretic Peptide, Brain; Peptides; Renin; Sheep; Time; Treatment Outcome; Vascular Resistance

Topics: Adrenomedullin; Animals; Cardiotonic Agents; Heart Failure; Humans; Myocardial Infarction; Peptides; Rats; Ventricular Remodeling; Wound Healing

We previously reported that plasma adrenomedullin (AM) levels increase in patients with acute myocardial infarction (MI) and AM inhibits growth of rat cardiac myocytes and fibroblasts. The aim of this study was to examine the effects of long-term administration of AM on left ventricular (LV) remodeling, hemodynamic and hormonal parameters in a rat model of MI.. Rats with MI induced by left coronary ligation were intravenously infused with 1.0 microg/h of recombinant human AM or saline by osmotic mini-pump. After infusion for 4 weeks, hemodynamic and hormonal studies were performed, and the myocyte size and collagen volume in non-infarct LV area were quantified morphometrically.. When compared with the MI rats infused with saline, continuous infusion of AM reduced the heart weight/body weight (4.4+/-0.2 vs. 3.6+/-0.1 g/kg, P<0.01), myocyte size (922+/-23 vs. 868+/-10 microm(2), P<0.05) and collagen volume fraction of non-infarct LV area (7.6+/-0.8 vs. 4.8+/-0.5%, P<0.05), without affecting the infarct size. The AM infusion had no significant effect on the arterial pressure, but decreased the LV end-diastolic pressure (8.8+/-1.8 vs. 4.4+/-0.5 mmHg, P<0.05) in the MI rats. The plasma level of endogenous rat AM in the MI rats infused with human AM was reduced by 27% (P<0.05), with a slight reduction of plasma atrial natriuretic peptide, compared with the control.. Continuous administration of AM had beneficial effects on LV remodeling and hemodynamics in MI rats, suggesting the possibility that this peptide could be a useful therapeutic tool for acute MI.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Cardiotonic Agents; Cell Size; Collagen; Heart Failure; Hemodynamics; Male; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Organ Size; Peptides; Rats; Rats, Wistar; Recombinant Proteins; Ventricular Remodeling

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.

Topics: Adrenomedullin; Angiotensin II; Animals; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Dipeptides; Drug Synergism; Female; Heart Failure; Hemodynamics; Kidney; Natriuretic Peptide, Brain; Neprilysin; Peptides; Protease Inhibitors; Renin; Sheep; Vasodilator Agents

Omapatrilat (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure.. We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D.. Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.

Topics: Adrenomedullin; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Disease Models, Animal; Diuretics; Dogs; Drug Therapy, Combination; Glomerular Filtration Rate; Heart Failure; Heart Function Tests; Hemodynamics; Kidney Function Tests; Male; Neprilysin; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors; Pulmonary Wedge Pressure; Pyridines; Renin; Thiazepines; Treatment Outcome

The expression of adrenomedullin (AM) and atrial natriuretic factor (ANF) were investigated in the myocardium of a rat model of chronic ischemic heart failure (CHF) compared with sham-operated controls. In addition, human myocardium of patients with end-stage heart failure due to idiopathic dilated cardiomyopathy compared with myocardium of normal subjects (NF) was studied. In CHF, similar AM levels but increased ANF expression were observed in left ventricular myocardium, as assessed by semiquantitative PCR. Functional experiments with freshly excised papillary muscles showed no influence of AM on myocardial contractility. In NF human myocardium, the expression of AM mRNA was threefold higher in atrial compared with ventricular tissue. In analogy, ANF mRNA was increased by approximately 15-fold in atrial tissue. In dilated cardiomyopathy, the expression of AM was significantly increased in right and left ventricles compared with NF. In parallel, ventricular ANF expression was enhanced.

Topics: Adrenomedullin; Adult; Animals; Atrial Natriuretic Factor; Gene Expression; Heart Failure; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Contraction; Peptides; Rats; Rats, Inbred SHR

In human heart failure (CHF), adrenomedullin (AM) counteracts vasoconstriction and sodium retention. We investigated circulating levels of proadrenomedullin N-20 peptide (PAMP) and AM, and left ventricular expression of preproAM and calcitonin receptor-like receptor (CRLR) mRNA. Peptide levels were determined from the left ventricle, pulmonary artery, coronary sinus, and antecubital vein in patients demonstrating severe CHF (n = 12; mean +/- SEM cardiac index, 1.9 +/- 0.2 l/min/m(2); pulmonary wedge pressure, 32 +/- 1 mmHg), moderate CHF (n = 11; cardiac index, 2.9 +/- 0.2; pulmonary wedge pressure, 14 +/- 2), and in controls (n = 11). Left ventricular mRNA was quantified using RT-PCR and Southern blot hybridization. Depending on sites of measurement, PAMP and AM in severe CHF were 1.3 - 2.0 and 1.2 - 1.9 times as high as in moderate CHF, and 3.8 - 4.6 and 2.3 - 2.8 times as high as in controls. Only patients with moderate CHF demonstrated pulmonary and coronary net release of both peptides, that is, significant step-ups in concentrations between the pulmonary artery, left ventricle, and coronary sinus. In failing ventricles, preproAM mRNA increased 2.9 times above control, but CRLR mRNA was unchanged. Altogether, the heart and the lungs release AM peptides in moderate CHF. This secretion breaks down in severe CHF: a process that may contribute to and indicate decompensation. Unlike AM, the CRLR is not transcriptionally upregulated in severe CHF.

Topics: Adrenomedullin; Calcitonin Receptor-Like Protein; Female; Heart Failure; Heart Ventricles; Hemodynamics; Humans; Lung; Male; Middle Aged; Myocardium; Nitroprusside; Peptide Fragments; Peptides; Protein Precursors; Proteins; Receptors, Calcitonin; RNA, Messenger; Vasodilator Agents

Advances in the treatment of heart failure may require manipulation of neurohumoral responses to cardiac impairment in addition to the established strategy of angiotensin-converting enzyme (ACE) inhibition. Importantly, since new treatments are likely to be used in conjunction with ACE inhibition therapy, the effects of the combination of agents need to be assessed. Adrenomedullin (ADM) is a peptide with potent vasodilator and natriuretic actions. ADM and an ACE inhibitor (captopril) were administered for 3 h both separately and together in eight sheep with heart failure. Both ADM and captopril alone reduced arterial pressure, left atrial pressure (greater with captopril) and peripheral resistance, and increased cardiac output (greater with ADM). Compared with either treatment separately, combined ADM+captopril produced directionally similar but significantly greater changes in all haemodynamic variables (particularly falls in blood pressure). ADM increased renal sodium and creatinine excretion and creatinine clearance, and maintained urine output. Captopril and ADM+captopril reduced creatinine excretion and creatinine clearance, while urine volume and sodium excretion were not significantly altered. Plasma renin activity rose with all active treatments, whereas angiotensin II levels rose during ADM, but fell during captopril and ADM+captopril. Aldosterone was reduced by all active treatments. ADM+captopril reduced plasma noradrenaline (norepinephrine). In conclusion, short-term co-treatment with ADM and an ACE inhibitor produced significantly greater decreases in ventricular filling pressures and cardiac afterload, and increases in cardiac output, compared with either treatment alone. Despite the greater falls in blood pressure (and presumably renal perfusion pressure), renal function was maintained at a level similar to that observed with captopril alone.

Topics: Adrenomedullin; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cardiotonic Agents; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Kidney; Peptides; Potassium; Sheep; Sodium; Vasodilator Agents

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent vasodilators in humans and improved myocardial ischemia is observed after CGRP administration. Receptors for CGRP and ADM were already identified in heart. Receptor activity-modifying proteins (RAMPs) determine the ligand specificity of the calcitonin receptor-like receptor (CRLR); co-expression of RAMP1 and CRLR results in a CGRP receptor, whereas the association of RAMP2 or RAMP3 with CRLR gives an ADM receptor. As CGRP and ADM may play a beneficial role in heart failure, we investigated whether the CGRP and ADM receptors are upregulated in chronic heart failure. We have used semi-quantitative RT-PCR and Western-blot analysis to detect and quantify the mRNA and the protein of RAMP1 and RAMP3 in both atria and ventricles of failing hearts 6 months after aortic banding in rats. Our results showed for the first time an up-regulation of RAMP1 and RAMP3 mRNAs and proteins in this model of cardiac failure. No change was observed in mRNAs coding for CRLR, RAMP2, RDC1 (canine orphan receptor), and ADM. The present results suggested after congestive heart failure in adult rats, an up-regulation of the CGRP receptor (by an increase in RAMP1 that is associated with CRLR) in atria and ventricles and of ADM receptor (by increased RAMP3 expression that is associated with CRLR) in atria. These findings support a functional role for CGRP and ADM receptors to compensate the chronic heart failure in rats.

Topics: Adrenomedullin; Animals; Aortic Valve Stenosis; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Chronic Disease; Disease Models, Animal; Heart Atria; Heart Failure; Heart Ventricles; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Myocardium; Peptides; Rats; Rats, Wistar; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Receptors, Cell Surface; Receptors, Chemokine; Receptors, CXCR; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Endothelial PAS domain protein 1 (EPAS1) has been identified as a member of the basic helix-loop-helix (bHLH)-PAS protein family, and plays a critical role in the regulation of hypoxia inducible genes. It remains unknown whether physiological stimuli other than hypoxia modulate EPAS1 expression. This study examined the inducible expression of EPAS1 by various cytokines and growth factors, and determined the target gene for EPAS1 in cardiac myocytes. In cultured cardiac myocytes, interleukin-1beta (IL-1beta) but not tumor necrosis factor alpha markedly increased the EPAS1 mRNA and protein levels in a time- and dose-dependent manner, whereas hypoxia increases the expression of EPAS1 protein but not its mRNA. Such an induction of EPAS1 by IL-1beta was efficiently inhibited by the pretreatment of the cells with Src kinase inhibitors, such as herbimycin A and PP1. The expression of adrenomedullin (AM) mRNA, which is also upregulated by IL-1beta, was dramatically increased in cardiac myocytes transduced with adenovirus expressing EPAS1. Transient transfection assays using the site-specific mutation of the AM promoter showed that EPAS1 overexpression increases the transcriptional activity through a sequence similar to the consensus HRE (hypoxia responsive element). These results suggest that IL-1beta induces the EPAS1 at the transcriptional level, which in turn activates the AM gene. Since IL-1beta has been implicated in the pathogenesis of heart failure and AM can ameliorate the cardiac function, our results suggest that EPAS1 plays a role in the adaptation of the cardiac myocytes during heart failure as well as in the regulation of gene expression by hypoxia.

Topics: Adrenomedullin; Animals; Basic Helix-Loop-Helix Transcription Factors; Gene Expression Regulation; Gene Transfer Techniques; Heart Failure; Inflammation; Interleukin-1; Myocytes, Cardiac; Peptides; Promoter Regions, Genetic; Rats; Rats, Wistar; RNA, Messenger; src-Family Kinases; Trans-Activators; Up-Regulation

Topics: Adrenomedullin; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Cytokines; Fibroblasts; Heart Failure; Heart Ventricles; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Peptides; Receptor Activity-Modifying Proteins; Receptors, Calcitonin

The recently discovered vasodilating and positive inotropic peptide, adrenomedullin (ADM), has strong natriuretic actions. ADM-induced natriuresis is caused by an increase in glomerular filtration rate and a decrease in distal tubular sodium reabsorption. Although ADM is activated in human and experimental heart failure, the role of ADM in the kidney in heart failure remains undefined.. The present study was performed to determine the renal hemodynamic and urinary excretory actions of exogenously administered ADM in a canine model of acute heart failure produced by rapid ventricular pacing. Experimental acute heart failure was characterized by a decrease in cardiac output and an increase in pulmonary capillary wedge pressure with an increase in plasma ADM concentration. Intrarenal infusion of ADM (1 and 25 ng/kg/min) induced an increase in urinary sodium excretion in the normal control dogs (change in urinary sodium excretion [Delta UNaV], +94.5 microEq/min during 1 ng/kg/min ADM infusion and +128.1 microEq/min during 25 ng/kg/min ADM infusion). In the acute heart failure dogs, intrarenal ADM infusion resulted in an attenuated increase in urinary sodium excretion (Delta UNaV, +44.8 microEq/min during 1 ng/kg/min ADM infusion and +51.8 microEq/min during 25 ng/kg/min ADM infusion). Both glomerular and tubular actions of ADM were attenuated in the acute heart failure group compared with responses in the normal control group.. The present study shows that the renal natriuretic responses to ADM are markedly attenuated in experimental acute heart failure. This study provides insight into humoral mechanisms that may promote sodium retention in heart failure via a renal hyporesponsiveness to natriuretic actions of ADM.

Topics: Adrenomedullin; Animals; Attention; Disease Models, Animal; Dogs; Heart Failure; Hemodynamics; Infusions, Intravenous; Kidney; Natriuresis; Natriuretic Agents; Peptides

We examined the effects of TCV-116, an angiotensin II type 1 receptor antagonist, on endothelial-cell nitric oxide synthase (eNOS), inducible NOS (iNOS), and adrenomedullin (ADM) expression in the left ventricle (LV) and evaluated these relation to myocardial remodeling in failing heart of Dahl salt-sensitive hypertensive rats (DS) fed a high-salt diet. TCV-116 (DSHF-T, 5 mg/kg/day, subdepressor dose) or vehicle (DSHF-V) were given from left ventricular hypertrophy to heart failure stage for 7 weeks. Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSHF-V was significantly ameliorated in DSHF-T. The eNOS mRNA and protein in the LV was significantly suppressed in DSHF-V compared with control rats (DR-C), and significantly increased in DSHF-T compared with DSHF-V. The iNOS mRNA and protein, ADM mRNA and immunoreactive ADM contents, and type I collagen mRNA in the LV were significantly increased in DSHF-V compared with DR-C, and significantly decreased in DSHF-T compared with DSHF-V. DSHF-V showed a significant increase of the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. In conclusion, myocardial remodeling and heart failure in DS rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of TCV-116, which may be due to a increased in eNOS and a decreased in iNOS mRNA and protein expression in the LV. Moreover, the ADM mRNA and immunoreactive ADM contents are upregulated in failing heart of DS rats fed a high-salt diet, and increased ADM expression may have a role in the defense mechanism against further cardiac dysfunction and impaired myocardial remodeling.

Topics: Adrenomedullin; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Disease Models, Animal; Endothelium, Vascular; Heart Failure; Hypertrophy, Left Ventricular; Immunohistochemistry; Male; Myocardial Reperfusion; Myocardium; Nitric Oxide; Organ Size; Peptides; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Ventricular Dysfunction, Left; Ventricular Remodeling

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

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

Adrenomedullin (ADM), a potent natriuretic and vasorelaxing peptide with inotropic properties, is elevated in plasma in human and experimental congestive heart failure (CHF). Recent studies suggest that angiotensin II stimulates ADM production and secretion from cardiac myocytes and fibroblasts. In the present study, we investigated cardiac ADM in experimental CHF, and tested the hypothesis that angiotensin converting enzyme (ACE) inhibition modulates cardiac ADM in CHF. Cardiac tissue ADM immunoreactivity and gene expression were assessed by radioimmunoassay, immunohistochemistry, in situ hybridization and Northern blot analysis in normal and CHF dogs in the presence and absence of ACE inhibition. Experimental CHF was produced by progressive rapid ventricular pacing and characterized by increased ventricular ADM concentrations as well as increased ventricular ADM gene expression. ACE inhibition abolished the increases in ventricular ADM concentrations and ventricular ADM gene expression in CHF. Ventricular ADM gene expression was localized to ventricular myocytes and correlated with left ventricular mass index, suggesting that ventricular ADM is a marker for ventricular hypertrophy. In contrast, atrial ADM concentrations and gene expression did not change in CHF with or without ACE inhibition. Increased plasma ADM concentrations in CHF were also abolished with ACE inhibition. The present study demonstrates that circulating and ventricular ADM are activated in pacing-induced experimental CHF and that ACE inhibition reverses ventricular ADM activation in CHF. This study also indicates that cardiac ADM gene expression is differently regulated between atrium and ventricle in CHF.

Topics: Adrenomedullin; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Northern; Dogs; Enalapril; Heart Atria; Heart Failure; Heart Ventricles; Hemodynamics; Hormones; Immunohistochemistry; In Situ Hybridization; Male; Myocardium; Peptides; RNA, Messenger; Ventricular Function, Left

Increased plasma adrenomedullin (ADM) levels have been reported in congestive heart failure (HF). The present study was designed to investigate myocardial regulation of the different components of the ADM signaling system (ADM, ADM receptor, and receptor-activity-modifying protein-2, RAMP-2) during ischemic HF in rats and to identify the cells in the myocardium displaying ADM-like immunoreactivity (ADM-ir). Furthermore, the effects of endothelin (ET) receptor antagonism on expression of the myocardial ADM system during HF were investigated.. Northern blot analysis revealed increased ADM mRNA expression in the nonischemic left ventricle, with maximal levels 28 days after induction of myocardial infarction (1.5-fold, P<0.05) compared with the sham group. Parallel elevations of myocardial ADM receptor and RAMP-2 mRNA levels were also observed (2.3- and 1.5-fold increase, respectively; P<0.05). In addition, high levels of ADM mRNA were seen in the ischemic region. Immunohistochemical analysis revealed a substantial increase of ADM-ir in microvascular endothelium and perivascular interstitial cells of myocardial tissue contiguous to the ischemic region. In addition, radioligand binding studies demonstrated a 1.6-fold increase of specific ADM binding sites in the failing left ventricle (P<0.05). Intervention with the mixed ET(A)/ET(B) receptor antagonist bosentan (100 mg. kg(-1). day(-1) PO) for 15 days prevented the increase of RAMP-2 mRNA.. The study demonstrates a concerted induction of several components of the myocardial ADM signaling system during postinfarction failure and that the vessels are the main source of myocardial ADM. Our observations indicate a role for ADM as an autocrine/paracrine factor during ventricular remodeling after myocardial infarction.

Topics: Adrenomedullin; Animals; Cardiotonic Agents; Gene Expression Regulation; Heart Failure; Hemodynamics; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardium; Peptides; Radioligand Assay; Rats; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger; Systole; Time Factors; Transcription, Genetic; Ventricular Function, Left

Adrenomedullin (AM), which is produced by various tissues and organs, also circulates in the blood. Circulating AM levels increase during disease states such as essential hypertension, heart failure, and renal failure. However, little is known about how circulating AM or AM production responds to volume overload (VOL).. Progressive VOL was induced in rats by an aortocaval shunt (AC) or by an aortocaval shunt with banding of the abdominal aorta distal to the shunt (AC + B), which created a larger shunt volume. Plasma and tissue AM concentrations, as well as AM gene expression levels, were measured at 1, 5, and 14 days after operation. Plasma concentrations of atrial natriuretic peptide (ANP), aldosterone, and renin activity (PRA) were also examined. Pulmonary congestion, pleural effusion, and ascites rapidly progressed in the AC + B group, suggesting that VOL caused more rapid heart failure under these conditions. Plasma AM concentrations in the AC + B and AC groups at day 1 compared with those in sham-operated rats were increased by 300% and 140%, respectively, and then gradually declined. The time course of plasma AM over 14 days was similar to that of plasma aldosterone and PRA, but not of plasma ANP or intracardiac filling pressure. The increase in plasma AM was accompanied by upregulated AM gene expression in the lung and aorta and by decreased AM concentrations in the atrium, ventricle, and adrenal gland. Cardiac AM gene expression levels were increased in the hypertrophied ventricles of AC and AC + B rats.. The major findings of the present study were 1) a rapid increase in plasma AM after the imposition of VOL in association with increased plasma aldosterone and PRA, 2) the contribution of several organs to this increase, and 3) a late increase in the AM messenger RNA (mRNA) level in the ventricles as VOL-induced ventricular hypertrophy developed.

Topics: Adrenomedullin; Aldosterone; Animals; Aorta, Thoracic; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Biomarkers; Cardiac Volume; Gene Expression; Heart Failure; Hemodynamics; Hypertrophy, Left Ventricular; Male; Peptides; Radioimmunoassay; Rats; Rats, Wistar; Renin; RNA, Messenger; Venae Cavae

Myocardial actions of the vasodilator peptide adrenomedullin (ADM) in the intact animal are unknown. Negative and positive inotropic actions have been reported in ex vivo experiments. Myocardial and load-altering actions of ADM in dogs before and after development of heart failure were studied. With controlled heart rate (atrial pacing) and after beta-blockade, ADM was administered to five normal dogs in doses of 20 ng. kg(-1). min(-1) iv, 100 ng. kg(-1). min(-1) iv, and 200 ng. kg(-1). min(-1) into the left ventricle (LV). LV peak systolic pressure and end-systolic volume decreased with each dose of ADM. End-systolic pressure decreased with the two higher doses. At the highest dose, arterial elastance and the time constant of LV isovolumic relaxation (tau) decreased, and LV end-systolic elastance (E(es)) increased. LV end-diastolic pressure and volume were unchanged. In five additional normal dogs receiving only the highest dose of ADM (200 ng. kg(-1). min(-1) intra-LV), to control for increased heart rate and sympathetic activation observed with the cumulative infusion, ADM produced arterial vasodilation but no change in E(es) or tau. In four dogs with pacing-induced heart failure, ADM (200 ng. kg(-1). min(-1) intra-LV) was without effect on tau, E(es), and systolic or diastolic pressure and volume. In vivo, ADM appears to be a selective arterial dilator without inotropic or lusitropic effects. The vasodilatory actions are attenuated in heart failure.

Topics: Adrenomedullin; Animals; Blood Pressure; Cardiac Pacing, Artificial; Cyclic AMP; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Epinephrine; Heart; Heart Failure; Heart Rate; Infusions, Intravenous; Male; Myocardial Contraction; Norepinephrine; Peptides; Vasodilation; Vasodilator Agents; Ventricular Function, Left

Adrenomedullin (ADM) is a vasodilator produced by vascular endothelium and smooth muscle cells. Although plasma ADM levels are increased in patients with hypertension, heart failure, and myocardial infarction, little information exists regarding the microvascular response to ADM in the human heart. In the present study we tested the hypothesis that ADM produces coronary arteriolar dilation in humans and examined the mechanism of this dilation. Human coronary arterioles were dissected and cannulated with micropipettes. Internal diameter was measured by video microscopy. In vessels constricted with ACh, the diameter response to cumulative doses of ADM (10(-12)-10(-7) M) was measured in the presence and absence of human ADM-(22-52), calcitonin gene-related peptide-(8-37), N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (Indo), (1)H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, or KCl (60 mM). ADM dilated human coronary arterioles through specific ADM receptors (maximum dilation = 69 +/- 11%). L-NAME or N-monomethyl-L-arginine attenuated dilation to ADM (for L-NAME, maximum dilation = 66 +/- 7 vs. 41 +/- 13%, P < 0.05). Thus the mechanism of ADM-induced dilation involves generation of nitric oxide. However, neither (1)H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one, SQ-22536, nor Indo alone altered dilation to ADM. High concentrations of KCl blocked dilation to ADM. The magnitude of ADM dilation was reduced in subjects with hypertension. We propose that, in human coronary arterioles, ADM elicits vasodilation in part through production of nitric oxide and in part through activation of K(+) channels, with little contribution from adenylyl cyclase. The former dilator mechanism is independent of the more traditional pathway involving activation of soluble guanylate cyclase.

Topics: Adenine; Adrenomedullin; Aged; Arterioles; Calcitonin Gene-Related Peptide; Coronary Circulation; Coronary Disease; Coronary Vessels; Enzyme Inhibitors; Female; Heart Failure; Humans; Hypertension; In Vitro Techniques; Male; Microcirculation; Middle Aged; Miotics; NG-Nitroarginine Methyl Ester; Nitric Oxide; omega-N-Methylarginine; Peptide Fragments; Potassium Channels; Vasodilation; Vasodilator Agents

In the biosynthesis of adrenomedullin (AM), an intermediate form, AM(1-52)-glycine-COOH (iAM), is cleaved from proAM and subsequently processed to a biologically active mature form, AM(1-52)-NH2 (mAM), by enzymatic amidation. We recently reported that immunoreactive AM in human plasma consists of mAM and iAM. To clarify the pathophysiological roles of mAM and iAM in heart failure, we established an assay method to specifically detect mAM, and we determined the plasma concentrations of mAM and iAM in 68 patients with congestive heart failure (CHF). The plasma mAM concentrations of the CHF patients classified as being class I or II of New York Heart Association (NYHA) functional classification were significantly greater than those of the 28 healthy controls, and a further increase was noted in the class III or IV patients. Similar increases in plasma iAM were also observed in these patients compared with controls. The increased plasma mAM and iAM in 12 patients with exacerbated CHF were significantly reduced by treatment of their CHF for 7 days. In addition, the plasma concentrations of both mAM and iAM were significantly correlated with pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, cardiothoracic ratio, heart rate, and the plasma concentrations of atrial and brain natriuretic peptides in the CHF patients. Thus the plasma concentrations of both mAM and iAM were increased progressively in proportion to the severity of CHF. These results suggest that, though the role of iAM remains to be clarified, mAM acts against the further deterioration of heart failure in patients with CHF.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptides; Precipitin Tests; Pulmonary Wedge Pressure; Statistics, Nonparametric

Heart failure is characterized by increased vascular resistance and water retention. Adrenomedullin is a peptide hormone with vasodilating and diuretic properties whose efficacy in heart failure has not been well established. We used an aortocaval shunt model of moderate heart failure in rats and infused increasing doses of adrenomedullin, both as bolus injections and 20-min infusions. In controls, a clear dose-dependent 4.8+/-1.0 to 13.6+/-2.3 mm Hg decrease in arterial blood pressure was observed after injection of 1 microg to 30 microg of adrenomedullin. In rats with aortocaval shunt, the hypotensive responses were significantly diminished. The urine flow rate, which was diminished at baseline in rats with aortocaval shunt, was increased and normalized by adrenomedullin administration. The glomerular filtration rate increased after infusion of adrenomedullin (0.5 microg/kg min(-1)) from 2.37+/-0.25 to 3.47+/-0.43 ml/min (P<0.01) in controls and from 1.79+/-0.33 to 2.58+/-0.49 (P<0.05) in rats with aortocaval shunt. Similarly, renal blood flow was significantly increased by adrenomedullin in both groups. Our results indicate a beneficial effect of adrenomedullin on renal function in rats with aortocaval shunt. These data suggest that adrenomedullin might be of potential therapeutic value in heart failure, without inordinately decreasing blood pressure.

Topics: Adrenomedullin; Animals; Arteriovenous Shunt, Surgical; Cardiotonic Agents; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Diuresis; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Kidney; Male; Natriuresis; Peptides; Rats; Rats, Wistar; Renal Circulation

Adrenomedullin (AM) is a peptide hormone with vasodilating and natriuretic properties. AM plasma concentrations are elevated in heart failure. Whether cardiac AM-mRNA synthesis is increased in heart failure is not known. We measured AM-mRNA/GAPDH-mRNA in all four heart chambers in compensated and overt heart failure in rats with two different sizes of aortocaval shunt. Left and right atrial AM-mRNA expressions were unchanged in both heart failure models. Similarly, left and right ventricular AM-mRNA expressions were unchanged in compensated heart failure. In overt heart failure, however, the AM-mRNA expression was significantly increased in the left ventricle (145+/-20 vs. 100+/-3% of control, p<0.05). The right ventricular AM-mRNA expression was significantly increased only in a subgroup of animals with pulmonary congestion (lung weight >2.0 g, 141+/-16 vs. 100+/-11% of control, p<0.05). Ventricular AM concentrations were elevated in both ventricles in overt heart failure. AM plasma concentrations were significantly higher in the subgroup with pulmonary congestion than in rats with compensated heart failure (496+/-95 vs. 143+/-7 pmol/l, p<0.01). These data indicate that ventricular AM-mRNA expression and AM concentrations were upregulated only in advanced stages of heart failure. However, the exact contribution of cardiac AM synthesis to the increased AM plasma levels remains to be established.

Topics: Adrenomedullin; Animals; Glyceraldehyde-3-Phosphate Dehydrogenases; Heart Atria; Heart Failure; Heart Ventricles; Hemodynamics; Lung; Male; Myocardium; Organ Size; Peptides; Rats; Rats, Wistar; RNA, Messenger

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

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

Topics: Adrenomedullin; Aorta; Heart Failure; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Peptides; Pulmonary Artery; Reference Values; Renal Insufficiency; Renal Veins; Time Factors

1. Adrenomedullin, a newly identified vasorelaxant peptide, participates in the regulation of the cardiovascular system. To investigate the pathophysiological significance of adrenomedullin in patients with acute myocardial infarction, we measured plasma levels of adrenomedullin. 2. Cardiac catheterization was performed on admission, after 1 day, and after 4 weeks in 36 patients with acute myocardial infarction. We measured plasma levels of adrenomedullin, atrial natriuretic peptide and brain natriuretic peptide in the right atrium, pulmonary artery and aorta. 3. Plasma levels of adrenomedullin in the right atrium (mean +/- SEM) were significantly increased on admission (4.2 +/- 2.6 h) in patients with acute myocardial infarction (10.6 +/- 1.0 pmol/l) compared with controls (5.2 +/- 0.3 pmol/l, P < 0.01). In addition, plasma levels of adrenomedullin were further elevated in patients with congestive heart failure (12.3 +/- 1.4 pmol/l) compared with patients without congestive heart failure (7.8 +/- 0.6 pmol/l, P < 0.01). In patients with congestive heart failure, plasma adrenomedullin on admission significantly correlated with atrial natriuretic peptide and brain natriuretic peptide. 4. These results suggest that plasma adrenomedullin increases in the early phase of acute myocardial infarction and that volume expansion may be one of the additional stimuli for the release of adrenomedullin in patients with acute myocardial infarction complicated by congestive heart failure.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Aorta; Atrial Natriuretic Factor; Female; Heart Atria; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptides; Pulmonary Artery; Vasodilator Agents

1. Adrenomedullin is a recently discovered vasodilating and natriuretic peptide whose physiological and pathophysiological roles remain to be established. Like atrial natiuretic peptide adrenomedullin is expressed in the left ventricle. Ventricular expression of atrial natriuretic peptide is known to be markedly increased by volume or pressure overload. In this study we investigated whether ventricular expression of adrenomedullin is similarly stimulated under such conditions. 2. Ventricular adrenomedullin and atrial natriuretic peptide mRNA levels as well as those of a loading control mRNA (glyceraldehyde-3-phosphate dehydrogenase) were quantified by Northern blot analysis in (a) rats with severe post-infarction heart failure induced by left coronary ligation at 30 days post-surgery and (b) in rats with pressure-related cardiac hypertrophy induced by aortic banding at several time points (0.5, 1 and 4 h, and 1, 4, 7 and 28 days) after surgery. Levels were compared with those in matched sham-operated controls. 3. The mRNA level of atrial natriuretic peptide was markedly increased (8-10-fold) in the left ventricle of animals with post-infarction heart failure. In contrast, there was only a modest (40%) increase in the level of adrenomedullin mRNA. In rats with pressure-induced cardiac hypertrophy the ventricular level of atrial natriuretic peptide mRNA was again markedly increased (maximum 10-fold). The increase was first noticeable at 24 h post-banding and persisted until 28 days. In contrast, there was no change in adrenomedullin mRNA level compared with sham-operated rats at any time point. 4. Despite having similar systemic effects, the expression of adrenomedullin and atrial natriuretic peptide in the left ventricle is differently regulated. The findings imply distinct roles for the two peptides. The results do not support an important role for ventricular adrenomedullin expression in the remodelling process that occurs during the development of cardiac hypertrophy but suggest that ventricular adrenomedullin participates in the local and/or systemic response to heart failure.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Blotting, Northern; Cardiomegaly; Gene Expression Regulation; Heart Failure; Heart Ventricles; Male; Myocardium; Peptides; Rats; Rats, Inbred WKY; Rats, Wistar; RNA, Messenger

Adrenomedullin is an intrinsic vasodilator which is metabolized mainly in the pulmonary circulation. We measured plasma levels of adrenomedullin in children with congenital cyanotic heart disease (CY group, n = 6), children with high pulmonary blood flow due to congenital heart disease (PH group, n = 8), and in adults with mitral valve disease (MV group, n = 7) before and 3 h after cardiopulmonary bypass (CPB). Before CPB, the adrenomedullin level was the highest in the MV group, possibly due to chronic heart failure. Three hours after CPB, the plasma adrenomedullin level (pg/ml) increased to 1712.7 +/- 498.4 in the CY group, 167.6 +/- 26.4 in the PH group, and 1404.3 +/- 313.7 in the MV group, the level in the PH group being significantly lower than the rest. In the PH group, there was statistically significant negative correlation between the mean pulmonary arterial pressure at the preoperative catheter study, and the adrenomedullin level 3 h after CPB. These results illustrate that the adrenomedullin level increased after CPB, but that the increase was less marked in the PH group, implying that where the pulmonary vasculature was damaged most, this results in increased vasoconstriction.

Topics: Adrenomedullin; Adult; Aged; Cardiopulmonary Bypass; Child, Preschool; Female; Heart Failure; Humans; Infant; Male; Middle Aged; Mitral Valve Insufficiency; Peptides; Postoperative Complications; Vasoconstriction

To characterize the determinants of circulating levels of adrenomedullin (AM), the plasma levels of this peptide were measured in 58 patients with end-stage renal disease on hemodialysis. Predialysis plasma levels of AM were more than twice as high in patients on hemodialysis as compared to controls. In hemodialysis patients with heart failure (NYHA classes II-IV) or hypertensive HD patients plasma levels of AM were significantly higher than in patients with end-stage renal disease only. Plasma levels of AM were not altered immediately by hemodialysis but decreased significantly 14-20 h after hemodialysis. AM plasma levels before hemodialysis and 14-20 h after hemodialysis were correlated with the corresponding mean arterial pressure.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Body Weight; Female; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Renal Dialysis; Ultrafiltration

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

1. Adrenomedullin is a potent vasodilating peptide first isolated from phaeochromocytoma and adrenal medulla but also found in the heart, lungs and kidneys. It may also be a paracrine factor because endothelial and smooth muscle cells synthesize adrenomedullin as well as express the receptors. Adrenomedullin induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of nitric oxide. 2. We have developed a specific radioimmunoassay and measured the immunoreactivity of human adrenomedullin in the plasma of 58 male subjects: eight with essential hypertension, 12 with heart failure, 10 with ascites due to cirrhosis, 12 with chronic renal failure, four with hypoxia due to chronic obstructive pulmonary disease and 12 control subjects. 3. Plasma levels (mean +/- SEM) in patients with essential hypertension (16.3 +/- 1.9 pmol/l), congestive heart failure (17.5 +/- 2.8 pmol/l) and renal failure (17.7 +/- 2.5 pmol/l) were raised compared with control subjects (7.8 +/- 1.4 pmol/l, P < 0.05), confirming previous reports. 4. In addition, we observed that plasma levels of adrenomedullin were significantly raised in patients with ascites due to liver cirrhosis (15.5 +/- 1.9 pmol/l) and chronic obstructive pulmonary disease with hypoxia (20.0 +/- 1.5 pmol/l). 5. We concluded that the plasma level of adrenomedullin is raised in a variety of diseases.

Topics: Adrenomedullin; Adult; Aged; Heart Failure; Humans; Hypertension; Hypoxia; Kidney Failure, Chronic; Liver Cirrhosis; Lung Diseases, Obstructive; Male; Middle Aged; Peptides; Radioimmunoassay; Vasodilator Agents

Topics: Adrenomedullin; Adult; Aged; Chromatography, High Pressure Liquid; Female; Heart Failure; Humans; Immunoassay; Male; Middle Aged; Peptide Fragments; Peptides; Proteins

Adrenomedullin (ADM) is a recently discovered hypotensive peptide that has been isolated from human pheochromocytoma cells. Observations that ADM is produced from cardiovascular tissue and is found in plasma suggest that it may be important in the regulation of regional vascular resistance.. Limb vascular responses to ADM were examined in 10 healthy subjects and compared with those in 18 patients with chronic heart failure (CHF). The peptide increased forearm blood flow (FBF) from 2.7 +/- 0.3 to 11.8 +/- 0.9 mL.min-1.100 mL-1 in the control group and from 2.4 +/- 0.3 to 6.5 +/- 0.7 mL.min-1.100 mL-1 in the CHF group. The ADM-induced FBF increase was significantly impaired in the CHF group (P < .01). After cessation of the infusion, an increased FBF level was sustained for > 60 minutes in the control group, whereas in the CHF group the response returned to the baseline in < 30 minutes. The ADM infusion increased forearm skin blood flow in both groups (P < .05), whereas the skin blood flow response was impaired in the CHF group (P < .01). The role of nitric oxide in ADM-induced vasorelaxation was also studied in 11 healthy subjects and 6 patients with CHF. FBF and skin blood flow responses during ADM administration were significantly attenuated by NG-monomethyl-L-arginine administration in healthy control subjects (P < .05), whereas both flow responses remained the same in the CHF group.. These observations demonstrate that ADM exerts a potent and long-lasting vasodilatory effect on skeletal muscle arteries with involvement of nitric oxide-dependent mechanisms in normal human peripheral vasculature and that these vascular effects are significantly attenuated in patients with CHF, in part because of impaired production of nitric oxide in the forearm resistance vessels.

Topics: Adrenomedullin; Adult; Blood Pressure; Female; Forearm; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Peptides; Plethysmography; Reference Values; Regional Blood Flow; Skin; Vascular Resistance; Vasodilation; Vasodilator Agents

The levels of adrenomedullin (ADM), a newly discovered vasodilating and natriuretic peptide, are elevated in plasma and ventricular myocardium in human congestive heart failure suggesting that cardiac synthesis may contribute to the plasma concentrations of ADM. To examine the time course of induction and mechanisms regulating cardiac ADM gene expression, we determined the effect of acute and short-term cardiac overload on ventricular ADM mRNA and immunoreactive ADM (ir-ADM) levels in conscious rats. Acute pressure overload was produced by infusion of arginine8-vasopressin (AVP, 0.05 microg/kg/min, i.v.) for 2 h into 12-week-old hypertensive TGR(mREN-2)27 rats and normotensive Sprague-Dawley (SD) rats. Hypertension and marked left ventricular hypertrophy were associated with 2.2-times higher ir-ADM levels in the left ventricular epicardial layer (178 +/- 36 vs. 81 +/- 23 fmol/g, P<0.05) and 2.6-times higher ir-ADM levels in the left ventricular endocardial layer (213 +/- 23 vs. 83 +/- 22 fmol/g, P<0.01). The infusion of AVP for 2 h in normotensive rats produced rapid increases in the levels of left ventricular ADM mRNA (epicardial layer: 1.6-fold, P<0.05) and ir-ADM (endocardial layer: from 83 +/- 22 to 140 +/- 12 fmol/g, P<0.05), whereas ventricular ADM mRNA and ir-ADM levels did not change significantly in hypertensive rats. Short-term cardiac overload, induced by administration of angiotensin II (33.3 microg/kg/h, s.c., osmotic minipumps) for two weeks in normotensive SD rats resulted in left ventricular hypertrophy (3.05 +/- 0.17 vs. 2.75 +/- 0.3 mg/g, P<0.05) and a 1.5-fold increase (P<0.05) in ventricular ADM mRNA levels. In conclusion, the present results show that pressure overload acutely stimulated ventricular ADM gene expression in conscious normotensive rats suggesting a potential beneficial role for endogenous ADM production in the heart against cardiac overload. Since pressure overload-induced increase in ADM synthesis was attenuated in hypertensive rats, alterations in the ADM system may contribute to the pathogenesis of hypertension in the TGR(mREN-2)27 rat.

Topics: Adrenomedullin; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Heart; Heart Failure; Heart Ventricles; Humans; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Peptide Biosynthesis; Peptides; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Transcription, Genetic

Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure.. Eight sheep with pacing-induced heart failure received human adrenomedullin(1-52) at 10 and 100 ng x kg(-1) x min(-1) I.V. for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose, P<.05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg x L(-1) x min(-1), P<.001), mean arterial pressure (9 mm Hg, P<.001), and left atrial pressure (5 mm Hg, P<.001) and increases in cardiac output (0.5 L/min, P<.001). Adrenomedullin increased urine sodium (threefold, P<.05), creatinine (P<.05) and cAMP excretion (P<.01), creatinine clearance (P<.05), and renal production of cAMP (P<.05), whereas urine output was maintained during infusion and raised after infusion (P<.05). Adrenomedullin reduced plasma aldosterone levels (P<.05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (P<.01 and P<.05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered.. Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.

Topics: Adrenomedullin; Animals; Blood Glucose; Blood Pressure; Calcium; Cardiac Output; Creatinine; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Epinephrine; Female; Heart Failure; Hemodynamics; Hydrocortisone; Norepinephrine; Pacemaker, Artificial; Peptides; Potassium; Renal Circulation; Sheep; Vasodilator Agents; Ventricular Dysfunction, Left

Adrenomedullin (ADM) is a new member of a family of vasodilating and natriuretic peptides that plays an important role in cardiorenal regulation. This study was designed to establish the plasma, urinary, cardiac, and renal tissue concentrations and immunohistochemical localizations of ADM in normal dogs and dogs with experimental congestive heart failure (CHF) produced by rapid ventricular pacing. Plasma ADM concentration was 5.6 +/- 0.4 pg/ml in normal dogs and significantly increased to 14.5 +/- 2.5 pg/ml in CHF dogs (P < 0.05). Ventricular and renal tissue ADM were significantly increased in CHF dogs compared with normals. Immunohistochemical examination revealed positive ADM immunostaining within the myocytes, and ventricular ADM immunoreactivity was significantly more intense in CHF dogs than in normals. ADM immunoreactivity was also observed in the glomerulus, distal tubules, and medullary collecting duct cells in the kidney, and the intensities of ADM immunoreactivity in these sites were increased in CHF dogs compared with normals. In addition, ventricular ADM was a powerful marker for left ventricular mass, and circulating ADM correlated positively with left ventricular end-diastolic pressure and inversely with cardiac output and ejection fraction. Despite an increase in renal tissue ADM, urinary ADM did not increase in CHF dogs. The current study demonstrates that plasma concentration of ADM is increased in experimental CHF and that ventricular and renal ADM is activated in the progression of CHF. Tissue and circulating ADM also are markers for the alterations in myocardial structure and function. This study supports a potential role for ADM in the neurohumoral activation in experimental CHF.

Topics: Adrenomedullin; Animals; Dogs; Heart Failure; Heart Ventricles; Hemodynamics; Immunohistochemistry; Kidney; Male; Myocardium; Peptides; Ventricular Function

Plasma adrenomedullin (AM) levels are reportedly increased in heart failure, but whether the cardiac production and secretion of AM is increased in heart failure remains unknown. To investigate the sites of production and secretion of AM in heart failure, we measured plasma AM levels and peptide and mRNA levels of AM in various tissues in rats with heart failure. We also examined whether the heart actually secretes AM into the circulation in patients with heart failure. We measured plasma and tissue AM levels by specific radioimmunoassay and AM mRNA by Northern blot analysis in rats with heart failure produced by aortocaval fistula. We also measured plasma AM levels in the coronary sinus and aorta in patients with left ventricular dysfunction before and after rapid right ventricular pacing. The increase in plasma AM levels in heart failure rats correlated with ventricular weight. Tissue AM levels were increased in the heart and lungs but not in the kidneys or adrenals of rats with heart failure. Similarly, tissue AM mRNA levels were also increased in the heart and lungs of heart failure rats. Plasma AM levels were higher in the coronary sinus than in the aorta in patients with left ventricular dysfunction. Rapid right ventricular pacing increased plasma atrial natriuretic peptide but not AM. These results suggest that plasma AM levels are increased in heart failure in proportion to the severity of heart failure and that cardiac production and secretion of AM is increased in heart failure rats. The lung may be another site for increased production of AM in heart failure rats. Human failing heart actually secretes AM into the circulation, and the regulation of AM secretion appears to differ from that of atrial natriuretic peptide.

Topics: Adrenal Glands; Adrenomedullin; Animals; Female; Heart; Heart Failure; Humans; Kidney; Lung; Male; Middle Aged; Myocardium; Organ Size; Peptides; Rats; Rats, Wistar; Reference Values; Regression Analysis; Ventricular Dysfunction, Left; Ventricular Function, Right

The present investigation was designed to determine the best endogenous plasma marker of early congestive heart failure (CHF).. Forty volunteers with mild CHF (New York Heart Association Class I, n = 12), moderate (Class II, n = 8), or severe (Class III and Class IV, each = n of 5) and 10 age-matched healthy individuals had the simultaneous evaluation of their respective plasma samples by the following radioimmunoassays: atrial natriuretic peptide, ANP; three N-terminal ANP prohormone assays, i.e., proANPs 1-30, 31-67, and 79-98 with the numbers referring to their amino acid (a.a.) sequences in their 126 a.a. prohormone; brain (BNP) and C-natriuretic peptides; N-terminal BNP prohormone; adrenomedullin; neuropeptide Y and endothelin.. ProANPs 31-67, 1-30 and 79-98 had 100% (P = 0.01), 83% (P = 0.09) and 50% (P = 0.74) sensitivity in differentiating Class I CHF subjects from healthy subjects. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y, and endothelin assays could not differentiate mild CHF subjects from healthy individuals. Logistic regression analysis revealed that only proANP 31-67 significantly (P = 0.0001) discriminated between early CHF (5226 +/- 377 pg/ml) and healthy individuals (1595 +/- 157 pg/ml). The positive and negative predicative values of proANP 31-67 were excellent (100% for each). The peptides measured in these assays were found to be independent markers of CHF with respect to left ventricular ejection fraction.. ProANPs 31-67 is the most sensitive marker in discriminating NYHA Class I CHF subjects from healthy individuals. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y and endothelin radioimmunoassays cannot discern mild CHF. These peptides are independent of left ventricular ejection fraction.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Endothelins; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Neuropeptide Y; Peptide Fragments; Peptides; Predictive Value of Tests; Protein Precursors; Regression Analysis

We measured plasma concentrations of adrenomedullin (AM), a novel bioactive peptide with potent vasodilator activity, in 21 patients with chronic congestive heart failure due to various heart diseases and compared them to levels in age- and sex-matched healthy subjects to examine the pathophysiological role of plasma AM in heart failure. In addition, the relationship between plasma AM and other hormones known to control the cardiovascular system was examined in these patients. The plasma AM level in the patients with heart failure was significantly (P < 0.01) higher than that in the control subjects (mean +/- SEM, 2.94 +/- 0.15 fmol/mL; n = 16), with a significantly (P < 0.05) higher concentration in patients in class III or IV (11.82 +/- 1.81 fmol/mL; n = 5) of the New York Heart Association functional classification than in those in class I or II (8.74 +/- 0.44 fmol/mL; n = 16). There were no significant correlations between plasma AM and catecholamine levels, whereas the plasma AM level was significantly correlated with the concentrations of plasma atrial natriuretic peptide (r = 0.58; P < 0.01), brain natriuretic peptide (r = 0.47; P < 0.05), and PRA (r = 0.77; P < 0.01) in the patients. Thus, the plasma AM concentration increased in proportion to the severity of heart failure along with the hormones known to modulate the development of congestive heart failure. The present findings suggest a possible role for AM as a circulating hormone participating in the defense mechanism against further deterioration of congestive heart failure in patients with heart disease.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptides; Renin

Adrenomedullin (ADM) is a newly discovered endogenous vasorelaxing and natriuretic peptide. Recently, we have reported that plasma ADM is increased in severe congestive heart failure (CHF) in humans and that increased immunohistochemical staining is observed in the failing human ventricular myocardium. The present study was designed to test the hypothesis that the failing human ventricle secretes ADM and that circulating ADM progressively increases with the severity of clinical CHF. Plasma ADM was significantly increased in human CHF (39.8 +/- 3.6 pg/ml, P < 0.001 vs. normal) as compared with normal subjects (14.4 +/- 2.7 pg/ml). Plasma ADM was increased in mild CHF (NYHA class II, 30.1 +/- 3.4 pg/ml, P < 0.01 vs. normal), moderate CHF (NYHA class III, 31.5 +/- 3.0 pg/ml, P < 0.01 vs. normal), and severe CHF (NYHA class IV, 66.1 +/- 9.4 pg/ml, P < 0.001 vs. normal). In 13 patients with CHF in whom plasma samples were obtained from aorta (AO), coronary sinus (CS) and anterior interventricular vein (AIV), there was a significant step-up in plasma ADM between AO and AIV (50.6 +/- 9.3 pg/ml and 62.1 +/- 11.1 pg/ml, respectively, P < 0.01) and between AO and CS (50.6 +/- 9.3 pg/ml and 58.6 +/- 11.4 pg/ml, respectively, P < 0.05). The current study demonstrates that the failing human heart secretes ADM in human CHF suggesting contribution to the increase in plasma ADM, and indicates for the first time an additional endocrine system of cardiac origin which is activated in human CHF and may function in cardiorenal regulation.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Creatinine; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Peptides; Vasodilator Agents

To investigate the role of adrenomedullin in the pathophysiology of heart failure, we measured plasma levels of adrenomedullin in patients with heart failure.. Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet adenosine 3',5'-cyclic monophosphate (cAMP). A significant level of adrenomedullin has been identified in human plasma. These findings suggest the possibility of adrenomedullin as a new circulating hormone that participates in the regulation of the cardiovascular system.. Venous blood samples at rest were obtained from patients with heart failure in New York Heart Association functional classes I (n = 15), II (n = 25), III (n = 16) and i.v. (n = 10) and from normal subjects (n = 27). Plasma adrenomedullin levels were determined by our newly developed radioimmunoassay. Other humoral factor levels measured simultaneously included norepinephrine, atrial natriuretic peptide, brain natriuretic peptide, plasma renin activity, aldosterone and cAMP. Left ventricular ejection fraction was measured by echocardiography. In eight patients with severe heart failure, plasma adrenomedullin levels were measured before and after treatment.. The mean (+/- SD) plasma level of adrenomedullin in control subjects was 2.52 +/- 0.75 pmol/liter. Plasma levels of adrenomedullin in patients with heart failure were unaffected in those in functional class I (2.85 +/- 0.62 pmol/liter) but tended to be increased in those in class II (3.54 +/- 0.82 pmol/liter) and were significantly increased in those in classes III and i.v. (4.78 +/- 1.218 and 8.74 +/- 3.43 pmol/liter, respectively). There was a significant correlation between plasma levels of adrenomedullin and norepinephrine (r = 0.618, p < 0.001), atrial natriuretic peptide (r = 0.696, p < 0.001) and brain natriuretic peptide (r = 0.692, p < 0.001). Left ventricular ejection fraction inversely correlated with plasma adrenomedullin levels (r = 0.485, p < 0.001). Plasma adrenomedullin levels significantly decreased after treatment (from 7.40 +/- 3.40 to 3.98 +/- 1.00 pmol/liter, p < 0.05).. These results suggest that plasma level of adrenomedullin are elevated in heart failure and that an increased plasma volume and an activated sympathetic nervous system in this condition may be related to its synthesis or secretion. Given that adrenomedullin exerts potent cardiovascular effects, increased adrenomedullin may be involved in the defense mechanism against further peripheral vascular resistance elevation in heart failure.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Case-Control Studies; Cyclic AMP; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Norepinephrine; Peptides; Radioimmunoassay; Renin; Time Factors

Adrenomedullin (ADM) is a newly discovered vasodilating and natriuretic peptide that may play an important role in cardiorenal regulation. Although ADM was originally isolated from human pheochromocytoma, ADM-like immunoreactivity has also been widely detected in various tissues, including the cardiovascular system.. In view of reports that ADM circulates in the body and that ADM gene and ADM-like immunoreactivity are present in the heart, the present study was designed to determine the plasma concentration of ADM in healthy subjects and in patients with congestive heart failure (CHF) and to investigate the immunohistochemical presence and localization of ADM in normal and failing human hearts. Plasma ADM concentration was 13.2 +/- 2.3 pg/mL in healthy subjects (n = 11) and increased to 47.3 +/- 6.7 pg/mL in patients with CHF (n = 11 P < .05 versus normal). Human cardiac tissues were obtained from five patients with end-stage CHF undergoing cardiac transplantation. Five normal donor hearts that were used for cardiac transplantation served as sources for normal atrial tissues. Normal ventricular myocardium was also obtained by endomyocardial biopsy from the right ventricles of these donor hearts immediately before cardiac transplantation. Positive immunostaining was detected within the myocardia in both atria and ventricles of healthy and severely failing human transplanted hearts and was more intense in the atria than in the ventricles. Although there were no significant differences in the intensity of immunoreactivity between normal and failing atria, ADM immunoreactivity was significantly more intense in the ventricular myocytes from failing hearts compared with normal hearts.. The present study demonstrates that plasma concentration of ADM is increased in patients with CHF and that ADM is present in the human heart. ADM immunoreactivity is markedly increased in the failing human ventricle, suggesting that ventricular ADM expression may be influenced by the circumstances associated with CHF. This supports a potential role for this newly identified vasoactive and natriuretic peptide, ADM, in the neurohumoral activation that characterizes human CHF.

Topics: Adrenomedullin; Aged; Antihypertensive Agents; Female; Heart Failure; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Peptide Biosynthesis; Peptides