Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current thinking views the progression of heart failure as the result of sustained activation of vasoconstrictor neurohormones. In this model, the sustained synthesis of vasoconstrictor neurohormones leads to disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse ventricular remodeling through myocyte cell loss and progressive myocardial fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-adrenergic and the renin-angiotensin-aldosterone systems. Although the observed decrease in mortality using this strategy in heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of vasodilator neurohormones, deserve stimulation. It is known a family of vasodilator neurohormones - the natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These peptides are degraded primarily by a neutral endopeptidase (NEP), an endothelial cell-surface zinc metallopeptidase, which shares a similar structure and catalytic site with the angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide, but also bradykinin and adrenomedullin. The recognition that ACE and NEP enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as vasopeptidase inhibitors. Preliminary clinical trials in heart failure with vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing vasodilator substances, holds promise as a valuable option in heart failure treatment for the near future.
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PMID:Vasopeptidase inhibitors: potential role in the treatment of heart failure. 1263 92

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.
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PMID:Adrenomedullin and heart failure. 1266 25

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.
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PMID:Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats. 1456 98

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive hormones was conducted together with echocardiography. Heart failure was diagnosed in 77 (of the 305) patients by rigorous application of predefined criteria. Plasma amino-terminal C-type natriuretic peptide concentrations were elevated in patients with heart failure, and by univariate analysis were related to age, renal function, and other hormones. On multivariate analysis, tertile of plasma N-CNP interacted with tertile of plasma amino-terminal B-type natriuretic peptide to predict heart failure independent of age, gender, renal function, or echocardiographic left ventricular fractional shortening. N-CNP showed significant relations to concurrent plasma CNP, atrial natriuretic peptide (ANP), N-ANP, B-type (or brain) natriuretic peptide (BNP), N-BNP, endothelin-1, and adrenomedullin but not to echocardiographic indicators of left ventricular systolic function. Plasma amino-terminal C-type natriuretic peptide is elevated in heart failure and is related to other plasma hormones in heart failure. These findings suggest a possible compensatory response from the peripheral vasculature to heart failure by an endothelium-based vasodilator peptide and mandate further exploration of the role of C-type natriuretic peptide in this condition.
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PMID:Amino-terminal pro-C-type natriuretic peptide in heart failure. 1465 55

In this paper we review pathophysiologic aspects of heart failure (HF). Mechanisms that normally act to prevent decrease in stroke volume and peripheral pressure are activated in HF and become maladaptive. These mechanisms lead to cardiac stimulation (inotropism, chronopism and lusotropism), peripheral vasoconstriction and sodium and water retention. HF progression is related to a) neurohumoral mechanisms, signaled by neurohumoral messengers; b) inflammatory activation; and c) ventricular remodeling that can be both cause and consequence of HF. We review the main neurohumoral mechanisms, some "regulators" (vasoconstrictors, antinatriuretics, inotropics and proliferatives) and some "counter-regulators" (vasodilators, natriuretics, negative inotropics and antiproliferatives). The first group includes the sympathetic nervous system, the renin angiotensin aldosterone system, arginine-vasopressive and endothelin, while in the second group natriuretic peptides, nitric oxide, bradykinin, vasodilator prostaglandins, the dopaminergic system, adrenomedullin and parasympathetic mechanisms are included. In inflammatory activation we review cytokines and oxidative stress. In ventricular remodeling we review modifications in myocyte function and morphology as well as modifications in the interstitium. Actions and interactions between these systems are the main factors leading to HF progression.
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PMID:[Physiopathology of heart failure]. 1522 47

Lysophosphatidic acid (LPA) is a bioactive phospholipid having growth factor-like activity on fibroblasts and is involved in cardiovascular diseases such as hypertension and heart failure by inducing vascular remodeling, characterized by fibroblast proliferation and migration in adventitia. Among various bioactive factors that LPA works with, adrenomedullin (ADM) is a multiple functional peptide with an important cytoprotective effect against cardiovascular damage. We studied rat aortic adventitia to explore the possible paracrine/autocrine interaction between endogenous ADM and LPA. LPA stimulation of the adventitia to secrete ADM and express its mRNA was concentration dependent. ADM inhibited LPA-induced proliferation in adventitial cells and attenuated the activity of mitogen-activated protein kinase (MAPK) stimulated by LPA. In contrast, treatment with specific antagonists of the ADM receptor potentiated the LPA-induced proliferation in adventitial cells. We concluded that LPA stimulates the adventitia to produce and secrete ADM, which in turn regulates the vascular biological effects of LPA.
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PMID:Effects of adrenomedullin on cell proliferation in rat adventitia induced by lysophosphatidic acid. 1525 73

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.
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PMID:Hemodynamic and hormonal actions of adrenomedullin. 1527 27

Increased plasma levels of adrenomedullin (ADM) have been reported in patients with congestive heart failure Immunohistochemical ADM has been identified in failing human ventricle, but the gene expression pattern of ADM messenger RNA (mRNA) in myocardial tissue of patients with heart failure has not been elucidated. In this study, gene expression of ADM mRNA (analyzed by northern blot) and tissue concentration of ADM (measured by radioimmunoassay) were assessed in the explanted hearts of 17 patients with idiopathic dilated cardiomyopathy (IDC) and in 7 organ donors with no cardiopathy (controls). Myocardial tissue samples of patients with IDC showed increased ADM mRNA gene expression (p < 0.05) and decreased immunoreactive ADM protein content (p < 0.02) compared with controls.
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PMID:Adrenomedullin messenger RNA expression is increased in myocardial tissue of patients with idiopathic dilated cardiomyopathy. 1553 29

The purpose of this study was to investigate the relationship between plasma adrenomedullin concentration levels and left-ventricular systolic function in patients with acute myocardial infarction (AMI), and to assess whether these findings can be used to predict clinical outcomes, including mortality. One hundred twenty-four consecutive first AMI attack subjects were successfully reperfused with primary percutaneous coronary intervention therapy. Plasma adrenomedullin concentrations were evaluated at 24 hours from onset. Left ventriculograms of all patients taken in the acute (soon after reperfusion therapy) and subacute (21 +/-9 days after onset) phases were used to evaluate left-ventricular ejection fraction (LVEF), and the difference in LVEF (delta-LVEF) between the two stages calculated. There were significantly more patients with cardiogenic shock in the H-Adm group (above the median value of plasma adrenomedullin concentrations > or =3.5 Fmol/mL) than in the L-Adm (< 3.5 Fmol/mL) group (p<0.0001). There was significantly higher mortality in the H-Adm group (p<0.01). Multivariate analysis identified plasma adrenomedullin concentrations alone as an independent predictor of mortality (p<0.05). There were no significant differences in acute-stage LVEF between the groups. LVEF in the subacute stage was, however, significantly lower in the H-Adm group than in the L-Adm group (52 +/-12% vs 59 +/-11%, p<0.05). Also, delta-LVEF was significantly lower in the H-Adm group than in the L-Adm group (1.9 +/-9.7% vs 6.3 +/-10.3%, p<0.01). Plasma adrenomedullin concentrations in the early phase of AMI correlate closely with the severity of heart failure, and may offer important prognostic information about the risk of mortality. Our data suggest that plasma adrenomedullin concentrations may be an independent predictor of the deterioration of left-ventricular systolic function.
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PMID:Relationship between adrenomedullin and left-ventricular systolic function and mortality in acute myocardial infarction. 1567 54

Diuretics, ACE inhibitors and betablockers form the cornerstone of pharmacological treatment of chronic heart failure (CHF), while angiotensin receptor blockers are gaining ground. However, despite optimal treatment CHF remains a syndrome with poor prognosis. For this reason, a large number of new agents have been developed as add-on treatment over the last few years. Vasopeptidase inhibitors, moxonidine, endothelin antagonists, vasopressin antagonists, and selective aldosterone antagonists, are some of the new agents that were designed to interfere with different neurohormonal pathways. Immunomodulating agents, growth hormone, caspase inhibitors, adrenomedullin, and erythropoietin have different modes of action, which in general are less understood. Although most of the agents exhibited efficacy in preclinical trials, the clinical results have not always been similarly positive. The results of trials involving vasopeptidase inhibitors, endothelin antagonists, immunomodulating agents, and growth hormone have been disappointing. Other compounds like caspase inhibitors, adrenomedullin, and vasopressin antagonists are still at the early stages of development. Currently, the two most promising agents seem to be erythropoietin and the selective aldosterone receptor blocker eplerenone. In the present article an overview of new pharmacological developments for CHF is given, and the clinical value of these developments is discussed.
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PMID:New pharmacological strategies in chronic heart failure. 1577 Apr 37


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