UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide. 1184 40

Omapatrilat was designed to inhibit simultaneously angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The ubiquitous involvement of the renin-angiotensin-aldosterone system, originally conceived as an axis of sodium and fluid metabolism in inflammation, thrombosis and cardiac and smooth muscle hypertrophy, is a major factor in disease progression for conditions as diverse as hypertension, heart failure, coronary artery disease and diabetes. Interruption of angiotensin II generation and bradykinin degradation by ACE inhibition is a major therapeutic advance in the management of these diseases. NEP metabolizes both bradykinin and the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, c-type natriuretic peptide and adrenomedullin). These peptides counter the adverse effects of angiotensin II by their vasodilator, natriuretic, diuretic and autonomic neural actions; by their antitrophic effects; and by suppressing plasma renin activity. These two systems can be considered key components of a cardiorenal axis that maintains blood pressure and cardiopulmonary blood volume within a stable range. This balance is compromised in the setting of heart failure and primary hypertension. The combination of ACE and NEP inhibition should augment the beneficial hemodynamic and tissue effects of bradykinin and the natriuretic peptides. Vasopeptidase inhibition, therefore, is a novel approach to cardiovascular therapy, with implications for hypertension, heart failure, renal function and ischemic heart disease.
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PMID:Vasopeptidase inhibition: a novel approach to cardiovascular therapy. 1187 87

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.
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PMID:Cessation of pulmonary and coronary secretion of adrenomedullin peptides in the progression of human heart failure. 1197 92

Vasopeptidase inhibitors represent a new class of cardiovascular drugs. They function as a combined angiotensin-converting enzyme (ACE) inhibitor and neutral endopeptidase (NEP) inhibitor, the latter of which potentiates the actions of atrial natriuretic peptide (ANP) by minimizing its degradation in the circulation. The consequence of such dual inhibition is a synergistic reduction of vasoconstriction and enhancement of vasodilation, thereby serving to more effectively reduce blood pressure. Furthermore, inhibition of the renin-angiotensin-aldosterone system (RAAS) prevents physiologic compensatory responses in vivo seen with NEP inhibition alone. Vasopeptidase inhibitors have also shown to potentiate bradykinin and adrenomedullin, which additionally contribute to cardiovascular regulation. The most extensively researched and promising agents within the class of VP inhibitors is omapatrilat, a mercaptoacyl derivative of a bicyclic thiazepinone dipeptide. It is a single molecule with equal potency and affinity for ACE and NEP inhibition. Although ACE inhibition tends to more selectively benefit high-renin models of hypertension, vasopeptidase inhibition has been shown to be equally efficacious in low-, normal-, and high-renin models. Contrary to NEP inhibition alone, omapatrilat has also demonstrated the ability to significantly reduce blood pressure in spontaneously hypertensive rats, the equivalent of essential hypertension in humans. Studies also suggest that omapatrilat has cardioprotective properties, especially in the setting of congestive heart failure. More specifically, animal models have demonstrated omapatrilat to be more effective than ACE inhibition alone in remodeling the heart and improving its contractile function. Human studies have documented the efficacy of omapatrilat in the treatment of both hypertension and, to a lesser extent, heart failure. Safety concerns (specifically angioedema) are currently being addressed before the widespread utilization of this promising new agent.
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PMID:Vasopeptidase inhibitors, neutral endopeptidase inhibitors, and dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. 1197 22

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.
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PMID:Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure. 1205 17

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.
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PMID:Endothelial PAS domain protein 1 (EPAS1) induces adrenomedullin gene expression in cardiac myocytes: role of EPAS1 in an inflammatory response in cardiac myocytes. 1209 9

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.
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PMID:Long-term adrenomedullin administration in experimental heart failure. 1241 60

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.
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PMID:Ventricular adrenomedullin system in the transition from LVH to heart failure in rats. 1262 52

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.
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PMID:Cardioprotective effect of adrenomedullin in heart failure. 1263 Aug 22

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.
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PMID:Adrenomedullin in heart failure. 1263 Aug 24

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