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

Alterations in the expression of myocardial regulatory proteins (e.g. beta-adrenoceptor, inhibitory G-proteins) in human heart failure are associated with excessive stimulation of the cAMP signalling pathway by endogenous catecholamines. The transcription factor cAMP response element binding protein (CREB) mediates cAMP-dependent transcriptional activation and is expressed in the human heart. Here, CREB protein was immunologically quantified in ventricular nuclear protein preparations from nonfailing donor hearts (n = 8) and from failing hearts transplanted due to dilative (n = 10) or ischemic cardiomyopathy (n = 6). CREB expression was unchanged in ventricular nuclei from failing hearts compared to the nonfailing controls suggesting that expressional alterations in human heart failure cannot be explained by altered expression of CREB.
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PMID:Quantification of the cAMP response element binding protein in ventricular nuclear protein from failing and nonfailing human hearts. 924 Apr 39

Heart failure is a problem of increasing importance in medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor down regulation) and impaired receptor function (receptor uncoupling). These changes in the beta-adrenergic receptor (beta-AR) system, may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by G-protein coupled beta-adrenergic receptors through the action of the second messenger cAMP. The beta-AR receptors themselves are regulated by a set of specific kinases, termed the G-protein-coupled receptor kinases (GRKs). The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted ("knockout") mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.
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PMID:Uncoupling of G-protein coupled receptors in vivo: insights from transgenic mice. 933 Jul 19

Until recently, clinical management of congestive heart failure was purely palliative. The drugs used in patients with failing hearts--digoxin, vasodilators, and positive inotropic agents--improved contractility, reversed hemodynamic abnormalities, and enhanced functional status, but they failed to confer a survival benefit. Indeed, the use of inotropic agents often resulted in excess mortality--a paradox explained in part by the pharmacological properties of these agents, which increase production of cAMP, the intracellular messenger for the beta-adrenergic system. The short-term pharmacological benefits of these drugs may be offset by deleterious long-term biological effects on the heart muscle itself. The use of beta-blockers in heart failure is counterintuitive, given that their initial pharmacological effect is to reduce heart rate and contractility in a faltering heart, thus producing an effect diametrically opposed to that of inotropic agents. However, it is becoming more clear that beta-blocker therapy in patients with heart failure not only improves left ventricular function, but may actually reverse pathological remodeling in the heart. Accumulating clinical evidence indicates that these beneficial changes are the result of secondary biological changes in the myocardium rather than a response to the pharmacological effects of the drugs themselves. Mounting evidence suggest that these agents may prolong survival in patients with heart failure, and ongoing clinical trials may soon confirm these preliminary findings.
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PMID:Restoring function in failing hearts: the effects of beta blockers. 952 36

The progression of heart failure is related to activation of neuroendocrine hormone systems. On the level of the myocardium, they contribute to hypertrophy, dilation and remodeling of the ventricles. In addition, vascular alterations with endothelial dysfunction and alterations of skeletal muscle contribute to clinical symptoms of heart failure patients. Changes in ventricular geometry during the progression of cardiac diseases are associated with specific subcellular alterations on the level of the myocytes. Especially, disturbed intracellular Ca2+ handling resulting in altered excitation contraction coupling may lead to impaired systolic and diastolic function. Disturbed Ca2+ homeostasis has been associated with reduced re-uptake capacity of the sarcoplasmic reticulum for Ca2+ and an enhanced activity of the sarcolemmal Na+/Ca2+ exchange. In consequence, alterations in force-frequency behavior were attributed to a decline in intracellular Ca2+ transients at higher stimulation rates. The reduced expression of myocardial beta-adrenoceptors and alterations on the level of the G-proteins result in a reduced activity of adenylate cyclase and reduction in intracellular cAMP content of the myocytes. In consequence, reduced phosphorylation of intracellular functional proteins in the failing human heart contributes to altered Ca2+ handling. The Frank-Starling-mechanism seems to be unaltered in failing isolated human myocardium. Endothelin and angiotensin may contribute to the regulation of myocardial contractility in the human heart, but their functional relevance in the regulation of myocardial contractility under clinical conditions remains to be evaluated.
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PMID:[New aspects of the pathophysiology of heart failure]. 965 96

Plasma vasopressin (AVP) levels are often elevated in congestive heart failure (CHF). To determine the significance of AVP in CHF, we performed clearance studies on the UM-X7.1 strain of cardiomyopathic (CM) hamsters with moderate heart failure and age-matched healthy controls. Exogenous AVP or a selective V2 agonist (0.3 ng.kg-1. min-1) reduced the fractional excretion of sodium (FENa) and water (FEH2O) by 40-46% in the control group. Although the CM hamsters exhibited a blunted physiological response to the V2 agonist, their urinary cAMP levels were fivefold that of normal and reflect an altered regulation of V2 receptor signalling during CHF. Additional studies also showed that infusion of a V2 antagonist (0.3 ng.kg-1. min-1) produced natriuresis and diuresis in CM hamsters (FENa: 7.9 +/- 1.1 vs. 4.8 +/- 0.6%, p < 0.05; FEH2O: 2.2 +/- 3 vs. 1.5 +/- 0. 2%, p < 0.05) but did not decrease fluid reabsorption in the normal hamsters. In conclusion, the attenuated renal response to exogenous AVP in CM hamsters may be attributed to an enhanced endogenous AVP response during CHF.
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PMID:Renal hypersensitivity to vasopressin in congestive heart failure. 969 66

In end-stage human heart failure, excessive beta-adrenergic stimulation of the cAMP-dependent signaling pathway due to enhanced endogenous catecholamines is hypothesized to contribute to expressional alterations of myocardial regulatory proteins. The cAMP response element modulator (CREM) regulates the transcription of cAMP-responsive genes and might be involved in the regulation of cardiac gene expression. Using the reverse transcription polymerase chain reaction, we identified a novel CREM mRNA, CREM-Ib deltaC-X, in the human heart. Overexpression of CREM-Ib deltaC-X decreased cAMP response element (CRE) -mediated gene transcription in HIT-T15 cells, and this activity was assigned to the part of the sequence encoding putative internally translated proteins. Two of three possible internally translated proteins were immunologically identified in cells overexpressing CREM-Ib deltaC-X tagged with the hemagglutinin epitope of the influenza virus. Both proteins were expressed in bacteria and showed CRE-specific DNA binding, formation of heterodimers with the cAMP response element binding protein (CREB), and inhibition of CREB's binding to the CRE. CREM expression was detected on the mRNA and protein levels in the human heart. We conclude that CREM-Ib deltaC-X generates internally translated repressors of CRE-mediated gene transcription, suggesting the first example for the existence and function of human cardiac CREM.
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PMID:Identification and expression of a novel isoform of cAMP response element modulator in the human heart. 973 22

"Adrenomedullin (AM)" is a novel hypotensive peptide discovered in human pheochromocytoma by monitoring the elevating activity of platelet cAMP. It has potent and long-lasting vasodilator effects in several vascular systems. In addition, a novel 20-residue hypotensive peptide, termed "proadrenomedullin N-terminal 20 peptide" (PAMP), is processed from proadrenomedullin. Although initially isolated from human pheochromocytoma tissue and porcine adrenal medullae, AM mRNA is highly expressed in several organs including cardiovascular tissues. Taken together with its widespread distribution and its ability to influence the bioactivity of cells in situ, AM may function as a paracrine or autocrine hormone rather than a classical endocrine system. Furthermore, ubiquitous expression of AM mRNA may indicate its various biological functions as well as the existence of a novel circulation control system. Plasma AM as well as PAMP concentrations significantly increased in various cardiovascular diseases including hypertension, chronic renal failure and cognestive heart failure. The present review summarizes the recent advances in AM research and showed that AM and PAMP are important vasoactive peptides, such investigations should enable the elucidation of the basic physiologic mechanisms of novel circulatory homeostasis.
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PMID:[Adrenomedullin and related peptides]. 979 67

A number of molecular and cellular alterations have been identified in the failing human heart that help to understand contraction and relaxation abnormalities. Cyclic AMP dependent pathways are desensitized due to quantitative changes in beta-adrenoceptors, beta-adrenoceptor kinase, and inhibitory G-proteins. Calcium homeostasis is impaired, characterized by a decreased calcium reuptake rate of the sarcoplasmic reticulum, an increased threshold of the calcium release channel, and an increased Na+/Ca2+ exchanger expression. Myofibrillar function may be affected by a decrease in Mg2(+)-ATPase activity and in troponin I phosphorylation, and by changes in TnT isoform expression. These alterations seem to occur independently of the underlying etiology of heart failure and are most likely consequences rather than primary causes of the disease. Most likely, chronic neurohumoral activation and abnormal mechanical load initiate the majority of the hitherto known changes in the myocardium and promote the further progression of cardiac failure as part of a vicious circle. Further extension of knowledge of pathophysiological mechanisms should improve therapeutical strategies which aim at slowing the progression of heart failure and at reversing secondary alterations by interrupting the deleterious influence of neurohumoral activation. Future progress will depend on answers to current gaps in our knowledge of heart failure, including the unknown primary cause of idiopathic dilated cardiomyopathy, factors underlying the greatly variable progression of pump failure, as well as the exact pathophysiological role of the molecular alterations as described in this review.
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PMID:Cellular and molecular aspects of contractile dysfunction in heart failure. 979 11

Abnormal beta-adrenergic signal transduction and intracellular Ca2+ handling appear to be a major cause of systolic and diastolic dysfunction in humans with heart failure. The precise mechanisms which cause an alteration in Ca2+ handling have been a subject of investigation in recent years. Several lines of evidence suggest that activation of neurohormonal systems plays a central role. Altered Ca2+-handling (increased diastolic concentrations, reduced systolic Ca2+ release) have a strong impact on diastolic and systolic performance of failing hearts. Sarcoplasmic reticulum Ca2+ ATPase is reduced in activity and in steady-state mRNA concentration. The Na+-Ca2+ exchanger is upregulated at the mRNA and protein levels. Phospholamban depends strongly on cAMP-dependent phosphorylation. A strong sympathetic activation has been shown to desensitize the cAMP system. At the receptor level, there is downregulation of beta1-adrenergic receptors. An uncoupling of beta2-adrenoceptors has been attributed to an increased activity and gene expression of beta-adrenergic receptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. Finally, recent evidence suggests that cAMP-dependent transcription mechanisms may play a role during beta-adrenergic stimulation and cardiomyopathy with heart failure - by means of altered actions of cAMP response element binding protein, the cAMP response element modulator, or the activating transcription factor 1. The exact characterization of signal transduction defects could offer novel approaches to the pharmacological treatment of heart failure.
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PMID:Molecular aspects of adrenergic signal transduction in cardiac failure. 982 19

In severe human heart failure, an increase in frequency of stimulations is accompanied by a reduced force of contraction in vivo and in vitro. This contrasts the findings in nonfailing human hearts. To investigate influences of inotropic stimulation on the force-frequency relationship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K(+)-ATPase inhibitor) and BDF 9148 (Na(+)-channel modulator) as well as of the beta-adrenoceptor agonist isoprenaline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally failing human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually declined following an increase in stimulation frequency. Moderate stimulation of contractility by isoprenaline reversed the negative force-frequency relationship in failing myocardium and preserved the positive force-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presence of high concentrations of isoprenaline the former positive force-frequency relationship became negative even in nonfailing myocardium. The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca(2+)-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulum (SR) in failing human myocardium. Therefore, the activity of the SR-Ca(2+)-ATPase (SERCA2) of crude membrane preparations was investigated and was significantly reduced in failing compared to nonfailing human myocardium. It is concluded that the negative force-frequency relationship may be due to alterations in the intracellular Ca(2+)-handling caused by an impaired function of the SERCA2 in failing human myocardium. The beneficial effects of cAMP-increasing agents on the force-frequency relationship in failing human hearts could result from an enhanced phosphorylation status of phospholamban in the presence of beta-adrenoceptor-stimulation. The effect of the [Na+]i-modulating agents BDF 9148 and ouabain demonstrates that the intracellular Na(+)-homeostasis influences intracellular Ca(2+)-handling as well. Differences observed in failing compared to nonfailing myocardium may be due to an altered expression or function of the Na+/Ca(2+)-exchanger, Na(+)-channels or the Na+/K(+)-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.
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PMID:Effect of inotropic interventions on the force-frequency relation in the human heart. 983 34


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