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

End-stage human heart failure is the common final manifestation of a group of heterogeneous diseases, and it is usually accompanied by myocardial hypertrophy. Studies on animal models have shown that myocardial hypertrophy is an adaptational process accompanied by characteristic changes in the expression of cardiac genes: reinduction of fetal isoforms of the myofilaments actin and myosin, downregulation of SR Ca(2+)-ATPase and phospholamban, downregulation of beta-adrenoceptors and increased expression of inhibitory G proteins (Gi). These alterations lead to reduced shortening velocity, slowed relaxation, and to desensitization of adenylyl cyclase, thereby probably increasing myocardial economy and lowering energy demand. Gene expression in human end-stage heart failure due to dilated cardiomyopathy exhibits some clear differences, but also significant parallels to gene expression in experimental hypertrophy: there is no isoform shift because fetal isoforms of the myofilaments are already predominant in the adult ventricle. However, like in animal models expression of SR Ca(2+)-ATPase and phospholamban is decreased, correlating with slowed relaxation of the diseased myocardium, beta-adrenoceptors are downregulated, and the expression of Gi is increased, leading to desensitization of the adenylyl cyclase pathway. These results suggest that alterations of gene expression in human end-stage myocardial failure, known so far, are secondary to chronic overload and are not a primary cause in the pathogenetic process. They are probably initially favorable adaptive processes to chronic overload, but finally cause a further deterioration of contractile performance of the myocardium.
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PMID:[Changes in gene expression in terminal myocardial failure]. 129 Mar 4

Studies in animal models have suggested that alterations affecting phospholamban-mediated stimulation of Ca2+ uptake by sarcoplasmic reticulum are involved in the pathophysiology of heart disease. A monoclonal antibody that binds to phospholamban and stimulates Ca2+ uptake was used to characterize phospholamban-mediated effects in human cardiac sarcoplasmic reticulum and to compare these effects in tissue from normal and failing hearts. Stimulation of Ca2+ uptake by anti-phospholamban monoclonal antibody simulated the effect of phosphorylation of phospholamban by cAMP-dependent protein kinase. Binding of anti-phospholamban antibody reduced the K0.5 of the Ca2(+)-transporting ATPase from 0.53 microM [( Ca2+]) to 0.29 microM [( Ca2+]), without affecting Vmax or nHill. At 0.2 microM Ca2+, stimulation was 1.93-fold in sarcoplasmic reticulum prepared from normal human left ventricular myocardium and 1.94-fold in sarcoplasmic reticulum prepared from the left ventricular myocardium of patients with heart failure resulting from idiopathic dilated cardiomyopathy. Stimulation of Ca2+ uptake in canine cardiac sarcoplasmic reticulum under identical conditions was 1.89-fold. Phospholamban-mediated stimulation of Ca2+ uptake in human cardiac sarcoplasmic reticulum is thus comparable in magnitude to that observed in other species and results from an increase in the apparent affinity of the Ca2(+)-transporting ATPase for Ca2+. The pathogenesis of heart failure in idiopathic dilated cardiomyopathy does not, however, appear to involve intrinsic alterations of this mechanism.
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PMID:Phospholamban-mediated stimulation of Ca2+ uptake in sarcoplasmic reticulum from normal and failing hearts. 213 70

The objective of this study was to elucidate the role of the sarcoplasmic reticulum (SR) in the transition from compensated pressure-overload hypertrophy (increased left ventricular [LV] mass, normal LV function, and no pulmonary congestion) to congestive heart failure (increased LV mass, depressed LV function, and pulmonary congestion). To address this issue, the descending thoracic aorta was banded for 4 and 8 weeks in adult guinea pigs, and the changes in isovolumic LV mechanics, SR Ca2+ transport, and SR protein levels were determined and compared with age-matched sham-operated control animals. A subgroup of the 8-week banded animals manifested the congestive heart failure phenotype with diminished developed LV pressure normalized by LV mass, reduced rates of LV pressure development and relaxation, and markedly increased lung weight-to-body weight ratios. The cardiac mechanical and morphometric changes were associated with depressed protein levels of the SR Ca(2+)-ATPase (85% of the control) and phospholamban (65% of the control) assessed by quantitative immunoblotting. Resultant rates of SR Ca2+ uptake (Vmax) and the affinity of SR Ca(2+)-ATPase for Ca2+ (EC50) were significantly depressed [32 +/- 6 nmol Ca2+.min-1.mg-1 and 0.59 +/- 0.12 (mumol/L)/L, respectively] compared with the 8-week sham-operated control animals [40 +/- 1 nmol Ca2+.min-1.mg-1 and 0.40 +/- 0.05 (mumol/L)/L, respectively]. We conclude that this model of pressure overload-induced cardiac failure is associated with (1) diminished LV force development, rates of pressure development, and decay; (2) depressed protein expression of the Ca(2+)-cycling proteins SR Ca(2+)-ATPase and phospholamban; and (3) decreased Vmax and affinity of the SR Ca(2+)-ATPase for Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure. 755 23

Selective and specific changes in gene expression characterize the end-stage failing heart. However, the pattern and relation of these changes to evolving systolic and diastolic dysfunction during development of heart failure remains undefined. In the present study, we assessed steady-state levels of mRNAs encoding a group of cardiac proteins during the early development of left ventricular dysfunction in dogs with pacing-induced cardiomyopathy. Corresponding hemodynamic assessments were made in the conscious state in the same animals and at the same time points at baseline, after 1 week of ventricular pacing, and at the onset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was undetectable in 7 of 12 hearts at baseline but was expressed in all hearts at 1 week (P < .01 by chi 2 test), and it increased markedly with progression to failure (P = .05). Creatine kinase-B mRNA also rose markedly with heart failure (P < .01). Levels of mRNA encoding beta-myosin heavy chain, mitochondrial creatine kinase, phospholamban, and sarcoplasmic reticulum Ca(2+)-ATPase did not significantly change from baseline, despite development of heart failure. Additional analysis to determine if these mRNA changes were related to the severity of diastolic or systolic dysfunction revealed that phospholamban mRNA decreased in hearts with larger net increases in end-diastolic pressure (+19.2 +/- 1.9 mm Hg) compared with those hearts in which it did not change (+4.0 +/- 4.9, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endomyocardial gene expression during development of pacing tachycardia-induced heart failure in the dog. 792 7

Several important questions remain to be answered by future research. First, it is unclear whether any abnormal index of diastolic function can be used to estimate disease severity, or to prognostically identify patients who will subsequently develop systolic abnormalities or frank left ventricular dysfunction. A temporal relationship between the appearance of diastolic dysfunction and ultimate left ventricular decompensation may, theoretically, exist, but such a relationship has yet to be established. Second, a growing body of evidence indicates that pharmacologic therapy with Ca2+ channel antagonists, beta-adrenergic agonists or antagonists, phosphodiesterase inhibitors, or angiotensin converting enzyme inhibitors may acutely or chronically benefit certain patients with diastolic dysfunction. Whether the impact of early recognition and therapeutic intervention in patients with diastolic dysfunction can be translated into an improvement of quality of life or enhanced survival remains unknown. Third, recent evidence indicates that fundamental changes in the biochemistry of the cardiac myocyte may represent a final common pathway for the development of congestive heart failure resulting from intrinsic cardiac disease. Altered expression of genes coding for the ATP-dependent Ca2+ pumps in the sarcolemma and the sarcoplasmic reticulum, regulatory proteins such as phospholamban, and the proteins composing the contractile apparatus have been identified that play critical roles in the pathophysiology of myocardial failure, and have important implications for potential pharmacologic therapy. Future research will more clearly elucidate these cellular and biochemical mechanisms of left ventricular failure. Lastly, although intravenous and inhalational anesthetics produce derangements in normal diastolic function to varying degrees, whether the effects of these agents on diastolic performance are exacerbated in disease processes manifested by abnormal diastolic mechanisms requires further evaluation.
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PMID:Left ventricular diastolic function in the normal and diseased heart. Perspectives for the anesthesiologist (2). 823 87

Recent studies have shown that intracellular Ca2+ handling is abnormal in the myocardium of patients with end-stage heart failure. Muscles from the failing hearts showed a prolonged Ca2+ transient and a diminished capacity to restore a low resting Ca2+ level during diastole. Accordingly, we examined whether this defect in Ca2+ transport function is due to alterations in sarcoplasmic reticulum gene expression. We determined the messenger RNA (mRNA) levels of sarcoplasmic reticulum Ca2+ transport proteins in failing human hearts from 17 cardiac transplant recipients with a diagnosis of dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The expression levels of each mRNA were compared with each other and then correlated with that of atrial natriuretic factor (ANF) mRNA in the failing ventricle. The mRNA levels for the calcium release channel (ryanodine receptor, RYR2), Ca2+ uptake pump (Ca(2+)-ATPase, SERCA2 isoform), and phospholamban differed significantly between heart samples but showed an inverse relation with that of ventricular ANF mRNA. In contrast, calsequestrin mRNA levels remained unchanged in these failing hearts. In addition, beta-myosin and alpha-cardiac actin mRNA levels also showed an inverse relation with ANF mRNA levels. These changes were observed in both right and left ventricles of hearts with congestive heart failure due to dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The results are consistent with the hypothesis that abnormal calcium handling in the sarcoplasmic reticulum of failing hearts is due to the altered expression of the genes encoding sarcoplasmic reticulum proteins.
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PMID:Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. 841 95

In end-stage heart failure the expression of different myocardial regulatory proteins involved in the beta-adrenergic cAMP signalling pathway is altered. The downregulation of beta 1-adrenoceptors and their uncoupling from the effector as well as an increased expression of the inhibitory GTP-binding protein seem to be the most important alterations. Since catecholamine levels are elevated in these patients and since some alterations can be 'restored' after treatment with beta-adrenoceptor antagonists it was hypothesized that excessive beta-adrenergic stimulation could be involved in these alterations. In this article the changes of beta-adrenergic receptors, GTP-binding proteins, sarcoplasmic reticulum Ca(2+)-ATPase and of phospholamban found in heart failure are addressed with its possible therapeutic implications.
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PMID:Adrenergic and muscarinic receptor regulation and therapeutic implications in heart failure. 873 55

Congestive heart failure is the final common pathway of diverse etiologies that result in impaired systolic and diastolic function, deleterious activation of neurohumoral pathways, and high morbidity and mortality. Many studies published in 1995 significantly added to our understanding of the pathophysiologies of heart failure at the cellular level. Because a common accompaniment to all forms of low output heart failure are hypertrophy and contractile dysfunction of the cardiomyocyte, applications of the techniques of molecular and cell biology to animal models that demonstrate this phenomenon are providing new insights into the mechanisms responsible for this important clinical problem. In the past year, critical information was derived from animal models that mimic human cardiac hypertrophy and failure. Likewise, genetically engineered mice in which a gene product of interest is overexpressed or eliminated provided critical information, in particular regarding the roles of phospholamban and beta-adrenergic receptor kinase 1 in mediating the contractile responses of the heart to beta-adrenergic stimulation. Furthermore, study of human myocardial tissue from patients with end-stage cardiomyopathy continues to provide insight into the diverse etiologies of heart failure. The recent applications of the techniques of molecular and cell biology to this clinical problem are likely to accelerate our understanding of the complex mechanisms responsible for this syndrome.
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PMID:The cellular pathophysiology of progression to heart failure. 883 65

Pressure overload on the heart is known to produce hypertrophy of cardiomyocytes and distinct changes in protein phenotype, including reduced expression of the gene for the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA2). In this study we have shown that the decrease in SERCA2 gene expression (normalized by poly(A)+ mRNA or 18 S rRNA) in rats with 8 wk of aortic constriction was prevented by treatment with etomoxir, an inhibitor of carnitine palmitoyltransferase 1. The reduction in steady-state mRNA levels for SR phospholamban (PLP) and Ca2+ release channel (CRC) in the pressure-overloaded animals was also prevented without any reduction in the extent of cardiac hypertrophy by treatment with etomoxir. Although no changes in mRNA levels for GAPDH were evident in rats with pressure overload, the expression of the alpha-skeletal actin was increased; this change was prevented by etomoxir. Similar beneficial effects of etomoxir treatment were also evident when the gene expression for SR SERCA2, PLP, and CRC in the hypertrophied heart was normalized with respect to mRNA for GAPDH. These results support the view that drugs such as etomoxir may increase the abundance of the mRNA for SR proteins in the hypertrophied heart and thus may prevent the transition of cardiac hypertrophy into heart failure.
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PMID:Modification of sarcoplasmic reticulum gene expression in pressure overload cardiac hypertrophy by etomoxir. 883 44

Abnormalities in intracellular Ca2+ handling play a crucial role in the pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has been explained by the impairment of Ca2+ uptake into the sarcoplasmic reticulum (SR) via the SR Ca2+ATPase. It is unclear whether Ca2+ATPase function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The present study examined SR Ca2+ATPase activity and both mRNA and protein levels of SR Ca2+ATPase, phospholamban, and Gi alpha 2 in left ventricular myocardium from eight nonfailing hearts, from eight hearts of patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to nonfailing myocardium, the activity of the SR Ca2+ATPase was significantly reduced in failing myocardium from patients with DCM (36%, P < 0.01) and from patients with ICM (37%, P < 0.001). Significantly lower levels of SR Ca2+ATPase mRNA levels (55% and -56%, P < 0.001 for DCM and ICM, respectively) and phospholamban mRNA (45%, P < 0.001 for DCM; 31%, P < 0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of proteins, Gi alpha 2 mRNA and protein levels were both significantly increased in failing myocardium. There were no differences between idiopathic dilated and ischemic cardiomyopathy concerning the examined parameter. It is concluded that reduced SR Ca2+ATPase activity contributes to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca2+ATPase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels provides evidence for a posttranscriptional or post-translational regulation of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.
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PMID:Sarcoplasmic reticulum Ca2+ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy. 886 13


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