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)

Amiodarone, a complex compound with variegated electropharmacologic and pharmacokinetic properties and an equally complex side-effect profile, continues to have a critical role in the control of ventricular and supraventricular tachyarrhythmias as the use of class I agents has declined. Such is also the case with sotalol. Unlike other so-called class III agents, amiodarone non-competitively blocks sympathetic stimulation, and its effects on repolarization are not associated with reverse use dependency. Rarely does it produce torsades de pointes despite its propensity to induce significant bradycardia and marked prolongation of the QT interval. During long-term therapy with the drug, there is no impairment of ventricular function; in fact, there are significant increases in the left ventricular ejection fraction during protracted amiodarone therapy in patients with heart failure. Long-term amiodarone administration consistently demonstrates marked efficacy in a wide spectrum of arrhythmias. The major limitation of amiodarone during long-term therapy is its unusual side-effect profile, although the increasing trend for low-dose drug therapy has demonstrated a major decline in the overall incidence of serious adverse reactions. Amiodarone is effective in controlling symptomatic ventricular tachycardia and fibrillation (VT/VF) in > 60-70% of patients when conventional agents (especially class I) are ineffective or not well tolerated. The efficacy of amiodarone compared with that of an implantable cardioverter-defibrillator in patients with VT/VF and in survivors of cardiac arrest remains uncertain when total mortality is used as the primary endpoint of comparison. Amiodarone suppresses ventricular ectopy and markedly suppresses nonsustained VT. It prevents inducible VT/VF in a small number of patients, but slows VT rate in a larger number. The role of the drug in prolonging survival in the postmyocardial infarction patient is unclear, although preliminary data from blinded studies suggest that the drug decreases arrhythmia-related mortality. Similarly, in heart failure, amiodarone has the potential to reduce total mortality but appears to be selectively effective in nonischemic rather than in ischemic cardiomyopathy. Intravenous amiodarone was recently introduced in the United States for the control of recurrent destabilizing VT or VF resistant to conventional therapy. There is also evolving data indicating that the drug might be the most potent agent in maintaining sinus rhythm in patients with atrial fibrillation or flutter converted chemically or electrically to sinus rhythm. However, blinded controlled comparative studies involving sotalol, quinidine, or pure class III drugs have not been carried out. The available data nevertheless suggest that, barring its side-effect profile, amiodarone is a desirable prototype of a broad-spectrum antifibrillatory and antiarrhythmic compound.
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PMID:Antiarrhythmic actions of amiodarone: a profile of a paradoxical agent. 878 Mar 28

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

Myocardial failure has been considered to be an irreversible and progressive process characterized by ventricular enlargement, chamber geometric alterations, and diminished pump performance. However, more recent evidence has suggested that certain types of medical therapy may lead to retardation and even reversal of the cardiomyopathic process. In the failing heart, long-term neurohormonal/autocrine-paracrine activation results in abnormalities in myocyte growth, energy production and utilization, calcium flux, and receptor regulation that produce a progressively dysfunctional, mechanically inefficient heart. Interventions such as ACE inhibition and beta-blockade result in a reduction in the harmful long-term consequences of neurohormonal/autocrine-paracrine effects and retard the progression of left ventricular dysfunction or ventricular remodeling. Furthermore, in subjects with idiopathic dilated or ischemic cardiomyopathy, antiadrenergic therapy with beta-blocking agents appears to be able to partially reverse systolic dysfunction and ventricular remodeling. Although the precise mechanisms underlying this latter effect have not yet been elucidated, the general mechanism appears to be via improvement in the biological function of the cardiac myocyte. Such an improvement in the intrinsic defect(s) responsible for myocardial failure will likely translate into important clinical benefits.
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PMID:Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. 890 84

To examine the relationship between age and outcome after implantable left ventricular assist system support, the authors investigated the results of 223 patients from 17 centers who were supported with a HeartMate (Thermo Cardiosystems, Inc., Woburn, MA) pneumatic left ventricular assist system between 1986 and 1994. In addition, the authors examined a single center's experience with 67 patients between 1992 and 1996. Ages are separated by decile and ranged from 10 to 69 years. Men dominated all age groups, averaging 82% of the total (range, 64-91%). Viral, idiopathic, and post partum cardiomyopathies were the indication for support in 88% of the patients younger than 39 years of age. Ischemic cardiomyopathy was the cause of myocardial failure in the majority of patients older than 40 years of age (40-49 years, 54%; 50-59 years, 57%; and 60-69 years, 67%). Patients aged 40-59 accounted for 64% of the patients supported, and had the best outcomes both on support and after transplantation. Survival to transplantation was not significantly different among the groups, although the patients older than 60 and younger than 69 years of age had higher mortalities on support, most commonly from cardiac failure. At the Cleveland Clinic Foundation, the survival to transplantation and survival to discharge were indistinguishable between age groups. Age does not appear to be significant risk factor for outcome after implantable left ventricular assist system support. These results predict acceptable mortality for patients supported who are older than the age of 60.
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PMID:Age related outcome after implantable left ventricular assist system support. 894 44

The elevated plasma norepinephrine concentrations closely correlate to the poor prognosis in heart failure. Inhibition of myocardial norepinephrine effects on the heart by beta-blocker treatment are reported to improve left ventricular ejection fraction and to a lesser extent exercise tolerance. The mechanisms are a restoration of beta-adrenergic signal transduction, an increase of contractile reserve and a protection from toxic catecholamine effects. Bradycardic effects improve energetic situation of the failing heart and directly reduce neuroendocrine activation (plasma norepinephrine concentrations, renin activity). Randomized studies have shown a good clinical effectiveness with carvedilol, metoprolol, bucindolol, and bisoprolol in combination with cardiac glycosides, diuretics and ACE inhibitors. Improvement of survival has been shown for carvedilol and bisoprolol and possibly for metoprolol in dilated cardiomyopathy. In ischemic cardiomyopathy, carvedilol appears to be effective to improve prognosis. Therapy has to be started at very low concentrations of the beta-blocker and the patients must be followed up closely. The beta-blocker therapy is evidenced on pathophysiological research findings and could prove to be useful as additional component of the standard therapy of heart failure when the issue of improvement of survival is solved by future studies.
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PMID:[Therapy of chronic heart failure with beta-receptor blockers]. 908 79

Heart failure secondary to ischemic cardiomyopathy is the primary cause of cardiovascular mortality. The promise of the collateral circulation lies in its potential to alter the course of the natural history of coronary heart disease. The collateral circulation of the heart is responsible for supplying blood and oxygen to the myocardium at ischemic risk following severe stenosis and reduced vasoelasticity function of a major coronary artery. In response to flow, stress, and pressure, collateral vessels are restructured and remodeled. Vascular remodeling by its very nature implies synthesis and degradation of extracellular matrix components in the vessel wall. Under normal physiological conditions proteinases that break down the specialized matrix are tightly regulated by antiproteinases. The balance between proteinase and antiproteinase influences is discoordinated during collateral development which leads to adaptive changes in the structure, function, and regulation of extracellular matrix components in the vessel wall. The role of extracellular matrix components in coronary collateral vessel formation in a canine model of chronic coronary artery occlusion has been demonstrated. The role of matrix proteinases and antiproteinases in the collateral vessel play a significant role in the underlying mechanisms of collateral development. This review presents new and significant information regarding the role of extracellular matrix proteinases and antiproteinases in vascular remodeling, function, and collateral development. Such information will have a significant impact on the understanding of the basic biology of the vascular extracellular matrix turnover, remodeling, and function as well as on elucidating potential avenues for pharmacological approaches designed to increase collateral formation and optimize myocardial blood flow in the treatment of ischemic heart disease.
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PMID:Vasculogenesis and angiogenesis: extracellular matrix remodeling in coronary collateral arteries and the ischemic heart. 913 94

Thirty-four patients with idiopathic dilated and ischemic cardiomyopathy underwent a symptom-limited cardiopulmonary exercise testing to evaluate the significance of postexercise blood pressure (BP) response. The postexercise BP response was useful in assessing the impaired exercise capacity and increased sympathetic activity in patients with heart failure.
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PMID:Delayed recovery of postexercise blood pressure in patients with chronic heart failure. 920 71

There is accumulating evidence that disturbed calcium homeostasis may play a key role in the pathophysiology of human heart failure. Because disturbed calcium handling could result from altered protein expression, levels of calcium handling proteins were quantitated by Western Blot analysis in failing and nonfailing human myocardium from hearts with endstage failing dilated or ischemic cardiomyopathy. Protein levels of the sarcoplasmic reticulum calcium release channel (ryanodine receptor) and of calcium storage proteins (calsequestrin and calreticulin) were similar in failing and nonfailing human myocardium. However, proteins involved in calcium removal from the cytosol were significantly altered in the failing human heart: 1) SR-Ca(2+)-ATPase, relevant for removal of calcium from the cytosol into the lumen of the sarcoplasmic reticulum, was decreased; 2) phospholamban, which inhibits the SR-Ca(2+)-ATPase in the basal unphosphorylated state, was slightly decreased; 3) the ratio of SR-Ca(2+)-ATPase to phospholamban was decreased; 4) the sarcolemmal Na(+)-Ca(2+)-exchanger, relevant for transsarcolemmal calcium extrusion was increased in the failing hearts. In summary, altered levels of proteins involved in calcium removal from the cytosol suggest an increase in transsarcolemmal calcium elimination relative to sarcoplasmic reticulum calcium removal. These findings support the concept that reduced function of the sarcoplasmic reticulum to accumulate calcium may reflect a major defect in excitation-contraction coupling in human heart failure.
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PMID:Calcium handling proteins in the failing human heart. 920 48

Experiments were performed to determine the relative contributions of direct Ca(2+)-entry through the L-type Ca(2+)-current and of Ca(2+)-release from the sarcoplasmic reticulum (s.r.) to the intracellular [Ca2+]i-transient in isolated human atrial and ventricular myocytes from patients with severe heart failure and from non-failing controls. Cells were isolated from explanted hearts of patients undergoing transplantation because of severe heart failure due to dilated or ischemic cardiomyopathy or from donor hearts which could not be transplanted for technical reasons. Ca(2+)-current densities were -2.1 +/- 0.6 pA/pF in atrial cells, -4.8 +/- 0.5 pA/pF in cells from patients with heart failure and -3.2 +/- 0.5 pA/pF in non-failing controls. [Ca2+]i-transients were significantly smaller in heart failure (370 +/- 33 nM) compared to ventricular cells from non-failing hearts (760 +/- 69 nM, p < 0.05). Atrial myocytes had average [Ca2+]i-transients of 505 +/- 38 nM. After incubation in ryanodine the average [Ca2+]i-transients were not significantly different between different cell types. The results indicate that the relative contribution of Ca(2+) released from the sarcoplasmic reticulum to the [Ca2+]i-transient is significantly smaller in heart failure. The absolute contribution of the L-type Ca(2+)-current to the transient seemed to be comparable in all cell types investigated. As the [Ca2+]i-transient in the presence of ryanodine was comparable in size in all cells, changes of the intracellular [Ca2+]i-transient in heart failure are mainly due to alterations of s.r. function in these cells.
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PMID:Contributions of Ca(2+)-influx via the L-type Ca(2+)-current and Ca(2+)-release from the sarcoplasmic reticulum to [Ca2+]i-transients in human myocytes. 920 50

To determine the cardiovascular protective effects of angiotensin-converting enzyme inhibitors, we examined the response to intensive vasodilator therapy in patients with ischemic cardiomyopathy and ongoing angina pectoris. We found that for patients with ischemic cardiomyopathy and ongoing active angina, intensive vasodilator therapy with angiotensin-converting enzyme inhibition and nitrates improved not only heart failure-related symptoms, but also resulted in a significant improvement in symptomatic ischemia and ischemia-related morbid events.
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PMID:Response of symptomatic myocardial ischemia in ischemic cardiomyopathy to intensive vasodilator therapy. 923 Jan 64


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