Is Depressed Myocyte Contractility Centrally Involved in Heart Failure?

Abstract

Abstract-This review examines the evidence for and against the hypothesis that abnormalities in cardiac contractility initiate the heart failure syndrome and drive its progression. There is substantial evidence that the contractility of failing human hearts is depressed and that abnormalities of basal Ca 2ϩ regulation and adrenergic regulation of Ca 2ϩ signaling are responsible. The cellular and molecular defects that cause depressed myocyte contractility are not well established but seem to culminate in abnormal sarcoplasmic reticulum uptake, storage, and release. There are also strong links between Ca 2ϩ regulation, Ca 2ϩ signaling pathways, hypertrophy, and heart failure that need to be more clearly delineated. There is not substantial direct evidence for a causative role for depressed contractility in the initiation and progression of human heart failure, and some studies show that heart failure can occur without depressed myocyte contractility. Stronger support for a causal role for depressed contractility in the initiation of heart failure comes from animal studies where maintaining or improving contractility can prevent heart failure. Recent clinical studies in humans also support the idea that beneficial heart failure treatments, such as ␤-adrenergic antagonists, involve improved contractility. Current or previously used heart failure treatments that increase contractility, primarily by increasing cAMP, have generally increased mortality. Novel heart failure therapies that increase or maintain contractility or adrenergic signaling by selectively modulating specific molecules have produced promising results in animal experiments. How to reliably implement these potentially beneficial inotropic therapies in humans without introducing negative side effects is the major unanswered question in this field.

Critical Evaluation of Cardiac Ca2+-ATPase Phosphorylation on Serine 38 Using a Phosphorylation Site-specific Antibody

“…Taken together, the data of Figs. 4 and 5B demonstrate that CaMKII was active (Fig. 4D), that the immunodetection of the Ser-38 phosphoepitope was performed with high sensitivity (Figs.…”

Excitation-contraction coupling and mitochondrial energetics

“…In chronic heart failure, contractile dysfunction is related to structural remodeling of the left ventricle and significant defects in EC coupling [13,84,94]. A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122].…”

“…A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122]. These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184], lead to a smaller and more dyssynchronous SR Ca 2+ release during an AP, resulting in slower rates of increase and decay of [Ca 2+ ] c , but higher diastolic [Ca 2+ ] c compared to normal cardiac myocytes [17,81,113,115,146,184].…”

“…During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212]. In this context, the elevation of [Na + ] i in cardiac failure and hypertrophy may be regarded as a beneficial and compensatory mechanism [94]. On the other hand, cariporide, an inhibitor of the NHE, reduced [Na + ] i and improved cytosolic Ca 2+ handling [5] and LV remodeling [6] in a rabbit heart failure model.…”

Targeting S100A1 in heart failure

“…3 In an attempt to maintain the necessary blood pressure for organ perfusion, chronic activation of autonomous regulatory mechanisms initiate a vicious cycle of maladaptive structural and functional events that progressively affects all parts of the cardiovascular system. 4,5 Commonly used drugs combating this process tend to attenuate the neurohormonal overactivation, however, by virtue of their mechanism, act enforcedly symptombased, and slow down disease progression only. 6,7 However, steady improvement of our understanding of cellular and molecular processes that contribute to HF pathogenesis prompts continuous development of innovative experimental therapeutic strategies.…”