Circulation Research. 2003;92:350-358
doi: 10.1161/01.RES.0000060027.40275.A6
doi: 10.1161/01.RES.0000060027.40275.A6
© 2003 American Heart Association, Inc.
Reviews |
Is Depressed Myocyte Contractility Centrally Involved in Heart Failure?
From the Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pa.
Correspondence to Dr Steven R. Houser, Cardiovascular Research Group, Temple University School of Medicine, 3400 N Broad St, Philadelphia, PA 19140. E-mail srhouser{at}unix.temple.edu
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 Ca2+ regulation and adrenergic regulation of Ca2+ 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 Ca2+ regulation, Ca2+ 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 ß-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.
Key Words: heart failure • Ca2+ regulation • contractility • hypertrophy • adrenergic regulation
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