Defective Ca2+ cycling as a key pathogenic mechanism of heart failure

Abstract

Structural and functional alterations in the Ca(2+) regulatory proteins present in the sarcoplasmic reticulum (SR) have recently been shown to play a crucial role in the pathogenesis of heart failure (HF), and lethal arrhythmia as well. Chronic activation of the sympathetic nervous system induces abnormalities in both the function and structure of these proteins. For instance, the diastolic Ca(2+) leak through the SR Ca(2+) release channel (ryanodine receptor) reduces the SR Ca(2+) content, inducing contractile dysfunction. Moreover, the Ca(2+) leak provides a substrate for delayed after depolarization that leads to lethal arrhythmia. There is a considerable body of evidence regarding the role of Ca(2+) cycling abnormality in HF.