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

Abstract

Structural and functional alterations in the Ca2+ 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 Ca2+ leak through the SR Ca2+ release channel (ryanodine receptor) reduces the SR Ca2+ content, inducing contractile dysfunction. Moreover, the Ca2+ leak provides a substrate for delayed afterdepolarization that leads to lethal arrhythmia. There is a considerable body of evidence regarding the role of Ca2+ cycling abnormality in HF.