Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target

Ca 2+ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca 2+ ([Ca 2+ ]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca 2+ -binding proteins. Defective regulation of [Ca 2+ ] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca 2+ ] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca 2+ -release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca 2+ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca 2+ leak as a shared Ca 2+ -dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca 2+ leak from the SR, are undergoing investigation in clinical trials. Dysregulation of intracellular Ca 2+ handling in cardiomyocytes occurs in heart failure and atrial fibrillation. In this Review, Marks and colleagues focus on diastolic Ca 2+ leak from the sarcoplasmic reticulum via RYR2 as a feature and potential therapeutic target in both heart failure and atrial fibrillation. Key points Cardiac ryanodine receptor 2 (RYR2) Ca 2+ -release channels are required for excitation–contraction coupling in the heart. Pathological oxidation and PKA-mediated hyperphosphorylation of RYR2 or inherited RYR2 mutations can cause RYR2 Ca 2+ leak from the sarcoplasmic reticulum during diastole, contributing to the progression of heart failure. Diastolic Ca 2+ leak from RYR2 in atrial and ventricular myocytes can also lead to atrial and ventricular arrhythmias, respectively. Inhibiting this Ca 2+ leak with the use of drugs that stabilize the interactions between calstabin 2 and RYR2 can reduce the progression of heart failure and the incidence of cardiac arrhythmias such as atrial