Chemistry

Ryanodine receptor 2

Atrial fibrillation

Contractility

Biology

Endoplasmic reticulum

Cell biology

Cardiology

Calsequestrin

Ryanodine receptor

Calcium

Internal medicine

Heart failure

Calcium in biology

Medicine

Intracellular

Nature Reviews Cardiology

Ca2+ 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 Ca2+ ([Ca2+]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca2+-binding proteins. Defective regulation of [Ca2+] 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 [Ca2+] 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) Ca2+-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 Ca2+ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca2+ leak as a shared Ca2+-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 Ca2+ leak from the SR, are undergoing investigation in clinical trials. Dysregulation of intracellular Ca2+ handling in cardiomyocytes occurs in heart failure and atrial fibrillation. In this Review, Marks and colleagues focus on diastolic Ca2+ leak from the sarcoplasmic reticulum via RYR2 as a feature and potential therapeutic target in both heart failure and atrial fibrillation.

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