Leaky ryanodine receptors in the failing heart: the root of all evil?

Abstract

This editorial refers to ‘The relationship between arrhythmogenesis and impaired contractility in heart failure: role of altered ryanodine receptor function’ by A.E. Belevych et al. , pp. 493–502, this issue. Over the past two decades, a significant contribution to the pathophysiology of heart failure (HF) has been attributed to alterations of Ca2+ handling, which has been observed in myocytes isolated from failing hearts. Initially, a reduced Ca2+ transient amplitude due to a reduced Ca2+ reuptake rate by SERCA and enhanced extrusion of Ca2+ to the extracellular space by the Na+/Ca2+ exchanger had been proposed as key alterations in Ca2+ handling in failing myocardium.1,2 More recently, alterations of the ryanodine receptor (RYR2), which releases Ca2+ from the intracellular sarcoplasmic reticulum (SR) Ca2+ stores, have attracted the attention of many researchers. It has been demonstrated that RYR2 is hyperphosphorylated in failing myocardium, which renders the channel more prone to diastolic spontaneous Ca2+ release events (Ca2+ leak).3–5 In other diseases, such Ca2+ leak might arise as a consequence of defective channel gating behaviour (e.g. catecholaminergic polymorphic ventricular tachycardia).6,7 These two views do not directly compete with each other, but SR Ca2+ leak would be expected to increase when the SR Ca2+ content is high, whereas measurements in failing ventricular myocytes under basal conditions have consistently demonstrated a reduced SR Ca2+ content.8 Therefore, many studies have suggested that enhanced Ca2+ reuptake is required to keep the SR Ca2+ content high enough for sustained Ca2+ leak from the SR to occur.5,6,9 Whether enhanced and sustained Ca2+ leak can …