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

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. 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). 5 In other diseases, such Ca2+ leak might arise as a consequence of defective channel gating behaviour (e.g. catecholaminergic polymorphic ventricular tachycardia). 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. 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. Whether enhanced and sustained Ca2+ leak can occur in failing cells with reduced SR Ca2+ content is thus far unknown. The study by Belevych et al. investigates the relation between RYR2 leakiness, SR Ca2+ content, Ca2+ transient amplitude, and the occurrence of spontaneous, proarrhythmic Ca2+ release events (sparks or waves) during the development of HF. The authors investigated cytosolic and SR Ca2+ transients in isolated ventricular myocytes from dogs undergoing rapid ventricular pacing. They demonstrate that, in their model, increased and sustained leak of Ca2+ from the SR can occur in the presence of reduced SR Ca2+ content. As the underlying mechanism they propose an impaired refractoriness of RYR2 to release Ca2+ from the SR. In failing myocytes, RYR2 opening occurred at a lower intra-luminal SR Ca2+ concentration and also earlier after reaching the threshold for Ca2+ release than in control myocytes.