The ryanodine receptor leak: how a tattered receptor plunges the failing heart into crisis

It has been persuasively shown in the last two decades that the development of heart failure is closely linked to distinct alterations in Ca²⁺ cycling. A crucial point in this respect is an increased spontaneous release of Ca²⁺ out of the sarcoplasmic reticulum during diastole via ryanodine receptors type 2 (RyR2). The consequence is a compromised sarcoplasmic reticulum Ca²⁺ storage capacity, which impairs systolic contractility and possibly diastolic cardiac function due to Ca²⁺ overload. Additionally, leaky RyR2 are more and more regarded to potently induce proarrhythmic triggers. Elimination of spontaneously released Ca²⁺ via RyR2 in diastole can cause a transient sarcolemmal inward current and hence delayed after depolarisations as substrate for cardiac arrhythmias. In this article, the pathological role and consequences of the SR Ca²⁺-leak and its regulation are reviewed with a main focus on protein kinase A and Ca²⁺-calmodulin-dependent kinase II. We summarise clinical consequences of “leaky RyR2” as well as possible therapeutic strategies in order to correct RyR2 dysfunction and discuss the significance of the available data.