Sarcoplasmic Reticulum Ca Dysregulation in the Pathophysiology of Inherited Arrhythmia: An Update.

Inherited arrhythmias are the leading causes for cardiac arrest and sudden cardiac death (SCD). Other than ion channel mutations, inherited arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), idiopathic ventricular fibrillation (IVF) and arrhythmogenic right ventricular cardiomyopathy (ARVC/D) may also be instigated by genetic mutations of sarcoplasmic reticulum (SR) proteins, including ryanodine receptor type-2 (RyR2), calsequestrin 2, SR Ca-ATPase type-2a (SERCA2a) and phospholamban. In cardiomyocytes, Ca is an essential ion in addition to Na and K ions with vital roles in arrhythmogenesis. SR plays a critical role in the maintenance of Ca homeostasis which can be disrupted by mutations in SR Ca regulatory proteins or abnormal SR-intracellular organelle interaction. Early afterdepolarizations, delayed afterdepolarizations and reentry are three primary mechanisms contributing to arrhythmias elicited by SR Ca dysregulation in cardiomyocytes. In this review, we will aim to summarize normal SR Ca regulation in cardiomyocytes, mechanisms of how Ca triggers arrhythmias and involvements of SR gene mutations in inherited arrhythmias as well as the possible arrhythmogenic effects of these mutations.