Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia.

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic syndrome characterized by exercise- or stress-induced polymorphic ventricular tachyarrhythmias and sudden cardiac death in the context of a structurally normal heart.1,2 It is estimated to occur in ≈1 in 10 000 of the population and has a poor prognosis, with up to 50% mortality by 20 years of age.3 The pathophysiology has been studied extensively since the first genetic mutation was first identified by Priori and colleagues in 2002.1,2 Abnormal calcium storage and release from the sarcoplasmic reticulum (SR) within the cardiomyocytes underpin the disease, with causative mutations in 2 critical proteins in the SR complex: the cardiac SR calcium release channel known as the ryanodine receptor (RyR2) and the calcium buffering and RyR2 regulatory protein calsequestrin (CASQ2). Mutations have been identified in the RyR2 or CASQ2 genes in ≈60% to 70% of individuals with the clinical syndrome. Article see p 2673 Diastolic SR calcium release via RyR2 is the molecular basis for delayed afterdepolarizations (DADs), triggered activity, and ventricular ectopy and, if oscillatory, can be sustained ventricular tachyarrhythmias, leading to cardiac arrest and sudden death. Increased sympathetic activity activates the cardiac β-adrenoceptor (βAR) pathways, leading to phosphorylation of RyR2 and increasing the RyR2 channel opening probability.4 βAR activation also increases sarcoplasmic endoplasmic reticular calcium ATPase2 (SERCA2a) activity via phosphorylation of the inhibitory protein phospholamban, increasing SR calcium loading. Both of these effects are important for the normal increase in cardiac inotropy during exercise or stress as part of the “flight or fight” response. Individuals with CPVT harbor mutations in RyR2 or CASQ2, lowering the threshold for abnormal SR calcium release during diastole, when the RyR2 channel should be closed.1 Hence, individuals with CPVT develop complex ventricular tachyarrhythmias secondary to maladaptive handling of …