Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by the absence of structural heart disease, syncope, and sudden cardiac death.1 Typically, acceleration of the heart rate during physical exercise or emotional distress provokes an increasing number of ventricular premature complexes followed by runs of bidirectional or polymorphic ventricular tachycardia (VT). During clinical testing, about 30–50% of the patients will reproducibly develop VT following exercise testing or catecholamine injection.1,2 The ECG morphology of ventricular tachyarrhythmias observed in patients with CPVT resembles that of VTs commonly described in digitalis toxicity (which is associated with cellular calcium overload), and in metabolic disturbances as seen in severe HF (which is associated with high adrenergic tone).3 In conditions of cytoplasmic Ca2+ overload or enhanced β-adrenergic signalling, cardiac myocytes exhibit greater ectopic activity. It has therefore been suggested that arrhythmias in CPVT are mediated by triggered activity and delayed afterdepolarizations (DADs), which are defined as oscillations in the membrane potential of the cardiac myocyte after repolarization of an action potential has been completed.1 The most common, autosomal-dominant form of CPVT is caused by genetic mutations in the gene encoding the cardiac ryanodine receptor ( RyR2 ), the principal intracellular Ca2+ release channel involved in excitation-contraction coupling.4 Although experimental studies have provided evidence that mutant RyR2 channels can give rise to DADs in isolated cardiomyocytes,5 the study by Paavola et al .6 demonstrates DADs in monophasic action potential (MAP) recordings for the first time in CPVT patients with RyR2 mutations. In contrast to conventional electrode catheter recordings, MAP recordings provide precise information not only about the local activation time, but also about the entire repolarization time course. Electrophysiological data for the occurrence of DADs in patients with CPVT have been scarce in the literature, with … *Corresponding author. Tel: +1 713 798 4261; fax: +1 713 798 3475. E-mail address : wehrens{at}bcm.edu