The Perfect Storm

Abstract

See related articles, pages 1039–1048 and 1049–1057 Primary electrical diseases of the heart such as the Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome (BrS), and Catecholaminergic polymorphic ventricular tachycardia (CPVT) are inherited monogenic disorders caused by mutations in ion channel genes (ie, channelopathies), calcium handling proteins, or related molecules that occur in the absence of overt structural abnormalities.1 Because these disorders are typically associated with a high incidence of ventricular tachyarrhythmias and sudden cardiac death (SCD), they are the subject of intense investigation. Although collectively, monogenic diseases underlie a minority of SCD cases in the general population, elucidation of the underlying mechanisms by which they promote electrical instability has provided a wealth of knowledge regarding the role of ion channel dysfunction in electrical remodeling and arrhythmogenesis at multiple levels of integration, linking single amino acid mutations in ion channel genes to electrical dysfunction at the intact cell, organ, and system levels. In recent years, numerous investigations have focused on mechanisms by which altered ion channel function and action potential properties can promote arrhythmias at the multi-cellular network level in various animal models of LQTS, SQTS, and BrS.2 In this issue of Circulation Research , Cerrone et al3 provide a strong mechanistic link between a known CPVT causing mutation and electrical instability arising from the His-Purkinje network of the intact heart in a tour de force study using high-resolution optical mapping, cellular electrophysiological measurements, a variety of pharmacological tools, and numerical simulations. CPVT is a heritable disorder that presents clinically as exercise- or stress- induced ventricular arrhythmias, syncope, or SCD.1 Electrocardiographically, patients with CPVT exhibit polymorphic VT (PVT), bidirectional VT with an alternating QRS axis (Bi-VT), and ventricular fibrillation (VF). Several mutations in the cardiac Ryanodine Receptor (RyR2) and Calsequestrin (CSQ) have been …