Recent evidence suggests that neuronal Na+ channels (nNavs) contribute to catecholamine-promoted delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The newly identified overlap between CPVT and long QT (LQT) phenotypes has stoked interest in the cross-talk between aberrant Na+ and Ca2+ handling and its contribution to early afterdepolarizations (EADs) and DADs. Here, we used Ca2+ imaging and electrophysiology to investigate the role of Na+ and Ca2+ handling in DADs and EADs in wild-type and cardiac calsequestrin (CASQ2)-null mice. In experiments, repolarization was impaired using 4-aminopyridine (4AP), whereas the L-type Ca2+ and late Na+ currents were augmented using Bay K 8644 (BayK) and anemone toxin II (ATX-II), respectively. The combination of 4AP and isoproterenol prolonged action potential duration (APD) and promoted aberrant Ca2+ release, EADs, and DADs in wild-type cardiomyocytes. Similarly, BayK in the absence of isoproterenol induced the same effects in CASQ2-null cardiomyocytes. In vivo, it prolonged the QT interval and, upon catecholamine challenge, precipitated wide QRS polymorphic ventricular tachycardia that resembled human torsades de pointes. Treatment with ATX-II produced similar effects at both the cellular level and in vivo. Importantly, nNav inhibition with riluzole or 4,9-anhydro-tetrodotoxin reduced the incidence of ATX-II–, BayK-, or 4AP-induced EADs, DADs, aberrant Ca2+ release, and VT despite only modestly mitigating APD prolongation. These data reveal the contribution of nNaVs to triggered arrhythmias in murine models of LQT and CPVT-LQT overlap phenotypes. We also demonstrate the antiarrhythmic impact of nNaV inhibition, independent of action potential and QT interval duration, and provide a basis for a mechanistically driven antiarrhythmic strategy.
Prevalence, Therapeutic Response, and Outcome of Ventricular Tachycardia in the Out-of-hospital Setting: A Comparison of Monomorphic Ventricular Tachycardia, Polymorphic Ventricular Tachycardia, and Torsades de Pointes
