Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: A simulation study of cellular mechanism

Objectives: Patients with a missense mutation of the calsequestrin 2 gene (CASQ2) are at risk for catecholarninergic polymorphic ventricular tachycardia. This mutation (CASQ2(D307H)) results in decreased ability of CASQ2 to bind Ca2+ in the sarcoplasmic reticulum (SR). In this theoretical study, we investigate a potential mechanism by which CASQ2(D307H) manifests its pro-arrhythmic consequences in patients. Methods: Using simulations in a model of the guinea pig ventricular myocyte, we investigate the mutation's effect on SR Ca2+ storage, the Ca2+ transient (CaT), and its indirect effect on ionic currents and membrane potential. We model the effects of isoproterenol (ISO) on Ca(V)1.2 (the L-type Ca2+ Current, I-Ca(L)) and other targets of beta-adrenergic stimulation. Results: ISO increases I-Ca(L), prolonging action potential (AP) duration (Control: 172 ms, +ISO: 207 ins, at cycle length of 1500 ms) and increasing CaT (Control: 0.79 mu M, +ISO: 1.61 mu M). ISO increases I-Ca(L) by reducing the fraction of channels which undergo voltage-dependent inactivation and increasing transitions from a non-conducting to conducting mode of channel gating. CASQ2(D307H) reduces SR storage capacity, thereby reducing the magnitude of CaT (Control: 0.79 mu M, CASQ2(D307H): 0.52 mu M, at cycle length of 1500 ms). The combined effect of CASQ2(D307H) and ISO elevates SR free Ca2+ at a rapid rate, leading to store-overload-induced Ca2+ release and delayed afterdepolarization (DAD). If resting membrane potential is sufficiently elevated, the Na+-Ca2+ exchange-driven DAD can trigger I-Na and 1(Ca)(L) activation, generating a triggered arrhythmogenic AP. Conclusions: The CASQ2(D307H) mutation manifests its pro-arrhythmic consequences due to store-overload-induced Ca2+ release and DAD formation due to excess free SR Ca2+ following rapid pacing and beta-adrenergic stimulation. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.