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 catecholaminergic 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_V1.2 (the L-type Ca²⁺ current, I_Ca(L)) and other targets of β-adrenergic stimulation. Results: ISO increases I_Ca(L), prolonging action potential (AP) duration (Control: 172 ms, +ISO: 207 ms, at cycle length of 1500 ms) and increasing CaT (Control: 0.79 μM, +ISO: 1.61 μM). 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 μM, CASQ2^D307H: 0.52 μM, 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 I_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 β-adrenergic stimulation.