Possible targets of therapy for catecholaminergic polymorphic ventricular tachycardia: Insight from a theoretical model

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a serious disease with a high mortality but its management is limited. The aim of this study was to investigate specific target sites for therapy in order to find potential management strategies for CPVT. Methods and Results: The mutant Ryanodine receptor 2 (RyR2) with reduced stored-overloaded-induced 2+ release (SOICR) threshold was incorporated into the Luo-Rudy dynamic (LRd) cell model to elucidate the underlying pathologies of CPVT. The simulations reveal that β-adrenergic stimulation increased the Ca2+ load in cardiac myocyte, which facilitates spontaneous SR Ca2+ leakage, resulting in triggered arrhythmias. Varied blockade (from 0% to 90%) in specific ion channels, including the Na+/Ca2+ exchanger (INaCa), fast Na+ channel (INa), RyR2 receptor (Irel), Ca2+-ATPase (SERCA) (Iup) or L-type Ca2+ channel (ICa(L)),was performed to simulate the action of specific drugs on target sites. Blockade of the INaCa (≤10% blockade), in contrast to the Iup (≤30% blockade), ICa(L) and INa (≤40% blockade), and followed by Irel (≤80% blockade), was most effective in suppressing the triggered arrhythmias in CPVT. Specifically, dual blockade of ICa(L)/Iup, INa/Irel or ICa(L)/Irel had a synergistic effect in CPVT management. Conclusions: Blockade of INaCa appears to be the most efficacious target for CPVT management. Dual blockade of ICa(L)/Iup, INa/Irel or ICa(L)/Irel has a synergistic effect in CPVT treatment.