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

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 Ca²⁺ 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 (I(NaCa)), fast Na⁺ channel (I(Na)), RyR2 receptor (I(rel)), Ca²⁺-ATPase (SERCA) (I(up)) or L-type Ca²⁺channel (I(Ca(L))),was performed to simulate the action of specific drugs on target sites. Blockade of the I(NaCa) (≤ 10% blockade), in contrast to the I(up) (≤ 30% blockade), I(Ca(L)) and I(Na) (≤40% blockade), and followed by I(rel) (≤ 80% blockade), was most effective in suppressing the triggered arrhythmias in CPVT. Specifically, dual blockade of I(Ca(L))/I(up), I(Na)/I(rel) or I(Ca(L))/I(rel) had a synergistic effect in CPVT management.

CONCLUSIONS: Blockade of I(NaCa) appears to be the most efficacious target for CPVT management. Dual blockade of I(Ca(L))/I(up), I(Na)/I(rel) or I(Ca(L))/I(rel) has a synergistic effect in CPVT treatment.