A MULTI-SCALE COMPUTATIONAL APPROACH TO UNDERSTAND THE CALCIUM DYNAMICS AND ARRHYTHMOGENIC DISORDERS CAUSED BY MUTATIONS IN RYR2/CASQ2 EXPRESSING GENES

Abstract

Whole-cell computational models are very beneficial to understand and predict the underlying cellular and ionic mechanism in the heart. We developed a stochastic ventricular myocyte model of Guinea pig with 20000 stochastically gating CRUs incorporating a six-state L-type Ca2+ channel (LCC) and a three-state ryanodine receptor (RyR2). The model was used to understand the Calcium (Ca2+) dynamics in the subcellular level with the computational analysis of Ca2+ sparks, their amplitudes and durations in the exploration of force-frequency relationship (FFR) and arrhythmogenesis of mutations in the genes expressing the luminal Ca2+ buffer, Calsequestrin (CASQ2) and sarcoplasmic reticulum (SR) Ca2+ channels, RyR2. In FFR, the model predicted that diastolic SR [Ca2+] and RyR2 adaptation increased with the increased stimulation frequency giving rise rising than falling amplitude of the cytoplasmic [Ca2+] transients. A simulation on the deletion mutation CASQ2G112+5X responsible for causing catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) found cardiac alternans (action potential duration (APD) and AP amplitude) and early afterdepolarizations (EADs) were the underlying mechanisms to cause arrhythmia in the myocytes during β-arrhythmogenic receptor (β-AR) stimulation. The arrhythmogenic mechanisms instigated by RyR2 mutations are explained by four different hypotheses: gain-of-function (GOF), loss-of-function (LOF), store-overload induced Ca2+ release (SOICR), and binding protein destabilization. Our model evaluated all these hypotheses with β-AR stimulation and it predicted that the EADs were the mechanism of CPVT1 in LOF mutation and APD and AP amplitude alternans were the mechanisms in GOF mutation. The abundance Ca2+ spark leaks in the binding protein mutation came short to develop any DADs and the SOICR phenomenon was unable to activate RyR2 in the absence of Ca2+ induced Ca2+ release (CICR).