Gain-of-Function and Loss-of-Function Mutations in the RyR2-Expressing Gene Are Responsible for the CPVT1-Related Arrhythmogenic Activities in the Heart.

Mutations in the ryanodine receptor (RyR2) gene have been linked to arrhythmia and possibly sudden cardiac death (SCD) during acute emotional stress, physical activities, or catecholamine perfusion. The most prevalent disorder is catecholaminergic polymorphic ventricular tachycardia (CPVT1). Four primary mechanisms have been proposed to describe CPVT1 with a RyR2 mutation: (a) gain-of-function, (b) destabilization of binding proteins, (c) store-overload-induced Ca release (SOICR), and (d) loss of function. The goal of this study was to use computational models to understand these four mechanisms and how they might contribute to arrhythmia. To this end, we have developed a local control stochastic model of a ventricular cardiac myocyte and used it to investigate how the Ca dynamics in the mutant RyR2 are responsible for the development of an arrhythmogenic episode under the condition of β-adrenergic (β-AR) stimulation or pauses afterward. Into the model, we have incorporated 20,000 distinct cardiac dyads consisting of stochastically gated L-type Ca channels (LCCs) and ryanodine receptors (RyR2s) and the intervening dyadic cleft to analyze the alterations in Ca dynamics. Recent experimental findings were incorporated into the model parameters to test these proposed mechanisms and their role in triggering arrhythmias. The model could not find any connection between SOICR and the destabilization of binding proteins as the arrhythmic mechanisms in the mutant myocyte. On the other hand, the model was able to observe loss-of-function and gain-of-function mutations resulting in EADs (Early Afterdepolarizations) and variations in action potential amplitudes and durations as the precursors to generate arrhythmia, respectively. These computational studies demonstrate how GOF and LOF mutations can lead to arrhythmia and cast doubt on the feasibility of SOICR as a mechanism of arrhythmia.