Key result
Simulated RyR2 mutations trigger arrhythmogenic early afterdepolarizations without supporting SOICR mechanisms.
Why the study?
To use computational models to understand four proposed mechanisms of CPVT1 with RyR2 mutations and how they might contribute to arrhythmia.
Do simulated gain-of-function and loss-of-function RyR2 mutations cause arrhythmogenic activities in a computational ventricular myocyte model?
Do simulated gain-of-function and loss-of-function RyR2 mutations cause arrhythmogenic activities in a computational ventricular myocyte model?
Computational modeling suggests that gain-of-function and loss-of-function RyR2 mutations, but not SOICR or binding protein destabilization, are responsible for CPVT1-related arrhythmogenic activities.
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 Ca2+ 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 Ca2+ 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 Ca2+ channels (LCCs) and ryanodine receptors (RyR2s) and the intervening dyadic cleft to analyze the alterations in Ca2+ 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.
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Paudel et al. (2024) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT1). Computational modeling of RyR2 mutations (gain-of-function, loss-of-function, SOICR, binding protein destabilization) vs. Wild-type myocyte model was evaluated on Development of arrhythmogenic episodes (EADs, DADs, action potential variations). Computational modeling demonstrated that gain-of-function and loss-of-function RyR2 mutations lead to arrhythmia precursors such as early afterdepolarizations, while casting doubt on SOICR as a mechanism.
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