The RyR2-R420Q mutation increased late calcium sparks and inward sodium/calcium exchange current, resulting in action potential prolongation and early afterdepolarizations in a murine model of CPVT.
BACKGROUND: leak during systole disrupts repolarization in a transgenic mouse model of CPVT. METHODS: Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes. RESULTS: sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs. CONCLUSIONS: -mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.
Zissimopoulos et al. (2025) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT). RyR2-R420Q mutation vs. Control was evaluated on Action potential prolongation and early afterdepolarizations. The RyR2-R420Q mutation increased late calcium sparks and inward sodium/calcium exchange current, resulting in action potential prolongation and early afterdepolarizations in a murine model of CPVT.
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