Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation

Zissimopoulos, Spyros, Kirilenko, Pavel, Braza-Boils, Aitana, Zorio, Esther, Wang, Yueyi, Gomez, Ana Maria, Cannell, Mark B, Latinkic, Branko ORCID: https://orcid.org/0000-0003-4952-123X and Fowler, Ewan 2025. Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation. Journal of Molecular and Cellular Cardiology 206 , pp. 127-140. 10.1016/j.yjmcc.2025.07.014

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Abstract

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca2+ cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca2+ 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 R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca2+ leak during the Ca2+ transient decay, in the form of late Ca2+ 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 Ca2+-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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences
Publisher:	Elsevier
ISSN:	0022-2828
Date of First Compliant Deposit:	31 July 2025
Date of Acceptance:	21 July 2025
Last Modified:	01 Aug 2025 09:30
URI:	https://orca.cardiff.ac.uk/id/eprint/180183

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