Sex-influenced mortality in a large Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cohort caused by RYR2 p.R420W

Abdel-Razek, Omar (2022) Sex-influenced mortality in a large Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cohort caused by RYR2 p.R420W. Masters thesis, Memorial University of Newfoundland.

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Background: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an arrhythmia syndrome causing sudden cardiac death (SCD). We have ascertained three multiplex, multigenerational families with CPVT due to RYR2 (p.R420W) disrupting calcium channel regulation. The effect of RYR2 p.R420W on survival is described. Methods: Cases of sudden death were ascertained from clinical and genetics chart reviews following informed research consent from individuals or their next of kin (Study ID 00-176). Individuals were considered well-ascertained if disease status of ≥ 50% of their sibship was known (n=60). Affected individuals included mutation positive, obligate carriers (OC), and/or documented SCD <50 years (n=32). Unaffected status was defined as mutation negative (n=23). Remaining individuals were designated unknown (n=5). Unaffected and Unknown groups were combined. Time to death was compared using Kaplan-Meier time-to-event analysis and multivariate Cox regression. Survival was compared to families with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) due to TMEM43 p.S358L. Results: Affected status with RYR2 p.R420W was significantly associated with mortality (RR=4, 95% CI: 1.1-14.5), with 24% mortality in the affected group by age 30. Affected males died earlier than females (RR=6, 95% CI: 1.7-20.4). Median survival in males with RYR2 p.R420W was 50 years (95% CI: 5.5-94.5), compared to TMEM43 44 years (95% CI: 42.0-46.8). Median survival in females with RYR2 was 76 years (95% CI: 37.7-115.2), compared to TMEM43 73 years (95% CI: 69.6-76.1). Conclusions: The RYR2 p.R420W mutation significantly affects mortality. There is a clear sex-influence. Median survival is comparable to another highly lethal mutation TMEM43 p.S358L causing ARVC.

Item Type: Thesis (Masters)
Item ID: 15732
Additional Information: Includes bibliographical references (pages 66-70)
Keywords: sudden cardiac death, Catecholaminergic Polymorphic Ventricular Tachycardia
Department(s): Medicine, Faculty of
Date: October 2022
Date Type: Submission
Digital Object Identifier (DOI):
Medical Subject Heading: Death, Sudden, Cardiac; Polymorphic catecholergic ventricular tachycardia; Arrhythmogenic Right Ventricular Dysplasia; Ryanodine Receptor Calcium Release Channel; Mutation

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