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Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives: We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods: Genetic testing was performed for 1404 relatives. Mutation-positive subjects were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results: We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD victims. No SCD was observed among treated mutation-positive subjects over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive subjects) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive subjects, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion: Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

© Heart Rhythm, 2015, vol. 12, núm. 7, p. 1636–1643

Elsevier

Author: Wangüemert, Fernando
Bosch Calero, Cristina
Pérez, Carmelo
Campuzano Larrea, Oscar
Beltrán Álvarez, Pedro
Scornik, Fabiana S.
Iglesias, Anna
Berne, Paola
Allegue, Catarina
Ruiz Hernandez, Pablo M.
Brugada Terradellas, Josep
Pérez González, Guillermo J.
Brugada, Ramon
Date: 2015
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives: We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods: Genetic testing was performed for 1404 relatives. Mutation-positive subjects were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results: We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD victims. No SCD was observed among treated mutation-positive subjects over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive subjects) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive subjects, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion: Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation
Format: application/pdf
ISSN: 1547-5271 (versió paper)
1556-3871 (versió electrònica)
Document access: http://hdl.handle.net/10256/10353
Language: eng
Publisher: Elsevier
Collection: Versió postprint del document publicat a: http://dx.doi.org/10.1016/j.hrthm.2015.03.033
Articles publicats (D-CM)
Is part of: © Heart Rhythm, 2015, vol. 12, núm. 7, p. 1636–1643
Rights: Tots els drets reservats
Subject: Arítmia
Arrhythmia
Mort sobtada
Sudden death
Title: Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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