Yusuke Fujii1, Hideki Itoh1, Seiko Ohno1, Takashi Murayama2, Nagomi Kurebayashi2, Hisaaki Aoki3, Malorie Blancard4, Yoshihisa Nakagawa5, Satoshi Yamamoto6, Yumie Matsui6, Mari Ichikawa1, Keiko Sonoda1, Tomoya Ozawa1, Kimie Ohkubo7, Ichiro Watanabe7, Pascale Guicheney4, Minoru Horie8. 1. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. 2. Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan. 3. Department of Pediatric Cardiology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan. 4. INSERM, UMR U1166, ICAN, Paris, France; Sorbonne Universites, UPMC Univ Paris 06, UMR S1166, Paris, France. 5. Department of Cardiovascular Medicine, Tenriyorozu Hospital, Nara, Japan. 6. Department of Cardiovascular Medicine, Saiseikai Izumio Hospital, Osaka, Japan. 7. Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan. 8. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. Electronic address: horie@belle.shiga-med.ac.jp.
Abstract
BACKGROUND: Ventricular fibrillation may be caused by premature ventricular contractions (PVCs) whose coupling intervals are <300 ms, a characteristic of the short-coupled variant of torsades de pointes (scTdP). OBJECTIVE: The purpose of this study was to analyze the underlying cardiac ryanodine receptor (RyR2) variants in patients with scTdP. METHODS: Seven patients with scTdP (mean age 34 ± 12 years; 4 men and 3 women) were enrolled in this study. The RyR2 gene was screened by targeted gene sequencing methods; variant minor allele frequency was confirmed in 3 databases; and the pathogenicity was investigated in silico analysis using multiple tools. The activity of wild-type and mutant RyR2 channels was evaluated by monitoring Ca2+ signals of HEK293 cells with a [3H]ryanodine binding assay. RESULTS: The mean coupling interval of PVCs was 282 ± 13 ms. The 12-lead electrocardiogram had no specific findings except PVCs with an extremely short-coupling interval. Genetic analysis revealed 3 novel RyR2 variants and 1 polymorphism, all located in the cytoplasmic region. p.Ser4938Phe was not detected in 3 databases, and in silico analysis indicated its pathogenicity. In functional analysis, p.Ser4938Phe demonstrated loss of function and impaired RyR2 channel Ca2+ release, while 2 other variants, p.Val1024Ile and p.Ala2673Val, had mild gain-of-function effects but were similar to the polymorphism p.Asn1551Ser. CONCLUSION: We identified an RyR2 variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia. The mechanisms of arrhythmogenesis remain unclear.
BACKGROUND:Ventricular fibrillation may be caused by premature ventricular contractions (PVCs) whose coupling intervals are <300 ms, a characteristic of the short-coupled variant of torsades de pointes (scTdP). OBJECTIVE: The purpose of this study was to analyze the underlying cardiac ryanodine receptor (RyR2) variants in patients with scTdP. METHODS: Seven patients with scTdP (mean age 34 ± 12 years; 4 men and 3 women) were enrolled in this study. The RyR2 gene was screened by targeted gene sequencing methods; variant minor allele frequency was confirmed in 3 databases; and the pathogenicity was investigated in silico analysis using multiple tools. The activity of wild-type and mutant RyR2 channels was evaluated by monitoring Ca2+ signals of HEK293 cells with a [3H]ryanodine binding assay. RESULTS: The mean coupling interval of PVCs was 282 ± 13 ms. The 12-lead electrocardiogram had no specific findings except PVCs with an extremely short-coupling interval. Genetic analysis revealed 3 novel RyR2 variants and 1 polymorphism, all located in the cytoplasmic region. p.Ser4938Phe was not detected in 3 databases, and in silico analysis indicated its pathogenicity. In functional analysis, p.Ser4938Phe demonstrated loss of function and impaired RyR2 channel Ca2+ release, while 2 other variants, p.Val1024Ile and p.Ala2673Val, had mild gain-of-function effects but were similar to the polymorphism p.Asn1551Ser. CONCLUSION: We identified an RyR2 variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia. The mechanisms of arrhythmogenesis remain unclear.
Authors: Christian Wolpert; Mara Vogel; Christian Nagel; Claudia Herrera-Siklody; Norman Rüb Journal: Herzschrittmacherther Elektrophysiol Date: 2017-05-22
Authors: Andrés R Pérez-Riera; Raimundo Barbosa-Barros; Marianne P C de Rezende Barbosa; Rodrigo Daminello-Raimundo; Augusto A de Lucca; Luiz C de Abreu Journal: Ann Noninvasive Electrocardiol Date: 2017-10-19 Impact factor: 1.468
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486