Zhong-He Zhang1, Hector Barajas-Martínez2, Hao Xia1, Bian Li3, John A Capra4, Jerome Clatot5, Gan-Xiao Chen1, Xiu Chen1, Bo Yang1, Hong Jiang1, Gary Tse6, Yoshiyasu Aizawa7, Michael H Gollob8, Melvin Scheinman9, Charles Antzelevitch2, Dan Hu10. 1. Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China. 2. Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA; Lankenau Heart Institute, Wynnewood, Pennsylvania, USA; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. 3. Department of Biological Sciences, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA. 4. Bakar Computational Health Sciences Institute, University of California, San Francisco, California, USA. 5. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 6. Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China; Kent and Medway Medical School, Canterbury, Kent, United Kingdom. 7. Department of Cardiovascular Medicine, School of Medicine 4-3, International University of Health and Welfare, Kozunomori, Narita, Chiba, Japan. 8. Department of Physiology and Division of Cardiology, University of Toronto, Toronto, Ontario, Canada. 9. Department of Cardiac Electrophysiology, University of California, San Francisco, California, USA. 10. Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China. Electronic address: hudan0716@hotmail.com.
Abstract
BACKGROUND: Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). OBJECTIVES: This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A. METHODS: Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure. RESULTS: The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%. CONCLUSIONS: These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.
BACKGROUND: Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). OBJECTIVES: This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A. METHODS: Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure. RESULTS: The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%. CONCLUSIONS: These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.
Authors: R Dumaine; J A Towbin; P Brugada; M Vatta; D V Nesterenko; V V Nesterenko; J Brugada; R Brugada; C Antzelevitch Journal: Circ Res Date: 1999-10-29 Impact factor: 17.367
Authors: Elena Burashnikov; Ryan Pfeiffer; Héctor Barajas-Martinez; Eva Delpón; Dan Hu; Mayurika Desai; Martin Borggrefe; Michel Häissaguerre; Ronald Kanter; Guido D Pollevick; Alejandra Guerchicoff; Ruben Laiño; Mark Marieb; Koonlawee Nademanee; Gi-Byoung Nam; Roberto Robles; Rainer Schimpf; Dwight D Stapleton; Sami Viskin; Stephen Winters; Christian Wolpert; Samuel Zimmern; Christian Veltmann; Charles Antzelevitch Journal: Heart Rhythm Date: 2010-10-14 Impact factor: 6.343
Authors: Andrew M Glazer; Yuko Wada; Bian Li; Ayesha Muhammad; Olivia R Kalash; Matthew J O'Neill; Tiffany Shields; Lynn Hall; Laura Short; Marcia A Blair; Brett M Kroncke; John A Capra; Dan M Roden Journal: Am J Hum Genet Date: 2020-06-12 Impact factor: 11.025
Authors: David S Park; Marina Cerrone; Gregory Morley; Carolina Vasquez; Steven Fowler; Nian Liu; Scott A Bernstein; Fang-Yu Liu; Jie Zhang; Christopher S Rogers; Silvia G Priori; Larry A Chinitz; Glenn I Fishman Journal: J Clin Invest Date: 2014-12-15 Impact factor: 14.808
Authors: Luciana Sacilotto; Hindalis Ballesteros Epifanio; Francisco Carlos da Costa Darrieux; Fanny Wulkan; Theo Gremen Mimary Oliveira; Denise Tessariol Hachul; Alexandre da Costa Pereira; Mauricio Ibrahim Scanavacca Journal: Arq Bras Cardiol Date: 2017-01 Impact factor: 2.000
Authors: Christian Veltmann; Hector Barajas-Martinez; Christian Wolpert; Martin Borggrefe; Rainer Schimpf; Ryan Pfeiffer; Gabriel Cáceres; Elena Burashnikov; Charles Antzelevitch; Dan Hu Journal: J Am Heart Assoc Date: 2016-07-05 Impact factor: 5.501
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
Authors: Hasina Masha Aziz; Michał P Zarzecki; Sebastian Garcia-Zamora; Min Seo Kim; Piotr Bijak; Gary Tse; Hong-Hee Won; Paweł T Matusik Journal: J Clin Med Date: 2022-03-30 Impact factor: 4.241