Daniel Toshio Harrell1, Takashi Ashihara2, Taisuke Ishikawa1, Ichiko Tominaga1, Andrea Mazzanti3, Kazuhiro Takahashi4, Yasushi Oginosawa5, Haruhiko Abe6, Koji Maemura7, Naokata Sumitomo8, Kikuya Uno9, Makoto Takano10, Silvia G Priori11, Naomasa Makita12. 1. Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 2. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Heart Rhythm Center, Shiga, Japan. 3. Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy. 4. Department of Pediatric Cardiology, Okinawa Children's Medical Center, Okinawa, Japan. 5. Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. 6. Department of Heart Rhythm Management, University of Occupational and Environment Health, Kitakyushu, Japan. 7. Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 8. Department of Pediatric Cardiology, Saitama International Medical Center, Hidaka, Japan. 9. Sapporo Heart Center, Sapporo, Japan. 10. Department of Physiology, Kurume University School of Medicine, Kurume, Japan. 11. Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy. 12. Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: makitan@nagasaki-u.ac.jp.
Abstract
BACKGROUND: Short QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated. METHODS AND RESULTS: We screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+14 mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3-6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35 ± 19 years, n = 30; SQT2: 17 ± 25 years, n = 8, SQT3-6: 19 ± 15 years, n = 15; p = 0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p < 0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p = 0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. CONCLUSION: We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.
BACKGROUND:Short QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated. METHODS AND RESULTS: We screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+14 mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3-6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35 ± 19 years, n = 30; SQT2: 17 ± 25 years, n = 8, SQT3-6: 19 ± 15 years, n = 15; p = 0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p < 0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p = 0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. CONCLUSION: We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.
Authors: Roberta Pereira; Oscar Campuzano; Georgia Sarquella-Brugada; Sergi Cesar; Anna Iglesias; Josep Brugada; Fernando E S Cruz Filho; Ramon Brugada Journal: Clin Res Cardiol Date: 2017-03-16 Impact factor: 5.460
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: Yibo Wang; Jiqing Guo; Laura L Perissinotti; James Lees-Miller; Guoqi Teng; Serdar Durdagi; Henry J Duff; Sergei Yu Noskov Journal: Sci Rep Date: 2016-10-12 Impact factor: 4.379