Mark J Perrin1, Arnon Adler1, Sharon Green1, Foad Al-Zoughool1, Petro Doroshenko1, Nathan Orr1, Shaheen Uppal1, Jeff S Healey1, David Birnie1, Shubhayan Sanatani1, Martin Gardner1, Jean Champagne1, Chris Simpson1, Kamran Ahmad1, Maarten P van den Berg1, Vijay Chauhan1, Peter H Backx1, J Peter van Tintelen1, Andrew D Krahn1, Michael H Gollob2. 1. From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.). 2. From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.). michael.gollob@uhn.ca.
Abstract
BACKGROUND: J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I(to))-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I(to) in patients with J waves on ECG. METHODS AND RESULTS: Comprehensive mutational analysis was performed on I(to)-encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave-associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the KCND2 gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type KCND2 with KChIP2 in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak I(to) density of 48% (P<0.05) in the heterozygous state. Using computer modeling, this increase in Ito resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural Ito gradient. The previously described KCNJ8-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome. CONCLUSIONS: These findings are the first to implicate the KCND2 gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in I(to)-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.
BACKGROUND: J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I(to))-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I(to) in patients with J waves on ECG. METHODS AND RESULTS: Comprehensive mutational analysis was performed on I(to)-encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave-associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the KCND2 gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type KCND2 with KChIP2 in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak I(to) density of 48% (P<0.05) in the heterozygous state. Using computer modeling, this increase in Ito resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural Ito gradient. The previously described KCNJ8-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome. CONCLUSIONS: These findings are the first to implicate the KCND2 gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in I(to)-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.
Authors: Charles Antzelevitch; Gan-Xin Yan; Michael J Ackerman; Martin Borggrefe; Domenico Corrado; Jihong Guo; Ihor Gussak; Can Hasdemir; Minoru Horie; Heikki Huikuri; Changsheng Ma; Hiroshi Morita; Gi-Byoung Nam; Frederic Sacher; Wataru Shimizu; Sami Viskin; Arthur A M Wilde Journal: Europace Date: 2017-04-01 Impact factor: 5.214
Authors: Olivia R Tonti; Hannah Larson; Sarah N Lipp; Callan M Luetkemeyer; Megan Makam; Diego Vargas; Sean M Wilcox; Sarah Calve Journal: Acta Biomater Date: 2021-04-18 Impact factor: 10.633