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JACC Clin Electrophysiol. 2017 Mar;3(3):276-288. doi: 10.1016/j.jacep.2016.09.019. Epub 2016 Dec 21.

Bundle Branch Re-Entrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia.

Author information

1
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada; Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California. Electronic address: jason.roberts@lhsc.on.ca.
2
Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
3
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Santa Clara Kaiser Medical Center, Santa Clara, California.
4
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Memorial University, St. John's, Newfoundland, Canada.
5
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
6
Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
7
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
8
Cardiac Electrophysiology Laboratories, Regions Hospital, St. Paul, Minnesota; Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
9
Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.
10
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California.
11
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.
12
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California.
13
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; Department of Medicine, California Institute for Quantitative Biosciences and Institute for Human Genetics, University of California-San Francisco, San Francisco, California.

Abstract

OBJECTIVES:

This study sought to investigate for an underlying genetic etiology in cases of apparent idiopathic bundle branch re-entrant ventricular tachycardia (BBRVT).

BACKGROUND:

BBRVT is a life-threatening arrhythmia occurring secondary to macro-re-entry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease.

METHODS:

Cases of BBRVT with normal biventricular size and function were recruited from 6 North American centers. Enrollment required a clinically documented wide complex tachycardia and BBRVT proven during invasive electrophysiology study. Study participants were screened for mutations within genes associated with cardiac conduction system disease. Pathogenicity of identified mutations was evaluated using in silico phylogenetic and physicochemical analyses and in vitro biophysical studies.

RESULTS:

Among 6 cases of idiopathic BBRVT, each presented with hemodynamic compromise and 2 suffered cardiac arrests requiring resuscitation. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Nav1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation, consistent with a loss-of-function. The SCN5A c.4719C>T splice site mutation has previously been reported as disease-causing in 3 cases of Brugada syndrome, whereas the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was noninducible in all cases and none experienced a clinical recurrence during follow-up.

CONCLUSIONS:

Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening arrhythmia, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing in this condition. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation.

KEYWORDS:

conduction system disease; genetics; sudden cardiac death; ventricular tachycardia

PMID:
29759522
DOI:
10.1016/j.jacep.2016.09.019
[Indexed for MEDLINE]
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