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

Jason D. Roberts, Michael H. Gollob, Charlie Young, Sean P. Connors, Chris Gray, Stephen B. Wilton, Martin S. Green, Dennis W. Zhu, Kathleen A. Hodgkinson, Annie Poon, Qiuju Li, Nathan Orr, Anthony S. Tang, George J. Klein, Julianne Wojciak, Joan Campagna, Jeffrey E. Olgin, Nitish Badhwar, Vasanth Vedantham, Gregory M. MarcusPui Yan Kwok, Rahul C. Deo, Melvin M. Scheinman

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)276-288
Number of pages13
JournalJACC: Clinical Electrophysiology
Volume3
Issue number3
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Publisher Copyright:
© 2017 American College of Cardiology Foundation

Keywords

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

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