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Genetic Architecture, Pathophysiology, and Clinical Management of Brugada Syndrome

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Cardiac Repolarization

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Abstract

Brugada syndrome (BrS) is a genetically complex and heterogeneous disorder characterized by ST-segment elevation in the right precordial leads and an increased risk of syncope and sudden cardiac death in the setting of an otherwise structurally normal heart. Over the last several years, advances at both the bench and the bedside have begun to question existing paradigms surrounding the genetic basis and pathophysiology of BrS as well as usher in novel approaches to the risk stratification and treatment of patients with this potentially fatal disorder. In this chapter, we examine the rapidly evolving understanding of the pathophysiological mechanism(s) underlying BrS, ongoing efforts to reappraise the genetic architecture of BrS, and advances in risk stratification and therapeutic approaches that are redefining how patients with BrS are managed clinically.

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Abbreviations

ACC:

American College of Cardiology

AHA:

American Heart Association

BrS:

Brugada syndrome

ClinGen:

Clinical Genome Resource

EHRA:

European Heart Rhythm Association

EPS:

Electrophysiology study

ESC:

European Society of Cardiology

ExAC:

Exome Aggregation Consortium

gnomAD:

Genome Aggregation Database

GUS:

Gene of uncertain significance

GWAS:

Genome-Wide Association Study

HRS:

Heart Rhythm Society

ICD:

Implantable cardioverter-defibrillator

PVC:

Premature ventricular contraction

RVOT:

Right ventricular outflow tract

SCD:

Sudden cardiac death

VF:

Ventricular fibrillation

VT:

Ventricular tachycardia

VUS:

Variant of uncertain significance

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Funding Sources

This work was supported by the Mayo Clinic Windland Smith Rice Sudden Comprehensive Sudden Cardiac Death Program (to Dr. Ackerman). Dr. Giudicessi thanks the Mayo Clinic Cardiovascular Diseases Fellowship and Clinician Investigator Training Programs for fostering an outstanding environment for physician-scientist training.

Conflict of Interest Disclosures

Dr. Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical. From 2004 to 2016, M.J.A. and Mayo Clinic received sales-based royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests. M.J.A. and Mayo Clinic have an equity/royalty relationship (without remuneration so far) with AliveCor, Blue Ox Health, and StemoniX. However, none of these entities participated in this study. Dr. Giudicessi declares no conflicts.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

    John R. Giudicessi

  2. Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Rochester, MN, USA

    Michael J. Ackerman

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  1. Department of Medicine and Physiology, State University of New York Downstate Medical Center, VA New York Harbor Healthcare Center, Brooklyn, NY, USA

    Nabil El-Sherif

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Giudicessi, J.R., Ackerman, M.J. (2020). Genetic Architecture, Pathophysiology, and Clinical Management of Brugada Syndrome. In: El-Sherif, N. (eds) Cardiac Repolarization. Springer, Cham. https://doi.org/10.1007/978-3-030-22672-5_17

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