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Genetics, Molecular Biology, and Emerging Concepts of Early Repolarization Syndrome

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Cardiac Repolarization

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Abstract

Early repolarization pattern (ERP) has traditionally been regarded as benign and is often encountered in apparently healthy individuals. In the absence of organic heart disease and when associated with ventricular tachycardia (VT) or fibrillation (VF), ERP is referred to as early repolarization syndrome (ERS) and is considered to be one of the J wave syndromes (JWS). To date, ERS has been associated with variants in seven different genes but a large number of variants remain in “genetic purgatory.” In ERS, an outward shift in the balance of current during the early phase of the left ventricular (LV) epicardial action potential (AP) secondary to genetic defects in either inward or outward currents is thought to lead to accentuation of the Ito-mediated action potential (AP) notch in ventricular epicardium but not endocardium, giving rise to a J wave in the ECG, particularly in the inferior LV. Loss of the AP dome at some epicardial sites but not others creates an epicardial dispersion of repolarization giving rise to phase 2 reentrant extrasystole. Loss of the epicardial AP dome also creates a transmural dispersion of repolarization giving rise to a vulnerable window across the ventricular wall which when captured by the closely coupled phase 2 reentrant extrasystole can induce VT/VF. Recent consensus statements and guidelines provide recommendations for therapy of ERS. The most effective therapy for the prevention of SCD in high-risk ERS patients is an implantable cardioverter defibrillator (ICD). The pharmacologic approach to therapy involves inhibition of Ito, augmentation of ICa or slowing of inactivation of INa. Experimental evidence has been advanced showing an ameliorative effect of radiofrequency ablation of the inferior LV epicardium; however clinical data are lacking at this time.

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Abbreviations

AP :

action potential

ECG :

electrocardiogram

EG :

electrogram

ERS :

early repolarization syndrome

BrS :

Brugada syndrome

JWS:

J wave syndromes

LV :

left ventricle

P2R :

phase-2-reentry

RFA :

radiofrequency ablation

RVOT:

right ventricular outflow tract

VF:

ventricular fibrillation

VT:

ventricular tachycardia

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Funding

We acknowledge support from NIH-NHLBI Grant #HL47678, the W.W. Smith Charitable Trust Grant #1820 and from the Martha and Wistar Morris Fund.

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Authors and Affiliations

  1. Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA, USA

    Charles Antzelevitch

  2. Lankenau Heart Institute, Wynnewood, PA, USA

    Charles Antzelevitch

  3. Sidney Kimmel Medical School, Thomas Jefferson University, Philadelphia, PA, USA

    Charles Antzelevitch

  4. Cardiovascular Division, Pietro Cosma Hospital, Padova, Italy

    Gregory Dendramis

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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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Antzelevitch, C., Dendramis, G. (2020). Genetics, Molecular Biology, and Emerging Concepts of Early Repolarization Syndrome. In: El-Sherif, N. (eds) Cardiac Repolarization. Springer, Cham. https://doi.org/10.1007/978-3-030-22672-5_14

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