Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome

J Mol Cell Cardiol. 2014 Mar;68:20-8. doi: 10.1016/j.yjmcc.2013.12.012. Epub 2013 Dec 28.

Abstract

Early repolarization pattern in the ECG has been associated with increased risk for ventricular tachycardia/fibrillation (VT/VF), particularly when manifest in inferior leads. This study examines the mechanisms underlying VT/VF in early repolarization syndrome (ERS). Transmembrane action potentials (APs) were simultaneously recorded from 2 epicardial sites and 1 endocardial site of coronary-perfused canine left-ventricular (LV) wedge preparations, together with a pseudo-ECG. Transient outward current (Ito) was recorded from epicardial myocytes isolated from the inferior and lateral LV of the same heart. J wave area (pseudo-ECG), epicardial AP notch magnitude and index were larger in inferior vs. lateral wall preparations at baseline and after exposure to provocative agents (NS5806+verapamil+acetylcholine (ACh)). Ito density was greater in myocytes from inferior vs. lateral wall (18.4 ± 2.3pA/pF vs. 11.6 ± 2.0pA/pF; p<0.05). A combination of NS5806 (7 μM) and verapamil (3 μM) or pinacidil (4 μM), used to pharmacologically model the genetic defects responsible for ERS, resulted in prominent J-point and ST-segment elevation. ACh (3 μM), simulating increased vagal tone, precipitated phase-2-reentry-induced polymorphic VT/VF. Using identical protocols, inducibility of arrhythmias was 3-fold higher in inferior vs. lateral wedges. Quinidine (10 μM) or isoproterenol (1 μM) restored homogeneity and suppressed VT/VF. Our data support the hypothesis that 1) ERS is caused by a preferential accentuation of the AP notch in the LV epicardium; 2) this repolarization defect is accentuated by elevated vagal tone; 3) higher intrinsic levels of Ito account for the greater sensitivity of the inferior LV wall to development of VT/VF; and 4) quinidine and isoproterenol exert ameliorative effects by reversing the repolarization abnormality.

Keywords: Electrophysiology; J wave syndrome; Parasympathetic tone; Transient outward potassium current; Ventricular fibrillation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / physiopathology*
  • Brugada Syndrome
  • Cardiac Conduction System Disease
  • Dogs
  • Female
  • Heart Conduction System / abnormalities*
  • Heart Conduction System / drug effects
  • Heart Conduction System / physiopathology
  • Heart Ventricles / physiopathology*
  • In Vitro Techniques
  • Male
  • Myocardial Contraction
  • Patch-Clamp Techniques
  • Pericardium / physiopathology
  • Phenylurea Compounds / pharmacology
  • Syndrome
  • Tetrazoles / pharmacology
  • Verapamil / pharmacology

Substances

  • 1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea
  • Anti-Arrhythmia Agents
  • Phenylurea Compounds
  • Tetrazoles
  • Verapamil