title: Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome.
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.
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Pharmacology & Pharmacotherapy, University of Szeged, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Pharmacology & Pharmacotherapy, University of Szeged, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Gurabi
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Pharmacology & Pharmacotherapy, University of Szeged, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: Bence
authors.initials: B
authors.lastname: Patocskai
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Panama
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Pharmacology & Pharmacotherapy, University of Szeged, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martínez
authors.affiliation: Department of Molecular Genetics, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA; Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA. Electronic address: ca@mmrl.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D004285:Dogs; D005260:Female; D006329:Heart Conduction System / Q000002:abnormalities* / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000503:physiopathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D013577:Syndrome; D013777:Tetrazoles / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: C541204:1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea; D000889:Anti-Arrhythmia Agents; D010671:Phenylurea Compounds; D013777:Tetrazoles; D014700:Verapamil
keywords: Electrophysiology; J wave syndrome; Parasympathetic tone; Transient outward potassium current; Ventricular fibrillation