title: Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone.
abstract: BACKGROUND
  Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patients with early repolarization (ER) pattern. This study examines the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome and examines the effectiveness of quinidine, cilostazol, and milrinone to prevent hypothermia-induced arrhythmias.
  
  
  RESULTS
  Transmembrane action potentials were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left ventricular wedge preparations, together with a pseudo-ECG. A combination of NS5806 (3-10 μmol/L) and verapamil (1 μmol/L) was used to pharmacologically model the genetic mutations responsible for ER syndrome. Acetylcholine (3 μmol/L) was used to simulate increased parasympathetic tone, which is known to promote ER. In controls, lowering the temperature of the coronary perfusate to induce mild hypothermia (32°C-34°C) resulted in increased J-wave area on the ECG and accentuated epicardial action potential notch but no arrhythmic activity. In the setting of ER, hypothermia caused further accentuation of the epicardial action potential notch, leading to loss of the action potential dome at some sites but not others, thus creating the substrate for development of phase 2 reentry and VT/VF. Addition of the transient outward current antagonist quinidine (5 μmol/L) or the phosphodiesterase III inhibitors cilostazol (10 μmol/L) or milrinone (5 μmol/L) diminished the ER manifestations and prevented the hypothermia-induced phase 2 reentry and VT/VF.
  
  
  CONCLUSIONS
  Hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities, leading to development of phase 2 reentry. Quinidine, cilostazol, and milrinone suppress the hypothermia-induced VT/VF by reversing the repolarization abnormalities.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Gurabi
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Bence
authors.initials: B
authors.lastname: Patocskai
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Nesterenko
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000077407:Cilostazol; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D007036:Hypothermia, Induced; D020105:Milrinone / Q000494:pharmacology*; D010477:Perfusion; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D011802:Quinidine; D020105:Milrinone; D000077407:Cilostazol
keywords: ST segment elevation; arrhythmia; phosphodiesterase 3 inhibitors; sudden cardiac death; tachycardia, ventricular; ventricular fibrillation