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. METHODS AND 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.
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. METHODS AND 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: Michel Haïssaguerre; Nicolas Derval; Frederic Sacher; Laurence Jesel; Isabel Deisenhofer; Luc de Roy; Jean-Luc Pasquié; Akihiko Nogami; Dominique Babuty; Sinikka Yli-Mayry; Christian De Chillou; Patrice Scanu; Philippe Mabo; Seiichiro Matsuo; Vincent Probst; Solena Le Scouarnec; Pascal Defaye; Juerg Schlaepfer; Thomas Rostock; Dominique Lacroix; Dominique Lamaison; Thomas Lavergne; Yoshifusa Aizawa; Anders Englund; Frederic Anselme; Mark O'Neill; Meleze Hocini; Kang Teng Lim; Sebastien Knecht; George D Veenhuyzen; Pierre Bordachar; Michel Chauvin; Pierre Jais; Gaelle Coureau; Genevieve Chene; George J Klein; Jacques Clémenty Journal: N Engl J Med Date: 2008-05-08 Impact factor: 91.245
Authors: Charles Antzelevitch; Gan-Xin Yan; Michael J Ackerman; Martin Borggrefe; Domenico Corrado; Jihong Guo; Ihor Gussak; Can Hasdemir; Minoru Horie; Heikki Huikuri; Changsheng Ma; Hiroshi Morita; Gi-Byoung Nam; Frederic Sacher; Wataru Shimizu; Sami Viskin; Arthur A M Wilde Journal: Europace Date: 2017-04-01 Impact factor: 5.214
Authors: Shreyas Yakkali; Sneha Teresa Selvin; Sonu Thomas; Viktoriya Bikeyeva; Ahmed Abdullah; Aleksandra Radivojevic; Anas A Abu Jad; Anvesh Ravanavena; Chetna Ravindra; Emmanuelar O Igweonu-Nwakile; Safina Ali; Salomi Paul; Pousette Hamid Journal: Cureus Date: 2022-07-13