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PRECLINICAL STUDY

Cellular Basis for Trigger and Maintenance of Ventricular Fibrillation in the Brugada Syndrome Model

High-Resolution Optical Mapping Study

Takeshi Aiba, MD, PhD^_*, Wataru Shimizu, MD, PhD^,_*, Ichiro Hidaka, MS^_*, Kazunori Uemura, MD^_*, Takashi Noda, MD, PhD^_*, Can Zheng, PhD^_*, Atsunori Kamiya, MD^_*, Masashi Inagaki, MD^_*, Masaru Sugimachi, MD, PhD^_* and Kenji Sunagawa, MD, PhD^_*

^_* Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Suita, Japan
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Japan.

Manuscript received November 10, 2005; revised manuscript received November 25, 2005, accepted December 13, 2005.

^_* Reprint requests and correspondence: Dr. Wataru Shimizu, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565 Japan. (Email: wshimizu{at}hsp.ncvc.go.jp).

Presented in part at the Scientific Session of the American Heart Association, November 7–10, 2004, and published in abstract form (Circulation 2004;110 Suppl III:III318).

OBJECTIVES: We examined how repolarization and depolarization abnormalities contribute to the development of extrasystoles and subsequent ventricular fibrillation (VF) in a model of the Brugada syndrome.

BACKGROUND: Repolarization and depolarization abnormalities have been considered to be mechanisms of the coved-type ST-segment elevation (Brugada-electrocardiogram [ECG]) and development of VF in the Brugada syndrome.

METHODS: We used high-resolution (256 x 256) optical mapping techniques to study arterially perfused canine right ventricular wedges (n = 20) in baseline and in the Brugada-ECG produced by administration of terfenadine (5 µmol/l), pinacidil (2 µmol/l), and pilsicainide (5 µmol/l). We recorded spontaneous episodes of phase 2 re-entrant (P2R)-extrasystoles and subsequent self-terminating polymorphic ventricular tachycardia (PVT) or VF under the Brugada-ECG condition and analyzed the epicardial conduction velocity and action potential duration (APD) restitutions in each condition.

RESULTS: Forty-one episodes of spontaneous P2R-extrasystoles in the Brugada-ECG were successfully mapped in 9 of 10 preparations, and 33 of them were originated from the maximum gradient of repolarization (GR_max: 176 ± 54 ms/mm) area in the epicardium, leading to PVT (n = 12) or VF (n = 5). The epicardial GR_max was not different between PVT and VF. Wave-break during the first P2R-extrasystole produced multiple wavelets in all VF cases, whereas no wave-break or wave-break followed by wave collision and termination occurred in PVT cases. Moreover, conduction velocity restitution was shifted lower and APD restitution was more variable in VF cases than in PVT cases.

CONCLUSIONS: Steep repolarization gradient in the epicardium but not endocardium develops P2R-extrasystoles in the Brugada-ECG condition, which might degenerate into VF by further depolarization and repolarization abnormalities.

Abbreviations and Acronyms   AP = action potential   APD = action potential duration   APD50 = action potential duration measured at 50% repolarization   BCL = basic cycle length   Brugada-ECG = coved-type ST-segment elevation   Delta-Epi interval = interval from the earliest to the latest epicardial activation   DR = dispersion of repolarization   ECG = electrocardiogram/electrocardiography   GRmax = maximum gradient of repolarization   ICa = inward calcium current   IK-ATP = ATP-sensitive potassium current   INa = sodium current   Ito = transient outward potassium current   P2R = phase 2 re-entrant/entry   RV = right ventricle/ventricular   Sti-Epi interval = interval from the stimulus to the earliest epicardial activation   VF = ventricular fibrillation   VT = ventricular tachycardia

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