Copyright © 2004, European Society of Cardiology
Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3
aHospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Münster, Germany
bDepartment of Medical Informatics and Biomathematics, University of Münster, Germany
* Corresponding author. Medizinische Klinik und Poliklinik C, -Kardiologie und Angiologie-Universitätsklinikum Münster, Albert-Schweitzer Str. 33, D-48149 Münster, Germany. Tel.: +49 251 834 5160; fax: +49 251 834 9943. Email address: milbergp{at}uni-muenster.de
Background: Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed and the role of transmural dispersion of repolarization for the development of proarrhythmia was evaluated.
Methods and results: In 11 Langendorff-perfused rabbit hearts, veratridine (0.1–0.5 µM), an inhibitor of sodium channel inactivation, led to a concentration-dependent increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p<0.05) and thereby mimicked LQT3. Veratridine reproducibly induced early afterdepolarizations (EADs) and TdP after lowering potassium concentration. In bradycardic (AV-blocked) hearts, the increase in MAP duration showed marked regional differences. It was significantly more pronounced on the left endocardium as compared to left or right epicardium. This resulted in a significant increase in dispersion of repolarization (24% at 0.1 µM, 92% at 0.25 µM, 208% at 0.5 µM; p<0.01). Left ventricular transmural dispersion of repolarization increased significantly more than interventricular dispersion (104 to 33 ms at 0.5 µM veratridine; p<0.05).
Conclusion: By inhibition of sodium channel inactivation, veratridine mimics LQT3 in this intact heart model. In bradycardic, hypokalemic hearts, it reproducibly induced EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization may be considered an important target for the prevention of TdP in patients with LQT3.
KEYWORDS Torsade de pointes; Long QT syndrome; Action potential; prolongation; Transmural dispersion; Veratridine
1 Dr. Haverkamp's present address is: Department of Cardiology, Campus Virchow Clinic, Charité-University Medicine Berlin, Germany.
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