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Increased Right Ventricular Repolarization Gradients Promote Arrhythmogenesis in a Murine Model of Brugada Syndrome
Article first published online: 6 APR 2010
© 2010 Wiley Periodicals, Inc.
Journal of Cardiovascular Electrophysiology
Volume 21, Issue 10, pages 1153–1159, October 2010
How to Cite
MARTIN, C. A., ZHANG, Y., GRACE, A. A. and HUANG, C. L.-H. (2010), Increased Right Ventricular Repolarization Gradients Promote Arrhythmogenesis in a Murine Model of Brugada Syndrome. Journal of Cardiovascular Electrophysiology, 21: 1153–1159. doi: 10.1111/j.1540-8167.2010.01767.x
Funding was provided by the British Heart Foundation, the Medical Research Council, the Wellcome Trust and the Biotechnology and Biological Research Council, UK. C. Martin was supported by a Medical Research Council Clinical Research Fellowship and a Sackler Studentship of the University of Cambridge School of Clinical Medicine. Y. Zhang was partially supported by the Chinese Nature Science Foundation (project numbers 30371571 and 30672209).
- Issue published online: 6 APR 2010
- Article first published online: 6 APR 2010
- Manuscript received 4 January 2010; Revised manuscript received 18 February 2010; Accepted for publication 22 February 2010.
- ion channels;
- sudden death;
- action potentials;
- conduction velocity;
- Brugada syndrome;
- sodium channels;
- ventricular tachycardia;
- antiarrhythmic drugs;
Repolarization Gradients in Brugada Syndrome. Introduction: Brugada syndrome (BrS) is associated with loss of Na+ channel function and increased risks of a ventricular tachycardia exacerbated by flecainide but reduced by quinidine. Previous studies in nongenetic models have implicated both altered conduction times and repolarization gradients in this arrhythmogenicity. We compared activation latencies and spatial differences in action potential recovery between different ventricular regions in a murine Scn5a+/− BrS model, and investigated the effect of flecainide and quinidine upon these.
Methods and Results: Langendorff-perfused wild-type and Scn5a+/− hearts were subjected to regular pacing and a combination of programmed electrical stimulation techniques. Monophasic action potentials were recorded from the right (RV) and left ventricular (LV) epicardium and endocardium before and following flecainide (10 μM) or quinidine (5 μM) treatment, and activation latencies measured. Transmural repolarization gradients were then calculated from the difference between neighboring endocardial and epicardial action potential durations (APDs). Scn5a+/− hearts showed decreased RV epicardial APDs, accentuating RV, but not LV, transmural gradients. This correlated with increased arrhythmic tendencies compared with wild-type. Flecainide increased RV transmural gradients, while quinidine decreased them, in line with their respective pro- and antiarrhythmic effects. In contrast, Scna5+/− hearts showed slowed conduction times in both RV and LV, exacerbated not only by flecainide but also by quinidine, in contrast to their differing effects on arrhythmogenesis.
Conclusion: We use a murine genetic model of BrS to systematically analyze LV and RV action potential kinetics for the first time. This establishes a key role for accentuated transmural gradients, specifically in the RV, in its arrhythmogenicity. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1153-1159)