Increased right ventricular repolarization gradients promote arrhythmogenesis in a murine model of Brugada syndrome.
BACKGROUND
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.


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.


CONCLUSIONS
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.
Martin
Claire A
CA
Physiological Laboratory, University of Cambridge, Downing Site, Cambridge, United Kingdom. clairemartin@gmail.com
Zhang
Yanmin
Y
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000200:Action Potentials; D000818:Animals; D053840:Brugada Syndrome / Q000503:physiopathology*; D004195:Disease Models, Animal; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D051379:Mice
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