Aims: 

We explored the distribution pattern of Na+ channels across ventricular wall, and its contribution to transmural electrophysiological heterogeneities, in the guineapig heart.

Methods: 

Nav protein expression levels were measured in ventricular tissue by Western blotting. Isolated, perfused heart preparations were used to record monophasic action potentials and volume-conducted ECG, and to assess effective refractory periods (ERP), pacing thresholds, and arrhythmic susceptibility, at epicardial and endocardial stimulation sites.

Results: 

In both ventricular chambers, Nav protein expression was higher at endocardium than epicardium, with midmyocardial layers showing intermediate expression levels. Endocardial stimulation sites showed higher excitability, as evidenced by lower pacing thresholds during regular stimulation, and downward displacement of the strength-interval curve reconstructed following extrasystolic stimulation, when compared to epicardium. The ERP restitution showed greater maximal slope and faster kinetics at endocardial than epicardial stimulation sites. Flecainide, a Na+ channel blocker, reduced the maximal ERP restitution slope, slowed restitution kinetics, and eliminated epicardial-to-endocardial difference in dynamics of electrical restitution. Greater excitability and steeper electrical restitution were associated with greater arrhythmic susceptibility of endocardium than epicardium, as assessed by measuring ventricular fibrillation threshold, inducibility of tachyarrhythmias by rapid cardiac pacing, and the magnitude of repolarization alternans.

Conclusion: 

Higher Na+ channel expression levels contribute to greater excitability, steeper electrical restitution slopes, and greater arrhythmic susceptibility, at endocardium than epicardium.