Mechanisms underlying increased right ventricular conduction sensitivity to flecainide challenge

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Abstract

Aims

The cardiac sodium current (INa) is a major determinant of conduction. Mechanisms underlying regionally heterogeneous conduction slowing secondary to reduced INa in diseases such as the Brugada syndrome and heart failure remain incompletely understood. Right precordial electrophysiological manifestations during flecainide challenge suggest a decreased right ventricular depolarization reserve. We hypothesized that heterogeneous cardiac sodium channel (Nav1.5) distribution between ventricles causes interventricular depolarization heterogeneities.

Methods and results

Western blotting analysis revealed Nav1.5, and Kir2.1 protein expressions were 18.2 and 12.0% lower, respectively, in the guinea pig right ventricle (RV) compared with the left ventricle (LV). Conduction velocity (θ) heterogeneities were quantified by optical mapping during LV or RV pacing. Although RV transverse θ (θT) was significantly greater than LV θT by 33.09 ± 1.38% under control conditions, there were no differences in longitudinal θ. During partial sodium channel blockade (flecainide, 0.5 µM), RV θ decreased by 35.3 ± 1.3%, whereas LV θ decreased by 29.2 ± 1.0%. These data demonstrate that the RV has an increased conduction dependence on sodium channel availability. Partial blockade of the inward rectifier potassium current (IK1) by BaCl2 (10 μm) significantly increased θ in both ventricles under control conditions. However, BaCl2 only increased conduction dependence on sodium channel availability in the LV. This suggests that the LV may have an increased depolarization reserve compared with the RV, but the larger IK1 depresses control LV θ.

Conclusion

Interventricular IK1 heterogeneities may underlie conduction heterogeneities observed under control conditions. However, under conditions where INa is functionally reduced in disease or during pharmacological sodium channel blockade, the heterogeneity in Nav1.5 expression may become a significant determinant of conduction heterogeneities.

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