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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 4, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm090
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Mechanisms Underlying Increased Right Ventricular Conduction Sensitivity to Flecainide Challenge

Rengasayee Veeraraghavan and Steven Poelzing, Ph.D

Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT

Address correspondence to: Steven Poelzing, Ph.D. Nora Eccles Harrison Cardiovascular Research and Training Institute University of Utah 95 South 2000 East, Salt Lake City, UT 84112-5000 TEL: (801) 585-1862 FAX: (801) 581-3128 e-mail: poelzing{at}cvrti.utah.edu

Aims: The cardiac sodium current (INa) is a major determinant of conduction. Mechanisms underlying regionally heterogeneous conduction slowing secondary to reduced INa in diseases like 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 guinea pig right ventricle (RV) compared to left ventricle (LV). Conduction velocity ({theta}) heterogeneities were quantified by optical mapping during LV or RV pacing. While RV transverse {theta} ({theta}T) was significantly greater than LV {theta}T by 33.09 ± 1.38% under control conditions, there were no differences in longitudinal{theta}. During partial sodium channel blockade (flecainide, 0.5 µM), RV {theta} decreased by 35.3 ± 1.3% while LV {theta} decreased by 29.2 ± 1.0%. These data demonstrate that the RV has an increased conduction dependence on sodium channel availability. Partial IK1 blockade by BaCl2 (10 µM) significantly increased {theta} 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 to the RV but the larger IK1 depresses control LV{theta}.

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

Time for primary review: 28


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