Mechanisms underlying increased right ventricular conduction sensitivity to flecainide challenge.
OBJECTIVE
The cardiac sodium current (I(Na)) is a major determinant of conduction. Mechanisms underlying regionally heterogeneous conduction slowing secondary to reduced I(Na) 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 (Na(v)1.5) distribution between ventricles causes interventricular depolarization heterogeneities.


RESULTS
Western blotting analysis revealed Na(v)1.5, 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 (theta) heterogeneities were quantified by optical mapping during LV or RV pacing. Although RV transverse theta((thetaT)) was significantly greater than LV (thetaT) by 33.09 +/- 1.38% under control conditions, there were no differences in longitudinal theta. During partial sodium channel blockade (flecainide, 0.5 microM), RV theta decreased by 35.3 +/- 1.3%, whereas LV theta 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 (I(K1)) by BaCl(2) (10 microm) significantly increased theta in both ventricles under control conditions. However, BaCl(2) 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 I(K1) depresses control LV theta.


CONCLUSIONS
Interventricular I(K1) heterogeneities may underlie conduction heterogeneities observed under control conditions. However, under conditions where I(Na) is functionally reduced in disease or during pharmacological sodium channel blockade, the heterogeneity in Na(v)1.5 expression may become a significant determinant of conduction heterogeneities.
Veeraraghavan
Rengasayee
R
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112-5000, USA.
Poelzing
Steven
S
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D017609:Barium Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D002712:Chlorides / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology*; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007008:Hypokalemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects*
D000889:Anti-Arrhythmia Agents; D017609:Barium Compounds; D002712:Chlorides; C489461:Kir2.1 channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C024986:barium chloride; D012964:Sodium; D005424:Flecainide; D011188:Potassium