Abstract 8633: Right Ventricular Origin of Arrhythmias in Scn5a+/- Mice Modeling Brugada Syndrome is Due to Reduced Na+ and Higher K+ Channel Expression and Function in the Right Ventricle
Brugada syndrome is associated with ventricular tachycardia originating in the right ventricle (RV); this has been attributed to either depolarization abnormalities or increased repolarization heterogeneities. We use a heterozygotic Scn5a+/- murine model to test these hypotheses. Nav1.5 mRNA and protein expression were lower in Scn5a+/- than wild-type (WT) hearts, with a further reduction in the RV (panel A, n = 4, significant differences: * = WT vs Scn5a+/-; # = LV vs RV). There were higher expression levels of Kv4.2, Kv4.3 and KChIP2 in RV than LV in both groups. Action potential (AP) upstroke velocity was decreased in Scn5a+/- (RV: 59.43 +/- 2.70 V/s to 30.26 +/- 4.03 V/s, p < 0.0001, n = 20), and furthermore was smaller in RV than LV. AP durations were smallest in the RV of Scn5a+/- myocytes. Transient outward current density (Ito) was greater in the RV of both WT and Scn5a+/- (panel B, n = 17), with similar voltage dependence of activation. Time constants of inactivation were larger in RV than LV, and voltage dependence of inactivation was shifted to more negative values in RV compared to LV, but to more positive values in Scn5a+/- compared to WT. Maximum Na+ current density (INa) was decreased in Scn5a+/-, with a further reduction in the RV (panels C, D, n = 17). Voltage dependence of activation was unchanged, but inactivation was shifted to more negative values in Scn5a+/-. Maximum persistent Na+ current density (IpNa) was decreased in a similar pattern to INa (RV: -0.30 +/- 0.03 pA/pF, n = 15 vs -0.17+/- 0.02 pA/pF, n = 22, p =0.0009). Our findings show preferential upregulation of the single Scn5a gene in the LV of the Scn5a+/- mice compared to RV. The reduced expression of Na+ channels in RV leads to smaller INa, resulting in slowed conduction, and smaller IpNa, which in combination with increased Ito, results in shorter AP durations and greater heterogeneity of repolarization, thus suggesting arrhythmogenesis may be initiated by both mechanisms in the RV of Scn5a+/- hearts.
- © 2011 by American Heart Association, Inc.