Abstract 16820: CaMKIIδc Transgenic Mice Develop Spontaneous Ventricular Arrhythmias Which Can Be Suppressed by Inhibition of Late Na+ Current

Abstract

Introduction: It has been shown that activated CaMKII can phosphorylate cardiac Na+ channels that leads to an enhanced late Na current (INaL). We hypothesized that enhanced INaL plays an important role in arrhythmogenesis linked to increased CaMKII activity. To test this hypothesis we determined the effect of a selective INaL inhibitor GS-967 on spontaneously occurring ventricular arrhythmias in mice overexpressing CaMKIIδc (TG). Methods: TG (n=6) and wild type (WT, n=3) mice at age 8 week (wk) were instrumented with telemetry transmitters to record ECG. ECG were recorded continuously starting 1 wk post- surgery (age 9 wk) until age 19 wk. Incidence and burden of arrhythmias were evaluated at ages 9, 11, 13, 15, 17 and 19 wks using DSI ECG Pro software. At age 17 wk, when arrhythmia burden was relatively stable, mice were treated with a single dose of GS-967 (1 mg/kg, i.p.) or vehicle. After 4 days of washout, the treatment was repeated in a cross-over manner. Arrhythmia burden was quantified over a duration of 15-hours post-treatment. Using patch clamp technique, INaL was measured in ventricular myocytes isolated from both TG and WT mice at 17 wk age. Results: Incidence and burden of spontaneous ventricular arrhythmias increased progressively with age in TG mice. Between age 9 and 11 wks, 50% of TG mice had an arrhythmia burden ≥ 5 minutes/24 hours. The incidence increased to 83% at wk 13, 15, 17 and to 100% at 19 wks and the burden increased to 71 ± 35 min/24 hr at 17 wk. A single dose of GS-967 significantly decreased arrhythmia burden from 42.5 ± 9.6 min (treated with vehicle) to 9.4 ± 4.3 min (p<0.05) during a 15-hr period. No arrhythmias were observed in WT mice during the course of the study. INaL was enhanced by more than 2-fold in myocytes isolated from TG mice compared to WT (0.2±0.03 vs. 0.08±0.02 pA/pF, n=16 each, p<0.05). GS-967 caused a concentration-dependent reduction of INaL (50.5±3.4% at 0.3 μM, n=7; and 91±5.2% at 1 μM, n=4). Conclusions: This is the first report to show a reduction of spontaneously occurring ventricular arrhythmias by inhibition of INaL indicating a key role for INaL in CaMKII associated arrhythmogenesis.