Abstract 1252: Cav1.3 L-type Calcium Channel Loss of Function in Mouse Results in Tachy-brady Syndrome
Recent works with Cav1.3-knockout mice have shown that the Cav1.3 L-type Ca2+ channel, which is expressed predominantly in the atria and nodes, plays a major role in the generation of cardiac pacemaker activity. This and the well-known relationship between sinoatrial node dysfunction (SND) and atrial fibrillation led us to focus on atrial arrhythmia susceptibility of Cav1.3-knockout mice, both homozygous (Cav1.3−/−) and heterozygous (Cav1.3+/−). Surface ECG recorded under anesthesia showed that Cav1.3−/− mice had a marked bradycardia (RR=236±36 ms; n=10) when compared to wild-type (WT; RR=143±7; n=10; p<0.05) or Cav1.3+/− mice (RR=138±7 ms; n=8; p<0.05). PQ interval duration was longer in Cav1.3−/− (57±3 ms) than in WT (42±1 ms; p<0.01) or Cav1.3+/− mice (38±2 ms; p<0.01). P wave duration was also prolonged (19±1 ms vs 15±1 ms in WT and 13±1 ms in Cav1.3+/−; p<0.05 for both), indicating conduction anomalies in the atria. Other ECG parameters were unaltered. Telemetric recordings showed that Cav1.3−/− mice had numerous sinus pauses and periods of wandering pacemaker associated with paroxysmal atrial fibrillation. Intracardiac electrophysiological recordings revealed that atrioventricular effective refractory period (ERP) was longer in Cav1.3−/− mice compared to WT and Cav1.3+/− (89±1 ms vs 65±4 ms and 57±4 ms; p<0.01; n=7, 10, 8). No difference was observed in the atrial and ventricular ERP between the groups. In 5/10 Cav1.3−/− mice, atrial extrastimuli induced severe atrial arrhythmias, either atrial flutter or fibrillation that could last >10 min. No arrhythmias were induced in WT mice. Only 2/8 Cav1.3+/− mice experienced short runs of atrial tachycardia. In conclusion, SND resulting from Cav1.3 loss-of-function provides a substrate for atrial fibrillation. Our findings highlight the importance of Ca2+ disturbance in the atria as a possible cause for remodeling and atrial fibrillation.