Abstract 2868: T-type Calcium Current Governs Ventricular Escape Rate and the Occurrence of Lethal Arrhythmias Following Acute Atrioventricular Block
Background: The T-type Ca2+-current (ICaT) is thought to play a role in cardiac pacemaking, but its precise importance is unknown. Knockout (KO) of Cav3.1 (the principal cardiac ICaT α-subunit) modestly but significantly slows sinus node pacemaker activity. Here, we investigated the role of Cav3.1 in governing cardiac rhythm following complete atrioventricular block (AVB) by studying KO mice lacking Cav3.1 (Cav3.1−/−) and wild type (WT) controls.
Methods: Adult male KO and WT mice implanted with ECG telemetry devices underwent radiofrequency AV-node ablation via an octapolar catheter inserted through the jugular vein to produce AVB.
Results: At baseline, KO mice showed sinus bradycardia (RR intervals 149±3 ms, n=10, vs WT 132±2 ms, n=10, p<0.01). Immediately after AV-node ablation, KO mice had substantially slower ventricular escape rates than WT mice (RR intervals 650±75 ms vs 331±30 ms, p<0.01). Ventricular escape rhythm became progressively slower over the next 4 hours in both KO and WT, but RR intervals continued to be longer in KO mice (1298±62 ms vs WT 806±38 ms, p<0.001). No differences were observed in ventricular effective refractory periods, either at baseline or after AVB. Bradycardia-related Torsades de Pointes (TdP) occurred more frequently in KO mice (10/11, 91%) than WT (3/7, 43%, p<0.05) over the first 24 hours after AV block. Seventy percent (7/10) of KO mice died vs 25% (2/8) of WT, during the first 24 hours after AVB. Among survivors at 4 weeks post-AVB, ventricular tachyarrhythmia (>5 consecutive beats) occurrence over 12 hours by telemetry was increased in KO vs WT mice (354±89 vs 108±41 episodes respectively, p<0.05). At 4 weeks post-AVB, ventricular escape rhythm continued to be slower in KO mice than WT (RR: 444±10 vs 353±7 ms respectively, p<0.001).
Conclusion: This study suggests that Cav3.1 (ICaT) plays an important role in spontaneous ventricular pacemaking and escape rhythms. Loss of Cav3.1 increases the risk of AVB-associated TdP, probably via more severe bradycardia-related remodeling. This work provides the first definitive evidence for a role of ICaT in ventricular-escape automaticity and suggests that the expression of Cav3.1 subunits may be an important determinant of the risk of lethal arrhythmias complicating acute AV block.