HCN212-channel biological pacemakers manifesting ventricular tachyarrhythmias are responsive to treatment with I-f blockade

Background: A potential concern about biological pacemakers is their possible malfunction, which might create ventricular tachycardias (VTs). Objective: The purpose of this study was to test our hypothesis that should VTs complicate implantation of HCN-channel-based biological pacemakers, they would be suppressed by inhibitors of the pacemaker current, If. Methods: We created a chimeric channel (HCN212) containing the N- and C-termini of mouse HCN2 and the transmembrane region of mouse HCN1 and implanted it in HEK293 cells. Forty-eight hours later, in whole-cell patch clamp recordings, mean steady state block induced by 3 μM ivabradine (IVB) showed HCN1 = HCN212 > HCN2 currents. The HCN212 adenoviral construct was then implanted into the canine left bundle branch in 11 dogs. Complete AV block was created via radiofrequency ablation, and a ventricular demand electronic pacemaker was implanted (VVI 45 bpm). Electrocardiogram, 24-hour Holter monitoring, and pacemaker log record check were performed for 11 days. Results: All dogs developed rapid VT (>120 bpm, maximum rate = 285 ± 37 bpm) at 0.9 ± 0.3 days after implantation that persisted through 5 ± 1 days. IVB, 1 mg/kg over 5 minutes, was administered during rapid VT, and three dogs received a second dose 24 hours later. While VT terminated with IBV in all instances within 3.4 ± 0.6 minutes, no effect of IVB on sinus rate was noted. Conclusion: We conclude that (1) If-associated tachyarrhythmias-if they occur with HCN-based biological pacemakers-can be controlled with If-inhibiting drugs such as IVB; (2) in vitro, IVB appears to have a greater steady state inhibiting effect on HCN1 and HCN212 isoforms than on HCN4; and (3) VT originating from the HCN212 injection site is suppressed more readily than sinus rhythm. This suggests a selectivity of IVB at the concentration attained for ectopic over HCN4-based pacemaker function. This might confer a therapeutic benefit.