Reversibility of both sinus node dysfunction and reduced HCN4 mRNA expression level in an atrial tachycardia pacing model of tachycardia-bradycardia syndrome in rabbit hearts

Objective: The aim of this study was to investigate potential reversible changes in sinus node function and mRNA expression levels of hyperpolarization-activated, cyclic nucleotide-gated ion channel subunit 4 (HCN4) in a tachycardia pacing model in rabbits. Methods: A total of 45 adult New Zealand white rabbits were randomized into the following three groups (n=15): pacing only, pacing-recovery and control. Following open thoracotomy, temporary pacing leads were attached to the right atrium. In the pacing only group, rapid atrial pacing was initiated at a rate of 350 stimuli per minute for 8 hours a day, continuing for 7 days. In the pacing-recovery group, the same pacing protocol was delivered, but pacing was then stopped for 7 days. In the control group, no tachycardia pacing was delivered. The following parameters were measured before and after intervention, and compared between the groups: resting heart rate, intrinsic heart rate (measured after metoprolol and atropine administration) and corrected sinus node recovery time (CSNRT). The rabbits were then killed, following which the sinus nodes were excised and used for testing of hyperpolarization-induced cyclic nucleotide gated (HCN) 4 mRNA expression. Results: In the pacing only group, the resting heart rate and intrinsic heart rate were decreased (219.71 ± 3.59 vs. 275.86 ± 13.31 bpm and 202.00 ± 4.76 vs. 227.14 ± 4.98 bpm, respectively; P < 0.05) and CSNRT was prolonged (96.00 ± 3.56 vs. 72.00 ± 2.31 ms) after tachycardia pacing. In the intervention-recovery group, similar changes in resting heart rate, intrinsic heart rate and CSNRT were observed after tachycardia pacing. After 7 days of recovery, all three parameters returned to normal values (resting heart rate: 264.67 ± 9.82 vs. 222.56 ± 5.90 bpm; intrinsic heart rate 219.33 ± 5.67 vs 213.86 ± 3.29 bpm; CSNRT 76.33 ± 5.89 vs. 99.44 ± 6.17 ms, all P < 0.05). The HCN4 mRNA expression level in the pacing only group was reduced compared to the control group (0.37 ± 0.04 vs 0.65 ± 0.04, P < 0.05). This recovered from 0.35 ± 0.04 to 0.60 ± 0.04 in the pacing-recovery group. Conclusion: Rapid atrial pacing led to reversible sinus node dysfunction, which was partly due to return of HCN4 expression. Electrophysiological remodeling of I_f may be important in sinus node dysfunction observed in tachycardia-bradycardia syndrome.