Abstract 11048: Downregulation of HCN4 and the Pacemaker Current (If) Underlies Exercise Training-Induced Sinus Bradycardia
Background: Sinus bradycardia, the most common arrhythmia in endurance athletes, is usually attributed to heightened vagus nerve activity. This may become maladaptive; endurance athletes have a higher incidence of sick sinus syndrome and pacemaker implantation. Here we tested an alternative hypothesis that electrophysiological remodelling of the key pacemaking ion channel, HCN4, and the corresponding pacemaker current (If) underlies endurance training-induced resting bradycardia.
Methods and results: Trained mice (TM; 60 min swimming twice daily for 28 days) were compared to sedentary mice (SM). TM were bradycardic (cycle length in vivo: SM, 81±1.3 ms; TM, 102±3 ms; n=6, p<0.05). The cycle length of the isolated, denervated sinus node (intrinsic heart rate) was also prolonged by exercise training (SM, 110±3 ms; TM, 150±5 ms; n=7, p<0.05). Block of If by 2 mM Cs+ increased the cycle length of the isolated sinus node (SAN) by 28±3% in SM, but only by 5±2% in TM (p<0.05), suggesting that If is downregulated by training. Patch clamp recordings showed a 47% reduction in If density in isolated sinus node cells from trained mice (n=17-18 cells/5 mice, p<0.05). qPCR showed a 60% reduction in the level of HCN4 mRNA in the SAN from TM compared to SM (n=6, p<0.05) and quantitative immunohistochemistry showed a 32% reduction in the protein level of HCN4 (n=4, p<0.05). microRNA-1 levels were increased and Tbx3 mRNA was decreased in the TM compared to SM (n=6, p<0.05), both of which are known transcriptional regulators of HCN4. Detraining for two weeks reversed the in vivo and intrinsic cycle length differences between groups, restored the response to block of If and reversed changes in HCN4, microRNA-1 and Tbx3 expression, although there was a rebound beyond the pre-training level in all cases.
Conclusions: Electrophysiological remodelling of the SAN, rather than increased vagal tone, is the primary mechanism underlying exercise training-induced bradycardia. The effects may be mediated via HCN4 transcriptional regulators, microRNA-1 and Tbx3.This is a new concept in the understanding of the heart rate adaptation to exercise and may offer insight into the early pathophysiology of sinus node disease in some athletes.
- © 2013 by American Heart Association, Inc.