Abstract
Rationale: Athletes present with atrioventricular node dysfunction manifesting as atrioventricular block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: Atrioventricular block in athletes is attributed to high vagal tone. Here, we investigated the alternative hypothesis that electrical remodeling of the atrioventricular node is responsible. Methods and Results: Radiotelemetry ECG data and atrioventricular node biopsies were collected in sedentary and trained Standardbred racehorses, a large-animal model of the athlete’s heart. Trained horses presented with longer PR intervals (that persisted under complete autonomic block) versus sedentary horses, concomitant with reduced expression of key ion channels involved in atrioventricular node conduction: L-type Ca 2+ channel subunit Ca V 1.2 and HCN4 (hyperpolarization-activated cyclic nucleotide-gated channel 4). Atrioventricular node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length, and atrioventricular node refractory period were observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected atrioventricular node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of Ca V 1.2 and HCN4. Correspondingly, patch-clamp recordings in isolated atrioventricular node myocytes demonstrated a training-induced reduction in I Ca, L and I f density that likely contributed to the observed lower frequency of action potential firing in trained cohorts. MicroRNA (miR) profiling and in vitro studies revealed miR-211-5p and miR-432 as direct regulators of Ca V 1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced atrioventricular node dysfunction is underscored by likely miR-mediated transcriptional remodeling that translates into reduced current density of key ionic currents involved in impulse generation and conduction. We conclude that electrical remodeling is a key mechanism underlying atrioventricular block in athletes.