Intrinsic Electrical Remodeling Underlies Atrioventricular Block in Athletes

Abstract

Rationale: Athletes present with atrioventricular node (AV node) dysfunction manifesting as AV block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: AV block in athletes is attributed to high vagal tone. Here we investigated the alternative hypothesis that electrical remodeling of the AV node is responsible. Methods and Results: Radio-telemetry ECG data and AV 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 AV node conduction: L-type Ca2+ channel subunit CaV1.2 and the hyperpolarization-activated cyclic nucleotide gated channel 4 (HCN4). AV node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length and AV node refractory period was observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected AV node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of CaV1.2 and HCN4. Correspondingly, patch clamp recordings in isolated AV node myocytes demonstrated a training-induced reduction in ICa,L and If 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 CaV1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced AV 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 AV block in athletes.

Electrocardiographic characteristics of trained and untrained standardbred racehorses

“…To our knowledge, a single study, conducted in our laboratory, evaluated the effect of training on 2AVB in a small group of horses, where a difference between trained and untrained horses was not identified and the types of 2AVB were not classified. However, in this study the trained horses had longer PR intervals, which supported altered AV conduction, possibly caused by intrinsic remodeling within the AV node 16 …”

“…56 In parallel, we previously documented prolongation of the PR interval that persisted in trained horses compared to untrained horses after simultaneous pharmacological blockage of both the sympathetic and parasympathetic nervous systems. 16 Also we identified down-regulation of important pacemaker ion channels, including the hyperpolarizationactivated cyclic nucleotide-gated channel 4 (HCN4) and the L-type calcium channels (Cav1.2) within the AV node in trained horses, which could be responsible for the slowed AV conduction seen in both human and equine athletes. 16…”

Editorial: Cardiac Pacemaking in Health and Disease: From Genes to Function

“…Finally, Bidaud et al demonstrate that genetic ablation of G-protein-gated inwardly rectifying potassium channels (responsible for I KAch current) counteracts slowed pacemaking induced by exercise training in mice by preventing transcriptional and electrical remodelling of pacemaking ion channels. This work builds on findings by D’Souza and Boyett demonstrating that a microRNA network orchestrates reduced sinus node ion channel expression in a range of situations where dysfunctional pacemaking is observed, including exercise training ( D'Souza et al, 2014 ; D'Souza et al, 2017 ; Mesirca et al, 2021 ) and heart failure ( Yanni et al, 2020 ). Based on the observations ranging from the whole animal to the microRNA, coupled with previous work by the team ( Mesirca et al, 2014 ; Mesirca et al, 2016 ) it is concluded that I KAch modulation may be an effective pharmacological strategy for SND rescue.…”

Arrhythmogenesis of Sports: Myth or Reality?

“…[ 38 ] More recently, evidence suggests significant electrical remodelling within the sinus node, with downregulation of potassium/sodium hyperpolarisation activated cyclic nucleotide-gated channel 4 (HCN-4). [ 39 , 40 ] A possible dose–response relationship has also been suggested, with a study of cross-country skiers demonstrating that those who participated in more races had a higher risk of sinus node disease or third-degree atrioventricular block. [ 24 ]…”