Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA053

Poster Communications

Electrical remodelling of the atrioventricular node causes heart block in athletes

A. D'Souza1, S. Nakao2, P. Mesirca3, T. Trussell1, M. Zi1, S. Logantha1, J. Li1, Y. Wang1, T. Jespersen4, R. Buhl4, E. J. Cartwright1, M. Mangoni3, M. R. Boyett1, H. Dobrzynski1

1. University of Manchester, Manchester, United Kingdom. 2. Ritsumeikan University, Kyoto, Japan. 3. CNRS Institut de Génomique Fonctionnelle, Montpellier, France. 4. University of Copenhagen, Copenhagen, Denmark.


Background: Athletes present with atrioventricular node (AVN) dysfunction manifesting as prolonged PR intervals and heart block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. The underlying aetiology is unexplored but previously we reported that exercise-induced bradycardia is due to electrical remodelling of the sinus node, the heart's primary pacemaker (D'Souza et al, 2014; 2017). Here we investigated the molecular basis of training-induced AVN dysfunction. Methods: 24 hour radio-telemetry ECG data were collected in sedentary and trained Standardbred racehorses (age:5-6 years), a translational, large-animal model of the athlete's heart . AVN electrophysiology and molecular profile were explored further in mice; ten-week-old C57BL/6j mice were trained by swimming for 60 min/day for 5 months following which AVN function was assessed by programmed electrical stimulation (PES) in vivo. mRNA levels of 96 ion channels, transporters and connexins were measured by qPCR in laser capture microdissected AVN. Protein levels of selected targets were assessed by immunohistochemistry and corresponding ionic currents measured in isolated AVN myocytes by patch clamp with suitable voltage clamp protocols. Values are given as mean±SEM, compared by ANOVA. Results: Trained horses presented with a longer PR interval (sedentary, 298±7.7 ms; trained, 361±18 ms; p<0.05, n=12) and a striking increase in the incidence of second-degree Mobitz type 1 heart block vs. sedentary horses (sedentary, 0.4±0.4; trained, 46.4±18.5 episodes/hour; p<0.0001, n=12), indicating training-induced AVN dysfunction. Similarly, trained mice showed prolonged PR intervals (sedentary, 40±1.0 ms; trained, 44.0±1.0 ms; P<0.05, n=7-8) and PES (n=8-9) revealed training-induced increases in Wenckebach cycle length (sedentary, 85.5±2.1 ms; trained, 99.8±1.4 ms; p<0.001) and AVN effective refractory period (sedentary, 62.6±2.8 ms; trained, 80.1±2.6 ms; p<0.05). These alterations were concomitant with widespread downregulation of ion channels in the trained AVN, notably the pacemaker HCN4 channel and the L-type Ca2+ channel subunit Cav1.2 (p<0.05, n=8/8). A 22% reduction in HCN4 protein levels in the trained AVN was confirmed by immunolabelling (p<0.05, n=4-5). Patch clamp recordings in isolated AVN myocytes demonstrated significantly reduced If (~60%) and ICa,L (~40%) current density in trained vs. sedentary mice (p<0.05, n=8-9). Conclusions: Endurance exercise causes AVN dysfunction characterised by striking transcriptional remodelling that translates into reduced current density of key ionic currents involved in AVN impulse generation and conduction. We conclude that AVN electrical remodelling is a key mechanism underlying heart block in athletes.

Where applicable, experiments conform with Society ethical requirements