Atrial fibrosis and local right atrial inflammation are characteristic of strenuous, but not moderate exercise, and underlie increased AF inducibility in heavily trained rats

Abstract

Abstract Introduction The U-shaped relationship between exercise load and atrial fibrillation (AF) risk, where moderate exercise is protective but strenuous training increases the risk of AF, is currently well accepted (1, 2). Clinical and experimental data suggest that atrial fibrosis and parasympathetic tone (PT) enhancement may underlie the excess risk of AF in endurance athletes (3). Delving into the atrial differences between moderate exercise and strenuous training may be important to understand the pathophysiology of exercise-induced AF. Purpose To compare the atrial structural, electrophysiological and molecular remodelling occurring after long-term moderate and strenuous exercise. Methods Male Wistar rats were randomly assigned to sedentary (SED), moderate (MOD, 35 cm/s, 45 minutes) or high intensity exercise (INT, 60 cm/s, 60 minutes) for 16 weeks. An electrocardiogram (ECG) and electrophysiological study (EPS) were performed before sacrifice. Left (LA) and right (RA) atrial samples were collected for fibrosis assessment and a mRNA array. Results After the exercise protocol, weight of SED rats was higher (486±77 g) compared with both the MOD (377±28 g) and INT groups (385±43 g). In the ECG (Figure 1), INT rats presented a prolonged P-wave compared with SED and MOD. Both trained groups presented with significant bradycardia compared with SED, along with enhanced PT (heart rate variability: low to high frequency ratio). The remaining ECG parameters were similar between groups. Consistent with an enhanced PT, the Wenckebach cycle length was similarly prolonged in both trained groups in the EPS. Conversely, the sinus node recovery time was prolonged in INT rats compared with SED and MOD. AF inducibility increased from SED to MOD to INT. Myocardial fibrosis was measured in atrial samples stained with Sirius red. In both the RA and LA, fibrosis was significantly higher in the INT group (6,3±0.8 %) compared with the SED (4,4±0.2 %) and MOD (4,3±0.5 %) groups. An mRNA array showed large differences between atria. 384 and 419 genes were deregulated between INT and MOD (nominal p<0.05) in the RA and LA, respectively. Only 19 genes were consistent between both atria. In pathway analyses, the inflammatory response pathway was enriched (upregulation) in the RA, but not in the LA, of INT rats compared with MOD (Figure 2). Conclusions In healthy rats, strenuous training promoted a differential, pathological remodelling involving atrial fibrosis and sinus node dysfunction, compared with moderate exercise. Local inflammation may play a role in strenuous exercise-induced fibrosis in the RA. PT enhancement was similar in both groups.Figure 1.Figure 2.