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Topal, L.

Publications and source records attributed to Topal, L..

2 recordsLinked to original sources
bioRxiv2025

Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate

BACKGROUNDAtrial fibrillation (AF) susceptibility is heightened in endurance athletes but the underlying mechanisms are incompletely understood. Because pulmonary vein (PV) myocyte triggers are critical determinants of AF, we investigated PV electrophysiological remodelling in animal models of the athletes heart. METHODSThe following experiments were performed in canines and mice after 16 or 6 weeks, respectively, of daily exercise training (ExT), and compared to sedentary (Sed) controls: ECG recording, echocardiography, pharmacological autonomic block, extrastimulus pacing, multielectrode array mapping, monophasic and intracellular action potential (AP) recording with custom-designed pattern recognition analysis, histology, RNAseq and spatial in situ transcriptomics. RESULTSAF propensity was significantly increased in ExT animals. Mapping studies identified heightened rotational activity in the PV-left atrial (LA) junction of ExT vs. Sed canines in vivo, and enhanced automaticity, triggered activity and AP duration variability ex vivo in ExT canines and mice. Intracellular recordings in mouse PV cardiomyocytes determined at least six AP subtypes with increased frequency of pacemaker-like APs in ExT PV, concomitant with increased expression of pacemaking HCN4, Cav1.3 and Cav3.1 channels. PV spontaneous excitability was also significantly enhanced. Subcellular resolution spatial transcriptomics in mouse PV-LA identified diffuse ion channel remodelling and activation of established AF-promoting pro-inflammatory and pro-fibrotic cytokines and chemokines in ExT PV cardiomyocytes. Conduction slowing in the ExT PV-LA junction was attributable to: gap junction remodelling, reduced Na+ channel expression and increased extracellular matrix deposition with enhanced myofibroblast number and proximity to PV cardiomyocytes. CONCLUSIONSEndurance exercise elicits proarrhythmic electro-anatomical remodelling of the PV-LA junction with enhanced pacemaking ion channel expression and immune-inflammatory pathway activation in PV myocytes as prominent contributors. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIThis work is the first demonstration that endurance training results in proarrhythmic electrophysiological remodelling of PV sleeve myocytes and extracellular matrix deposition in the PV-LA junction. C_LIO_LIWe register electrical and molecular heterogeneity of the PV-LA junction at single cell and subcellular resolution, and for the first time identify the molecular events that underlie increased proarrhythmic activity of the trained PV. These include enhanced pacemaking ion channel expression (e.g., HCN4, Cav1.3, and Cav3.1), pro-inflammatory cytokine activation (e.g., TNF, IL-6), increased myofibroblasts and extracellular matrix deposition. C_LI What are the clinical implications?O_LIWe identify the molecular determinants of PV proarrhythmic activity in the trained heart and present new therapeutic targets for AF prevention in athletes. C_LIO_LIOur findings provide mechanistic rationale for the efficacy of pulmonary vein isolation for AF in athletes. C_LI

physiology↗
bioRxiv2022

Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise

The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. While some studies after endurance training have been performed in small animals these have limited translation value. Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 213.6{+/-}2.8 ms vs. 237.1{+/-}3.4 ms, n=12; APD90: 370.1{+/-}32.7 ms vs. 472.8{+/-}29.6 ms, n=25 vs. 29), decreased transient outward potassium current (8.8{+/-}0.9 pA/pF vs. 6.4{+/-}0.5 pA/pF at 50 mV, n=42 vs. 54) and increased the short term variability of repolarization (17.5{+/-}4.0 ms vs. 29.5{+/-}3.8 ms, n=18 vs. 27). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of extrasystoles: 4/hour vs. 366/hour) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs). Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training.

physiology↗