Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice

Abstract

Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, intensely exercised mice showed similar adverse atrial changes and increased AF vulnerability, which required tumor necrosis factor (TNF) signaling, even though ventricular structure and function improved. To identify some of the molecular factors underlying the chamber-specific and TNF-dependent atrial changes induced by exercise, we performed transcriptome analyses of hearts from wild-type and TNF-knockout mice following exercise for 2 days, 2 or 6 weeks of exercise. Consistent with the central role of atrial stretch arising from elevated venous pressure in AF promotion, all 3 time points were associated with differential regulation of genes in atria linked to mechanosensing (focal adhesion kinase, integrins and cell-cell communications), extracellular matrix (ECM) and TNF pathways, with TNF appearing to play a permissive, rather than causal, role in gene changes. Importantly, mechanosensing/ECM genes were only enriched, along with tubulin- and hypertrophy-related genes after 2 days of exercise while being downregulated at 2 and 6 weeks, suggesting that early reactive strain-dependent remodeling with exercise yields to compensatory adjustments. Moreover, at the later time points, there was also downregulation of both collagen genes and genes involved in collagen turnover, a pattern mirroring aging-related fibrosis. By comparison, twofold fewer genes were differentially regulated in ventricles vs. atria, independently of TNF. Our findings reveal that exercise promotes TNF-dependent atrial transcriptome remodeling of ECM/mechanosensing pathways, consistent with increased preload and atrial stretch seen with exercise. We propose that similar preload-dependent mechanisms are responsible for atrial changes and AF in both CVD patients and athletes.

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

“…Electrophysiological remodelling, fibrosis, bradycardia and the possibility for enhanced risk of AF have been reported recently in rodents [4,8,11,12,30,31]. As far as we know, however, relatively scanty data has been obtained in large animal models of endurance training and proarrhythmic risk.…”

“…Since in our working hypothesis we focused on possible repolarization abnormalities to the molecular mechanism of increased fibrosis was not investigated in the present study. However earlier work by others investigated this issue in a great detail in mice and rat [4,11,30].…”

The AFLETES Study: Atrial Fibrillation in Veteran Athletes and the Risk of Stroke

“…34 Fibrosis has been observed to a larger degree in exercised animals and human athletes when compared with controls. [39][40][41] Because the atria have less capacity to increase wall thickness, wall stress is proportionally higher when compared with the ventricles, and this may explain the predominance of fibrosis in the atria. 42 There is little evidence that suggest that athletes are at a higher risk of developing ventricular arrythmias, suggesting that fibrosis may have some role in arrhythmogenesis in athletes.…”

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

“…Specific AF-related gene variants were studied in rat and murine model systems and in one human iPSC atrial CM study [ 23 , 55 , 56 , 57 , 61 ]. These variants include SNPs, point mutations, and the introduction of transgenic constructs or gene knockouts and indicate the involvement of several signaling pathways in structural remodeling, electrical remodeling and AF susceptibility.…”