Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise
- University of Szeged, Hungary
- Hungarian Academy of Sciences, Hungary
Abstract
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. 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: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms, n=29 vs. 25), decreased transient outward potassium current (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF at 50 mV, n=54 vs. 42) and increased the short term variability of repolarization (29.5±3.8 ms vs. 17.5±4.0 ms, n=27 vs. 18). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of escape beats from 0/hour to 29.7±20.3/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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 - 7 and Table 1 and 2.
Article and author information
Author details
Funding
National Research, Development and Innovation Office (NKFIH K 135464)
- András Varró
Eötvös Loránd Research Network and Albert Szent-Györgyi Medical School institutional grant (SZTE ÁOK-KKA 2021)
- László Virág
National Research, Development and Innovation Office (NKFIH PD-125402 and FK-129117)
- Norbert Nagy
National Research, Development and Innovation Office (NKFIH K 128851)
- István Baczkó
National Research, Development and Innovation Office (SNN-134497)
- Viktória Venglovecz
National Research, Development and Innovation Office (GINOP-2.3.2.-15-2016-00047)
- Alexandra Polyák
- Leila Topal
- János Prorok
- Péter Gazdag
- Norbert Jost
- László Virág
- Norbert Nagy
- István Baczkó
- Attila S Farkas
- András Varró
National Research, Development and Innovation Office (TKP2021-EGA-32)
- Norbert Jost
- László Virág
- István Baczkó
- András Varró
Ministry of Human Capacities Hungary (20391 3/2018/FEKUSTRAT)
- László Virág
- István Baczkó
- András Varró
Ministry of Human Capacities Hungary (EFOP-3.6.2-16-2017-00006)
- János Prorok
- Péter Hegyi
- Viktória Venglovecz
- Zoltán Husti
- Péter Gazdag
- Norbert Jost
- László Virág
- Norbert Nagy
- István Baczkó
- Attila S Farkas
- András Varró
Hungarian Academy of Sciences (János Bolyai Research Scholarship)
- Norbert Nagy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal maintenance and research were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All procedures using animals were approved by the Ethical Committee for the Protection of Animals in Research of the University of Szeged, Szeged, Hungary (approval numbers: I-74-15-2017 and I-74-24-2017) and by the Department of Animal Health and Food Control of the Ministry of Agriculture and Rural Development (authority approval numbers XIII/3330/2017 and XIII/3331/2017) and conformed to the rules and principles of the 2010/63/EU Directive.
Copyright
© 2023, Polyák et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 991
- views
-
- 171
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise
eLife 12:e80710.
https://doi.org/10.7554/eLife.80710
Further reading
-
- Medicine
- Neuroscience
Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer’s disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson’s disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.
-
- Medicine
Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Recently, we identified reserpine as a lead molecule for maintaining rod survival in mouse and human retinal organoids as well as in the rd16 mouse, which phenocopy Leber congenital amaurosis caused by mutations in the cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, we show the therapeutic potential of reserpine in a rhodopsin P23H rat model of autosomal dominant RP. At postnatal day (P) 68, when males and females are analyzed together, the reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to the controls with little or no change in scotopic a-wave or cone-derived photopic b-wave. Interestingly, the reserpine-treated female rats display enhanced scotopic a- and b-waves and photopic b-wave responses at P68, along with a better contrast threshold and increased outer nuclear layer thickness. The female rats demonstrate better preservation of both rod and cone photoreceptors following reserpine treatment. Retinal transcriptome analysis reveals sex-specific responses to reserpine, with significant upregulation of phototransduction genes and proteostasis-related pathways, and notably, genes associated with stress response. This study builds upon our previously reported results reaffirming the potential of reserpine for gene-agnostic treatment of IRDs and emphasizes the importance of biological sex in retinal disease research and therapy development.
