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

  1. Alexandra Polyák

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  2. Leila Topal

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  3. Noémi Zombori-Tóth

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  4. Noémi Tóth

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  5. János Prorok

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  6. Zsófia Kohajda

    MTA-SZTE Research Group for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  7. Szilvia Déri

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  8. Vivien Demeter-Haludka

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  9. Péter Hegyi

    Department of Internal Medicine, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  10. Viktória Venglovecz

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  11. Gergely Ágoston

    Institute of Family Medicine, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  12. Zoltán Husti

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  13. Péter Gazdag

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  14. Jozefina Szlovák

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  15. Tamás Árpádffy-Lovas

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  16. Muhammad Naveed

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  17. Annamária Sarusi

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  18. Norbert Jost

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  19. László Virág

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  20. Norbert Nagy

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    For correspondence
    nagy.norbert@med.u-szeged.hu
    Competing interests
    The authors declare that no competing interests exist.
  21. István Baczkó

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    For correspondence
    baczko.istvan@med.u-szeged.hu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9588-0797
  22. Attila S Farkas

    Department of Internal Medicine, University of Szeged, Szeged, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  23. András Varró

    Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    For correspondence
    varro.andras@med.u-szeged.hu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0745-3603

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.

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  1. Alexandra Polyák
  2. Leila Topal
  3. Noémi Zombori-Tóth
  4. Noémi Tóth
  5. János Prorok
  6. Zsófia Kohajda
  7. Szilvia Déri
  8. Vivien Demeter-Haludka
  9. Péter Hegyi
  10. Viktória Venglovecz
  11. Gergely Ágoston
  12. Zoltán Husti
  13. Péter Gazdag
  14. Jozefina Szlovák
  15. Tamás Árpádffy-Lovas
  16. Muhammad Naveed
  17. Annamária Sarusi
  18. Norbert Jost
  19. László Virág
  20. Norbert Nagy
  21. István Baczkó
  22. Attila S Farkas
  23. András Varró
(2023)
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

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https://doi.org/10.7554/eLife.80710

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