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.
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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
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Background:
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined.
Methods:
We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints.
Results:
We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression.
Conclusions:
JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS.
Funding:
NIAMS, Global Down Syndrome Foundation.
Clinical trial number:
