Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart
- Brown University, United States
- Rhode Island Hospital, United States
- University of California, Los Angeles, United States
- University of Surrey, United Kingdom
- Medical University of South Carolina, United States
Abstract
Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a twelve-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age.
Data availability
All data generated or analyzed during this study are included in the provided Source Data file.
Article and author information
Author details
Patrycja Dubielecka
Funding
NHLBI Division of Intramural Research (R01HL139467)
- John Sedivy
- Gideon Koren
NHLBI Division of Intramural Research (1R1AG049608-01)
- John Sedivy
- Gideon Koren
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christopher L-H Huang, University of Cambridge, United Kingdom
Ethics
Animal experimentation: This investigation conformed with the current Guide for Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication, Revised 2011) as well as the standards recently delineated by the American Physiological Society ("Guiding Principles for Research Involving Animals and Human Beings") and was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital (Permits numbers 5001-21 and 5040-22).
Version history
- Preprint posted: December 23, 2021 (view preprint)
- Received: October 10, 2022
- Accepted: May 18, 2023
- Accepted Manuscript published: May 19, 2023 (version 1)
- Version of Record published: June 7, 2023 (version 2)
- Version of Record updated: November 16, 2023 (version 3)
Copyright
© 2023, Baggett 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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Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart
eLife 12:e84088.
https://doi.org/10.7554/eLife.84088
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