Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart

  1. Brett C Baggett
  2. Kevin R Murphy
  3. Elif Sengun
  4. Eric Mi
  5. Yueming Cao
  6. Nilufer N Turan
  7. Yichun Lu
  8. Lorraine Scofield
  9. Tae Yun Kim
  10. Anatoli Y Kabakov
  11. Peter Bronk
  12. Zhilin Qu
  13. Patrizia Camelliti
  14. Patrycja Dubielecka
  15. Dmitry Terentyev
  16. Federica del Monte
  17. Bum-Rak Choi
  18. John Sedivy
  19. Gideon Koren  Is a corresponding author
  1. Brown University, United States
  2. Rhode Island Hospital, United States
  3. University of California, Los Angeles, United States
  4. University of Surrey, United Kingdom
  5. 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

  1. Brett C Baggett

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kevin R Murphy

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elif Sengun

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eric Mi

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yueming Cao

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nilufer N Turan

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yichun Lu

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lorraine Scofield

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Tae Yun Kim

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Anatoli Y Kabakov

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter Bronk

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9067-2016
  12. Zhilin Qu

    School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Patrizia Camelliti

    School of Biosciences and Medicine, University of Surrey, Surrey, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Patrycja Dubielecka

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3987-0647
  15. Dmitry Terentyev

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Federica del Monte

    Medical University of South Carolina, Charleston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Bum-Rak Choi

    Cardiovascular Research Center, Rhode Island Hospital, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. John Sedivy

    Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Gideon Koren

    Brown University, Providence, United States
    For correspondence
    gideon_koren@brown.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6211-5837

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

  1. 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

  1. Preprint posted: December 23, 2021 (view preprint)
  2. Received: October 10, 2022
  3. Accepted: May 18, 2023
  4. Accepted Manuscript published: May 19, 2023 (version 1)
  5. Version of Record published: June 7, 2023 (version 2)
  6. 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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  1. Brett C Baggett
  2. Kevin R Murphy
  3. Elif Sengun
  4. Eric Mi
  5. Yueming Cao
  6. Nilufer N Turan
  7. Yichun Lu
  8. Lorraine Scofield
  9. Tae Yun Kim
  10. Anatoli Y Kabakov
  11. Peter Bronk
  12. Zhilin Qu
  13. Patrizia Camelliti
  14. Patrycja Dubielecka
  15. Dmitry Terentyev
  16. Federica del Monte
  17. Bum-Rak Choi
  18. John Sedivy
  19. Gideon Koren
(2023)
Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart
eLife 12:e84088.
https://doi.org/10.7554/eLife.84088

Share this article

https://doi.org/10.7554/eLife.84088

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