Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart

Brett C. Baggett, Kevin R. Murphy, Elif Sengun, Eric Mi, Yueming Cao, Nilufer N. Turan, Yichun Lu, Lorraine Schofield, Tae Yun Kim, Anatoli Y. Kabakov, Peter Bronk, Zhilin Qu, Patrizia Camelliti, Patrycja Dubielecka, Dmitry Terentyev, Federica Del Monte, Bum Rak Choi, John Sedivy, Gideon Koren

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhyth-mias. 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 investi-gated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmo-genic 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 12-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.

Original languageEnglish
Article numbere84088
StatePublished - May 2023
Externally publishedYes


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