Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart

• DOI: 10.7554/elife.84088
• Publication Date: 2023-05-19T12:15:13Z
• Authors: 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
• Keywords: Myofibroblast; Senescence; Cardiac Fibrosis; Ventricular remodeling

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little known about pro-arrhythmic changes aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. interfere function outcome post-MI age, studies have not been performed larger the mechanisms are unknown. Specifically, timecourse of senescence related inflammation fibrosis understood. Additionally, cellular systemic role its inflammatory milieu influencing arrhythmogenesis clear, particularly large animal models electrophysiology more similar to humans than previously models. Here, we investigated regulating inflammation, fibrosis, infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality arrhythmogenic electrophysiological at infarct border zone (IBZ) compared Studies revealed persistent myofibroblast signaling over a 12-week timecourse. IBZ myofibroblasts appear be coupled myocytes, our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) facilitates conduction block permissive human ventricles show levels consistent rabbits, also couple myocytes. Our findings suggest therapeutic interventions targeting may mitigate arrhythmias age.