Key result
Advanced age in infarcted rabbits was associated with significantly higher peri-procedural mortality (36% vs 19%, p=0.0120) and incidence of ventricular tachycardia/fibrillation.
Why the study?
Post-myocardial infarction arrhythmogenic tissue remodeling is well studied in young animals, but mechanisms and pro-arrhythmic changes involving cellular senescence in aged large animals are unknown.
Absolute Event Rate: 36% vs 19%
p-value: p=0.0120
Persistent myofibroblast senescence in aged infarcted hearts promotes arrhythmogenic remodeling, suggesting a potential therapeutic role for senolytic drugs post-MI.
Senescence may promote post-MI arrhythmias in aged hearts; leaves open mechanisms and clinical translation.
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 large animals, and the mechanisms are unknown. 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 senolytic drugs may mitigate arrhythmias post-MI.
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Baggett et al. (2021) studied Myocardial Infarction (n=172). Advanced age vs. Young age was evaluated on Peri-procedural mortality (p=0.0120). Advanced age in infarcted rabbits was associated with significantly higher peri-procedural mortality (36% vs 19%, p=0.0120) and incidence of ventricular tachycardia/fibrillation.
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