Scarring and Arrhythmia in the Aged Infarcted Heart: The Role of Senescent Fibroblasts

Abstract

Arrhythmogenic tissue remodeling after myocardial infarction (MI) has been well described in young animals, but how this wound healing process changes with age and leads to increased risk of sudden cardiac death (SCD) post‐MI is not well understood. Cellular senescence is an irreversible cell cycle arrest process which regulates tumor suppression and wound healing, however accumulation of senescent cells in various tissues is thought to drive aging pathology. We hypothesize that with age, persistent cardiac myofibroblast (CMF) senescence promotes persistent inflammation in the scar and thereby facilitating arrhythmogenesis. Using the New Zealand White Rabbit as a model of the aging heart, we show that aged infarcted rabbits display increased peri‐procedural arrhythmic death. Optical mapping studies at 3‐ and 12‐weeks post MI revealed prolonged action potential duration (APD) in the infarct border zone (IBZ) as compared to the remote zone (RZ) in aged rabbits while in young rabbits IBZ’s APD was shorter than RZ’s APD. We also observed slowed conduction and APD alternans at the IBZ which correlated with anchoring of higher frequency ventricular fibrillation in the IBZ of aged rabbits. We show no change in scar size or geometry between young and aged rabbits over the first 12 weeks post‐MI. However, we observed delayed and persistent CMF senescence in the aged scar, even until 12 weeks post‐MI. Using immunohistochemistry and immunofluorescence, we show most senescent cells in the scar are myofibroblasts. We also demonstrate increased expression of senescence‐associated markers in the aged IBZ and scar compared to young, and colocalization of senescent CMFs and inflammatory macrophages in the aged scar and IBZ. Finally, we observe an increase in circulating inflammatory factors from aged rabbit blood samples compared to young, some of which further increased post‐MI. In conclusion, we demonstrate the infarcted aged heart heals differently than young, including delayed and persistent scar CMF senescence, increased VT/VF, and electrophysiological remodeling. Our data support our hypothesis that altered CMF senescence with age induces pathological tissue remodeling post‐MI, underlying the increased risk of SCD.Support or Funding InformationThe authors would like to acknowledge our supporting NIH funding sources, R21 grant 1R21AG049608‐01 and R01 grant R01HL139467