The Role of Myofibroblast Senescence in Arrhythmogenesis of the Aged Infarcted Heart

Abstract

Aging is associated with a more than 5‐ to 40‐fold increase in the incidence of sudden cardiac death. Our laboratory has established the female New Zealand White rabbit as a model of the aging heart, as young (5–9 months) and old (4–6 years) rabbits recapitulate human cardiac pathophysiology. Previously we developed a minimally invasive procedure involving coil embolization of the left coronary artery to reproducibly induce myocardial infarction (MI) of 25–35% of the left ventricular free wall (Morrissey 2017). Aged rabbits experience increased periprocedural ventricular fibrillation, electrophysiological remodeling, and in rabbits that survive MI, an increased incidence of sudden cardiac death comparable to the pathology of MI in aged humans.Cellular senescence, a cell cycle arrest process, is critically important for wound healing in many tissues including the heart. Senescence of cardiac myofibroblasts (CMFs) in the short‐term limits fibrosis and scar formation and improves cardiac function post‐MI (Zhu 2013). In the liver and epidermis, aging is associated with a detrimental long‐term persistence of senescent cells which promotes chronic inflammation, but changes in CMF senescence and the physiological consequences in the heart remain elusive. We hypothesized that the CMF senescence response changes with age and these changes contribute to the increased arrhythmogenic pathology observed in the aging heart. To test this, we infarcted young and old rabbits and after three weeks, performed histological and biochemical assays on rapidly frozen tissue sections. We used senescence‐associated beta galactosidase (SA‐βGal) staining to characterize senescence in the scar zone, infarct border zone (IBZ), and remote zone (RZ). Compared to young rabbits, we observed an increase in senescent CMFs in the aged scar three weeks post‐MI. To investigate the temporal dynamics of senescence, we measured senescence via SA‐βGal staining across a three‐week time course. The results showed a delayed and persistent senescence response in the aged infarcted rabbit heart. Additionally, to probe for changes in senescence‐associated gene expression we used qPCR to measure the expression of genes involved in senescence regulation as well as senescence associated secretory phenotype (SASP) genes from the scar, IBZ, and RZ. SASP factors include pro‐inflammatory cytokines and matrix remodeling proteins, and correlate with age‐associated chronic inflammation. We observed a significant increase in senescence and SASP gene expression in the aged rabbits, particularly the scar zone. Our data demonstrate age‐associated changes in the onset and magnitude of CMF senescence in the rabbit heart. We propose these changes in CMF senescence lead to chronic inflammation that facilitates arrhythmias around the scar zone. Therefore, limiting long‐term senescence in the heart post‐MI may be a novel target to reduce lethal arrhythmogenesis and preserve cardiac function with ageSupport or Funding InformationThis dissertation is based upon work supported by NIH grants R01‐HL110791 (to G. Koren), R21‐AG049608 (to J. Sedivy and G. Koren), and by T32AG041688 (to J. Sedivy).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.