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The role of cellular senescence in profibrillatory atrial remodeling associated with cardiac pathology
Mozhdeh Mehdizadeh 1 2, Patrice Naud 1 3, Issam H Abu-Taha 4, Roddy Hiram 1 3, Feng Xiong 1, Jiening Xiao 1, Arnela Saljic 4 5, Markus Kamler 6, Nhung Vuong-Robillard 7, Eric Thorin 1 8, Gerardo Ferbeyre 7, Jean-Claude Tardif 1, Martin G Sirois 1 9, Jean Francois Tanguay 1, Dobromir Dobrev 1 4 10, Stanley Nattel 1 2 3 4 9 11
Abstract:
Aims: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to: 1) Evaluate AF-susceptibility and senescence-marker expression in rat models of aging and myocardial infarction (MI); 2) Study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI-rats; 3) Assess senescence markers in human atrial tissue as a function of age and the presence of AF.
Methods and results: AF-susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital-PCR or RT-qPCR (mRNA). A previously-validated senolytic combination, dasatinib and quercetin (D + Q), (or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment-assignment. Burst pacing-induced AF was seen in 100% of aged rats, 87.5% of young MI-rats and 10% of young-control rats (P≤0.001 vs. each). Conduction velocity was slower in aged (both left atrium, LA and right atrium, RA) and young-MI (LA) rats versus young-control rats (P≤0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young-MI (LA) versus young-control rats (P < 0.05 for each). Senolytic therapy reduced AF-inducibility in MI-rats (from 8/9 rats, 89% in MI-vehicle, to 0/9 rats, 0% in MI-D + Q, P < 0.001) and attenuated LA-fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence-markers were upregulated in older (≥ 70 years) and longstanding-AF patients versus individuals ≤ 60 and sinus-rhythm controls respectively.
Conclusions: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
Methods and results: AF-susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital-PCR or RT-qPCR (mRNA). A previously-validated senolytic combination, dasatinib and quercetin (D + Q), (or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment-assignment. Burst pacing-induced AF was seen in 100% of aged rats, 87.5% of young MI-rats and 10% of young-control rats (P≤0.001 vs. each). Conduction velocity was slower in aged (both left atrium, LA and right atrium, RA) and young-MI (LA) rats versus young-control rats (P≤0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young-MI (LA) versus young-control rats (P < 0.05 for each). Senolytic therapy reduced AF-inducibility in MI-rats (from 8/9 rats, 89% in MI-vehicle, to 0/9 rats, 0% in MI-D + Q, P < 0.001) and attenuated LA-fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence-markers were upregulated in older (≥ 70 years) and longstanding-AF patients versus individuals ≤ 60 and sinus-rhythm controls respectively.
Conclusions: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
PMID: 38181429
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