Senolytic therapy with dasatinib and quercetin reduced atrial fibrillation inducibility in myocardial infarction rats from 89% to 0% (P<0.001).
Does senolytic therapy with dasatinib and quercetin reduce atrial fibrillation susceptibility in rat models of myocardial infarction?
Senolytic therapy with dasatinib and quercetin significantly reduces atrial fibrillation inducibility and atrial fibrosis in a rat model of myocardial infarction, suggesting cellular senescence plays a key role in AF pathophysiology.
Tasa de eventos absoluta: 0% vs 89%
valor p: p=<0.001
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 (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) 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 polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). 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 (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) 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 vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. 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 long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION: 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.
Mehdizadeh et al. (Fri,) conducted a other in Atrial fibrillation. Dasatinib and quercetin (D+Q) vs. Vehicle was evaluated on Atrial fibrillation inducibility in myocardial infarction rats (p=<0.001). Senolytic therapy with dasatinib and quercetin reduced atrial fibrillation inducibility in myocardial infarction rats from 89% to 0% (P<0.001).