Essential Role And Mechanism Of Atrial Cardiomyocytes Senescence In Valvular Atrial Fibrillation

Background Radiofrequency(RF)maze procedure is a reasonably effective intervention to treat concomitant atrial fibrillation(AF).However,outcomes and clinical predictors of AF early recurrences that occur with 3-6 months after RF maze procedure remains poorly studied.Methods We retrospectively analyzed 131 consecutive persistent AF patients with valvular heart diseases who were followed up 3-6 month after RF maze procedure.Their clinical data were recorded.Logistic regression analyses were performed for significant predictors,followed by early recurrence-risk nomogram construction.Receiver operating characteristic(ROC)analysis was used for validation with corresponding area under the curve.Results At a mean follow-up of 3.73±1.3 months,70 patients(53.4%)had developed AF recurrence.Patients with early recurrence were older,longer AF duration history,larger left atrial diameter(LAD),higher C reactive protein level(CRP),lower triglycerides(TG)and total cholesterol(TC)(P<0.05).Furthermore,LAD(OR 1.9,95%CI 1.2-3.1,P=0.009),CRP(OR 1.47,95%CI 1.17-1.84,P=0.001)and TG(OR0.18,95%CI 0.07-0.5,P=0.001)were independent risk factors of AF early recurrence.Early recurrence-risk nomogram was constructed with the 3 clinical risk factors and demonstrated considerable discrimination(area under the curve = 0.826,sensitivity74.0%,specificity 85.0%).Conclusions About 50-55% valvular AF patients suffered early recurrence after RF maze procedure and LAD,CRP,TG are independent risk factors.Early recurrence prediction model based on combined clinical parameters was developed and well predicted of AF early recurrence after RF maze procedure.Objective Atrial fibrillation(AF)is the most common clinical arrhythmia with a strong tendency to progress in time and is characterized by sustained high atrial activation.Large sample based epidemiology and our previous research indicated that ageing is the biggest risk factor for AF.The incidence and recurrence of AF increases with age.Alterations in structure and function of atria associated with aging provide the substrate for AF.Cellular senescence has been implicated in age-related tissue dysfunction.Premature senescent cells accumulate with age and after genotoxic stress or a variety of cardiac diseases,contributing to tissue ageing and has been implicated in age-related tissue dysfunction due to the accumulation of damaged cells at sites of tissue injury and remodelling.Senescent cells are characterized by alterations in structure and function which leads to the degeneration or loss of cell intrinsic function.Another characteristic of senescent cells is that they remain metabolically active and able to secrete a large number of factors,known as the senescence-associated secretory phenotype(SASP)or senescence-messaging secretome that can affect the tissue microenvironment and lead to tissue dysfunction.In recent years,there is growing evidence suggested that cell senescence is involved in various cardiovascular diseases such as cardiac injury,myocardial fibrosis,atherosclerosis,aneurysms etc.AF,as an age-related disease,knowledge of the intrinsic effects and possible mechanism of cellular senescence on AF have yet to be identified.In this study,the link between AF and cell senescence were defined by using clinical samples and experimental AF models.Further,we explored the possible role and mechanisms of atrial cardiomyocyte senescence in AF progression.Methods HL-1 atrial myocytes were subjected high increase in rate over basal values by rapid electrical stimulation(RES)which can be used for experimental AF models.SA-β-gal staining,western blot and real-time PCR were used to detect senescent cell,senescence associate genes and proteins in clinical samples and experimental AF.Immunofluorescence was used to determine the type of senescent cell.Statistical analysis,western blot,real-time PCR,si RNA transfection,and immunofluorescence were used to elucidate the effect and possible mechanism of cellular senescence on AF.Results 1.SA-β-Gal and P16,P21,P53 level were significantly up-regulated in AF clinical samples and experimental AF.Further,atrial cardiomyocyte senescence was involved in AF development.2.RES induced atrial cardiomyocyte senescence was accompanied by a significant increase in SASP level,profibrosis and prohypertrophic markers.Expression pattern of SERCA2 a,PLB and Ry R2 are closely related to RES induced atrial cardiomyocyte senescence.3.AF is precipitated by excessive poly(ADP)-ribose polymerase 1(PARP1)activation in response to DNA damage.PARP1 substrate NAD+ Replenishment precludes hydrogen peroxide and RES induced atrial cardiomyocyte senescence.Conclusion AF induced cardiomyocyte senescence involved in deleterious atrial remodeling in disease progression.DNA damage induced PARP1 activation is closely related to atrial cardiomyocyte senescence in AF.PARP1 as a possible therapeutic target in AF.