| Background and objectiveAtrial fibrillation (AF) is the most common continual cardiac arrhythmia in clinic which is the major reason for stroke and heart failure. It results in a substantial mortality and morbidity. Aging plays an important role in AF genesis. The prevalence of AFincreases with aging , about 0.1% at age 40 years, 6% at 65 years, and 10% at 80 years or older. However, the mechanism of aging-induced AF is not fully elucidated. The heterogeneous of atrial substrate and electrophysiology is considered to play an important role in the mechanisms of AF occurrence. Aging has been shown to promote the atrial interstitial fibrosis, decrease conduction velocity, change action potential characteristics, and alter calcium regulation in cardiomyocytes. All of these effects may facilitate AF occurrence.Clinical and experimental evidences suggest that the autonomic tone plays an important role in the pathogenesis of AF. Vagally released acetylcholine (ACh) stimulates M2-muscarinic receptors. This creates an arrhythmogenic substrate which played an important role in the initiation and development of AF.As mediation of vagus, muscarinic type 2 receptors (M2R) which partly provide the substrate for AF. M2R has recently been reported distribution heterogeneity in heart and is higher in atria than ventricles. Previous studies on atrial M2R distribution did not make a general agreement and the results were controversial. The heterogeneous distribution of M2R in the atria may contribute to AF inducibility. Several studies have showed that muscarinic cholinergic receptor subtypes undergo age-related changes in cerebral cortex, airway and urinary bladder. And to a different extent, these modifications influence the functions of the organs investigated. However, it is still unclear whether M2R distribution in the atrium changes with age and whether this change affects the occurrence of AF. The purpose of this study is to investigate the change of M2R in the process of ageing and evaluate its effects on AF vulnerability.MethodsExpression of M2R in the atrial myocardium (LAFW substitutes for left atrial free wall, LAA for left atrial appendage, RAFW for right atrial free wall, and RAA for right atrial appendage) was evaluated by immunostaining and western blot in three groups, twelve 3–months-old rabbits (young group), twelve18–months-old ones ( mature group) and twelve 36-48-months-old ones (senescent group). AF inducibility was recorded with and without cervical vagal stimulation(VS)in vivo of all groups. AF inducibility, atrial effective refractory period (AERP) and monophasic action potential (MAP) were recorded in additional seven senescent rabbits before and after tropicamide administration topically. Results1 . In each group, the rank order of M2R protein expression was LAFW>LAA>RAFW> RAA. LAFW had a higher level of M2R expression than LAA (young: p<0.05; mature: p<0.01; senescent: p<0.01), RAFW (p<0.01, three group), RAA (p<0.01, three group). LAA had a higher level of M2R expression than RAFW and RAA (young: p<0.05; mature: p<0.01; senescent: p<0.01). There was no significant difference between RAFW and RAA in each group.2.Compared to young group, M2R expression had no change in all of the four parts of mature group. Compared to mature group, senescent group had a significant increase of M2R expression in LAFW (p<0.01), no change was observed in other three parts.3.In all of the groups, there was no successful AF induction without VS except two times in the senescent group. The comparison of AF induction was with background of VS. AF inducibility was higher in the senescent group than in the other two groups (young: p<0.05; mature: p<0.05), however there was no significant increase in mature group compared to young group. After tropicamide administration of senescent rabbits, AF inducibility decreased significantly (p<0.05).4.The AERP and MAPD90 of LAFW and LAA with VS decreased when compared to baseline (LAFW: p<0.01; LAA: p<0.05). There was no significant change of AERP and MAPD90 with VS in right atrium compared to baseline. After tropicamide administration, the VS-induced AERP and MAPD90 of LAFW decrease were attenuated (p<0.05). No same change was observed at other three parts. The dAERP and dMAPD90 with VS increased when compared to baseline (p<0.05). After tropicamide administration, the VS-induced dAERP and dMAPD90 increase were attenuated (p<0.05).Conclusion1.The M2R distribution is spatial heterogeneous in the atria of the rabbit, with the highest M2R density in LAFW and higher M2R density in epicardial side than endocardial side.2.M2R modifications was accompanied with senescence more likely than with growth.3.The change of M2R distribution in atria with age facilitated AF inducibility. (4) Greater heterogeneous distribution of M2R increased dAERP and dMAPD90 with VS, and facilitated the inducibility of AF In conclusion, the M2R distribution is spatial heterogeneous in the atria of the rabbit, M2R distribution changed with senescence and aggravated the heterogeneity of M2R distribution. This increased dAERP and dMAPD90 with VS, and facilitated the inducibility of AF. These indicated that the heterogeneity of M2R distribution participated in the change of age-related AF vulnerability and will provide novel strategy and theoretic evidence to prevention and treatment of atrial fibrillation. |
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