PDF(Pubmed)
Abstract：
Desmoglein-2 mutations are detected in 5-10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant (Dsg2mt/wt) or haploinsufficient (Dsg20/wt) mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old Dsg2mt/wt and Dsg20/wt mice and in young Dsg2mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg20/wt and Dsg2mt/wt mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in Dsg2mt/wt mice but not in wild types. Dsg2mt/wt hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult Dsg2mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2mt/wt mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients.
摘要：
在5-10％的致心律失常性右心室心肌病（ARVC）患者中检测到Desmoglein-2突变。耐力训练加速ARVC表型的发展，导致更早的心律失常事件。纯合Dsg2突变小鼠发展出严重的ARVC样表型。杂合突变体（Dsg2mt/wt）或单倍体不足（Dsg20/wt）小鼠的表型仍未得到很好的理解。评估年龄和耐力游泳训练的影响，我们研究了久坐的一岁Dsg2mt/wt和Dsg20/wt小鼠以及接受耐力游泳训练的年轻Dsg2mt/wt小鼠的心脏形态和功能。心脏结构仅在年龄较大的Dsg20/wt和Dsg2mt/wt小鼠中偶尔受到影响，表现为小的纤维化病灶和连接蛋白43的移位。耐力游泳训练增加了Dsg2mt/wt小鼠的右心室（RV）直径并降低了RV功能，但野生型小鼠则没有。Dsg2mt/wt心脏显示心室激动时间增加和起搏引起的室性心律失常，无明显纤维化或炎症。训练期间的预负荷减少疗法可防止RV扩大并减轻电生理表型。一起来看,耐力游泳训练诱导年轻成年Dsg2mt/wt小鼠ARVC的特征。因此，经过训练的Dsg2mt/wt小鼠心脏中延长的心室激活时间是增加心律失常风险的潜在机制。前负荷减少疗法可预防训练诱导的ARVC表型，从而为人类患者提供有益的治疗选择。
