Kirchhof Paulus, Fabritz Larissa, Zwiener Melanie, Witt Henning, Schäfers Michael, Zellerhoff Stephan, Paul Matthias, Athai Timur, Hiller Karl-Heinz, Baba Hideo A, Breithardt Günter, Ruiz Patricia, Wichter Thomas, Levkau Bodo
Department of Cardiology and Angiology, Hospital of the University of Muenster, Germany.
Circulation. 2006 Oct 24;114(17):1799-806. doi: 10.1161/CIRCULATIONAHA.106.624502. Epub 2006 Oct 9.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice.
Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin+/-) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all P<0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin+/- hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin+/- mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals.
Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.
致心律失常性右室心肌病（ARVC）是一种遗传性疾病，可导致年轻人猝死和右室心力衰竭。临床数据表明，竞技运动可能会在易感人群中诱发ARVC。从遗传学角度来看，桥粒蛋白（盘状球蛋白、桥粒斑蛋白或桥粒珠蛋白）的功能丧失突变与ARVC有关。为了验证桥粒蛋白表达降低会导致ARVC这一假说，我们研究了小鼠杂合性桥粒珠蛋白缺乏的心脏效应。
10月龄杂合性桥粒珠蛋白缺乏小鼠（桥粒珠蛋白+/-）右室容积增加、右室功能降低且出现自发性室性早搏（均P<0.05）。左室大小和功能未改变。与野生型心脏相比，离体灌注的桥粒珠蛋白+/-心脏出现右室起源的自发性室性心动过速且右室传导时间延长。耐力训练加速了桥粒珠蛋白+/-小鼠右室功能障碍和心律失常的发展。组织学和电子显微镜检查未发现受影响动物右室有异常。
杂合性桥粒珠蛋白缺乏会诱发ARVC。耐力训练会加速该表型的表现。这表明桥粒珠蛋白和训练在ARVC的发生发展中起功能性作用。
