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(Circulation. 2006;114:1799-1806.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice

Paulus Kirchhof, MD; Larissa Fabritz, MD; Melanie Zwiener, VetD; Henning Witt, PhD; Michael Schäfers, MD; Stephan Zellerhoff, MD; Matthias Paul, MD; Timur Athai, BS; Karl-Heinz Hiller, PhD; Hideo A. Baba, MD; Günter Breithardt, MD; Patricia Ruiz, PhD; Thomas Wichter, MD; Bodo Levkau, MD

From the Department of Cardiology and Angiology (P.K., L.F., M.Z., S.Z., M.P., T.A., G.B., T.W.) and Department of Nuclear Medicine (M.S.), Hospital of the University of Muenster, Muenster, Germany; Interdisciplinary Center for Clinical Research (P.K., L.F., M.Z., H.W., M.S., T.W.), University of Muenster, Muenster, Germany; Center for Cardiovascular Research (H.W., P.R.), Charité Universitätsmedizin Berlin, Berlin, Germany; Department of Experimental Physics (K.-H.H.), University of Wuerzburg, Wuerzburg, Germany; and Department of Pathology (H.A.B.) and Institute of Pathophysiology (B.L.), Hospital of the University of Duisburg-Essen, Duisburg-Essen, Germany.

Correspondence to Paulus Kirchhof, MD, Department of Cardiology and Angiology, Hospital of the University of Muenster, Albert-Schweitzer-Straße 33, D-48149 Münster, Germany. E-mail kirchhp{at}uni-muenster.de

Received March 12, 2006; revision received July 17, 2006; accepted July 21, 2006.

Background— 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.

Methods and Results— 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.

Conclusions— 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.

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