Published Online
on October 9, 2006

A more recent version of this article appeared on October 24, 2006

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Submitted on March 12, 2006
Revised on July 17, 2006
Accepted on July 21, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: kirchhp{at}uni-muenster.de.

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.

Key words: adherens junctions • arrhythmia • cardiomyopathy • conduction • death, sudden • desmosomes • exercise

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