Published Online
on March 20, 2006

A more recent version of this article appeared on April 4, 2006

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Submitted on June 14, 2005
Revised on November 16, 2005
Accepted on December 16, 2005

Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2

Darshan Dalal MD, MPH, Lorraine H. Molin BS, MS, Jonathan Piccini MD, Crystal Tichnell MGC, Cynthia James PhD, ScM, Chandra Bomma MD, Kalpana Prakasa MD, Jeffrey A. Towbin MD, Frank I. Marcus MD, Philip J. Spevak MD, David A. Bluemke MD, PhD, Theodore Abraham MD, Stuart D. Russell MD, Hugh Calkins MD, and Daniel P. Judge MD^*

From the Division of Cardiology (D.D., L.H.M., J.P., C.T., C.J., C.B., K.P., D.A.B., T.A., S.D.R., H.C., D.P.J.), Department of Radiology (D.A.B.), and Division of Pediatric Cardiology (P.J.S.), Johns Hopkins University School of Medicine, Baltimore, Md; Section of Cardiology, Sarver Heart Center, University of Arizona, Tucson (F.I.M.); and Department of Pediatrics (Cardiology), Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex (J.A.T.).

^* To whom correspondence should be addressed. E-mail: djudge{at}jhmi.edu.

Background--Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations.

Methods and Results--DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28±11 years) than in those without (36±16 years) (P<0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P<0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P<0.05).

Conclusions--Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.

Key words: arrhythmia • cardiomyopathy • genetics • sudden death • tachyarrhythmias

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