Clinical Features of Arrhythmogenic Right Ventricular Dysplasia

Abstract & Commentary

By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.

Synopsis: The various identified defects in cell adhesion proteins in ARVD/C lead to the same clinical consequences.

Source: Dalal D, et al. Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated with Mutations in Plakophilin-2. Circulation. 2006;113:1641-1649.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a clinical syndrome characterized by right ventricular dysfunction and ventricular arrhythmias. It has been recognized that this disorder may be associated with a number of different genetic mutations. In this paper, Dalal and colleagues report on the clinical features of patients with one of the more common mutations associated with ARVD/C—those involving plakophilin-2.

Dalal et al identified 58 unrelated ARVD/C patients from the Johns Hopkins registry. Their medical histories were tabulated, as were results of noninvasive testing, including electrocardiography, signal averaged electrocardiography, Holter monitoring, and imaging studies. Most patients underwent electrophysiologic study, and 48 of the patients eventually received an implantable cardioverter defibrillator during chronic follow-up. Relevant data from these patients were also analyzed.

Among the 58 patients, Dalal et al identified 25 with the mutation in PKP-2, the gene encoding Plakophilin-2. Thirteen different mutations were identified among the 25 individuals. Among the 13 mutations identified, 6 were insertion-deletion mutations, 3 altered a critically conserved nucleotide that formed the intron/exon splice site, 2 were nonsense mutations, and 2 were missense mutations. Patients with the PKP2 mutations tended to be younger than the ARVD/C patients without the mutation, 28 ± 11 years vs 36 ± 16 years. There was a slight male predominance in both groups. Palpitations and syncope were the most common presenting symptom in both groups, and there was no difference in clinical presentation between those with and without the PKP2 mutation. Clinical characteristics and noninvasive testing also were not statistically different between the 2 groups. There were a similar proportion of patients with severe right ventricular dilatation and local ventricular aneurysms between the 2 groups. ECG abnormalities, including the prolongation of the QRS in V1 through V3, the presence of delta waves, and the T-wave inversions in V1 through V3 were similarly distributed. The signal-averaged ECG was abnormal in 60% of those without a PKP2 mutation vs 17 of 23 (74%) patients with the PKP2 mutation. Fifty-six percent of the patients without a PKP2 mutation vs 48% of those with a PKP2 mutation had experienced an ICD discharge after insertion. It was interesting to note that among the patients with PKP2 mutation and inducible ventricular arrhythmias at electrophysiologic study, the presence of severe right ventricular dysfunction and the presence of spontaneous VT on Holter were not predictors of ICD intervention, whereas these risk factors appear to be valid predictors of ICD intervention in patients without the PKP2 mutation.

Dalal et al conclude that mutations in Plakophilin-2 are common and are associated with the clinical syndrome of ARVD/C. Although there was little difference in the clinical pattern between those patients with and without PKP2 mutations, they proposed that genetic testing for PKP2 mutations would be useful criteria for establishing the diagnosis.


Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a genetic cardiomyopathy that has been linked to defects in cell adhesion proteins, including plakoglobin, desmoplakin, plakophilin-2, and desmoglobin-2. This paper shows that PKP2 mutations are perhaps the most common genetic cause for ARVD/C. Previously, the diagnosis of ARVD/C was made on the basis of major and minor diagnostic criteria. These criteria might include the family history, the presence of ECG conduction or repolarization abnormalities, a clinical history of arrhythmias, regional dysfunction, most prominent in the right ventricle, and fibrofatty replacement of right ventricular myocardium seen at autopsy or in biopsy specimens. As ARVD/C has become better recognized and several registries have been established, more specific diagnostic criteria are beginning to emerge. Unfortunately, the limited data presented in these 2 reports don't show much difference between patients with and without one of the more commonly identified mutations. The natural history of the disease in both groups seems to be fairly similar. Perhaps as more insights into the mechanisms underlying ARVD/C are identified, more specific treatment approaches based on specific genetic profiles may be developed. However, at the present time, it appears that all of the identified defects in cell adhesion proteins lead to similar clinical consequences. For now, management recommendations will be similar for all patients with ARVD/C.