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Background The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging because the clinical presentation is highly variable and genetic penetrance is often low.
Methods To determine whether a change in the distribution of desmosomal proteins can be used as a sensitive and specific diagnostic test for ARVC, we performed immunohistochemical analysis of human myocardial samples.
Results We first tested myocardium from 11 subjects with ARVC; of these samples, 8 had desmosomal gene mutations. We also tested myocardium obtained at autopsy from 10 subjects with no clinical or pathological evidence of heart disease as control samples. All ARVC samples but no control samples showed a marked reduction in immunoreactive signal levels for plakoglobin (also known as
Conclusions Routine immunohistochemical analysis of a conventional endomyocardial-biopsy sample appears to be a highly sensitive and specific diagnostic test for ARVC.
-catenin), a protein that links adhesion molecules at the intercalated disk to the cytoskeleton. Other desmosomal proteins showed variable changes, but signal levels for the nondesmosomal adhesion molecule N-cadherin were normal in all subjects with ARVC. To determine whether a diminished plakoglobin signal level was specific for ARVC, we analyzed myocardium from 15 subjects with hypertrophic, dilated, or ischemic cardiomyopathies. In every sample, levels of N-cadherin and plakoglobin signals at junctions were indistinguishable from those in control samples. Finally, we performed blinded immunohistochemical analysis of heart-biopsy samples from the Johns Hopkins ARVC registry. We made the correct diagnosis in 10 of 11 subjects with definite ARVC on the basis of clinical criteria and correctly ruled out ARVC in 10 of 11 subjects without ARVC, for a sensitivity of 91%, a specificity of 82%, a positive predictive value of 83%, and a negative predictive value of 90%. The plakoglobin signal level was reduced diffusely in ARVC samples, including those obtained in the left ventricle and the interventricular septum.
Source Information
From the Departments of Pathology (A.A., J.E.S.) and Medicine (S.G.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Heart Hospital, University College London Hospitals National Health Service Trust, London (A.A., W.J.M.); the Departments of Medicine (H.T., H.C.) and Pathology (M.K.H.), Johns Hopkins Medical Institutions, Baltimore; the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (H.H.); the Cardiovascular Pathology Unit, University of Padua Medical School, Padua, Italy (C.B., G.T.); and Yiannis Protonotarios Medical Center, Naxos, Greece (A.T., N.P.).
Address reprint requests to Dr. Saffitz at the Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, or at jsaffitz{at}bidmc.harvard.edu.
Related Letters:
Arrhythmogenic Right Ventricular Cardiomyopathy
Tavora F., Creswell N., Burke A. P., Kohn M. A., Newman T. B., Saffitz J. E., Asimaki A., Gautam S.
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N Engl J Med 2009;
360:2784-2786, Jun 25, 2009.
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