A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy.
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 gamma-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.


CONCLUSIONS
Routine immunohistochemical analysis of a conventional endomyocardial-biopsy sample appears to be a highly sensitive and specific diagnostic test for ARVC.
Asimaki
Angeliki
A
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Tandri
Harikrishna
H
Huang
Hayden
H
Halushka
Marc K
MK
Gautam
Shiva
S
Basso
Cristina
C
Thiene
Gaetano
G
Tsatsopoulou
Adalena
A
Protonotarios
Nikos
N
McKenna
William J
WJ
Calkins
Hugh
H
Saffitz
Jeffrey E
JE
D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis* / Q000473:pathology; D001706:Biopsy; D015820:Cadherins / Q000032:analysis*; D016022:Case-Control Studies; D051180:Desmoplakins / Q000032:analysis* / Q000235:genetics; D005799:Genes, Dominant; D006331:Heart Diseases / Q000175:diagnosis; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007365:Intercellular Junctions / Q000737:chemistry*; D020125:Mutation, Missense; D009206:Myocardium / Q000737:chemistry*; D032383:Myocytes, Cardiac / Q000737:chemistry; D051191:Plakophilins / Q000032:analysis*; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D015398:Signal Transduction
D015820:Cadherins; D051180:Desmoplakins; C495337:PKP2 protein, human; D051191:Plakophilins