Abstract 2767: A New Diagnostic Test For Arrhythmogenic Right Ventricular Cardiomyopathy
The clinical diagnosis of ARVC remains challenging. Although current diagnostic standards (International Task Force criteria) are relatively specific, they are not highly sensitive. We have previously observed decreased immunoreactive signal for the desmosomal protein plakoglobin (plk) at intercalated disks in patients with rare recessive forms of ARVC. To determine whether diminished localization of plk at cell-cell junctions is diagnostic of more common forms of ARVC, we used immunostaining to characterize the distribution of junction proteins in 11 cardiac specimens from patients with documented ARVC due to various dominant mutations in plakoglobin, desmoplakin, plakophilin-2 and desmoglein-2. Myocardium from 10 age-matched subjects with no clinical history or pathological evidence of heart disease served as controls. All ARVC specimens but no controls showed marked reduction in the amount of immunore-active signal for plk at myocyte junctions. Other desmosomal proteins showed variable localization but signal for the non-desmosomal adhesion molecule N-cadherin was always normal in ARVC patients. Next, to determine whether diminished plk signal is specific for ARVC, we analyzed right and left ventricular samples from transplant patients with hypertrophic, dilated or ischemic cardiomyopathies (n=5 for each). In every specimen, strong plk signal was seen at junctions in amounts indistinguishable from controls. N-cadherin signal was also normal. Finally, to test the specificity and sensitivity of reduced plk signal as a diagnostic test for ARVC, we performed blinded analysis of 30 heart biopsies from 29 patients from the Johns Hopkins ARVC registry. We correctly diagnosed 8 of 10 patients with documented ARVC and correctly ruled out ARVC in 9 of 11 patients without ARVC. Plk signal was reduced in 3 of 4 patients in whom Task Force criteria for ARVC were equivocal. In 5 patients, signal for N-cadherin was reduced indicating poor tissue quality and precluding diagnostic interpretation. Reduced plk signal occurred diffusely in all ARVC samples including LV and septal areas. These results indicate that routine immunohistochemistry in a conventional RV septal biopsy may be used as a highly sensitive and specific diagnostic test for ARVC.