56-04: Myocardial Expression of Non-Desmosomal Molecules in Arrhythmogenic Right Ventricular Cardiomyopathy/dysplasia Compared to Dilated Cardiomyopathy and Healthy Controls

Purpose: In arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) pathogenic mechanisms, especially involving non-desmosomal molecules remain unclear. Thus, our aim was to investigate myocardial expression profiles of candidate molecules that are involved in the pathogenesis of ARVC/D. Methods: The mNRA expression of 56 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, 6 adipogenic molecules, and 6 inflammatory molecules was studied. The averaged mRNA expression in right ventricular myocardium obtained by endomyocardial biopsy or heart transplantation from patients with ARVC/D (n = 10) was compared to samples from patients with non-familial dilated cardiomyopathy (DCM, n = 10) and healthy controls (n = 8). Immunohistochemistry and quantitative protein analysis was performed for significantly upregulated mRNAs. Next-generation exome sequencing was performed in all ARVC/D patients to search for pathogenic mutations. Conclusions: There was a significant upregulation of following mRNA levels in ARVC/D compared to DCM and controls: phospholamban (p = 0.005 vs DCM; p = 0.002 vs controls), tumor protein 53 apoptosis effector (PERP) (p = 0.008 vs DCM; p = 0.008 vs controls), and carnitine palmitoyltransferase 1 beta (CPT1B) (p = 0.05 vs DCM; p = 0.008 vs controls). Analysis of patients with plakophilin-2 mutations (n = 4) demonstrated that phospholamban, PERP and CPT1B were also increased in this subgroup of patients. Immunohistochemistry along with quantitative protein expression revealed significantly increased levels of phosphorylated phospolamban, PERP and CPT1B in ARVC/D. Conclusion: Changes in the expression profiles of sarcolemmal calcium channel regulators, pro-apoptotic molecules, and pro-adipogenic molecules suggest that these pathways may play a critical role in the pathogenesis of ARVC/D.