Key result
ARVC/D was associated with significantly increased myocardial expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β compared to DCM and controls.
Observational (n=28)
p-value: p=≤.001
Molecular pathways involving sarcolemmal calcium channel regulation, apoptosis, and adipogenesis are upregulated in ARVC/D, suggesting a critical role in its pathogenesis independent of underlying genetic mutations.
These ARVC/D expression differences are hypothesis-generating; larger studies needed before any diagnostic or therapeutic implications.
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an autosomal dominant disease characterized by fibrofatty infiltration of the right ventricle, leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. OBJECTIVE: The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. METHODS: Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D. RESULTS: Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation. CONCLUSION: Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis, and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of the underlying genetic mutations.
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Akdiş et al. (2015) conducted an observational in Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (n=28). Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) vs. Dilated cardiomyopathy (DCM) and healthy controls was evaluated on Myocardial mRNA expression of candidate molecules (p=≤.001). ARVC/D was associated with significantly increased myocardial expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β compared to DCM and controls.
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