Abstract 13928: Asymmetric Dimethylarginine (ADMA) Mediates the Effect of miRNA-762 on All-Cause Mortality in Patients With Coronary Artery Disease

Abstract

Introduction: Plasma concentrations of the endogenous L-arginine homologue asymmetric dimethylarginine (ADMA) independently predict cardiovascular and all-cause mortality. We sought to identify miRNAs that mediate the effects of ADMA on mortality or influence mortality through regulation of ADMA concentrations. Methods: In 993 participants of the Ludwigshafen Risk and Cardiovascular Health study (age 63.0±10.5 years, 31.4% females and 74.7% with coronary artery disease (CAD)) we measured ADMA and miRNAs concentrations in citrate plasma and investigated associations between them and with all-cause mortality. Results: miRNA-762 was positively and significantly correlated with ADMA concentrations (p=0.0013) and with all-cause mortality after adjusting for age and sex (HR (95%CI: 1.51(1.26-1.81); p=7.37E-06). The association remained significant after additionally adjusting for body mass index, CAD, arterial hypertension, diabetes, smoking, lipids, C-reactive protein, fibrinogen, renal function, homocysteine and medication (p=0.04). Mediation analyses showed that ADMA mediated 67% of the effect of miRNA-762 on mortality while miRNA-762 only mediated 8% of the effect of ADMA. Conclusions: miRNA-762 is an independent predictor of all-cause mortality in patients with CAD. The effects of miRNA-762 on mortality might be at least partially mediated by ADMA. miRNA-762 has been recently shown to regulate apoptosis in cardiomyocytes in myocardial infarction. We are currently investigating the effects of miRNA-762 on ADMA metabolism and stress responses in cultured cardiomyocytes and endothelial cells.