P62Role of microRNAs associated with non-alcoholic fatty liver disease in sudden cardiac death from coronary artery disease

Abstract

Purpose: Coronary artery disease (CAD) is the leading cause of sudden cardiac death (SCD). It has recently been pointed to non-alcoholic fatty liver disease (NAFLD) as a new risk factor for the development of CAD. The possible mechanisms linking NAFLD and CAD include inflammation, dyslipidaemia, insulin resistance, and direct impact of NAFLD on coronary arteries. microRNAs (miRNAs) are 21–22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in several diseases. And they have been related to the cholesterol homeostasis, therefore they could contribute to the development of NAFLD. The aim of this study is 1) to evaluate the relationship between NAFLD and SCD from severe CAD in forensic autopsies and 2) to quantify the expression of several liver miRNAs related to lipid metabolism and NAFLD and to correlate the expression levels of these liver miRNAs with the presence of steatohepatitis (NASH), obesity and lipid profile. Methods: 133 cases of SCD due to CAD (CAD-SCD) and 106 cases of non-CAD sudden death (control group, non-CAD-SD) were prospectively included from 2008 to 2013 following a broad protocol created by our study group to offer a multidisciplinary approach of SCD. miRNAs -122-5p, -33a-5p, -34a-3p, -21-5p, -29c-3p, -27a-3p and -106b-5p were quantified by qRT-PCR in frozen liver tissues. Forensic investigation included compilation of circumstances of death and premortem clinical information, autopsy examination including body mass index (BMI) and abdominal circumference (AC). Results: In both groups a male predominance was observed. The presence of NAFLD was significantly higher in the CAD-SCD group than in the group of non-CAD-SD (62% vs 26%, p<0.001), with more advanced forms of the disease (NASH). In both groups, the presence of hepatic disorder correlated with BMI and AC (p<0.01). A significant increase of miR-34a-3p (p<0.05) and a significant decrease in miR-122-5p and -29c-3p (p<0.01) in the CAD-SCD with NASH group versus non-CAD-SD without NAFLD group were observed. A significant inverse correlation (p<0.05) between miRNAs -29c-3p and -122-5p and AC or BMI were obtained. Moreover, we found a significant inverse correlation (p<0.05) between miR-122-5p and LDL/HDL ratio; and a significant direct correlation (p<0.05) between miR-34a and GGT was observed. Conclusions: The CAD-SCD is associated with NAFLD and NASH. The miRNAs studied appear to be associated with NAFLD severity.