Plasma proANP and SDMA and microRNAs are associated with chronic mitral regurgitation in a pig model

OBJECTIVE: Non-ischemic mitral regurgitation (MR) is primarily caused by myxomatous mitral valve (MV) disease leading to adaptive remodeling, enlargement, and dysfunction of the left ventricle. The aim of this study was to examine the regulation of plasma markers and several cardiac key genes in a novel porcine model of non-ischemic MR. METHODS AND RESULTS: Twenty-eight production pigs (Sus scrofa) were randomized to experimental MR or sham surgery controls. MR was induced by external suture(s) through the posterior MV leaflet and quantified using echocardiography. The experimental group was subdivided into mild MR (mMR, MR=20–50%, n=10) and moderate/severe MR (sMR, MR >50%, n=6) and compared with controls (CON, MR ≤10%, n=12). Eight weeks postoperatively, follow-up examinations were performed followed by killing. Circulating concentrations of pro-atrial natriuretic peptide (proANP), l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine (SDMA) were measured. MV, anterior papillary muscle, and left ventricular free wall tissues were collected to quantify mRNA expression of eNOS (NOS3), iNOS (NOS2), MMP9, MMP14, ANP (NPPA), BNP (NPPB), and TGFB1, 2, and 3 and five microRNAs by quantitative real-time PCR. Pigs with sMR displayed markedly increased plasma proANP and SDMA concentrations compared with both controls and mMR (P<0.05). The expression of all genes examined differed significantly between the three localizations in the heart. miR-21 and miR-133a were differently expressed among the experimental groups (P<0.05). CONCLUSIONS: Plasma proANP and SDMA levels and tissue expression of miR-21 and miR-133a are associated with severity of chronic MR in an experimental porcine model.