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Published on: May 19, 2020
Plasma proANP and SDMA and microRNAs are associated with chronic mitral regurgitation in a pig model
Susanna Cirera1, Sophia G Moesgaard, Nora E Zois
1Department of Veterinary Clinical and Animal SciencesFaculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark Novo Nordisk A/SMaaloev, Denmark Department of Clinical BiochemistryCopenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Department of Cardiothoracic and Vascular SurgeryAarhus University Hospital, Aarhus, Denmark Department of Clinical BiochemistryAarhus University Hospital, Aarhus, Denmark Department of Veterinary Disease BiologyFaculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark Department of Clinical ChemistryVU University Medical Center, Amsterdam, The Netherlands.
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.
Insights
Plasma pro-atrial natriuretic peptide (proANP) and symmetric dimethylarginine (SDMA) levels, along with specific microRNAs, correlate with the severity of non-ischemic mitral regurgitation (MR) in a new porcine model.
Area of Science:
- Cardiovascular Research
- Translational Medicine
- Molecular Cardiology
Background:
- Non-ischemic mitral regurgitation (MR) stems from myxomatous mitral valve disease, causing left ventricular remodeling and dysfunction.
- Understanding the molecular and plasma marker changes in MR is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate plasma marker regulation and cardiac gene expression in a novel porcine model of non-ischemic MR.
- To establish a preclinical model for studying the pathophysiology of MR.
Main Methods:
- Twenty-eight pigs underwent either MR induction or sham surgery.
- MR severity was classified as mild (mMR) or moderate/severe (sMR) via echocardiography.
- Plasma markers (proANP, l-arginine, ADMA, SDMA) and cardiac tissue gene/microRNA expression were analyzed.
Main Results:
- Pigs with sMR showed significantly elevated plasma proANP and SDMA compared to controls and mMR.
- Differential expression of cardiac genes and microRNAs (miR-21, miR-133a) was observed across heart localizations and experimental groups.
- Gene expression patterns varied significantly among the mitral valve, papillary muscle, and left ventricular free wall.
Conclusions:
- Plasma proANP and SDMA levels are sensitive indicators of MR severity in this experimental model.
- Tissue expression of miR-21 and miR-133a is associated with the degree of chronic MR.
- The porcine model effectively mimics key aspects of human non-ischemic MR, offering a platform for further research.
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