Abstract
Circulating biomarkers available in clinical practice do not allow to stratify patients with coronary heart disease (CHD) prior the onset of a clinically relevant event. We evaluated the methylation status of specific genomic segments and gene expression in peripheral blood of patients undergoing Cardiac Computed Tomography (CCT) for CHD (n = 95).We choose to investigate cholesterol metabolism. Methylation and gene expression of low density lipoprotein receptor (LDLR), sterol regulatory element-binding factor 2 (SREBF2) and ATP-binding cassette transporter 1 (ABCA1) were evaluated by qRT-PCR. Calcium score (CACS), stenosis degree, total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV) and plaque burden (PB) were assessed in all CHD patients (n = 65). The percentage of methylation at the specific analyzed segment of LDLR promoter was higher in CHD patients vs healthy subjects (HS) (n = 30) (p = 0.001). LDLR, SREBF2 and ABCA1 mRNAs were up-regulated in CHD patients vs HS (p = 0.02; p = 0.019; p = 0.008). SREBF2 was overexpressed in patients with coronary stenosis ≥50% vs subjects with stenosis <50% (p = 0.036). After adjustment for risk factors and clinical features, ABCA1 (p = 0.005) and SREBF2 (p = 0.010) gene expression were identified as independent predictors of CHD and severity. ROC curve analysis revealed a good performance of ABCA1 on predicting CHD (AUC = 0.768; p<0.001) and of SREBF2 for the prediction of disease severity (AUC = 0.815; p<0.001). Moreover, adjusted multivariate analysis demonstrated SREBF2 as independent predictor of CPV, NCPV and TPV (p = 0.022; p = 0.002 and p = 0.006) and ABCA1 as independent predictor of NCPV and TPV (p = 0.002 and p = 0.013).CHD presence and characteristics are related to selected circulating transcriptional and epigenetic-sensitive biomarkers linked to cholesterol pathway. More extensive analysis of CHD phenotypes and circulating biomarkers might improve and personalize cardiovascular risk stratification in the clinical settings.
Highlights
Despite advances in diagnosis, treatment and prognosis, coronary heart disease (CHD) is still the most prevalent cause of mortality and morbidity worldwide [1].The main pathophysiological process underlying the development of CHD is represented by coronary atherosclerosis whose pathogenesis involves an imbalanced lipid metabolism and impaired immune response
Given the central role both of the epigenetics and immune system in the pathogenesis of atherosclerosis and CHD development through dynamic changes of molecular patterns [26,29,30], in this observational study we investigated the association between gene expression/epigenetic markers and CHD features
We evaluated by quantitative realtime PCR the methylation status of specific genomic segments and the relative expression of genes in peripheral blood mononuclear cells (PBMNCs) of patients with suspected CHD underwent to Cardiac Computed Tomography (CCT) aiming to find a possible screening methodology for non-invasive and non-radiation-utilizing detection of CHD
Summary
The main pathophysiological process underlying the development of CHD is represented by coronary atherosclerosis whose pathogenesis involves an imbalanced lipid metabolism and impaired immune response. These phenomena contribute to endothelial dysfunction and chronic inflammation, with the consequent formation of the atherosclerotic plaque, erosion and unstable atheroma, and vessel lumen stenosis [2,3]. Several studies reported an implication of epigenetic modifications in the pathogenesis of multifactorial diseases such as CHD, focusing on the evaluation of global DNA methylation in atherosclerotic tissues, and in peripheral blood cells of CHD patients [4,5,6,7,8,9]. The expression pattern was found to correlate with the severity of CHD and gene expression in vascular tissues, suggesting a mirroring between circulating cells and changes in the atherosclerotic coronary wall [10,11,12,13,14]
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