Regulation of microRNAs in coronary atherosclerotic plaque.

Aim: Identification of microRNAs (miRNAs) associated with atherosclerosis may unravel novel therapeutic targets and biomarkers. We studied miRNAs differentially expressed between coronary atherosclerotic plaques (CAP) and healthy arteries. Materials & methods: Paired CAP and internal mammary arteries (IMA) were collected from 14 coronary artery disease patients. The miRNA profiles between diseased (CAP) and healthy (IMA) tissues were compared using microarrays and quantitative PCR. Results: Thirty-one miRNAs were differentially expressed between CAP and IMA. Among these, miR-486-5p showed a high level of regulation (12-fold), had predicted interactions with atherosclerosis-associated genes and correlated with triglyceride levels and arterial stenosis. Regulation of miR-486-5p was validated by PCR (p = 0.004). Conclusion: The miRNAs are regulated in the atherosclerotic plaque. We highlight miR-486-5p whose role in atherosclerosis requires further investigation.

Circulating microRNAs to predict heart failure after acute myocardial infarction in women.

Left ventricular remodeling after acute myocardial infarction affects cardiac function and increases the risk of developing heart failure. Despite the emergence of biomarkers associated with remodeling, the ideal biomarker to accurately predict the risk of developing heart failure after acute myocardial infarction is still to be discovered. Female and male hearts cope differently with ischemic stress, leading to different consequences on cardiac morphology and function. As biomarkers reflect the pathogenesis of remodeling, utilization of sex-specific biomarkers might improve risk stratification. Expressed in cardiac and inflammatory cells, microRNAs regulate several biological pathways triggering the remodeling process. In addition, circulating microRNAs are associated with the risk of developing heart failure after acute myocardial infarction, hence their biomarker potential. Interestingly, multiple microRNAs display sex-specific expression profiles as they can be modulated by sexual hormones and escape X-inactivation, for those located on the X-chromosome. This review article aims to discuss the potential of circulating microRNAs to predict heart failure after acute myocardial infarction in a sex-specific manner.

Cyclin dependent kinase inhibitor 1 C is a female-specific marker of left ventricular function after acute myocardial infarction.

BACKGROUND: A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner. METHODS: CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up. RESULTS: In the test cohort, CDKN1C was lower in patients with a reduced EF (<40%) compared to patients with preserved EF (≥50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort. CONCLUSION: CDKN1C is a novel female-specific biomarker of LV function after AMI.

A 3-gene panel improves the prediction of left ventricular dysfunction after acute myocardial infarction.

BACKGROUND: Identification of patients at risk of poor outcome after acute myocardial infarction (MI) would allow tailoring healthcare to each individual. However, lack of prognostication tools renders this task challenging. Previous investigations suggested that blood transcriptome analysis may inform about prognosis after MI. We aim to independently confirm the value of gene expression profiles in the blood to predict left ventricular (LV) dysfunction after MI. METHODS AND RESULTS: Five genes (LMNB1, MMP9, TGFBR1, LTBP4 and TNXB) selected from previous studies were measured in peripheral blood samples obtained at reperfusion in 449 MI patients. 79 patients had LV dysfunction as attested by an ejection fraction (EF) ≤40% at 4-month follow-up and 370 patients had a preserved LV function (EF>40%). LMNB1, MMP9 and TGFBR1 were up-regulated in patients with LV dysfunction and LTBP4 was down-regulated, as compared with patients with preserved LV function. The 5 genes were significant univariate predictors of LV dysfunction. In multivariable analyses adjusted with traditional risk factors and corrected for model overfitting, a panel of 3 genes - TNXB, TGFBR1 and LTBP4 - improved the prediction of a clinical model (p=0.00008) and provided a net reclassification index of 0.45 [0.23-0.69], p=0.0002 and an integrated discrimination improvement of 0.05 [0.02-0.09], p=0.001. Bootstrap internal validation confirmed the incremental predictive value of the 3-gene panel. CONCLUSION: A 3-gene panel can aid to predict LV dysfunction after MI. Further independent validation is required before considering these findings for molecular diagnostic assay development.

Long non-coding RNAs in the atherosclerotic plaque.

BACKGROUND AND AIMS: Genetic and environmental factors are important components of the development of atherosclerosis. Long non-coding RNA (lncRNAs) have emerged as regulators of multiple pathophysiological pathways in the cardiovascular system. Here, we investigated potential associations between lncRNAs and atherosclerosis. METHODS: Tissue samples from atherosclerotic coronary artery plaques and non-atherosclerotic internal mammary artery were obtained from 20 patients during coronary artery bypass surgery. Expression levels of five lncRNAs known to be associated with coronary artery disease were measured using quantitative PCR. RESULTS: Cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL) and myocardial infarction-associated transcript (MIAT) were more expressed in the atherosclerotic arteries compared to the non-atherosclerotic arteries. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was less expressed in the atherosclerotic plaques. Expression levels of potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) and hypoxia inducible factor 1A antisense RNA 2 (aHIF) were comparable between atherosclerotic and non-atherosclerotic arteries. In the atherosclerotic plaque, expression levels of MALAT1, MIAT, KCNQ1OT1 and aHIF were inversely correlated with age. CONCLUSIONS: We report significant associations between lncRNAs and atherosclerosis. These findings support a role for lncRNAs in coronary artery disease development.