ABC | Volume 111, Nº5, November 2018

Review Article Silva et al miRNAs and cardiovascular disease Arq Bras Cardiol. 2018; 111(5):738-746 Figure 2 – Circulating biomarkers. Some of the serum and plasma miRNAs that could be used as diagnostic or prognostic biomarkers in cardiovascular diseases are here illustrated. One limitation of the use of circulating miRNA is the lack of normalization of its quantification as compared with tissue miRNA. 23 Despite these limitations, miR-1 is highly sensitive in early identifying AMI. Several studies have suggested a higher diagnostic accuracy of miR-499 compared with troponin T for AMI. 24,25 MiR-499 has the advantage of being detectable in the blood within the next four hours after the AMI, whereas troponin can be detected only later. 26 Therefore, miR-499 could enhance the accuracy of troponin T in the early diagnosis of AMI. The HUNT study investigated 179 miRNAs in 212 healthy subjects aiming to predict AMI in these individuals. Several circulating miRNAs were significantly different between individuals who suffered from fatal AMI and those who remained healthy during the follow-up period. Logistic regression analysis revealed that five miRNAs (miR‑106a‑5p, miR-424-5p, let-7g-5p, miR-144-3p and miR-660-5p) composed the best model for predicting AMI, providing 77% correct classification for both genders. 27 Jia et al. 28 showed that miR-30d-5p and -125b-5p also have diagnostic value for AMI, in a study on acute coronary syndrome patients. 28 In an animal model of AMI, serum miR-208a was increased at 4 hours and 24 hours after AMI. 25 Several studies have been conducted aiming at evaluating prognostic and/or diagnostic value of miRNAs in heart failure (HF), as well as in HF treatment. There is evidence that miRNAs have an important role in both the initiation and progression of HF. Although brain natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT‑proBNP) are considered the gold standard for HF diagnosis, miRNAs have been exhaustively studied as potential biomarkers. For example, a recent systematic review with meta‑analysis showed that miR-423-5p, as associated with atrial natriuretic peptide (ANP) would have a potential diagnostic value for HF detection. 29 In chronic HF, Cakmak et al. 30 showed that miR‑182 has a higher prognostic value for cardiovascular mortality, characterized by unexplained sudden death, decompensated HF or hemodynamically significant arrhythmia, as compared with NT-proBNP and high‑sensitivity C-reactive protein (CRP) by ROC curve analysis in patients with compensated HF (NYHA II, n = 20) and decompensated HF (NYHA III, n = 22) compared with healthy controls (n = 15). 30 A more comprehensive overview of miRNAs involved in acute and chronic HF can be found in a recent review by Vegter et al. 31 Studies on atrial fibrillation (AF) patients have shown that patients with stable chronic HF, AF and ejection fraction < 40% show a significant reduction in plasma miR-150 compared with healthy controls. 32 Harling et al. 33 analyzed the plasma obtained at 24 h before myocardial revascularization to evaluate diagnostic accuracy of miRNA in post-operative AF. The authors showed a predictive accuracy of 78%, 33 indicating that miR483-5 is a potential biomarker of post-operative AF. There is evidence that miR-23a and miR-26a could also predict post-operative AF, since their levels are reduced in the postoperative period of patients undergoing coronary bypass artery grafting surgery. 34 Reduced circulating levels of miR-126 is a potential biomarker of the development, progression and severity of AF and HF, according to a study conducted with patients with AF, HF or both. 35 Also, Gorem et al. 36 showed reduced expression of miR-150 in both platelets and serum of patients with chronic systolic HF associated with AF, compared with individuals without AF. 36 A study 37 reported the synthesis of endothelial cell‑derived apoptotic bodies containing high levels of miR-126 in atherosclerotic vascular disease. These molecules triggered the production of the chemokine CXCL12 in recipient vascular cells. 37 Circulating miR-212 has been suggested by Jeong et al. 38 as a biomarker of atherosclerosis, as it improves the prediction of atherosclerosis when combined with hemoglobin A1c, HDL and lipoprotein(a). Elevated plasma miR-29a levels were associated with increased carotid intima- media thickness in atherosclerosis patients. 39 Cardiac remodeling Ventricular remodeling is one of the mechanisms involved in the progression of HF and involves cardiomyocyte apoptosis and hypertrophy, interstitial fibrosis caused by collagen deposition, and vascular rarefaction (Figure 3). Despite evidence of an important role ofmiRNAs onpathologic remodeling,manymiRNAs involved in this process remain to be identified. Also, there have been conflicting results on the association of miRNAs with diseases. 740