Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review

Abstract

The aim of the present study is to identify microRNAs (miRs) with high potential to be used as biomarkers in plasma and/or serum to clinically diagnose, or provide accurate prognosis for survival in, patients with atherosclerosis, coronary artery disease, and acute coronary syndrome (ACS). A systematic search of published original research yielded a total of 72 studies. After review of the risk of bias of the published studies, according to Cochrane Collaboration and the QUADUAS Group standards, 19 studies were selected. Overall 52 different miRs were reported. In particular, miR-133a/b (5 studies), miR-208a/b (6 studies), and miR-499 (7 studies) were well studied and found to be significant diagnostic and/or prognostic markers across different cardiovascular disease progression stages. miR-1 and miR-145b are potential biomarkers of ACS; miR-1 with higher sensitivity for all acute myocardial infarction (AMI), and miR-145 for STEMI and worse outcome of AMI. But when miRs were studied across different ACS study populations, patients had varying degrees of coronary stenosis, which was identified as an important confounder that limited the ability to quantitatively pool the study results. The identified miRs were found to regulate endothelial function and angiogenesis (miR-1, miR-133), vascular smooth muscle cell differentiation (miR-133, miR-145), communication between vascular smooth muscle and endothelial cell to stabilize plaques (miR-145), apoptosis (miR-1, miR-133, miR-499), cardiac myocyte differentiation (miR-1, miR-133, miR-145, miR-208, miR-499), and to repress cardiac hypertrophy (miR-133). Their role in these processes may be explained by regulation of shared RNA targets such as cyclin-dependent kinase inhibitor 1A (or p21), ETS proto-oncogene 1, fascin actin-bundling protein 1, hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, insulin-like growth factor 1 receptor LIM and SH3 protein 1, purine nucleoside phosphorylase, and transgelin 2. These mechanistic data further support the clinical relevance of the identified miRs. miR-1, miR-133a/b, miR-145, miR-208a/b, and miR-499(a) in plasma and/or serum show some potential for diagnosis of cardiovascular disease. However, biased selection of miRs in most studies and unexplained contrasting results are major limitations of current miR research. Inconsistencies need to be addressed in order to definitively identify clinically useful miRs. Therefore, this paper presents important aspects to improve future miR research, including unbiased selection of miRs, standardization/normalization of reference miRs, adjustment for patient comorbidities and medication, and robust protocols of data-sharing plans that could prevent selective publication and selective reporting of miR research outcomes.

Expression of miR-208b and miR-499 in Greek Patients with Acute Myocardial Infarction

“…verifying their utility for the early diagnosis of AMI (12). Despite all these achievements, it is essential to carry out clinical studies, including groups of individuals who have genetic differences that might influence miR expression.…”

“…In contrast, the levels of circulating plasma miRs can be measured rapidly using realtime PCR, offering two main advantages over standard antibody-based assays: increased sensitivity and specificity. Several studies have already considered circulating cardiacspecific or -enriched miRs as new biomarkers for the early diagnosis of AMI (8)(9)(10)(11)(12).…”

“…In fact, the vast majority of these studies have been performed in Asian populations, while limited studies from European populations are also available (12). Consequently, better validation through larger studies is required for the establishment of miRs as biomarkers in clinical practice.…”

Epigenetic Programming of Cardiovascular Disease by Perinatal Hypoxia and Fetal Growth Restriction

“…Conversely, abrogation of Nos3 promoter DNA methylation increases basal eNOS mRNA expression in vitro and protects against hind limb ischemia injury in vivo [75]. Similarly, growing evidence suggests a central role of miRNAs in the genesis of cardiometabolic dysfunction, also proposed as sensitive molecular markers of vascular disease [76]. In fact, we recently reported that circulating levels of miRNA Let-7 and miR-126 are associated with different traits of cardiometabolic dysfunction in children as well as have a predictive value for metabolic syndrome in these subjects [77].…”

The role of circulating microRNAs in acute coronary syndromes: ready for prime time?

“…Furthermore the promising role of miR-1 (3 studies) in the diagnosis of acute coronary syndromes and the regulation of miR-145 in STEMI patients is highlighted. A meta-analysis, however, is not presented because of heterogeneous study designs and analytical reasons (1).…”