Lately, miRNAs are given immense importance in managing autophagy, necrosis, and apoptosis of cardiomyocytes, hence its function in myocardial infarction . Investigations have additionally examined the pieces of evidence that miRNAs are seeped into the circulation from the heart following a myocardial injury, causing a dynamic increase in their levels [27,28]. Consequently, miRNAs which circulate in the plasma or blood have newly surfaced as promising biomarkers for the AMI diagnosis and/or AMI prognosis because of their reproducibility, specificity, and stability.
Our study reviews 20 articles which examine miRNAs in ACS patients. The enrolment criteria for patients with ACS or AMI in all investigations were standardized according to the international definitions of STEMI, NSTEMI, and unstable angina . This review reveals the upregulated behavior of cardiac-specific miRNAs which were studied (miR-1, miR-133, miR-208, and miR-499) in an isolated or collective manner in each study, except in one study in which downregulation of two miRNAs, miR-122 and miR-375, were reported . Aside from these miRNAs, several other upregulations occurred in miRNAs. Wang et al. reported miR-328, Oliveri et al. reported miR-423-5p, Oerleman et al. reported miR-21, and Li C et al. reported miR-223, miR-134 and miR-186 [6,17-19]. The microRNA retrieval sources were whole blood, serum, and plasma. miRNAs which circulate in the blood are stable. The real-time PCR assay was a well-known technique employed to quantify microRNA.
For the first time, Wang et al. in 2010 published a study that stated, among the four miRNAs investigated, the plasma levels observations of miR-208a could be implemented for AMI clinical diagnosis . In terms of diagnosing AMI, miR-208a possessed greater specificity and sensitivity. miR-208a was readily identified in patients with AMI within four hours since the onset of chest pain. However, compared to CTnI, its diagnostic significance was inferior. No remarkable distinction in sex and age was mentioned in the study.
Another study by Adachi et al. in 2010 revealed that plasma concentrations of miR-499 were increased in AMI patients within 48 hours . The concentration was noted to peak in about six hours to 12 hours and later undetectable upon hospital discharge . The upregulation of miR-499 was associated with the level of CK-MB.
Corsten et al. in 2010 found a notable rise in miR-208b and miR-499, correlating positively with the level of CTnI and CTnT . The plasma levels of microRNAs were not influenced by a broad array of clinical confounding factors, which involve age, sex, systolic blood pressure, kidney function, body mass index, and white blood cell count.
Another study by D’Alessandra et al. in 2010 presented an increased level of miR-1, miR-133a, miR-133b, and miR-499-5p and a decreased level miR-122 and miR-375, which are also positively correlated with CTnI . It is unusual in a sense that the reduction in the concentration of miR-122 and miR-375 has not been examined in any medical condition, not in humans or the animal models of human diseases.
In 2010, Ai et al. revealed a remarkable elevation in miR-1 in patients with AMI, which also positively correlated with cardiac troponins . An elevation in circulating miR-1 was not correlated with gender, age, blood pressure, diabetes mellitus state, and AMI biomarkers. Additionally, miR-1 has positively correlated also with the levels of CK-MB .
A remarkable elevation of miR-133a and miR-328 concentrations in patients with AMI and the correlation of CTnI with miR-133 or miR-328 concentrations were also confirmed by Wang et al. . Nevertheless, the levels of miR-133 and miR-328 peaked faster compared to CTnI. No statistical deviations were reported between the control groups and the AMI groups for each of the analyzed variables, except for the levels of low-density lipoprotein (LDL) and total cholesterol (TC), which seemed to increase in AMI patients.
The upregulation of miR-1, miR-133a/b, miR-208a/b, and miR-499 levels and their correlation with CTnT was observed by Widera et al. . miR-133a and miR-208b were correlated with all-cause mortality in six months, despite adjusting for sex and age. However, these miRNAs missed their correlation with the end results upon adjustment for hs-CTnT, which showed that, to a sensitive myonecrosis marker, these biomarkers do not contribute to prognostic information.
In 2011, Kuwabara et al. presented the upregulation of miR-1 and miR-133a and their positive correlation with the level of CTnT . Levels of serum miR-1 and miR-133a were found to elevate in Takotsubo cardiomyopathy and UA but without an increase of cardiac troponins or CK concentrations in the serum.
Gidlof et al. in 2011 showed that, while other miRNAs did not associate with CTnT or EF, the upregulation of serum miR-1, miR-133a, miR-208b, miR-4995p, and miR-208b imposed positive correlation with CTnT and negative correlation with EF . Even when patients with MI were distinguishable from patients of non-MI based on their miR-208b and miR-499-5p plasma levels, the precision was more inferior compared to CTnT, the modern gold standard of the cardiac marker.
In 2012, Devaux et al. noted that the concentration of miR-208b and miR-499 were more prominent in patients with MI since levels of plasma miRNAs rise starting from one hour after symptoms onset . The peak concentration of CTnT and CK corresponded with the levels of both miRNAs. Additionally, there was an inverse relationship with EF, which mean that miRNAs may render data on the prognosis, despite producing only a moderate left ventricular dysfunction prognosis.
Another study by Olivieri et al. in 2013 revealed that miR-1, miR-21, miR-133a, miR-423-5p, and miR-499-5p levels were elevated in patients with NSTEMI compared to control. The concentration of miR-499-5p and miR-21 also a markedly elevated in NSTEMI patients compared to CHF . Impressively, mir-499-5p was analogous to CTnT in distinguishing NSTEMI versus CHF and control patients. Its accuracy for diagnosis was more powerful than traditional hs-cTnT in distinguishing NSTEMI versus control. No meaningful impact of systemic arterial hypertension and type-2 diabetes mellitus was observed on the expression levels of miR-499-5p.
Oerlemans et al. in 2012 defined the inherent significance of miR-1, miR-21, miR-146a, miR-208a, and miR-499 in a group of 332 suspected patients with ACS. They noticed that, compared with hs-CTnT, the aggregate of miR-1, miR-21, and miR-499 have a greater diagnostic value . The implementation of multivariate logistic regression was done to examine the independent predictability of ACS in miRNAs, after adjusting for important covariates, such as the history of the patient (sex, age, previous episode of MI, surgery or percutaneous intervention) and risk factors for cardiovascular diseases (hypercholesterolemia, hypertension, family history, diabetes mellitus, and smoking status).
In 2013, Li et al. measured levels of six serum miRNAs (miR-1, miR-134, miR-186, miR-208, miR-223 and miR-499) in patients with AMI and found that there was an upregulation in those patients versus control group . For diagnosing AMI, measuring the assays of those six miRNAs is proved to be more solid predictive value than assessing a single miRNA individually. For the early and accurate diagnosis of AMI, collective assays of miRNAs can be used to supplement the cardiac troponins. All six miRNAs exhibited variances which are statistically significant between the AP and AMI. Moreover, the concentration of miR-208 and miR-499 were elevated more in AP than in AMI patients. The condition may be hinting that the miRNAs have a greater sensitivity for AP diagnosis. No significant variation in the gender, age, and ethnicity among the controls and the patients.
In 2013, Gidlof et al. pointed that the concentrations of three miRNAs with cardio-enriched traits (miR-1, miR-208a, and miR-499-5p) were elevated in patients with NSTEMI compared to non-MI. They were foind to be elevated in patients with STEMI compared to NSTEMI, although, the precision was more inferior than CTnT, the modern gold standard of the cardiac marker . A multivariate analysis was done, and the statistical significance level for all associations was not influenced despite adjustment for sex, age, and sampling time.
The levels of miRNA-1, miRNA-133a, miRNA-208b, and miRNA-499 were found to be elevated significantly in post-AMI patients compared to normal volunteers who were paired for sex and age . Even though positive correlations were observed between cTnT and the four circulating miRNAs in 12 hours after the onset of the symptoms, for prompt diagnosis of AMI, no miRNAs was reported to be superior to CTnT.
The level of serum miR-1 rose swiftly hours after symptoms of AMI . Over 20-fold increase in the level of serum miR-1 was detected within 24 hours of AMI. Furthermore, there was a positive correlation which links CK-MB and serum miR-1. The report also proposed that miR-1 may additionally be associated with the size of myocardial infarction in humans.
Chen et al. have also pointed out that plasma levels of miR-499 markedly elevated 12 hours after the onset in patients with AMI, and imposed positive correlation with cardiac biomarkers . Remarkably, they noticed that miR-499 concentration in two- and three-vessel CAD was considerably greater than single-vessel CAD; therefore, the biomarker corresponds positively with coronary stenosis severity. miR-499 levels in patients with AMI in 24 hours following an emergency percutaneous intervention (PCI) were notably more profound than the non-PCI group and those at admission.
Zhao et al. reported that miR-499 concentration in patients with AMI was markedly more elevated than the control group, despite having moderate specificity and sensitivity than CTnI . The half-life of plasma miR-499 is low; its levels markedly elevate in three hours following the AMI onset, peaked at 12 hours, before progressively decreasing. We anticipate that this conclusion would be instrumental for re-infarction diagnosis following an initial AMI. No notable variation in gender and age within the groups.
As explained by Bialek et al., miR-208a, exclusively synthesized in the heart, rises in conditions such as STEMI and/or myocardial injury induced by reperfusion . During admission (less than three hours of the onset) in STEMI patients when CTnI was not increased yet, miR-208a concentration in plasma elevated to 10-fold increase. miRNA-208a also peaked in advance of both CK-MB and CTnI mass. This condition exhibits a favorable relationship with the traditional biomarkers of myocardial injury.
Lastly, Agiannitopoulos et al. reported a study of Greek AMI patients where the upregulation of miR-208b and miR-499 occurred . An immediate collection of blood samples were performed once the patient is being admitted. Interestingly, the results of the Greek AMI group are concomitant with those from Asian groups, implying that the genetic background does not influence the expression levels of miRNA-208b and miRNA-499. No remarkable distinctions were observed between both groups, particularly in gender, age, smoking condition, and any additional clinicopathological characteristics.
Multiple limitations developed during the development of this study. First, not every study cohort was gender- and age-matched or matched with additional cofounding factors. Second, the population size of some trials was relatively modest. Third, the timing for retrieving blood samples was not discussed in several studies, despite having significance to faithfully label microRNA as a useful cardiac biomarker in the prompt diagnosis of AMI. Fourth, microRNA levels should be investigated in CKD patients to eliminate false positive outcomes. There is a need to carry extensive randomized cohort studies to approach these limitations and assess the potential advantages of having microRNAs as a novel cardiac biomarker.