**1. Introduction**

Cardiovascular disease (CVD) is the leading cause of death in the United States [1] and accounts for nearly \$219 billion in spending annually and 647,000 deaths [2]. Coronary artery disease (CAD) is the most prevalent form of CVD with upwards of 365,000 American mortalities each year, primarily as a result of acute myocardial infarction (AMI) [2]. With over 800,000 Americans suffering AMIs annually [3], early detection is crucial to improving clinical outcomes and decreasing mortality.

Currently used circulating biomarkers such as cardiac troponins and creatine kinase MB act as sensitive and specific tests for myocardial damage, yet, they may be negative early in the process of ischemia. Their increase in the setting of ST-elevation MI (STEMI), a process that nearly always results from coronary plaque rupture and thrombosis formation, is usually reflective of the extent of the infarct and approximates the mass of cardiomyocytes that damaged in the process of AMI. In the setting of non-ST elevation myocardial infarction (NSTEMI), increases in different biomarkers may be suggestive of a specific underlying pathophysiology, although data is limited on such associations. For instance, it was suggested that extreme levels of cardiac troponins are suggestive of total occlusion (TO) of the culprit artery [4], but the results were not used to assess correlations with other entities of myocardial injury, and data on such a possible association is limited. At present, biomarkers are not used to differentiate specific coronary pathologies, or assess the extent of vascular occlusion, nor are they used to detect non-CAD related myocardial cell damage [5].

Early reperfusion, usually through percutaneous coronary intervention (PCI) is a primary factor in the prognosis and clinical outcome of AMI [6,7]. Although electrocardiographic signs of the ST segment elevation are a sensitive and specific sign of coronary TO in the setting of STEMI, approximately only 25.5–34% of NSTEMI patients were found to have TO [8,9]. Patients suffering from TO are commonly underdiagnosed, receive delayed intervention, and have increased rates of complications and mortality [8]. Additionally, it may be challenging to distinguish between NSTEMI resulting from coronary atherosclerosis, and other processes of myocardial damage associated with inflammation, microvascular damage, toxic injury, vasoconstriction, etc.

Thus, highly sensitive and specific circulating biomarkers capable of diagnosing AMI (and specifically patients with TO) shortly after symptoms begin are of great clinical importance and may reduce mortality as well as improve patient outcomes.

In recent years multiple circulating micro-RNAs (MiRNAs) have been identified and investigated for their possible diagnostic and prognostic utility in CVD [10–14]. Specifically, Micro-RNA 133a (Mir-133a) has been reported as a potentially powerful biomarker for AMI and CVD. Mir-133a is a short non-coding RNA molecule, which serves to regulate target genes through post-transcriptional suppression. It has been found that Mir-133a is critical for proper cardiac development, playing an important role in early differentiation and cardiogenesis, as well as mediating various cardiac processes including apoptosis, cardiac remodeling, hypertrophy, conductance, and automaticity [15]. Increased serum levels of Mir-133a have been observed in the setting of AMI and CVD. This is most likely the result of damaged myocardium releasing Mir-133a during cellular lysis, or adjacent border zone myocardium releasing Mir-133a containing vesicles in response to the cardiac insult [16]. The research on Mir-133a's diagnostic potential, however, is strongly conflicted, with some papers reporting weak correlations between circulating Mir-133a concentrations and AMI [10,17], and others reporting strong correlations with excellent sensitivity and specificity [11,18–22]. In light of these contradictory findings, this meta-analysis synthesizes data from existing literature in order to examine the true potential of Mir-133a as a biomarker in AMI. Additionally, we analyzed the time frames in which Mir-133a was quantified, and their effect on the increases in plasma concentration, to ascertain whether Mir-133a may be useful as a very early diagnostic marker. Lastly, we compared the data of STEMI patients with those of NSTEMI patients to determine if Mir-133a might be used to distinguish between these two types of AMI. We hypothesized that TO in the setting of NSTEMI, and other specific entities of myocardial injury, may be characterized by distinct Mir-133a increase patterns, and aimed to evaluate the literature in that regard. Notably, correct identification of high risk NSTEMIs has a critical impact on the course of treatment [8], and therefore Mir-133a may serve as a valuable biomarker in this respect.
