Circulating microRNA-1 in the diagnosis and predicting prognosis of patients with chest pain: a prospective cohort study

Acute myocardial infarction (AMI) is a severe cardiac disease with high mortality and poor prognosis, and acute chest pain (ACP) causes hospital admission worldwide. It is critically significant to differentially diagnose whether patients with ACP are suffering from AMI or not without delay [1]. Firstly, the rapid and accurate diagnosis of AMI is critical for the initiation of effective evidence-based medical management and treatment [2–4]. Secondly, there is a potential to enhance the efficiency of emergency department (ED) by rapidly and reliably rule-out AMI, which also reduce patients’ anxiety and rational managing medical resources [5, 6]. At present, atypical AMI have occurred frequently, resulting in difficult diagnosis and delayed treatment. Accordingly, sometimes we have to combine with Cardiac troponin (cTn), a representative of myocardial enzyme, to make a correct diagnosis. However, cTn usually begins to rise about 3 h after the onset of AMI, reaches a peak around 24 h, and increases in patients with aortic dissection (AD), end-stage renal damage (ESRD), pulmonary embolism (PE) and acute heart failure (AHF) [7, 8]. If there is a contraindication of coronary angiography (CAG) or patients and their families refuse to undergo invasive treatment at this time, a diagnostic and therapeutic dilemma will occur [9].

MicroRNAs (MiRs) are small RNAs that regulate expression of proteins by acting on the 3’untranslated region (UTR) of target genes encoding these proteins [10–12]. They participate in the regulation of a variety of signal pathways and maintain the homeostasis of the body environment, and there is a significant difference in the expression profiles between healthy and various disease patients, while being stable in the peripheral blood and having the potential for diagnosis and treatment of AMI [13]. MicroRNA-1 (MiR-1) is one of miRs which is expressed in cardiomyocytes, and it is the first miR found to be associated with cardiovascular development [14]. Moreover, some studies suggest that miR-1 directly participates in the regulation of the whole pathological process of AMI and AMI prognosis can be optimized by detecting the expression of miR-1 and upstream regulation [15–17].

In this prospective cohort study of 341 patients within 3 h after the onset of ACP and 100 non-ACP patients, we evaluated the diagnostic and prognostic value of plasma levels of miR-1. This study suggested that circulating miR-1 levels in patients with early AMI were significantly higher than those non-AMI patients and controls, consistent with the findings of some studies [21, 24–26]. The study had demonstrated that a timely revascularization treatment within 3 h after AMI would repair the ischemic myocardium and ultimately reduce the mortality to get an optimistic prognosis [27]. Hence, the aim of this study was to evaluate the early diagnostic and prognostic value of miR-1 in patients with AMI, including patients whose symptom onset time was < 3 h, and no reperfusion treatment was performed before the sample was taken in the way to avoid affecting the outcomes. Although this study showed that the diagnostic efficacy of miR-1 on AMI is comparable to that of cTnI, combined diagnosis could reduce the risk of delaying in missed diagnosis. Based on the current studies of the early diagnosis of AMI in circulating miR series, we found most evidences of miR-1, miR-499 and miR-208b. Devaux Y et al. [28] recruited 1155 suspected of AMI patients and eventually diagnosed with 224 cases AMI. Although diagnosed patients had significantly elevated miR-499 and miR-208b, their diagnostic efficacy was no better than cTnI, even combined diagnosed with miR-499 and miR-208b. Furthermore, miR-499 and miR-208b did not show any advantage in predicting the prognosis of AMI patients for 2 years follow-up. Widera C et al. [29] suggested that in the differential diagnosis of AMI and UA, miR-499, miR-208b did not show significant differences. Researches showed that miR-1 was the most abundantly expressed miR in cardiomyocytes and played an important role in maintaining normal physiological functions of cardiomyocytes, such as regulation of endothelial function, angiogenesis, and apoptosis [25]. The study established animal models to compare the expression of miR-1 in drug-induced secondary myocardial ischemia and myocardial infarction, suggested that miR-1 might be superior in the diagnosis of myocardial infarction to myocardial injury in animal model [30]. So far, the benefit of miRs in prognostic value was not well studied as the potential diagnostic benefit in cardiovascular medicine. Ai J et al. [31] manifested that increased miR-1 had prompted the role of myocardial contractility and diastolic dysfunction after AMI. Cheng Y et al. [25] indicated that elevated circulating miR-1 can predict ventricular arrhythmias after AMI. Qipshidze Kelm N et al. [32] designed a mouse model of AMI which was established by ligation of the anterior descending coronary artery of mice with different ages, and the levels of circulating miR-1 and miR-133a were measured. This study suggested that miR-1 elevation was more pronounced, and increased circulating miR-1 levels in older mice are positively associated with increased heart dysfunction after AMI. Further clinical trial found that the levels of circulating miR-1 after AMI significantly correlated with absolute change in infarct volume and showed a trend for correlation with absolute change of left ventricular ejection fraction [17]. These researches provided the basis for miR-1 to evaluate the prognosis of AMI patients. In our study, miR-1 can predict the prognosis of ACP patients, which may be attributed to its diagnostic value in the early occurrence of AMI in ACP patients. In addition, there are several points need to be clarified in this study. First, cTnI testing results was not blind to clinician, which was susceptible to become the subjective factors of clinicians, but miR-1 made the results more objective. Second, the adjudication of AMI was performed by using the criteria by universal definition, putting cTn in a decisive position. Therefore, it was inevitable to cause test bias leading to embarrassment of new biomarker to be superior to cTn. Third, our study suggested that the sensitivity of cTnI was relatively low when AMI onset was within 3 h, combined with miR-1 parallel test method could improve the sensitivity of the diagnosis at this time (sensitivity 95.98%, specificity 74.85%). Fourth, there were many reports that miR-1 had a relationship with tumor at present, thus this study excluded patients with cancer to avoid bias [33]. Fifth, no conclusions could be made about patients with ESRD as they were excluded from the study. Of note, the concentrations of miR-499 and cTn were identified increasing in patients with ESRD without any evidence of cardiac injury [34]. Sixth, this study was inevitably affected by the sample size and by individual differences, complications, conditions, clinical time in different patients, which might cause the standard deviations of the data dispersed. Further study of the role of circulating miRs in the diagnosis and prognosis of AMI needs to improve and enrich the AMI evaluation system, in conjunction with the global acute coronary event registration score (GRACE) and emergency medical score (REMS), which makes greater sense for clinical medicine. The usage of miRs in clinical applications of AMI still requires large-scale, multi-center, registration studies to validate.

Our study suggested that circulating miR-1 might diagnose early AMI in patients with ACP, which was almost equal to cTnI, and diagnostic accuracy could be elevated when combined miR-1 with cTnI. Furthermore, miR-1 might play a role in predicting the prognosis of patients with suspected AMI.