A Potential Role Of Monocyte Subsets And Monocyte-platelet Aggregates In Risk Stratification Of Patients With Unstable Angina

Objectives:Acute coronary syndromes (ACS) are a leading cause of morbidity and mortality worldwide, which are composed of a spectrum of clinical presentations ranging from unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), to ST-elevation myocardial infarction (STEMI). It is estimated that among ACS patients, approximately30%were due to UA and70%to myocardial infarction. In recent years, studies have demonstrated distinct clinical outcomes in patients with UA, which lacks effective method to identify high-risk group. A serial of basic experiments highlight the critical role of monocyte in the atherosclerosis and thrombosis, suggesting that monocyte may also plays a role in the pathophysiological process of ACS. Monocyte could be differentiated into three subpopulations:the CD14++CD16-(the classical monocytes, Monl), the CD14++CD16+(the intermediate monocytes, Mon2), and the CD14+CD16++(the non-classical monocytes, Mon3). The pathophysiological function of three monocyte subsets is different, therefore draws more attention recently, especially CD14++CD16+monocyte subset. Additionally, monocyte-platelet aggregates (MPAs) could be a sensitive marker for circulating platelet activation. MPAs is a new early marker for inflammatory and thrombotic disease which emerges within4hours after myocardial infarction, and earlier than CK-MB. We aimed to solve two questions among UA patients,1) Specify whether functional and proportional imbalance of monocyte subsets and MPAs exists in UA patients.2) Specify whether monocyte subsets and MPAs are capable of prognostic value to assess the patients with intermediate-to-high risk which is assessed by Global Registry of Acute Coronary Events (GRACE) score.Methods:Patients with suspected ACS presenting consecutively to the Heart Center of Pingjin Hospital, Logistics University of the Chinese People’s Armed Police Forces were recruited in this study. Based on demographic information and lab testing results, stratify the risk of UA patients with GRACE score, GRACE score<108was defined as low risk group, GRACE score>108was defined as intermediate-high risk group. Age-and-sex matched stable coronary heart disease (CHD) subjects served as control group. The3monocyte subsets of2groups, as well as subset-specific MPAs, were measured by flow cytometry.Results:Compared with CHD patients, UA patients had increased Mon2, Mon3and CD16+(Mon2+Mon3) monocyte counts (Mon2:18.75(12.21-36.67) vs.10.73(6.79-12.62), P＜0.001; Mon3:38.07(25.49-57.38) vs.21.11(18.24-25.57), P＜0.001; CD16+monocyte:59.51(42.86-106.30) vs.30.53(26.97-35.67), P＜0.001, described as median with interquartile range). Meanwhile, the counts of Mon2MPAs, Mon3MPAs and total MPAs (Monl MPAs+Mon2MPAs+Mon3MPAs) was higher in UA group than that in CHD group (Mon2MPAs:5.50(2.56-19.06) vs.2.86(2.14-3.84), P＜0.001; Mon3MPAs:4.76(3.12-7.82) vs.2.14(1.54-2.69), P＜0.001; total MPAs:67.07(37.91-126.00) vs.51.10(41.97-61.21), P=0.045)For UA subjects, compared with GRACE score-determined low risk patients (GRACE Score≤108, n=70), intermediate-to-high risk patients (GRACE Score>108, n=25) had higher level of mean age and ST-segment Deviation (age:63.44±8.29vs.57.33±8.34, P=0.002; ST-segment Deviation:14(56.0%) vs.3(4.29%), P<0.001), but lower level of SBP (130.20±12.07vs.139.80±17.88, P=0.014). For the data about monocyte and MPAs, the counts of Mon2and total MPAs, as well as Monl-and Mon2-associated MPAs was higher (Mon2:30.95(12.51-48.72) vs.17.30(11.37-29.00), P=0.038; total MPAs:89.86(48.73-178.00) vs.60.98(35.95-108.40), P=0.019; Monl MPAs:69.74(41.64-117.10) vs.48.29(28.97-81.12), P=0.029; Mon2MPAs:7.47(4.11-39.79) vs.5.10(1.84-10.33), P=0.031). Additionally, the receiver operating characteristic curve (ROC) curve analysis showed that the counts of Mon2subset and total MPAs, and the counts of Monl-and Mon2-associated MPAs, all had statistical discriminative values for GRACE score-determined low-risk and intermediate-to-high risk subjects (Mon2:AUC=0.640,[95%CI:0.508-0.771], P=0.038; Monl MPAs:AUC=0.647,[95%CI:0.525-0.769], P=0.030; Mon2MPAs: AUC=0.644,[95%CI:0.523-0.767], P=0.032; total MPAs:AUC=0.658,[95%CI:0.537-0.780], P=0.019). Whereas no statistical differences were observed among these four parameters when multiple ROC comparisons were done (Monl MPAs vs. Mon2MPAs, P=0.960; Mon2MPAs vs. Mon2, P=0.913; Mon2MPAs vs. total MPAs, P=0.688; Monl MPAs vs. Mon2, P=0.914; Monl MPAs vs. total MPAs, P=0.473; Mon2vs. total MPAs, P=0.744). Adjusted binary logistic regression analysis revealed that increased counts of Mon2subset (for per5cells/μL increase, OR1.186,95%CI1.044to1.347,P=0.009), Mon2MPAs (for per5cells/μL increase, OR1.228,95%CI1.062to1.421, P=0.006) and total MPAs (for per5cells/μL increase, OR1.072,95%CI1.010to1.137, P=0.022) independently discriminated GRACE score-determined low risk and intermediate-to-high risk UA patients.Conclusions:Our results demonstrate for the first time that the level of Mon2and MPAs increases in UA patients. Meanwhile, we find the level of Mon2subset, Mon2-associated MPAs and total MPAs is correlated with GRACE score-determined high-risk UA patients, which is independent of traditional risk factors. Notably, clinical cardiovascular research with larger samples is needed to further illustrate the role of monocyte subsets and MPAs in the risk stratification.