| Objective: Mounting evidence has shown that the imbalance of monocyte subset proportion and dysfunction is an important pathophysiological basis for many immune related diseases. Currently, human circulating monocytes are at least composed of three subsets with distinct physiological functions, including classical (CD14++CD16-,[Monl]), intermediate (CD14++CD16+,[Mon2]), and non-classical (CD14+CD16++,[Mon3]) monocytes. Among them, the "pro-inflammatory" Mon2subset has been received a great attention due to their active participation in cardiovascular pathophysiology. In addition, the formation of monocyte-platelet aggregates (MPA) is the structural basis for subsequent inflammatory and pro-thromboembolic activations. A recent study has confirmed a positive correlation between the Mon2monocyte subset quantity changes and elevated cardiac enzymes in patients with ST-segment elevation myocardial infarction (STEMI). These results indicate that changes in monocyte subsets after myocardial infarction, especially the increased number of Mon2monocytes, may be a novel marker for decompensated post-infarction heart failure and long-term prognosis. The present study was designed to investigate the following unresolved issues in a Chinese population suffered from STEMI:1) the dynamic profile of the monocyte subsets and their associations with MPAs in the acute phase (within7days) after STEMI;2) the prognostic values of monocyte subsets and MPAs for the occurrence of major cardiovascular events (MACE) after myocardial infarction.Methods:A total of100consecutive STEMI patients admitted for emergency primary percutaneous coronary intervention (PCI) in the Heart Center of Pingjin Hospital, Logistics University of the Chinese People’s Armed Police Forces, were recruited in this study (78male, aged58.20±11.00;22female, aged64.11±9.10). Their venous blood was serially collected at time of admission, day2, day3, day5and day7after STEMI for flow cytometry (FCM) analysis of circulating monocyte subsets and MPAs using a four-color platform (CD14-FITC, CD16-PE, CD86-PE-Cy5and CD41-PE-Cy7). Transthoracic echocardiography was performed within24hours after symptom attack and on day7post infarction. According to laboratory test results on admission, the GRACE score, the CRUSADE score and the SYNTAX score based on coronary angiography were calculated. MACE, which was defined as cardiovascular death, fetal and non-fetal ischemic stroke, re-infarction, target vessel revascularization, and re-hospitalization due the heart failure and/or angina, were recorded in hospital and in one-month after discharge.Results:1) MACE occurrence:Among all100STEMI patients,48cases had left ventricular (LV) anterior wall infarction, and52cases with LV inferior wall infarction. A total of7MACE was recorded:4in hospital and3after discharge. Among the in-hospital MACE,1case suffered from non-fatal ischemic stroke, and another3cases died (one case finished only one FCM analysis, one case with two FCM tests, and one case finished all FCM tests). Among the3events occurred after discharge,1case died after discharge, and2cases underwent re-hospitalization for target vessel revascularization.2) Dynamic changes of white blood cell (WBC) count, total monocyte and MPA count:The WBC count reached its plateau level when the first blood test was carried out on admission, and underwent a gradual decreasing trend thereafter. Total monocyte count gradually increased from the onset and reached the peak level on day3, and then presented with a decreasing trend. The total MPA count and MPA percent to total monocytes also underwent gradual decreasing trend from day1, and reached the nadir on day5.3) Dynamic Changes of Monl and Monl MPA:Monl count was gradually increased from the onset and reached the peak on day3, then decreased till day5. Monl percent to total monocytes underwent a significantly decrease on day2, followed by an increasing trend, and reached the peak level on day3. Monl MPA count presented with a similar changing pattern with that of total MPA count.4) Dynamic Changes of Mon2and Mon2MPA:Compared with day1, there was a rapid increase of the Mon2subset count [24.67cells/μL (14.96-45.73cells/μL) vs.48.78cells/μL (22.89-79.45cells/μL),P＜0.0001(shown as median with interquartile range)] as well as its percent to total monocytes [6.60%(4.38%-9.50%) vs.11.26%(7.56%-18.16%), P<0.0001] on day2after STEMI, peaking on day3[74.13cells/μL (27.77-86.27cells/μL)] followed by a gradual decrease, which was accompanied by a paralleled change in Mon2associated MPAs.5) Dynamic Change of Mon3and Mon3MPA: Mon3count, Mon3percent to total monocytes, and Mon3MPA count were all gradually decreased from the onset to the first three days, followed by a gradual increase from day3. There was no obvious change in Mon3MPA percent during the investigation.6) LVEF and Mon2count correlation analysis:Among the85patients who had undergone transthoracic echocardiography on day7, the accumulative effect of Mon2subset count (determined by area under curve [AUC] of Mon2count dynamics) was negatively correlated with LV ejection fraction (LVEF) on day7(Pearson r=-0.247,P=0.023, n=85). Specifically, the relationship between Mon2count AUC and LVEF was more obvious in patients suffered from anterior MI (Pearson r=-0.318,P=0.046, n=40), but not in patients with inferior wall MI (Pearson r=-0.092,P=N.S, n=45). In addition, the peak level of Mon2count and LVEF were negatively correlated (Pearson r=-0.227,P=0.037). Specifically, the relationship between peak Mon2count and LVEF was more obvious in patients suffered from anterior MI (Pearson r=-0.329,P=0.038, n=40), but not in patients with inferior wall MI (Pearson r=-0.064,P=NS, n=45).7) The correlation between Mon2count and Mon2MPA count:The Mon2count and Mon2MPA count was positively correlated on day1(Pearson r=0.881, P<0.0001, n=100), and on day3(Pearson r=0.841,P<0.0001, n=98).8) Logistic regression analysis:The risk factor adjusted multivariate stepwise Logistic regression analysis showed that day1Mon2MPA count was the only independent risk factor associated with in-hospital and one month MACE (for every10cells/μL increase, OR=2.37,[95%CI:1.265-4.44],P=0.007). After excluding2cases of early death who did not complete all flow cytometry analysis, Logistic regression analysis showed Mon2count on day3was the only independent risk factors for in-hospital and one month MACE (for every10cells/μL increase, OR=1.248,[95%CI:1.029-1.513],P=0.024). The receiver operating characteristic (ROC) curve analysis showed that Mon2count on day3 had a clinical acceptable value for discriminating STEMI patients with and without in-hospital and one month (AUC=0.823,[95%CI:0.679-0.964], P=0.016)9) Using43.4cells/μL as the cutoff point value (median of Mon2count on day3, n=98), the Kaplan-Meier survival analysis showed that no MACE occurred in patients with Mon2count (day3)<43.4cells/μL (P=0.0224for Log-rank test).Conclusions: The present study for the first time provides the detailed monocyte subset kinetics in acute phase after STEMI in humans. Specifically, a dramatic increase of the Mon2subset (CD14++CD16+) occurs on day2and peaks on day3, and then presents with a decreasing trend. The clinical significance of this dynamic profile is supported by the fact that Mon2count on day3and Mon2MPA count on day1, independently predict in-hospital and one month MACE in patients suffered from STEMI. This is the first study that linking monocyte subsets with "hard" clinical end points, and provides a new marker for risk stratification in patients with STEMI. Future long-term follow-up studies are required to validate our findings. |
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