ST段抬高型心肌梗死后CD14~(++)CD16~+单核细胞升高与左室功能下降:基于中介分析的预后研究
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摘要
目的:通过中介分析研究ST段抬高型心肌梗死(STEMI)后CD14~(++)CD16~+单核细胞升高与左室功能下降相关的不良心血管预后之间的关系。方法:纳入行急诊经皮冠状动脉介入(PCI)治疗的初发STEMI患者,利用流式细胞术(Flow Cytometry,FCM)检测STEMI后第2天外周血经典型单核细胞(CD14~(++)CD16~-单核细胞),中间型单核细胞(CD14~(++)CD16~+单核细胞)和非经典型单核细胞(CD14~+CD16~(++)单核细胞);随访3年内患者的主要不良心血管事件(MACE);利用受试者工作特征曲线(ROC曲线)计算与MACE相关的CD14~(++)CD16~+单核细胞最佳截断值,对CD14~(++)CD16~+单核细胞和心功能下降指标与预后进行中介分析。结果:221例STEMI患者在3年随访中有67例发生MACE(MACE组),154例未发生MACE(无MACE组)。与无MACE组的患者相比,MACE组患者年龄更大[(63.72±11.58)岁∶(60.14±11.63)岁,P=0.036]、CD14~(++)CD16~+单核细胞计数水平更高[32.26(16.71,69.69)×10~9/L∶21.83(12.07,43.55)×10~9/L,P=0.004],同时空腹血糖水平更高[7.90(5.90,10.30)mmol/L∶6.80(5.90,8.50)mmol/L,P=0.028],而左室射血分数(LVEF)值明显降低[47.00(39.00,53.00)%∶52.00(45.00,55.00)%,P=0.001]。MACE组和无MACE组患者的用药无显著差异。ROC曲线分析显示CD14~(++)CD16~+单核细胞预测MACE发生的最佳截断值为32.2cells/μl。对MACE组和无MACE组的差异指标进行多因素logistic回归校正后显示,LVEF下降(<50%)(OR2.12,95%CI 1.10～4.09,P=0.024)和CD14~(++)CD16~+单核细胞升高(≥32.2cells/μl)(OR1.81,95%CI 1.31～2.52,P<0.001)是STEMI后患者发生MACE的独立危险因素。未经校正的中介分析显示LVEF下降相关的MACE增加有9.6%是由CD14~(++)CD16~+单核细胞升高引起的;经年龄和空腹血糖校正后CD14~(++)CD16~+单核细胞升高参与了15.9%LVEF下降相关的MACE增加。结论:STEMI后第2天CD14~(++)CD16~+单核细胞升高参与了左室功能下降相关的3年MACE增加,提示STEMI后心功能下降可部分通过影响天然免疫系统功能,进而导致不良心血管事件发生。
Objective:To investigate the relationship between elevated CD14~(++)CD16~+monocytes and adverse cardiovascular outcomes associated with decreased left ventricular function after ST-segment elevation myocardial infarction(STEMI)by median analysis.Method:We enrolled patients with de novo STEMI treated with primary percutaneous coronary intervention(PCI).Flow cytometry(FCM)was used to detect peripheral blood circulation monocyte subsets on the 2nd day after STEMI onset:classical monocytes(CD14~(++)CD16~-monocytes),intermediate monocytes(CD14~(++)CD16~+)Monocytes and non-classical monocytes(CD14~+CD16~(++)monocytes),and the main adverse cardiovascular events(MACE)in patients were followed up for 3years.The receiver operating characteristic curve(ROC curve)was used to calculate the optimal cut-off value of the CD14~(++)CD16~+monocytes for MACE prediction.Causal mediation analysis was performed to medication examine the relationship between left ventricular ejection fraction(LVEF)and MACE,mediated by increased CD14~(++)CD16~+monocyte counts.Result:A total of 221STEMI patients were enrolled,with 67cases of first MACE recorded during follow-up.Compared with patients without MACE(n=154),patients in the MACE group were older[(63.72±11.58)vs(60.14±11.63),P=0.036]and with higher CD14~(++)CD16~+monocytes counts[32.26(16.71,69.69)cells/μl vs 21.83(12.07,43.55)cells/μl,P=0.004]and higher fasting blood glucose level[7.90(5.90,10.30)mmol/L vs 6.80(5.90,8.50)mmol/L,P=0.028],as well as compromised LVEF[47.0%(39.0,53.0)%vs 52.0%(45.0,55.0)%,P=0.001].There was no significant difference in medication between patients with MACE group and those without MACE.The optimal cutoff value of CD14~(++)CD16~+monocytes for MACE prediction by using ROC curve analysis was 32.2cells/μl.Multivariate adjusted logistic regression showed that decrease in LVEF(<50%)(OR2.12,95%CI1.10to 4.09,P=0.024)and CD14~(++)CD16~+monocytes elevation(≥32.2cells/μl)(OR1.81,95%CI1.31to 2.52,P<0.001)were independent risk factors for 3-year MACE.Univariate mediation analysis showed that CD14~(++)CD16~+monocytes could explain 9.6%(P<0.05)increase in MACE caused by decreased LVEF;After adjustment for age and fasting glucose level,mediation analysis showed that CD14~(++)CD16~+monocytes can explain 15.9%(P<0.05)the decreased LVEF→MACE association.Conclusion:Our results showed that the CD14~(++)CD16~+monocytes elevation of the 2nd day after STEMI mediates decreased LVEF induced 3-year MACE after STEMI,which shed new light on the associations among left ventricular function,alterations in innate immunity and MACE after STEMI.
Objective:To investigate the relationship between elevated CD14~(++)CD16~+monocytes and adverse cardiovascular outcomes associated with decreased left ventricular function after ST-segment elevation myocardial infarction(STEMI)by median analysis.Method:We enrolled patients with de novo STEMI treated with primary percutaneous coronary intervention(PCI).Flow cytometry(FCM)was used to detect peripheral blood circulation monocyte subsets on the 2nd day after STEMI onset:classical monocytes(CD14~(++)CD16~-monocytes),intermediate monocytes(CD14~(++)CD16~+)Monocytes and non-classical monocytes(CD14~+CD16~(++)monocytes),and the main adverse cardiovascular events(MACE)in patients were followed up for 3years.The receiver operating characteristic curve(ROC curve)was used to calculate the optimal cut-off value of the CD14~(++)CD16~+monocytes for MACE prediction.Causal mediation analysis was performed to medication examine the relationship between left ventricular ejection fraction(LVEF)and MACE,mediated by increased CD14~(++)CD16~+monocyte counts.Result:A total of 221STEMI patients were enrolled,with 67cases of first MACE recorded during follow-up.Compared with patients without MACE(n=154),patients in the MACE group were older[(63.72±11.58)vs(60.14±11.63),P=0.036]and with higher CD14~(++)CD16~+monocytes counts[32.26(16.71,69.69)cells/μl vs 21.83(12.07,43.55)cells/μl,P=0.004]and higher fasting blood glucose level[7.90(5.90,10.30)mmol/L vs 6.80(5.90,8.50)mmol/L,P=0.028],as well as compromised LVEF[47.0%(39.0,53.0)%vs 52.0%(45.0,55.0)%,P=0.001].There was no significant difference in medication between patients with MACE group and those without MACE.The optimal cutoff value of CD14~(++)CD16~+monocytes for MACE prediction by using ROC curve analysis was 32.2cells/μl.Multivariate adjusted logistic regression showed that decrease in LVEF(<50%)(OR2.12,95%CI1.10to 4.09,P=0.024)and CD14~(++)CD16~+monocytes elevation(≥32.2cells/μl)(OR1.81,95%CI1.31to 2.52,P<0.001)were independent risk factors for 3-year MACE.Univariate mediation analysis showed that CD14~(++)CD16~+monocytes could explain 9.6%(P<0.05)increase in MACE caused by decreased LVEF;After adjustment for age and fasting glucose level,mediation analysis showed that CD14~(++)CD16~+monocytes can explain 15.9%(P<0.05)the decreased LVEF→MACE association.Conclusion:Our results showed that the CD14~(++)CD16~+monocytes elevation of the 2nd day after STEMI mediates decreased LVEF induced 3-year MACE after STEMI,which shed new light on the associations among left ventricular function,alterations in innate immunity and MACE after STEMI.
引文
[1] Anderson JL,Morrow DA.Acute Myocardial Infarction[J].N Engl J Med,2017,376(21):2053-2064.
[2]葛洪霞,祖凌云,高炜.急性ST段抬高性心肌梗死患者远期死亡的危险因素分析[J].临床心血管病杂志,2014,30(4):308-311.
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[5] Ruparelia N,Godec J,Lee R,et al.Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes,prior to recruitment,and identified through conserved transcriptional responses in mice and humans[J].Eur Heart J,2015,36(29):1923-1934.
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[8] Heine GH,Ulrich C,Seibert E,et al.CD14(++)CD16+monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients[J].Kidney Int,2008,73(5):622-629.
[9] Zhou X,Li J,Guo J,et al.Gut-dependent microbial translocation induces inflammation and cardiovascular events after ST-elevation myocardial infarction[J].Microbiome,2018,6(1):66-66.
[10]Zhou X,Liu XL,Ji WJ,et al.The kinetics of circulating monocyte subsets and monocyte-platelet aggregates in the acute phase of ST-elevation myocardial infarction:associations with 2-year cardiovascular events[J].Medicine(Baltimore),2016,95(18):e3466.
[11]Zhou X,Zhang L,Ji WJ,et al.Variation in dietary salt intake induces coordinated dynamics of monocyte subsets and monocyte-platelet aggregates in humans:implications in end organ inflammation[J].PloS One,2013,8(4):e60332.
[12]Task Force on the management of STseamiot,ESoC,Steg PG,James SK et al.ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[J].Eur Heart J,2012,33(20):2569-2619.
[13]杨国红,卢芮伊,孙海英,等.四色流式分析冠心病患者外周血单核细胞亚群及单核细胞-血小板聚集体的变化[J].临床心血管病杂志,2013,29(1):29-33.
[14]Ji WJ,Lu RY,Liu JX,et al.The influence of different anticoagulants and time-delayed sample processing and measurements on human monocyte subset and monocyte-platelet aggregate analyses[J].Cytometry B Clin Cytom,2017,92(5):371-379.
[15]Hicks R TD.Causal mediation analysis[J].Stata J,2011,11(4):609-615.
[16]Frangogiannis NG.The inflammatory response in myocardial injury,repair,and remodelling[J].Nat Rev Cardiol,2014,11(5):255-265.
[17]Rogacev KS,Zawada AM,Emrich I,et al.Lower Apo A-I and lower HDL-C levels are associated with higher intermediate CD14++CD16+monocyte counts that predict cardiovascular events in chronic kidney disease[J].Arterioscler Thromb Vasc Biol,2014,34(9):2120-2127.
[18]Antonelli L,Katz M,Bacal F,et al.Heart failure with preserved left ventricular ejection fraction in patients with acute myocardial infarction[J].Arq Bras Cardiol,2015,105(2):145-150.
[19]Ng VG,Lansky AJ,Meller S,et al.The prognostic importance of left ventricular function in patients with ST-segment elevation myocardial infarction:the HORIZONS-AMI trial[J].Euro Heart J Acute Cardiovas Care,2014,3(1):67-77.
[20]MacKinnon DP,Pirlott AG.Statistical approaches for enhancing causal interpretation of the M to Y relation in mediation analysis[J].Pers Soc Psychol Rev,2015,19(1):30-43.
[2]葛洪霞,祖凌云,高炜.急性ST段抬高性心肌梗死患者远期死亡的危险因素分析[J].临床心血管病杂志,2014,30(4):308-311.
[3] Seropian IM,Toldo S,Van Tassell BW,et al.Anti-inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction[J].JACC,2014,63(16):1593-1603.
[4] Tapp LD,Shantsila E,Wrigley BJ,et al.The CD14++CD16+monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction[J].J Throm Haemost,2012,10(7):1231-1241.
[5] Ruparelia N,Godec J,Lee R,et al.Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes,prior to recruitment,and identified through conserved transcriptional responses in mice and humans[J].Eur Heart J,2015,36(29):1923-1934.
[6] Dutta P,Courties G,Wei Y,et al.Myocardial infarction accelerates atherosclerosis[J].Nature,2012,487(7407):325-329.
[7] van der Laan AM,Ter Horst EN,Delewi R,et al.Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir[J].Eur Heart J,2014,35(6):376-385.
[8] Heine GH,Ulrich C,Seibert E,et al.CD14(++)CD16+monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients[J].Kidney Int,2008,73(5):622-629.
[9] Zhou X,Li J,Guo J,et al.Gut-dependent microbial translocation induces inflammation and cardiovascular events after ST-elevation myocardial infarction[J].Microbiome,2018,6(1):66-66.
[10]Zhou X,Liu XL,Ji WJ,et al.The kinetics of circulating monocyte subsets and monocyte-platelet aggregates in the acute phase of ST-elevation myocardial infarction:associations with 2-year cardiovascular events[J].Medicine(Baltimore),2016,95(18):e3466.
[11]Zhou X,Zhang L,Ji WJ,et al.Variation in dietary salt intake induces coordinated dynamics of monocyte subsets and monocyte-platelet aggregates in humans:implications in end organ inflammation[J].PloS One,2013,8(4):e60332.
[12]Task Force on the management of STseamiot,ESoC,Steg PG,James SK et al.ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[J].Eur Heart J,2012,33(20):2569-2619.
[13]杨国红,卢芮伊,孙海英,等.四色流式分析冠心病患者外周血单核细胞亚群及单核细胞-血小板聚集体的变化[J].临床心血管病杂志,2013,29(1):29-33.
[14]Ji WJ,Lu RY,Liu JX,et al.The influence of different anticoagulants and time-delayed sample processing and measurements on human monocyte subset and monocyte-platelet aggregate analyses[J].Cytometry B Clin Cytom,2017,92(5):371-379.
[15]Hicks R TD.Causal mediation analysis[J].Stata J,2011,11(4):609-615.
[16]Frangogiannis NG.The inflammatory response in myocardial injury,repair,and remodelling[J].Nat Rev Cardiol,2014,11(5):255-265.
[17]Rogacev KS,Zawada AM,Emrich I,et al.Lower Apo A-I and lower HDL-C levels are associated with higher intermediate CD14++CD16+monocyte counts that predict cardiovascular events in chronic kidney disease[J].Arterioscler Thromb Vasc Biol,2014,34(9):2120-2127.
[18]Antonelli L,Katz M,Bacal F,et al.Heart failure with preserved left ventricular ejection fraction in patients with acute myocardial infarction[J].Arq Bras Cardiol,2015,105(2):145-150.
[19]Ng VG,Lansky AJ,Meller S,et al.The prognostic importance of left ventricular function in patients with ST-segment elevation myocardial infarction:the HORIZONS-AMI trial[J].Euro Heart J Acute Cardiovas Care,2014,3(1):67-77.
[20]MacKinnon DP,Pirlott AG.Statistical approaches for enhancing causal interpretation of the M to Y relation in mediation analysis[J].Pers Soc Psychol Rev,2015,19(1):30-43.
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