Clinical And Immunoinflammatory Predictors Of In-hospital Outcome In Patients With ST-elevation Myocardial Infarction

Acute myocardial infarction(AMI) is a medical emergency with high morbidity and mortality.The benefit of primary percutaneous coronary intervention over thrombolytic therapy for ST-elevation myocardial infarction has been well established. As the early strategy of percutaneous transluminal coronary angioplasty was associated with higher risk of restenosis and acute reocclusion,the combined use of stents and platelet glycoproteinⅡb/Ⅲa inhibiotor has been introduced and validated. Along with the improvement in treatment and outcome,clinical investigation has constantly focused on the risk factors related to adverse events.Multivessel disease has been reported to be present in 40-50%patients with AMI.In prior studies the result of whether multivessel coronary artery disease exerts an adverse impact directly or indirectly upon the in-hospital prognosis of patients with AMI did not reach a consensus.It is also noted that a certain proportion of these patients were identified with a chronic total occlusion in the non-infarct related artery.Whether the contemporary reperfusion modalities,including stents and glycoproteinⅡb/Ⅲa inhibitor,are able to mitigate the adverse prognostic implications of multivessel disease is unknown.Furthermore,the prognostic impact of chronic total occlusion in the non-infarct related artery in patients with AMI remains to be elucidated.Besides the clinical factors also immunoinflammatory process likely influences ischemic injury and clinical outcome in patients with AMI.The inflammatory cascade in AMI,that is neutrophil infiltration,elevated production of proinflammatory cytokines(TNF-alpha,IL-6) and chemokines(MCP-1,MIP-1),has demonstrated to potentially influence myocardial damage and clinical outcome.In exploration of the key link between initial ischemic insult and the resultant inflammatory response,a growing body of evidence suggests an early innate immune response in priming the cascade of immunoinflammation in ischemic injury.Dendritic cells(DC),the most potent antigen-presenting cells with a unique ability to initiate a primary immune response by activation of naive T cells,are detected to accumulate into the ischemic lesion of the heart,brain,liver and kidney in animal experiments..In the antigen-free condition of ischemic injury,they recognize the endogenous damage/danger-associated molecular pattern(DAMP) signals released from ischemic cells or disrupted tissue and produce a key series of proinlammatory cytokines and chemokines in vivo and vitro.Extracellular high mobility group box-1(HMGB1) is the most characterized DAMP,exerting a dual chemotactic and activating effect on DC.Recent researches have represented feasibility to modulate ischemic injury by depletion of DC or blockage of HMGB1.In spite of the relevant advances in clarifying the mechanism of ischemic injury induced immune reaction,direct clinical evidence of DC implication in patients of MI is limited.This study is carried out to specify the dynamic change of circulating DC subset in MI and its relationship to myocardial injury and prognosis.PartⅠClinical characteristics related to in-hospital outcome of patients with myocardial infarction:the prognostic implication of multivessel disease and chronic total occlusionObjective:We sought to investigate whether the contemporary reperfusion modalities, including stents and glycoproteinⅡb/Ⅲa inhibitor,are able to mitigate the adverse prognostic implications of multivessel disease.Furthermore,the prognostic impact of chronic total occlusion(CTO) in the non-infarct related artery in patients with ST-elevation myocardial infarction(STEMI) remains to be elucidated.Methods:We retrospectively analyzed patients of STEMI underwent primary stenting in our hospital from September,2005 to December,2007.Clinical and angiographic characteristics were compared among patients with single and multivessel disease as well as patients with and without CTO in the non-infarct related artery.The multivariate analysis was applied to identify independent risk factors of adverse in-hospital outcome.Results:A total of 345 patients were included.180(53.6%) were identified with multivessel disease and 20(5.8%) with CTO in the non-infarct related artery.They had a high risk clinical and angiographic profile.Patients of multivessel disease were older and had a higher incidence of hypertension and cardiogenic shock,while those with CTO in the non-infarct related artery had impaired left ventricular systolic function and higher incidence of heart failure and lower procedure success.The overall incidence rate of in-hospital major adverse cardiac events(MACE) is 10.4%(36/345).Patients of multivessel disease did not discriminate from those with single-vessel disease in clinical outcome.In contrast,patients with CTO in the non-infarct related artery had significant higher rates of in-hospital MACE.By multivariate analysis,the presence of CTO in the non-infarct related artery was not an independent predictor of in-hospital MACE.Conclusion:Patients with or without multivessel disease had similar post procedural TIMI flow and in-hospital outcome after the combined use of primary stenting and glycoproteinⅡb/Ⅲa inhibitor.But patients with CTO in the non-infarct related artery had reduced reperfusion success and poorer in-hospital prognosis.Further studies regarding the optimal treatment of these high-risk patients are warranted.PartⅡDendritic cells in the pathogenesis and prognosis of ST-elevation myocardial infarctionObjective:This study is carried out to specify the dynamic change of circulating DC subset in ST-elevation myocardial infarction(STEMI) and its relationship to myocardial injury and prognosis.Methods:41 STEMI patients who underwent primary percutaneous coronary intervention(PCI) were included and grouped according to the presence(complicated MI,abbreviated as comMI,n=15) or absence(uncomplicated MI,abbreviated as uncomMI,n=26) of adverse cardiac events:combined incidence of cardiogenic shock and heart failure.The control group consisted of 24 healthy subjects.Venous blood samples were obtained just before PCI for analysis of blood routine,circulating DC and plasma inflammatory markers(HMGB1,hsCRP,IL-6)(day 1) in MI patients.The same analyses were repeated about 2 days after the procedure(day 3).Results:TC and LDL-ch were elevated while restoration of postprocedual TIMI 3 flow was reduced in comMI.An early and substantial depletion of circulating MDC and PDC was detected in MI groups on day 1.The relative and absolute numbers of MDC was significantly reduced in both uncomMI group(percentages:0.03%,0 to 0.16%,P＜0.001;counts:2750/ml,0 to 17360/ml,P＜0.001) and comMI group(percentages:0.015%,0 to 0.11%,P＜0.001;counts:2105/ml,0 to 15840/ml,P＜0.001) compared with the controls(percentages:0.15%,0.06 to 0.37%;counts: 8045/ml,3300 to 29280/ml).It is the similar pattern of PDC in uncomMI group and comMI group.DC subsets did not differ significantly between MI groups on day 1.A follow up analysis on day 3 revealed reconstitution of both DC subsets in the uncomMI patients,with comparable percentages and counts of DC to the level of controls.In contrast,comMI patients with adverse clinical outcome manifested defective DC restoration at the follow up.HMGB1 concentration was elevated in uncomMI and comMI groups on day 1 compared with the controls.Concentration of both groups declined to the control level on day 3.In contrast,both CRP and IL-6 concentration were constantly elevated throughout the observation period in MI groups.The comMI discriminated from the uncomMI of IL-6 concentration on day 1 and day 3,CRP on day 3,but not HMGB1.Circulating DC subsets on day 1 significantly correlated with marker of myocardial necrosis and DAMP in serum. Both MDC(r=-0.420,p=0.008 and r=-0.383,p=0.016 for relative and absolute numbers of MDC respectively) and PDC(r=-0.348,p=0.03 and r=-0.299,p=0.064 for relative and absolute numbers of PDC respectively) inversely correlated to peak CK-MB concentration.A comparable association between DC subsets and HMGB1 on day 1 was observed.Interestingly,there was a strong correlation between HMGB1 in serum on day 1 and peak concentrations of the marker of myocardial necrosis CK-MB.In comparison,DC counts on day 3 were in association with the inflammatory marker CRP and LVEF.Both MDC(r=-0.368,p=0.021 and r=-0.405, p=0.01 for relative and absolute numbers of MDC respectively) and PDC counts(r=-0.344,p=0.032 for relative numbers of PDC) inversely correlated with CRP measured at the same time point.We also detected a marginally positive correlation between MDC counts and LVEF.Of note,LVEF correlated negatively with peak CK-MB concentration and CRP on day 3.In addition,a significant correlation was also demonstrated between peak CK-MB concentration and CRP.The interplay among LVEF,CK-MB and CRP confirmed the relationship between myocardial damage and systemic inflammation. Conclusion:The present study provides further insights into the nature of immunoinflammatory response in MI.We detected deep reduction of circulating DC early after MI onset,which is correlated to CK-MB and HMGB1.Our observation would suggest that DC is involved in the pathogenesis of MI and its recruitment to ischemic myocardium is regulated by myocardial necrosis.A follow up study indicate that impaired DC restoration on day 3 is related to cardiogenic shock,heart failure or in-hospital cardiogenic death,in association with increased serum IL-6 and CRP level. This result suggests that the prolonged DC depletion is predictive of poor clinical outcomes through an excessive inflammatory response.Acting as both sensor and effector in innate immune response,DC may potentially link myocardial injury and the consequent inflammation.PartⅢInfluence of coronary multivessel disease and chronic total occlusion on myocardial infarction-associated immunoinflammationObjective:We sought to investigate the influence of coronary multivessel disease and chronic total occlusion on ST-elevation myocardial infarction(STEMI)-associated immunoinflammation.Methods:The participants were enrolled in partⅡ.They were divided by the presence or absence of coronary multivessel disease(Single,n=19;Multivessel,n=22) and chronic total occlusion in the non-infarct related artery(non-CTO,n=36;CTO, n=5).Circulating DC and hsCRP levels were compared between MI groups and with controls.Results:Patients in Multivessel group were older,had higher incidence of diabetes, hypertension and smoking,lower rate of acute occlusion in LAD compared with those in Single groups;non-CTO and CTO groups had comparable clinical characteristics. The circulating DC subsets in MI groups changed in a similar pattern of that in partⅡ.Multivessel and CTO groups showed partly impaired restoration of DC subsets compared with control levels.Results on day 3 identified no significant difference of circulating DC between Single and Multivessel groups;circulating MDC(percentages: 0.05%,0.04-0.08%vs 0.11%,0.02-0.40%,P=0.027) and PDC(percentages:0.01%, 0-0.04%vs 0.04%,0.01-0.20%,P=0.016;counts:1330/mL,0-3600/mL vs 3655/mL, 600-20000/mL,P=0.042) were significantly lower in CTO group on day 3 than in non-CTO group,hsCRP was elevated in MI groups but did not differ among the groups.Single and Multivessel groups had comparable risk of developing in-hospital adverse cardiac events,but patients of CTO group had significantly higher risk than those in non-CTO group.Conclusion:STEMI Patients with or without multivessel disease had comparable circulating DC numbers on day 3 as well as comparable risk of developing in-hospital adverse cardiac events.STEMI Patients with chronic total occlusion in the non-infarct related artery showed further depletion of circulating DC subsets compared with those without CTO,which suggests an enhanced myocardial infarction-associated immunoinflammation and may potentially lead to development of adverse cardiac events.