Clinical implications of elevated serum interleukin-6, soluble CD40 ligand, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in patients with acute ST-segment elevation myocardial infarction

BACKGROUND: Atherosclerosis is widely accepted as a chronic inflammatory disease. Research paid much attention to sensitive specific serum biomarkers for vulnerable plaques. The markers not only serve as diagnostic tools for the identification of patients with acute coronary syndrome (ACS), but also help us to identify high-risk patients. However, the existing data are limited and have been conflicting. HYPOTHESIS: Circulating interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) might correlate with the onset and the cardiac mortality of patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Serum levels of IL-6, sCD40L, MMP-9, and TIMP-1 were measured by sandwich enzyme-linked immunosorbent assay (ELISA) in 263 patients with STEMI and 262 age- and gender-matched control subjects without coronary artery disease (CAD). The patients with STEMI were then followed prospectively for 24 mo for the occurrence of cardiac mortality. RESULTS: Compared with the control subjects, patients with STEMI exhibited higher levels of IL-6 (p < 0.001), sCD40L (p < 0.001), MMP-9 (p < 0.001), TIMP-1 (p = 0.045), and MMP-9/TIMP-1 ratio (p = 0.007). Significant and positive correlations between MMP-9 and TIMP-1 (r = 0.610, p相似文献   

Anti-inflammatory cytokine profile in acute coronary syndromes: behavior of interleukin-10 in association with serum metalloproteinases and proinflammatory cytokines

BACKGROUND: The anti-inflammatory cytokine interleukin-10 (IL-10) downregulates the production of metalloproteinases (MMPs) and upregulates the production of their tissue inhibitors (TIMPs). The aim of this study was to assess the levels of IL-10 in patients with acute myocardial infarction (AMI) and unstable angina (UA), as well as to investigate the relationship of circulating IL-10 with the levels of MMPs (MMP-1, -2, -9), their tissue inhibitor (TIMP-1), pro-inflammatory cytokines (IL-6, tumor necrosis factor (TNF)-alpha) and serum lipids in the same patient population. METHODS: Serum MMP-1, -2, -9, TIMP-1, IL-6, TNF-alpha and IL-10 were measured by ELISA assays in 23 patients with AMI and 20 patients with UA after their hospital admission, as well as in 16 healthy controls subjects. The lipid profile was assessed by measuring the serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides. RESULTS: AMI patients exhibited significantly higher serum levels of IL-10 as compared with those of UA patients and healthy controls (both P=0.005). In contrast, there was no significant difference in IL-10 levels between UA patients and healthy controls. In AMI patients there was a statistically significant positive correlation of serum IL-10 with the levels of MMP-9 (rho=0.588, P=0.003), IL-6 (rho=0.502, P=0.015) and HDL-cholesterol (rho=0.697, P<0.001), as well as a significant negative correlation with the levels of triglycerides (rho=-0.417, P=0.048). CONCLUSIONS: Our results suggest that UA is associated with low serum activity of IL-10, while a significant elevation of this anti-inflammatory cytokine accompanies the peripheral immune responses of AMI. This observation indicates that different patterns of inflammatory reactions are implicated in the pathophysiology of two clinical conditions.     

急性冠状动脉综合征患者外周血中脂联素水平与基质金属蛋白酶-9及其组织抑制因子-1关系的探讨

目的:探讨急性冠状动脉综合征患者(ACS)外周血中脂联素与基质金属蛋白酶-9(MMP-9)及基质金属蛋白酶组织抑制因子-1(TIMP-1)水平及其相关性的研究。方法:急性心肌梗死组19例,不稳定性心绞痛组31例,稳定性心绞痛组13例,正常对照组22例,检测各组外周血中脂联素、MMP-9、TIMP-1的浓度。各组间采用独立样本的t检验,各参数之间进行单因素的相关分析。结果:急性心肌梗死组、不稳定性心绞痛组分别与正常对照组比较:外周血清中脂联素的浓度、TIMP-1的浓度均显著降低(P<0.05～0.01),MMP-9/TIMP-1及MMP-9的浓度则均显著升高(P<0.05～0.01);急性心肌梗死组、不稳定性心绞痛组与稳定性心绞痛组比较,脂联素的浓度显著降低(P<0.05～0.01),MMP-9/TIMP-1升高(P<0.05～0.01);稳定性心绞痛组与正常对照组比较各指标间无明显差异。相关性分析中:脂联素与MMP-9之间无相关性(r=-0.248,P>0.05),脂联素与TIMP-1有显著相关性(r=0.408,P<0.01),脂联素与MMP-9/TIMP-1之间有显著相关性(r=-0.478,P<0.001)。结论:ACS患者中,脂联素的分泌减少,导致TIMP-1的分泌也减少,MMP-9/TIMP-1平衡破坏,可能是急性冠状动脉综合征发生的重要因素。     

Prognostic value of interleukin-6 during a 3-year follow-up in patients with acute ST-segment elevation myocardial infarction

Accumulating evidence suggests that inflammation plays an essential role in the pathogenesis of atherosclerosis. This recognition has stimulated the evaluation of different inflammatory markers as potential predictors of cardiovascular risk. However, the existing data are limited and controversial. This study was designed to simultaneously measure serum levels of interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with acute ST segment elevation myocardial infarction (STEMI) and to evaluate their ability to predict prognosis. A prospective cohort study was conducted with 263 patients with first STEMI who were admitted to our institute within 6 h of symptoms onset. Clinical data were recorded and serum admission levels of IL-6, sCD40L, MMP-9, and TIMP-1 were measured by sandwich enzyme-linked immunosorbent assay. The patients were then followed prospectively for the occurrence of cardiovascular mortality for 3 years. Follow-up information was available for 228 patients (86.7%) from the 263 STEMI patients; 34 patients died from cardiovascular causes during the 3-year follow-up period. Kaplan-Meier plots demonstrated a significant increase in cardiovascular mortality with increasing IL-6 levels (χ² = 14.13, P = 0.0002, by log-rank test). Logistic regression analysis revealed that IL-6 was an independent predictor for cardiovascular mortality. The present study indicates that elevated admission level of IL-6 could provide valuable information for long-term risk stratification in patients with STEMI.     

蛋白芯片法联检急性冠状动脉综合征患者血中细胞因子的意义

目的 探讨急性冠状动脉综合征(ACS)患者血中炎性细胞因子、炎性细胞相关因子及心肌损伤因子浓度的变化及临床意义.方法 运用蛋白芯片技术同步联检经冠状动脉造影及临床表现证实为ACS患者104例及对照者50例血清或血浆中10种细胞因子水平;同时对不稳定性心绞痛(UA)患者按Braunwald分级进行分析.结果 急性心肌梗死(AMI)组和UA组血清中C反应蛋白(CRP)、白介素(IL)-6、可溶性CD40L(sCD40L)、基质金属蛋白酶(MMP)-9、心脏型脂肪酸结合蛋白(H-FABP)、肌钙蛋白Ⅰ(cTnⅠ)及血浆中的IL-8、内皮素(ET)-1、可溶性血管细胞黏附分子(sVCAM)-1、氨基酸N末端脑钠肽原(NT-proBNP)浓度高于对照组,差异有统计学意义(P＜0.01);AMI组cTnⅠ[(11.08±10.49) μg/L]和H-FABP[(19.80±4.60)μg/L]浓度高于UA组[cTnⅠ:(0.69±0.18)μg/L,H-FABP:(4.12±2.45)μg/L,P＜0.01],而CRP、IL-6、MMP-9、sCD40L及ET-1浓度,两组比较差异无统计学意义;UA组MMP-9、sCD40L及H-FABP的浓度与Braunwald分级存在显著正相关(分别r=0.653,r=0.745,r=0.933,均P＜0.01).随着心绞痛严重程度的增加,MMP-9、sCD40L及H-FABP水平明显升高,心绞痛Ⅰ级＜心绞痛Ⅱ级＜心绞痛Ⅲ级(P＜0.01).结论 ACS患者血中存在多种细胞因子浓度异常,其中MMP-9、sCD40L、H-FASP的浓度与UA患者心绞痛严重程度存在良好的相关性.提示上述细胞因子参与和促使了ACS的发生、发展,为ACS的危险分层、预后判断提供了可能的分子标志物依据.     

Patients with non-ST-elevation myocardial infarction and without chest pain are treated less aggressively and experience higher in-hospital mortality

BACKGROUND: Lack of chest pain or atypical pain does not exclude acute coronary syndrome (ACS). AIM: To assess demographic and clinical characteristic as well as treatment strategies in patients with atypical chest pain on admission in hospitals without on-site invasive facility (IF). METHODS: Twenty-nine community hospitals participated in the Registry of Acute Coronary Syndromes. A total of 2382 patients with ACS were enrolled. Patients admitted to hospitals with suspected ACS were stratified according to their pain symptoms as either typical (TS) or atypical which also included lack of pain (ATS). RESULTS: Of all patients with initial ACS diagnosis 152 (6.4%) presented without chest pain on admission. Patients from group ATS in comparison to group TS were more often women (49 vs. 39%; p=0.01), and less frequently had past medical history of coronary artery disease (54.3 vs. 72.5%; p <0.0001), myocardial infarction (15.2 vs. 32.1%; p <0.0001), arterial hypertension (65.6 vs. 74.5; p <0.0001) or renal insufficiency (1.3 vs. 5%; p=0.04). Invasive treatment was undertaken in 9.2% of patients from group ATS and in 14.6% from group TS (p=0.049). In-hospital mortality among all patients remaining in community hospitals for conservative treatment was similar in both groups (ATS vs. TS: 8.7 vs. 5.9%; p=NS). Among patients with typical and atypical symptoms the occurrence of ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) was similar. Patients with NSTEMI and UA with atypical symptoms were less likely transferred for invasive diagnostic, for NSTEMI 9.4 vs. 18.1% (p=0.03) and for UA 6.1 vs. 12.9% (p=0.04). In-hospital mortality was similar among typical and atypical groups in STEMI and UA patients. However, it was significantly higher among NSTEMI patients with atypical chest pain treated conservatively (3.6 vs. 0%; p=0.05). CONCLUSIONS: There is a significant group of ACS patients without chest pain on admission who are usually women with less severe past medical history. This subset of patients is treated less aggressively in terms of antiplatelet therapy and invasive approach. It is patients with diagnosis of NSTEMI who due to being misdiagnosed due to their atypical chest pain have poorer outcome.     

The A-to-Z Trial: Methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy

BACKGROUND: Previous studies on atherectomy specimens from patients with acute coronary syndrome (ACS) implicated the role of proteolytic enzymes. We examined whether the plasma levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were increased in the coronary circulation in ACS. METHODS AND RESULTS: The plasma levels (nanograms per milliliter) of MMP-9 and TIMP-1 in the aorta (Ao) and great cardiac vein (GCV) were measured in 29 patients with ACS (20 with acute myocardial infarction [group 1] and 9 with unstable angina [group 2]), 17 with stable effort angina (group 3), and 20 control subjects (group 4). Group 1 patients had occlusion in the left anterior descending artery (LAD), and groups 2 and 3 patients had culprit lesion in the LAD. In group 1 blood samples were obtained at the time of direct coronary angioplasty done within 12 hours after the onset. The Ao level of either MMP-9 or TIMP-1 did not differ among the 4 groups. The GCV-Ao differences in MMP-9 and TIMP-1 were both significantly increased in groups 1 and 2 compared with those in group 4. Neither of them was different between groups 3 and 4. Neither the GCV-Ao difference in MMP-9 or TIMP-1 level was correlated with the maximal creatine kinase level in group 1. CONCLUSIONS: Increased plasma levels of MMP-9 and TIMP-1 were detected in the coronary circulation in ACS patients, suggesting a process of active plaque rupture in ACS.     

Serum profiles of matrix metalloproteinases and their tissue inhibitor in patients with acute coronary syndromes. The effects of short-term atorvastatin administration

There is increasing evidence that abnormal cytokine expression and increased metalloproteinase activity are implicated in the pathophysiology of acute coronary syndromes. This study investigates the serum profiles of representative metalloproteinases (MMP-1, -2, -9) and their tissue inhibitor (TIMP-1) in patients with myocardial infarction (MI) and unstable angina (UA) in relation to circulating proinflammatory cytokine (TNF-alpha and IL-6) activity. Furthermore, we examined the effects of a 30-day treatment with atorvastatin on serum levels of these inflammatory factors. Serum concentrations of MMP-1, -2, -9, TIMP-1, IL-6 and TNF-alpha were measured (enzyme-linked immunosorbent assay (ELISA) method) in 23 acute myocardial infarction patients and 20 unstable angina patients on 0 day, 1st, 3rd, 7th and 30th day after admission. Sixteen normal volunteers were used as healthy controls. Additionally, 12 patients of myocardial infarction group and 11 patients of unstable angina group were treated with atorvastatin (20 mg/day) for 30 days in a randomized design. In patients with myocardial infarction and unstable angina, serum levels of MMP-2, -9, TIMP-1, TNF-alpha and IL-6 were significantly higher than those of healthy controls in all time frames (p<0.05). In the group of unstable angina patients, we observed a statistically significant reduction in the levels of MMP-9, TIMP-1 and IL-6 after the 30-day atorvastatin administration. Our results suggest that serum MMPs, TIMP-1 and proinflammatory cytokines play an important role in the pathophysiology of the acute coronary syndromes. The reduction of these factors by short-term atorvastatin administration may provide a new insight into the pleiotropic effects of statins on unstable coronary artery disease.     

辛伐他汀对不同血脂水平急性冠状动脉综合征患者血清基质金属蛋白酶水平的影响

目的　研究正常血脂和高血脂急性冠状动脉综合征 (ACS)患者应用辛伐他汀对抑制动脉粥样硬化斑块细胞外基质降解 ,减少炎症反应 ,稳定斑块的作用。方法　采用双盲、随机、对照方法 ,将正常血脂 (NC组 )和高血脂 (HC组 )ACS患者分为他汀治疗组 (辛伐他汀 2 0mg d ,共 8周。NC组 ,n =33;HC组 ,n =36 )和他汀对照组 (NC组 ,n =32 ,HC组 ,n =36 ) ;于治疗前后分别测定血清基质金属蛋白酶 (MMP) 1、MMP 9、基质金属蛋白酶抑制因子 (TIMP) 1、MMP 9 TIMP 1、高敏C 反应蛋白(hs CRP)水平。结果　 (1)治疗前NC、HC各组的血清MMP 1、MMP 9、MMP 9 TIMP 1、TIMP 1、hs CRP水平均较健康对照组 (n =6 0 )明显增高 ,与血脂水平不相关。 (2 )经辛伐他汀治疗 8周后 ,两治疗组血清MMP 1、MMP 9、MMP 9 TIMP 1、hs CRP水平均明显降低 ,血清TIMP 1水平无显著性差异。HC他汀治疗组血清总胆固醇 (TC)、甘油三酯 (TG)、低密度脂蛋白胆固醇 (LDL C)水平明显降低 ,高密度脂蛋白质胆固醇 (HDL C)水平略有上升 ;NC他汀治疗组血清TC、LDL C水平明显下降 ,TG、HDL C水平略有上升和下降 ,但无显著差异。结论　在正常血脂和高血脂ACS患者中 ,早期应用他汀治疗 ,可减少斑块基质成分的降解和炎症反应 ,具有稳定斑块作用。     

冠心病患者外周血单个核细胞基质金属蛋白酶9/组织型金属蛋白酶抑制剂1及磷酸化c-Jun蛋白表达改变与冠状动脉病变特征的相关性

目的 结合冠状动脉造影结果 ,探讨冠心病患者外周血单个核细胞基质金属蛋白酶9、组织型金属蛋白酶抑制剂1和磷酸化c-Jun蛋白表达水平改变与冠状动脉病变特征的关系.方法 40例经冠状动脉造影确诊的冠心病患者分为急性冠状动脉综合征组(n=24)和稳定型心绞痛组(n=16).另选取同期经冠状动脉造影证实无冠状动脉病变患者15例为对照组.采用免疫印迹法分别检测外周血单个核细胞基质金属蛋白酶9、组织型金属蛋白酶抑制剂1和磷酸化c-Jun蛋白表达水平,计算基质金属蛋白酶9/组织型金属蛋白酶抑制剂1比值,并结合Gensini冠状动脉病变积分标准评价其与冠状动脉管腔病变程度的线性关系及其在反映冠状动脉粥样硬化斑块稳定性中的作用.结果 ①急性冠状动脉综合征组基质金属蛋白酶9、组织型金属蛋白酶抑制剂1、磷酸化c-Jun蛋白表达水平及基质金属蛋白酶9/组织型金属蛋白酶抑制剂1比值较稳定型心绞痛组和对照组明显增高(均P<0.001).②基质金属蛋白酶9、磷酸化c-Jun及基质金属蛋白酶9/组织型金属蛋白酶抑制剂1比值与Gensini冠状动脉病变积分呈正相关(r分别为0.433、0.476和0.457,均P<0.01);组织型金属蛋白酶抑制剂1蛋白表达水平与Gensini冠状动脉病变积分无相关性.③磷酸化c-Jun与基质金属蛋白酶9蛋白表达水平呈显著正相关(r=0.839,P<0.001).结论 ①急性冠状动脉综合征患者基质金属蛋白酶9、组织型金属蛋白酶抑制剂1蛋白表达水平较稳定型心绞痛患者明显增高,其比例严重失调,反映了急性冠状动脉综合征患者冠状动脉管腔病变程度更为复杂且血管壁具有更多易损斑块;②核转录因子c-Jun活化可能参与了动脉粥样硬化中基质金属蛋白酶9表达的调控.     

Serum interleukin 6 (il-6A) concentration correlates with matrix metalloproteinases and their tissue inhibitors in rheumatoid arthritis

We explored whether the serum concentration of interleukin 6 (IL-6) is associated with matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in rheumatoid arthritis (RA) patients. Serum levels of IL-6, interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase B (MMP-9), TIMP-1 and TIMP-2 were assessed with an ELISA technique in 30 RA patients. We observed the association between IL-6 and MMP-1 (p < 0.001), MMP-3 (p < 0.05), MMP-9 (p < 0.001), TIMP-1 (p < 0.01) and TIMP-2 (p < 0.05). Additionally, serum IL-6, measured MMPs and TIMP-1 correlated with the erythrocyte sedimentation rate, C reactive protein plasma level and the number of swollen joints. We suggest that assessing the serum IL-6, MMP-1, MMP-3, MMP-9 and TIMP-1 levels may be helpful in the prediction of the RA activity.     

CRP, interleukin-6, secretory phospholipase A2 group IIA, and intercellular adhesion molecule-1 during the early phase of acute coronary syndromes and long-term follow-up

OBJECTIVES: The objectives of this study were to examine the time course of the inflammatory response in acute coronary syndromes (ACS) and to assess the markers of inflammation and their relation to disease severity. METHODS: We prospectively studied 134 patients with ACS who survived for at least 30 months. The patients were divided into four groups: acute myocardial infarction (MI) with (n=54) or without (n=46) ST-segment elevation and unstable angina with (n=14) or without (n=20) increased risk. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), secretory phospholipase A2 group IIA (sPLA2-IIA), and intercellular adhesion molecule-1 (ICAM-1) were measured on days 1 and 4 and after 3 and 30 months. RESULTS: The highest levels of CRP and sPLA2-IIA were seen on day 4 but for IL-6 on day 1. These three markers, but not ICAM-1, were significantly related to disease severity, CKMB, and ejection fraction. Patients in Killip class II-IV had higher levels than those in Killip class I. The individual acute-phase responses correlated with marker levels at 3 and 30 months. ICAM-1 correlated with the development of congestive heart failure. CONCLUSIONS: In ACS there seems to be an individual predisposition to inflammatory response. Plasma IL-6 is the first marker to rise, while sPLA2-IIA and CRP peak later. All three markers, especially CRP, may discriminate between MI and non-MI. ICAM-1 seems to reflect other aspects of the inflammatory processes than the other markers. The results emphasize the complexity of the inflammatory response in ACS and stress the need for further studies involving multiple markers.     

Systemic inflammation in unstable angina is the result of myocardial necrosis

OBJECTIVES: We investigated whether the source of the acute phase response in unstable angina (UA) lay within the culprit coronary plaque or distal myocardium. BACKGROUND: An inflammatory response is an important component of the acute coronary syndromes. However, its origin and mechanism remain unclear. METHODS: In 94 stable patients undergoing coronary angiography, the relationship between systemic levels of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6) and C-reactive protein (CRP) and extent of atherosclerosis was studied. The temporal relationship between these markers and troponin T (TnT) was determined in 91 patients with UA. Cytokine levels were measured in the aortic root and coronary sinus of 36 unstable patients. RESULTS: There was no relationship found between stable coronary atherosclerosis and inflammatory marker levels. Compared with this group, admission levels of IL-6 (3.6 +/- 0.3 ng/ml vs. 10.7 +/- 1.7 ng/ml, p < 0.05) and CRP (2.3 +/- 0.1 mg/l vs. 4.6 +/- 0.6 mg/l, p < 0.05) were elevated in patients with UA. In this group, IL-6 and CRP remained elevated in those who subsequently experienced major adverse cardiac events. This inflammatory response occurred in parallel to the appearance of TnT. Both TNF-alpha (19.2 +/- 3.4 ng/ml vs. 17.1 +/- 3.3 ng/ml, p < 0.001) and IL-6 (10.3 +/- 1.4 ng/ml vs. 7.7 +/- 1.1 ng/ml, p < 0.01) were elevated in the coronary sinus compared with aortic root in patients with UA. This was principally observed in those who were TnT positive. There was no cytokine gradient across the culprit plaque. CONCLUSIONS: There is an intracardiac inflammatory response in UA that appears to be the result of low-grade myocardial necrosis. The ruptured plaque does not appear to contribute to the acute phase response.     

Enhanced Exhalation of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Patients with COPD Exacerbation: A Prospective Study

Background: Matrix metalloproteinase-9 (MMP-9) and its inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1) are involved in the pathogenesis of airway inflammation in patients with chronic obstructive pulmonary disease (COPD). However, no study so far has addressed their value as noninvasive biomarkers of airways inflammation. Objective: To evaluate MMP-9 and TIMP-1 concentrations in the exhaled breath condensate (EBC) of patients with stable COPD and also during the exacerbation episode. Methods: EBC and serum samples were collected in 17 stable-phase COPD patients who were current smokers as well as during their first exacerbation episode, and in 22 asymptomatic smokers. EBC and serum levels of MMP-9 and TIMP-1 were measured with ELISA kit. Results: Mean EBC MMP-9 and TIMP-1 levels were higher in patients with stable COPD than in asymptomatic smokers. Exacerbation of COPD increased 2-fold the exhalation of MMP-9 (18.5 ± 10.1 ng/ml vs. 8.9 ± 6.2 ng/ml, p = 0.01) and TIMP-1 (to 41.1 ± 20.4 ng/ml vs. 16.4 ± 6.8 ng/ml, p < 0.001). Both, MMP-9 and TIMP-1 in EBC correlated negatively with FEV(1) (% predicted) at baseline (r = -0.78, p < 0.001 and r = -0.73, p < 0.001) and during the exacerbation episode (r = -0.57, p = 0.02 and r = -0.65, p = 0.005). Similar negative correlations were noted with FVC (% predicted), except for MMP-9 in EBC at exacerbation. Exhaled MMP-9 and TIMP-1 did not correlate with serum concentrations in COPD patients, either at baseline or during exacerbation. Conclusion: Exhaled MMP-9 and TIMP-1 increased during COPD exacerbation and was negatively correlated with spirometric variables, which suggests the usefulness of their measurement in EBC for the monitoring of airways inflammation. However, to better assess their diagnostic or prognostic value larger studies are necessary.     

C-reactive protein in patients with acute coronary syndrome: correlation with diagnosis, myocardial damage, ejection fraction and angiographic findings

BACKGROUND: C-reactive protein (CRP) plasmatic levels increase in patients with acute coronary syndromes (ACS). Correlations between CRP levels, myocardial functional damage and cardiomyocyte lysis remain to be defined. METHODS: 192 consecutive patients with acute coronary syndromes (64.97 +/- 11.08 mean age, 71.35% male gender) were included in the study; 138 patients (71.87%) were discharged with an acute myocardial infarction (AMI) diagnosis (28 with non Q-wave AMI) and 54 with an unstable angina (UA) diagnosis (28.13%). In all patients CRP, CK, LDH, CK-MB and troponin I plasmatic concentrations were evaluated every 6 h for 48 h and every 24 h for the following 2 days from the onset of symptoms. Ejection fraction was estimated by bidimensional echocardiography and extension of myocardial lysis by cardiac enzymes plasmatic release. 92 patients (67 with AMI, 25 with UA) underwent coronary-angiography. Incidence of adverse cardiac events was recorded in a 6 months follow up. RESULTS: Mean CRP levels in Q-wave MI showed a statistically significant increase in the different blood samples with baseline. Mean CRP levels of the three groups were not statistically different at baseline and after 6, 12, and 18 h. Q-wave AMI CRP levels showed a statistically significant difference as against non Q-wave AMI at 36 (p < 0.05), 48 (p < 0.05) and 72 h (p < 0.05) and UA at 24 (p < 0.01), 30 (p < 0.01), 48 (p < 0.0001), 72 (p = 0.0001) and 96 h (p = 0.0003); non Q-wave AMI CPR levels showed a statistically significant difference as against UA at 48 h (p < 0.01). CRP peak mean levels were significantly different when comparing Q-wave AMI patients with UA patients (8.21 +/- 7.85 vs. 2.75 +/- 3.33 mg/dl, p < 0.001). In patients with Q-wave AMI there was a correlation between CRP peak concentrations and CK (r = 0.264, p = 0.008) and LDH (r = 0.32, p = 0.001), while correlation with CK-MB peak concentrations was not statistically significant (r = 0.196, p = 0.051). In the same patient group, there was also a correlation between CRP plasmatic concentrations and troponin I plasmatic concentrations from the 30th to 96th h after the onset of symptoms (r = 0.38-0.53, p < 0.05). No correlation was found between CRP levels and ejection fraction and angio-coronarography findings (number of stenotic vessels, culprit lesions, ruptured plaques). Peak CRP levels were associated in a 6 months follow up with an increased incidence of major adverse cardiac events (MACEs) in patients with Q-wave AMI (HR 1.1649, 95% C.I. 1.0197-1.3307, p < 0.05). CONCLUSIONS: CRP plasmatic concentrations showed a different release curve in patients with Q-wave AMI in comparison with patients with non Q-wave AMI and with patients with UA. CRP peak concentrations did not correlate with ejection fraction and angiographic findings, but correlate with incidence of MACE. The increase in CRP levels during Q-wave MI seems to be linked to the extension of myocardial damage rather than pre-existing inflammation.     

The interleukin-6 -174 G>C promoter polymorphism is associated with a higher risk of death after an acute coronary syndrome in male elderly patients

BACKGROUND: Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are key mediators of inflammation and their increased plasma levels are associated with acute coronary syndrome (ACS). Polymorphisms in the promoter region of IL-6 (-174 G>C) and TNF-alpha (-308 G>A) demonstrated to affect gene expression were analyzed to test their predictive power for cardiovascular death over one year follow-up in elderly male ACS patients. METHODS: We assessed the IL-6 -174 G>C polymorphism and TNF-alpha -308 G>A polymorphism in 139 consecutive elderly male patients affected by an ACS, such as ST-Elevation (STEMI), No ST-Elevation (NSTEMI) Myocardial Infarction and Unstable Angina. The presence of well known risk factors for Coronary Heart Diseases (CHD) were also assessed in all ACS patients. Survival rate was assessed after one year follow-up. RESULTS: We found that IL-6 -174 G>C polymorphism is an independent predictor of cardiovascular death after an ACS in male patients. In particular ACS patients carrying the IL-6 -174 C- (GG) genotypes showed a marked increase in one year follow-up mortality rate (HR=3.89, 95% CI 1.71-8.86, p=0.001). Moreover CRP serum levels > or = 5.5 mg/dl (HR= 3.79, 95% CI 1.71-8.42, p=0.001), a history of CHD (HR=2.96, 95% CI 1.22-7.20, p=0.016) and the absence of statins treatment (HR=3.27, 95% CI 1.17-9.18, p=0.021), significantly increased one year risk of death in male ACS patients. CONCLUSIONS: These data suggest that IL-6 -174 G>C polymorphism can be added to other clinical markers in order to identify a subgroup of elderly ACS male patients at higher risk of death.     

Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes

Acute coronary syndrome (ACS) groups different cardiac diseases whose development is associated with inflammation. Here we have analyzed the levels of inflammatory cytokines and of members of the TLR/IRAK pathway including IRAK-M in monocytes from ACS patients classified as either UA (unstable angina), STEMI (ST-elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction). Circulating monocytes from all patients, but not from healthy individuals, showed high levels of pro-inflammatory cytokines, TNF-alpha and IL-6, as well as of IRAK-M and IL-10. TLR4 was also up-regulated, but IRAK-1, IRAK-4 and MyD88 levels were similar in patients and controls. Further, we investigated the consequences of cytokines/IRAK-M expression on the innate immune response to endotoxin. Ex vivo responses to LPS were markedly attenuated in patient monocytes compared to controls. Control monocytes cultured for 6 h in supplemented medium (10% serum from ACS patients) expressed IRAK-M, and LPS stimulation failed to induce TNF-alpha and IL-6 in these cultures. Pre-incubation of the serum with a blocking anti-TNF-alpha antibody reduced this endotoxin tolerance effect, suggesting that TNF-alpha controls this phenomenon, at least partially. We show for the first time that inflammatory responses associated with ACS induce an unresponsiveness state to endotoxin challenge in circulating monocytes, which correlates with expression of IRAK-M, TLR4 and IL-10. The magnitude of this response varies according to the clinical condition (UA, STEMI or NSTEMI), and is regulated by TNF-alpha.     

Procalcitonin in patients with acute coronary syndromes and cardiogenic shock submitted to percutaneous coronary intervention

Procalcitonin (PCT) is known to be a biological diagnostic marker for severe sepsis, or septic shock in critically ill patients. There are still contrasting data about a role of procalcitonin in patients with acute myocardial infarction or cardiogenic shock, and in those with acute coronary syndromes, that is, non-ST-elevation myocardial infarction or unstable angina. We evaluated plasma levels of procalcitonin and C-reactive protein (CRP) in 52 patients admitted to our intensive cardiac care unit (ICCU): 14 patients with cardiogenic shock (CS) following ST-elevation myocardial infarction (STEMI), 15 patients with uncomplicated ST-elevation myocardial infarction (STEMI), and 24 with non-ST-elevation myocardial infarction or unstable angina (NSTEMI/UA). In all patients, infective processes were excluded. Procalcitonin values were significantly higher in CS patients with respect to the other two subgroups (P < 0.001, P < 0.001) while CRP levels were higher than NSTEMI/UA patients (P < 0.001) but not with respect to STEMI patients (P = 0.063). No correlations were found in cardiogenic shock patients between CRP and PCT values (R = 0.02; P = 0.762, ns). Procalcitonin levels measured on ICCU admission are significantly higher in patients with cardiogenic shock following the acute myocardial infarction, and they are not correlated with those of CRP. The degree of myocardial ischemia (clinically indicated by the whole spectrum of ACS, from unstable angina to cardiogenic shock ST-elevation following myocardial infarction) and the related inflammatory-induced response are better reflected by CRP (which was positive in most acute cardiac care patients of all our subgroups), than by PCT which seems more reflective of a higher degree of inflammatory activation, being positive only in all CS patients.     

急性冠脉综合征患者血浆sCD40L与血清基质金属蛋白酶水平的变化及其意义

目的：观察急性冠脉综合征（ACS）患者可溶性CD40配体（sCD40L）及血清基质金属蛋白酶-9（MMP-9）、血清组织金属蛋白酶抑制物-1（TIMP-1）水平变化及其相关性。方法：采用酶联免疫吸附法测定70例冠心病患者[ACS患者35例、稳定型心绞痛（SAP）患者35例]、35例非冠心病患者（正常对照组）sCD40L、MMP-9、TIMP-1的水平。结果：与正常对照组及SAP组比较,ACS组sCD40L[（2.73±0.92）μg/ml比（3.05±0.98）μg/ml比（4.72±1.15）μg/ml]、MMP-9[（152.38±54.22）ng/ml比（341.12±69.96）ng/ml比（574.2±139.20）ng/ml]水平明显升高（P均〈0.01）,而TIMP-1[（415.92±13.96）ng/ml比（249.32±36.80）ng/ml比（172.20±40.10）ng/ml]水平明显降低（P〈0.01）;且MMP-9与sCD40L呈正相关（r=0.42,P〈0.05）。结论：急性冠脉综合征患者可溶性CD40配体、血清基质金属蛋白酶-9水平升高,血清组织金属蛋白酶抑制物-1水平下降提示这两指标与粥样斑块不稳定相关,可作为判断粥样斑块不稳定的血清学指标。     

Metalloproteinase activity of the blood in patients with arterial hypertension with paroxysmal form of atrial fibrillation

Aim of the study was to investigate interrelationship between serum markers of myocardial fibrosis: matrix metalloproteinase -1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and parameters of echocardiography in patients with arterial hypertension (AH) and paroxysmal form of atrial fibrillation (n=39). We revealed positive correlation of levels of TIMP-1 with thickness of interventricular septum in diastole (r=0,47, p=0,02), peak velocity of late filling of the right ventricle (r=0,46, p=0,01), and negative relation between MMP-1 levels and degree of mitral and tricuspid regurgitation (r=0,43, p=0,005 and r=0,38, p=0,04, respectively). In the group of patients with increased left ventricular myocardial mass index (LVMMI) TIMP-1 level was significantly higher than in patients with normal LVMMI (p < 0,05). In the group combining patients with concentric and eccentric LV hypertrophy TIMP-1 level was significantly higher than in the group combining patients with LV concentric remodeling and normal geometry (p < 0,05). No correlations were revealed between MMP-1 and TIMP-1 levels and parameters of diastolic dysfunction. In patients with AH increase of serum concentrations of TIMP-1 was associated with increased thickness of interventricular septum, increase of LVMMI, and with prognostically unfavorable types of LV remodeling.