interleukin-8 and Myocardial-Infarction

Myocardial infarction is associated with an inflammatory response leading to leukocyte recruitment, healing and formation of a scar. Members of the chemokine superfamily are rapidly induced in the infarcted myocardium and may critically regulate the post-infarction inflammatory response. CXCL8/Interleukin (IL)-8 is upregulated in the infarcted area and may induce neutrophil infiltration. In addition, mononuclear cell chemoattractants, such as the CC chemokines CCL2/Monocyte Chemoattractant Protein (MCP)-1, CCL3/Macrophage Inflammatory Protein (MIP)1alpha, and CCL4/MIP-1beta are expressed in the ischemic area, and may regulate monocyte and lymphocyte recruitment. However, chemokines may have additional effects on healing infarcts beyond their leukotactic properties. The CXC chemokine CXCL10/Interferon-y inducible Protein (IP)-10, a potent angiostatic factor with antifibrotic properties, is induced in the infarct and may prevent premature angiogenesis and fibrous tissue deposition, until the infarct is debrided and provisional matrix necessary to support granulation tissue ingrowth is formed. Chemokine induction in the infarct is transient, suggesting that inhibitory mediators (such as transforming growth Factor (TGF)-beta) may be activated suppressing chemokine synthesis and leading to resolution of inflammation and transition to fibrosis. Brief repetitive ischemia in mice also results in chemokine upregulation followed by suppression of chemokine synthesis and interstitial fibrosis, in the absence of myocardial infarction. Chemokine expression may play a role in the pathogenesis of non-infarctive ischemic cardiomyopathy, where early ischemia-induced chemokine expression may be followed by activation of inhibitory mediators that suppress inflammation, but induce fibrosis.

Topics: Animals; Chemokine CCL2; Chemokines; Fibrosis; Humans; Interleukin-8; Myocardial Infarction; Myocardial Reperfusion; Myocarditis; Receptors, Cytokine; Ventricular Remodeling

No data from controlled trials exists regarding the inflammatory response in patients with de novo heart failure (HF) complicating ST-elevation myocardial infarction (STEMI) and a possible role in the recovery of contractile function. We therefore explored the time course and possible associations between levels of inflammatory markers and recovery of impaired left ventricular function as well as levosimendan treatment in STEMI patients in a substudy of the LEvosimendan in Acute heart Failure following myocardial infarction (LEAF) trial.. A total of 61 patients developing HF within 48 hours after a primary PCI-treated STEMI were randomised double-blind to a 25 hours infusion of levosimendan or placebo. Levels of IL-6, CRP, sIL-6R, sgp130, MCP-1, IL-8, MMP-9, sICAM-1, sVCAM-1 and TNF-α were measured at inclusion (median 22 h, interquartile range (IQR) 14, 29 after PCI), on day 1, day 2, day 5 and 6 weeks. Improvement in left ventricular function was evaluated as change in wall motion score index (WMSI) by echocardiography.. Only circulating levels of IL-8 at inclusion were associated with change in WMSI from baseline to 6 weeks, r = ÷ 0.41 (p = 0.002). No association, however, was found between IL-8 and WMSI at inclusion or peak troponin T. Furthermore, there was a significant difference in change in WMSI from inclusion to 6 weeks between patients with IL-8 levels below, compared to above median value, ÷ 0.44 (IQR ÷ 0.57, ÷ 0.19) vs. ÷ 0.07 (IQR ÷ 0.27, 0.07), respectively (p < 0.0001). Levosimendan did not affect the levels of inflammary markers compared to control.. High levels of IL-8 in STEMI patients complicated with HF were associated with less improvement in left ventricular function during the first 6 weeks after PCI, suggesting a possible role of IL-8 in the reperfusion-related injury of post-ischemic myocardium. Further studies are needed to confirm this hypothesis.. ClinicalTrials.gov NCT00324766.

Topics: Aged; Biomarkers; C-Reactive Protein; Cardiotonic Agents; Female; Heart Failure; Humans; Hydrazones; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Morpholines; Myocardial Contraction; Myocardial Infarction; Pyridazines; Receptors, Interleukin-6; Recovery of Function; Simendan; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Ventricular Function, Left

Left ventricular (LV) systolic function is a significant prognostic factor in patients after myocardial infarction (MI). Multiple angiogenic and inflammatory factors are involved in postinfarction LV remodelling process. In addition, CD34+progenitor cells mobilised from bone marrow and tissue niches participate in regeneration of the infarcted myocardium.. To examine relationships between LV ejection fraction (LVEF) and wall motion score index (WMSI) and the number of CD34+ cells and plasma levels of vascular endothelial growth factor (VEGF), angiogenin and such inflammatory factors as interleukin 6 (IL-6), interleukin 8 (IL-8), and high-sensitivity C-reactive protein (hsCRP) in patients with ST-elevation MI (STEMI).. The study group included 61 patients with STEMI treated with primary percutaneous coronary intervention (PCI)involving bare metal stent implantation. Plasma levels of the evaluated angiogenic and inflammatory factors were measured by flow cytometry at 4 time points (just before PCI, 24 h later, at hospital discharge, and 30 days after STEMI). LVEF and WMSI were measured by echocardiography at hospital discharge, 1 month later, and 6 months later. We compared angiogenic and inflammatory factor levels in patients with no improvement of the LV systolic function during the follow-up (group 1, n = 22)vs. those with improved LV systolic function (group 2, n = 39).. No differences in the levels of VEGF, angiogenin, IL-6, IL-8, and hsCRP, and the number of CD34+ cells were observed between the two groups. Despite this, we found significant negative correlations between hsCRP level and LVEF,and positive correlations between hsCRP level and WMSI in both patient groups, but these correlations were much stronger in group 1. We also found a significant negative correlation between WMSI at 6 months and the number of CD34+ cells measured 24 h after PCI.. 1. Evaluation of plasma VEGF, angiogenin, IL-6, IL-8, and hsCRP levels and the number of CD34+ cells at different time points in patients with STEMI did not allow predicting the direction of changes in LVEF and WMSI. 2. Observed significant correlations between hsCRP level and LVEF and WMSI may suggest a harmful effect of inflammation on postinfarction myocardial remodelling. 3. A significant negative correlation between the number of CD34+ and WMSI suggests that increased mobilisation of these cells might have a beneficial effect on systolic function after MI.

Topics: Antigens, CD34; C-Reactive Protein; Female; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Ribonuclease, Pancreatic; Stroke Volume; Ultrasonography; Vascular Endothelial Growth Factor A

Myocardial infarction (MI) is the most common cause of cardiac injury in the Western world. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Inflammatory cytokines and vascular cell adhesion molecules (VCAM) promote adhesive interactions between leukocytes and endothelial cells, resulting in the transmigration of inflammatory cells into the site of injury. Low vitamin D levels are associated with higher prevalence of cardiovascular risk factors and a higher risk of MI. In this paper, we examine the effects of short-term vitamin D supplementation on inflammatory cytokine levels after an acute coronary syndrome. We recruited patients arriving to the hospital with an acute MI. All patients received optimal medical therapy and underwent a coronary catheterization. Half of the patients were randomly selected and treated with a daily supplement of vitamin D (4,000 IU) for 5 days. A short course of treatment with vitamin D effectively attenuated the increase in circulating levels of inflammatory cytokines after an acute coronary event. Control group patients had increased cytokine and cellular adhesion molecules serum concentrations after 5 days, while the vitamin D-treated group had an attenuated elevation or a reduction of these parameters. There were significant differences in VCAM-1 levels, C-reactive protein, and interleukin-6. There were trends toward significance in interleukin-8 levels. There were no significant differences in circulating levels of intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and tumor necrosis factor-α. These findings provide information on the anti-inflammatory effects of vitamin D on the vascular system and suggest mechanisms that mediate some of its cardioprotective properties. There is place for further studies involving prolonged vitamin D treatment in patients suffering from ischemic heart disease.

Topics: Acute Coronary Syndrome; Adult; Aged; C-Reactive Protein; Cardiac Catheterization; Coronary Vessels; Female; Finland; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Risk Factors; Vascular Cell Adhesion Molecule-1; Vitamin D; Vitamin D Deficiency

To investigate the interrelationship between cardiac surgery, age, circulating concentrations of the vitamin D hormone 1,25-dihydroxyvitamin D, and clinical outcome.. Prospective, monocentric, two-arm parallel study.. Tertiary Heart and Diabetes Center in the Federal State of North Rhine-Westphalia, Germany.. Twenty-nine cardiac surgical patients aged ≤ 65 yrs and 30 patients ≥ 75 yrs.. We assessed 1,25-dihydroxyvitamin D and other biochemical parameters of mineral metabolism (calcium, phosphate, 25-hydroxyvitamin D, and parathyroid hormone), various inflammatory markers (C-reactive protein, interleukin-6 and 8), and different immunological parameters (CD4 and CD8 cells, monocyte HLA-DR expression). We collected blood samples preoperatively, immediately after surgery, and on postoperative days 1, 5, and 30. In addition, we assessed adverse outcome until discharge as a composite of myocardial infarction, low cardiac output syndrome, infection, stroke, or in-hospital death.. There were significant transient cardiac surgery-related fluctuations in 1,25-dihydroxyvitamin D and the aforementioned parameters of mineral metabolism, inflammation, and immune status. Compared to younger patients, older patients had consistently lower 1,25-dihydroxyvitamin D and phosphate levels (p = .013 and p = .036, respectively) and significantly higher interleukin 6 and 8 levels (p = .008 and p < .001, respectively). Circulating 1,25-dihydroxyvitamin D was directly related to glomerular filtration rate (R(2) = .227; p < .001) and inversely related to interleukin 6 (R(2) = .105; p = .012). The rate of adverse outcome tended to be higher in older than in younger patients (20.0% vs. 3.5%; p = .081). In risk score-adjusted logistic regression analysis, adverse outcome risk decreased by 7.7% (SE: 3.7%) for each pmol/L increment in 1,25-dihydroxyvitamin D (p = .037).. Circulating 1,25-dihydroxyvitamin D levels fluctuate in relation to cardiac surgery. Low 1,25-dihydroxyvitamin D levels are associated with inflammatory processes and age-related differences in clinical outcome. Future studies should determine whether therapies aimed at treating low 1,25-dihydroxyvitamin D levels can improve the outcome in older cardiac surgery patients.

Topics: Age Factors; Aged; C-Reactive Protein; Calcium; Cardiac Output, Low; CD4-CD8 Ratio; Coronary Artery Bypass; Female; Glomerular Filtration Rate; Heart Valve Prosthesis Implantation; HLA-DR Antigens; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Length of Stay; Logistic Models; Male; Middle Aged; Monocytes; Myocardial Infarction; Outcome Assessment, Health Care; Parathyroid Hormone; Phosphates; Prospective Studies; Surgical Wound Infection; Vitamin D

Recent data derived primarily from studies in animal models suggest that fractalkine (CX3CL1) and its cognate receptor, CX3CR1, play a role in atherogenesis. We, therefore, hypothesized that enhanced CX3CL1/CX3CR1 expression may promote atherogenesis in patients with coronary artery disease (CAD).. We examined the plasma levels of CX3CL1 and CX3CR1 expression in peripheral blood mononuclear cells (PBMC) in various CAD populations (30 patients with previous myocardial infarction, 40 patients with stable angina, 40 patients with unstable angina, and a total of 35 controls) and used various experimental approaches to characterize CX3CL1-mediated leukocyte responses. We found that the plasma levels of CX3CL1 are greatly increased in CAD, particularly in unstable disease. The parallel increase of CX3CR1 expression in PBMC was predominantly attributable to an expansion of the (CX3CR1+)(CD3+)(CD8+) T cell subset and was associated with enhanced chemotactic, adhesive, and inflammatory responses to CX3CL1. Statin therapy for 6 months reduced the expression of CX3CL1 and CX3CR1, reaching statistical significance for both parameters only during aggressive (atorvastatin, 80 mg qd) but not conventional (simvastatin, 20 mg qd) therapy. Consequently, the functional responses of the PBMC to CX3CL1 including migration, adhesion, and secretion of interleukin-8 were attenuated by the treatments.. Our results suggest that the CX3CL1/CX3CR1 dyad may contribute to atherogenesis and plaque destabilization in human CAD.

Topics: Angina, Unstable; Atorvastatin; Cell Adhesion; Cells, Cultured; Chemokine CX3CL1; Chemokines, CX3C; Chemotaxis; Cholesterol, LDL; Coronary Artery Disease; CX3C Chemokine Receptor 1; Endothelium, Vascular; Gene Expression; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-8; Leukocytes, Mononuclear; Membrane Proteins; Myocardial Infarction; Pyrroles; Receptors, Chemokine; Simvastatin; Umbilical Veins

The aim of our study was to evaluate whether a single dose of cerivastatin at the time of admission of patients with unstable angina pectoris (UAP) or non-Q-wave myocardial infarction (NQMI) can influence the serum level of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) 24 h later. Forty-four patients with rest chest pain and subendocardial ischemia on ECG were randomized to receive cerivastatin 0.3 mg at the time of admission (group C+) to standard therapy or to remain just on standard therapy (group C-). Blood samples for determination of troponin I (TI), CRP, IL-6 and IL-8 were collected at admission (entry level) and 24 h later (final level). Patients with non-physiological baseline levels of TI, as well as patients with progression to Q wave MI were excluded. All baseline, clinical and demographic data and final values of TI were comparable in the two groups. In patients treated with cerivastatin (group C+, n = 13) we observed decrease in the CRP level (-6.73 +/- 3.93 mg/L); on the other hand, in group C- (n = 17) the CRP level increased (+7.92 +/- 2.77 mg/L, p = 0.004). Similar differences were observed also in IL-6: in group C+ the level was significantly reduced as compared with the increase in group C- (-0.76 +/- 0.52 vs. 4.58 +/- 1.49 ng/L, p = 0.005). The level of IL-8 was not affected. Our results suggest that early treatment with cerivastatin can decrease the serum level of CRP and IL-6 in patients with UAP/NQMI; this might positively influence their prognosis. Nevertheless, further studies are needed to support this hypothesis.

Topics: Aged; Angina, Unstable; C-Reactive Protein; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Pyridines

The aim of this randomised, double-blind, placebo controlled, parallel group study was to assess the effect of trimetazidine (TMZ), a potent antiischaemic drug, on plasma C-reactive protein (C-RP), cytokine and adhesion molecule levels. The study population consists of 18 patients (16 males, 2 females, average age 56.45 +/- 10.97 years) with acute myocardial infarction admitted within 6 hours after onset of symptoms and treated with streptokinase. Blood samples were taken at 3-hour intervals during the time of treatment. All patients were randomised blindly using a centralised randomisation process, between trimetazidine (40 mg bolus i.v. then 60 mg per day for 48 hours intravenously in glucose infusion) or placebo group. Plasma C-RP level was significantly lower in TMZ group (39.5 mg/ml +/- 9.7 mg/ml) as compared to placebo (75.7 +/- 29.4 mg/ml, p < or = 0.001) and peaked 28 hours later in TMZ group. Plasma interleukin 6 (IL 6) level showed a sharp peak 9 hours after the onset of the symptoms in TMZ group (116.9 +/- 180.2 pg/ml vs. 45.4 +/- 37.9 pg/ml) and was increased up to 30 hours after the onset of the symptoms. Plasma interleukin 1 beta (IL 1 beta) was also higher in TMZ group notably 21 hours after the onset of symptoms (26.4 +/- 9.3 pg/ml vs. 16.2 +/- 2.4 pg/ml). TMZ group showed lower plasma E-selectin levels. Plasma IL 8, TNF alpha and ICAM 1 levels were without statistical significant differences. The present study demonstrates a significant reduction of plasma C-reactive protein level in the course of acute myocardial infarction treated with streptokinase and intravenous trimetazidine infusion compared with the group of patients without trimetazidine treatment.

Topics: C-Reactive Protein; Cell Adhesion Molecules; Combined Modality Therapy; Cytokines; Double-Blind Method; E-Selectin; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Thrombolytic Therapy; Trimetazidine; Tumor Necrosis Factor-alpha; Vasodilator Agents

Cardiac inflammatory responses appear to play a pivotal role in scar formation after acute myocardial infarction. Monocyte chemotactic and activating factor (MCAF) monocyte chemoattractant protein-1 (MCP-1) is a cytokine with chemotactic activity for mononuclear phagocytes, but also for NK cells, T cells, mast cells, and basophils. To investigate the possible involvement of MCAF/MCP-1 in the pathogenesis, its course was studied in patients with acute myocardial infarction. Twenty-three consecutive patients with acute myocardial infarction and 18 patients with angina pectoris were studied. Cytokines were measured by enzyme-linked immunosorbent assay. Plasma levels of interleukin IL-1alpha, IL-1beta, and IL-2 were below the detection limit of our method. IL-6 and interferon-gamma were detected in 17.4%, and tumor necrosis factor-alpha in 13.0% of patients with acute myocardial infarction, but the frequency was not statistically significantly different from that in angina pectoris. The plasma level of MCAF/MCP-1 in myocardial infarction tended to increase at 3 h after the onset of chest pain (133 +/- 19 pg/ml, P= 0.06) and was significantly elevated at 9 h (143 +/- 20 pg/ml) when compared with that in angina pectoris (87 +/- 6 pg/ml, P<0.05). The MCAF/MCP-1 level remained increased during the 24-hours observation period (P<0.01), and maximum level (168 +/- 13 pg/ml) was seen at 24 hour. The level of MCAF/ MCP-1 correlated significantly with the plasma level of another chemokine, IL-8, at 12 h after the onset of chest pain (r=0.51, P<0.05), suggesting that common stimuli mediate the release of both cytokines in myocardial infarction. The identification of MCAF/MCP-1 as an inflammatory mediator in acute myocardial infarction suggests that mononuclear phagocytes may play an important role in the early stage of the disease.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Chemokine CCL2; Cytokines; Female; Humans; Interleukin-8; Linear Models; Male; Middle Aged; Myocardial Infarction

Topics: Adult; Aged; Angina, Unstable; Biomarkers; Coronary Disease; Creatine Kinase; Female; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myoglobin; Pilot Projects; Predictive Value of Tests

Inflammatory cytokines are implicated in the development of atherosclerosis and cardiomyocyte injury during acute myocardial infarction (AMI). This study aimed to investigate the correlation of eight common inflammatory cytokines with major adverse cardiac event (MACE) risk and further establish a prognostic model in AMI patients.. Serum samples of 210 AMI patients and 20 angina pectoris patients were, respectively, collected at admission, to detect tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17A, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) via enzyme-linked immunosorbent assay.. TNF-α, IL-6, IL-8, IL-17A, VCAM-1, and ICAM-1 were elevated (all p < 0.050); IL-10 (p = 0.009) was declined; IL-1β (p = 0.086) was not varied in AMI patients compared with angina pectoris patients. TNF-α (p = 0.008), IL-17A (p = 0.003), and VCAM-1 (p = 0.014) were elevated in patients with MACE occurrence compared to patients without MACE occurrence; meanwhile, they possessed a relatively good value for identifying MACE risk via receiver-operating characteristic (ROC) analysis. Subsequent multivariate logistic regression analysis revealed that the independent risk factors for MACE contained TNF-α (odds ratio (OR) = 1.038, p < 0.001), IL-1β (OR = 1.705, p = 0.044), IL-17A (OR = 1.021, p = 0.009), history of diabetes mellitus (OR = 4.188, p = 0.013), history of coronary heart disease (OR = 3.287, p = 0.042), and symptom-to-balloon time (OR = 1.064, p = 0.030), whose combination disclosed a satisfying prognostic value for MACE risk (area under the curve: 0.877, 95% CI: 0.817-0.936).. Elevated levels of serum TNF-α, IL-1β, and IL-17A independently correlated with MACE risk in AMI patients, which perhaps provide novel auxiliary for AMI prognostic prediction.

Topics: Angina Pectoris; Cytokines; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-17; Interleukin-1beta; Interleukin-6; Interleukin-8; Myocardial Infarction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

This article aimed to investigate the role of miR-208 in the apoptosis of myocardial tissues in acute myocardial infarction (AMI) mice. The AMI mouse model was constructed. Then, miR-208 expression in AMI mice was regulated by transfection. The mouse myocardial tissues were subject to hematoxylin-eosin (HE) staining, TUNEL assay, and immunofluorescence analysis. H9c2 cell transfection and hypoxia induction were then completed, and cell apoptosis and cytokine levels were tested. Additionally, RNA pull-down and dual luciferase reporter gene assays were conducted for exploring the relation of miR-208 with programmed cell death 4 (PDCD4). Additionally, fluorescence in situ hybridization (FISH) was conducted for investigating miR-208 and PDCD4 colocalization within H9c2 cells. AMI mice had severe damage, apoptosis, decreased miR-208 expression, increased IL-1β, IL-6, IL-8 levels, whereas reduced IL-10 level within myocardial tissues. H9c2 cells under hypoxia induction exhibited decreased miR-208 expression, promoted apoptosis, increased protein expression of Bax and cleaved-caspase-3, decreased protein expression of Bcl-2 and caspase-3, elevated IL-1β, IL-6, IL-8 levels and decreased IL-10 level. miR-208 upregulation alleviated the damage and apoptosis of myocardial tissues in AMI mice. AMI mice with miR-208 upregulation showed decreased expression of Bax and cleaved-caspase-3, increased expression of Bcl-2 and caspase-3, reduced levels of IL-1β, IL-6, IL-8, whereas an increased level of IL-10. miR-208 showed direct inhibition of PDCD4. PDCD4 and miR-208 were mainly co-expressed in the cytoplasm. The upregulated PDCD4 expression abolished miR-208's suppression of H9c2 cell apoptosis induced by hypoxia. Besides this, miR-208 inhibited myocardial tissue apoptosis in AMI mice by inhibiting PDCD4 expression.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Caspase 3; Hypoxia; In Situ Hybridization, Fluorescence; Interleukin-10; Interleukin-6; Interleukin-8; Mice; MicroRNAs; Myocardial Infarction; Myocytes, Cardiac; Proto-Oncogene Proteins c-bcl-2

The aim of this study was to investigate the association between inflammatory markers and 28-day mortality in patients with ST-elevation myocardial infarction (STEMI).. In 398 STEMI patients recorded between 2009 and 2013 by the population-based Myocardial Infarction Registry Augsburg, 92 protein biomarkers were measured in admission arterial blood samples using the OLINK inflammatory panel. In multivariable-adjusted logistic regression models, the association between each marker and 28-day mortality was investigated. The values of the biomarkers most significantly associated with mortality were standardized and summarized to obtain a prediction score for 28-day mortality. The predictive ability of this biomarker score was compared to the established GRACE score using ROC analysis. Finally, a combined total score was generated by adding the standardized biomarker score to the standardized GRACE score.. The markers IL-6, IL-8, IL-10, FGF-21, FGF-23, ST1A1, MCP-1, 4E-BP1, and CST5 were most significantly associated with 28-day mortality, each with FDR-adjusted (false discovery rate adjusted) p-values of < 0.01 in the multivariable logistic regression model. In a ROC analysis, the biomarker score and the GRACE score showed comparable predictive ability for 28-day mortality (biomarker score AUC: 0.7859 [CI: 0.6735-0.89], GRACE score AUC: 0.7961 [CI: 0.6965-0.8802]). By combining the biomarker score and the Grace score, the predictive ability improved with an AUC of 0.8305 [CI: 0.7269-0.9187]. A continuous Net Reclassification Improvement (cNRI) of 0.566 (CI: 0.192-0.94, p-value: 0.003) and an Integrated Discrimination Improvement (IDI) of 0.083 ((CI: 0.016-0.149, p-value: 0.015) confirmed the superiority of the combined score over the GARCE score.. Inflammatory biomarkers may play a significant role in the pathophysiology of acute myocardial infarction (AMI) and AMI-related mortality and might be a promising starting point for personalized medicine, which aims to provide each patient with tailored therapy.

Topics: Biomarkers; Blood Proteins; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Myocardial Infarction; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; ST Elevation Myocardial Infarction

Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing.. Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2-34.9) vs. 12.6% (IQR 8.3-27.2);. Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

Topics: Animals; Antibodies; Antilymphocyte Serum; Cardiotonic Agents; CD3 Complex; Chemokine CCL2; Cicatrix; Disease Models, Animal; Exosomes; Extracellular Vesicles; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Leukocytes, Mononuclear; Male; MicroRNAs; Myocardial Infarction; Neovascularization, Physiologic; Proteome; Rats; Rats, Sprague-Dawley

Interleukin 8 (IL-8) is an important pro-inflammatory cytokine that recruits neutrophil to the areas of inflammation and has been implicated in myocardial ischemia reperfusion injury (MIRI). This study aimed to apply IL-8 targeted myocardial contrast echocardiography (MCE) to evaluate MIRI in rabbits. MCE imaging with IL-8 targeted microbubbles (MB

Topics: Animals; Contrast Media; Echocardiography; Interleukin-8; Male; Microbubbles; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Rabbits

Heart failure (HF) secondary to acute myocardial infarction (AMI) is a public health concern. The current study aimed to investigate differentially expressed genes (DEGs) and their possible function in HF post‑myocardial infarction. The GSE59867 dataset included microarray data from peripheral blood samples obtained from HF and non‑HF patients following AMI at 4 time points (admission, discharge, and 1 and 6 months post‑AMI). Time‑series DEGs were analyzed using R Bioconductor. Functional enrichment analysis was performed, followed by analysis of protein‑protein interactions (PPIs). A total of 108 DEGs on admission, 32 DEGs on discharge, 41 DEGs at 1 month post‑AMI and 19 DEGs at 6 months post‑AMI were identified. Among these DEGs, 4 genes were downregulated at all the 4 time points. These included fatty acid desaturase 2, leucine rich repeat neuronal protein 3, G‑protein coupled receptor 15 and adenylate kinase 5. Functional enrichment analysis revealed that these DEGs were mainly enriched in 'inflammatory response', 'immune response', 'toll‑like receptor signaling pathway' and 'NF‑κβ signaling pathway'. Furthermore, PPI network analysis revealed that C‑X‑C motif chemokine ligand 8 and interleukin 1β were hub genes. The current study identified candidate DEGs and pathways that may serve important roles in the development of HF following AMI. The results obtained in the current study may guide the development of novel therapeutic agents for HF following AMI.

Topics: Adult; Aged; Computational Biology; Databases, Genetic; Down-Regulation; Fatty Acid Desaturases; Female; Gene Expression Regulation; Heart Failure; Humans; Interleukin-1beta; Interleukin-8; Male; Membrane Glycoproteins; Membrane Proteins; Middle Aged; Myocardial Infarction; Neoplasm Proteins; Protein Interaction Mapping

Myocardial infarction (MI) is a common cause of chronic heart failure (HF). Increasing evidence has revealed that trimethylamine N‑oxide (TMAO), a gut‑microbiota‑derived metabolite, contributes to the pathogenesis of cardiovascular disease by promoting inflammation. Elevated levels of circulating TMAO have been reported in patients following MI and were associated with unfavorable outcomes. The present study examined whether reductions in circulating TMAO could attenuate the progression of HF in rats following MI. Sprague‑Dawley rats underwent coronary ligation to induce MI or a sham operation. Echocardiography confirmed MI and cardiac dysfunction one day following coronary ligation. MI and sham rats were then treated with either vehicle (tap water) or 1.0% 3,3‑dimethyl‑1‑butanol (DMB, a trimethylamine formation inhibitor) in tap water, for 8 weeks. At the end of the experiment, TMAO plasma levels were markedly elevated in vehicle‑treated MI rats compared with vehicle‑treated sham rats; however, TMAO plasma levels were reduced in DMB‑treated MI rats compared with vehicle‑treated MI rats. Both MI groups exhibited cardiac hypertrophy, lung congestion, left ventricular remodeling and impaired cardiac function, according to the results of anatomical analysis, echocardiography and left ventricular hemodynamics; however, these manifestations of MI‑induced HF were significantly improved in DMB‑treated MI rats compared with vehicle‑treated MI rats. The plasma levels of the chemokine interleukin (IL)‑8, and cardiac expression of IL‑8 and its receptors were significantly increased in vehicle‑treated MI rats compared with vehicle‑treated sham rats; however, these were normalized in DMB‑treated MI rats. In addition, elevated TMAO plasma level was positively correlated with increased IL‑8 plasma level in MI groups. Notably, DMB treatment of sham rats also reduced plasma TMAO, but did not alter other parameters. These results indicated that reducing circulating TMAO may ameliorate the development of chronic HF following MI in rats, potentially by inhibiting IL‑8 secretion. The results from the present study suggested that inhibition of TMAO synthesis may be considered as a novel therapeutic approach for the prevention and treatment of patients with chronic MI‑induced HF.

Topics: Animals; Gastrointestinal Microbiome; Heart Failure; Hexanols; Interleukin-8; Male; Methylamines; Myocardial Infarction; Rats; Rats, Sprague-Dawley

Percutaneous coronary intervention-induced myocardial infarction (PMI) has prognostic significance. Identifying patients at high risk for PMI is desirable as it may alter strategy and facilitate early preventative therapy. We therefore sought to establish whether preprocedural demographic, interventional (plaque characteristics and coronary microcirculatory function), and inflammatory, endothelial damage, and platelet-derived biomarker data could predict the risk of PMI.. We performed target vessel pressure wire to assess fractional flow reserve, index of microcirculatory resistance (IMR) and coronary flow reserve, plaque characterization by virtual histology intravascular ultrasound, and assayed peripheral biomarkers before uncomplicated PCI in 88 patients. We then analyzed post-PCI cardiac troponin level to adjudicate PMI based on the third universal definition of myocardial infarction.. Overall incidence of PMI was 27%. Women [10/15 (66%) vs. 14/73 (19%), P<0.001] and those with low body mass (27.1±3.9 vs. 29.7±5.5 kg/m; P=0.02) were at significantly higher risk of PMI. Preprocedural coronary flow reserve was lower in individuals with a subsequent PMI (1.8±1.2 vs. 2.1±1.3. P=0.03), and patients with higher pre-PCI IMR were more likely to sustain PMI [IMR>22: 10/23 (44%) vs. ≤22: 14/65 (22%), P=0.04], although neither was predictive after multivariate analysis. Plaque characterization by virtual histology intravascular ultrasound did not discriminate those at risk of PMI. However, peripheral venous interleukin (IL)-18 and IL-8 levels were independently negatively and positively associated with PMI, respectively.. Women and those with low BMI, particularly when associated with high IL-8 and low IL-18 levels, appear to be at increased risk of PMI.

Topics: Aged; Biomarkers; Coronary Vessels; Endothelium, Vascular; Female; Fractional Flow Reserve, Myocardial; Humans; Interleukin-18; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Predictive Value of Tests; Preoperative Care; Risk Assessment; Sex Factors; Troponin T; Ultrasonography, Interventional; Vascular Resistance

Since development of plasmid gene therapy for therapeutic angiogenesis by J. Isner this approach was an attractive option for ischemic diseases affecting large cohorts of patients. However, first placebo-controlled clinical trials showed its limited efficacy questioning further advance to practice. Thus, combined methods using delivery of several angiogenic factors got into spotlight as a way to improve outcomes. This study provides experimental proof of concept for a combined approach using simultaneous delivery of VEGF165 and HGF genes to alleviate consequences of myocardial infarction (MI). However, recent studies suggested that angiogenic growth factors have pleiotropic effects that may contribute to outcome so we expanded focus of our work to investigate potential mechanisms underlying action of VEGF165, HGF and their combination in MI. Briefly, Wistar rats underwent coronary artery ligation followed by injection of plasmid bearing VEGF165 or HGF or mixture of these. Histological assessment showed decreased size of post-MI fibrosis in both-VEGF165- or HGF-treated animals yet most prominent reduction of collagen deposition was observed in VEGF165+HGF group. Combined delivery group rats were the only to show significant increase of left ventricle (LV) wall thickness. We also found dilatation index improved in HGF or VEGF165+HGF treated animals. These effects were partially supported by our findings of c-kit+ cardiac stem cell number increase in all treated animals compared to negative control. Sporadic Ki-67+ mature cardiomyocytes were found in peri-infarct area throughout study groups with comparable effects of VEGF165, HGF and their combination. Assessment of vascular density in peri-infarct area showed efficacy of both-VEGF165 and HGF while combination of growth factors showed maximum increase of CD31+ capillary density. To our surprise arteriogenic response was limited in HGF-treated animals while VEGF165 showed potent positive influence on a-SMA+ blood vessel density. The latter hinted to evaluate infiltration of monocytes as they are known to modulate arteriogenic response in myocardium. We found that monocyte infiltration was driven by VEGF165 and reduced by HGF resulting in alleviation of VEGF-stimulated monocyte taxis after combined delivery of these 2 factors. Changes of monocyte infiltration were concordant with a-SMA+ arteriole density so we tested influence of VEGF165 or HGF on endothelial cells (EC) that mediate angiogenesis and inflammat

Topics: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Proliferation; Chemokine CCL2; Disease Models, Animal; Gene Expression; Genetic Therapy; Hepatocyte Growth Factor; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Male; Monocytes; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; NF-kappa B; Plasmids; Rats; Rats, Wistar; Recombinant Proteins; Vascular Endothelial Growth Factor A

Topics: Goals; Humans; Inflammation; Interleukin-8; Myocardial Infarction; ST Elevation Myocardial Infarction

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Apolipoprotein C-III; Cohort Studies; Consanguinity; Coronary Disease; Cytochrome P450 Family 2; Dietary Fats; DNA Mutational Analysis; Exome; Fasting; Female; Gene Deletion; Gene Frequency; Genes; Genetic Association Studies; Homozygote; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Neuregulins; Pakistan; Pedigree; Phenotype; Phosphoproteins; Postprandial Period; Reverse Genetics; RNA Splice Sites; Sodium-Hydrogen Exchangers; Triglycerides

Stem cell therapy for acute myocardial infarction (AMI) seemed to be a promising therapy, however, large clinical trials brought differential outcome. It has been shown that paracrine effects of secretomes of stem cells rather than cell therapy might play a fundamental role. The present study seeks to compare cell processing protocols of clinical trials and investigate effects of differential cell culture conditions on chemokine secretion and functional effects. Different secretomes are compared regarding IL-8, VEGF, MCP-1, and TNF-alpha secretion. Secretome mediated effects are evaluated on endothelial cell (HUVEC) tube formation and migration. Cardioprotective signaling kinases in human cardiomyocytes are determined by Western immunoblotting. Cells processed according to the REPAIR-AMI protocol secrete significantly higher amounts of IL-8 (487.3 ± 1231.1 vs 9.1 ± 8.2 pg mL

Topics: Bone Marrow Cells; Cell Movement; Clinical Trials as Topic; Culture Media, Conditioned; Cytokines; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Myocardial Infarction; Signal Transduction; Stem Cell Transplantation; Stem Cells

Thrombospondin (TSP) 1 and 4 are extracellular matrix glycoproteins that me-\ diate cell proliferation, platelet aggregation and inflammatory response. Conflicting data addressed the\ possible contribution of TSP-1 and TSP-4 gene polymorphisms to acute myocardial infarction (AMI).. Our study aimed to examine the association of TSP-1 (N700S) and TSP-4 (A387P) genetic\ variants with the incidence of AMI in Egyptians. It also correlated TSP-1 variants to TSP-1 and TNF-α\ serum concentrations while TSP-4 variants to IL-8 concentration identifying TSPs' contribution to vascular inflammation.. Genotyping was done in 214 subjects; 114 AMI patients and 100 controls using PCR-RFLP\ analysis. Serum Tsp-1, TNF-α and IL-8 levels were measured by ELISA assay.. For TSP-4, (GC and CC) genotype distribution and the (C) allele frequency were significantly\ higher in AMI patients than controls (p = 0.0186), (p = 0.0117) respectively. In contrast, TSP-1 genotypes\ and allele frequencies showed no significant difference between AMI and controls (p = 0.7124 and p =\ 0.7201, respectively). Serum TSP-1, TNF-α and IL-8 concentrations were significantly elevated in AMI\ compared to controls (p = 0.0146, p < 0.0001 and p = 0.0057) respectively. Serum IL-8 levels had a significant difference among TSP-4 genotypes (p= 0.0368), being highest in the mutant C allele. Serum\ TSP-1 and TNF-α concentrations showed no significant difference among TSP-1 genotypes, but there\ was a positive correlation between both concentrations in AMI patients (p = 0.0014), (r = 0.4125).. TSP-4 A387P polymorphism, but not TSP-1 polymorphism, is an independent risk factor\ for AMI in the Egyptians.

Topics: Acute Disease; Adult; Case-Control Studies; Egypt; Female; Gene Frequency; Humans; Incidence; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Risk Factors; Thrombospondin 1; Thrombospondins; Tumor Necrosis Factor-alpha

β-Catenin has been implicated in various developmental and physiological processes. Defective Wnt signaling can result in different cardiac and vascular abnormalities and is activated under pathological conditions such as inflammation and obesity. In this study, roles of β-catenin in inflammation in cardiomyocytes were investigated. 10 samples from hearts of patients with acute infarction and 10 from normal ones were collected in order to access roles of β-catenin in cardiomyocytes. H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes were transfected with porcine cytomegalovirus (pCMV)-β-catenin plasmid in order to overexpress β-catenin. Protein level of β-catenin protein was increased in human acute infarction tissues compared to ones from normal patients. The transcription factor had increased nuclear localization in cardiomyocytes of the Wistar rats with cardiac hypertension. Furthermore, expression of fibrosis protein markers increased. Protein expression of β-catenin was increased in human acute infarction inflammatory heart tissues and in hearts of inflammatory obesity rats. After pCMV-β-catenin plasmid was transfected in a dose-dependent manner, inflammation protein markers, TNF-α and IL-8, were upregulated in hypertensive neonatal rat cardiomyocytes and H9c2 cardiomyoblasts. In addition, overexpression of β-catenin induced activation and nuclear localization of NF-κB. Therefore, β-catenin is a potential molecular target for treatment of inflammation and fibrosis in cardiomyocytes.

Topics: Animals; beta Catenin; Cells, Cultured; Cytokines; Humans; Immunohistochemistry; Interleukin-8; Myocardial Infarction; Myocardium; Myocytes, Cardiac; NF-kappa B; Plasmids; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Levosimendan is a positive inotropic drug for the treatment of acute decompensated heart failure (HF). Clinical trials showed that levosimendan was particularly effective in HF due to myocardial infarction. Myocardial necrosis induces a strong inflammatory response, involving chemoattractants guiding polymorphonuclear neutrophils (PMN) into the infarcted myocardial tissue. Our aim was to examine whether levosimendan exhibits anti-inflammatory effects on human adult cardiac myocytes (HACM) and human heart microvascular endothelial cells (HHMEC). Cardiac myocytes and endothelial cells were stimulated with interleukin-1β (IL)-1β (200 U/ml) and treated with levosimendan (0.1-10 µM) for 2-48 hours. IL-1β strongly induced expression of IL-6 and IL-8 in HACM and E-selectin and intercellular adhesion molecule-1 (ICAM-1) in HHMEC and human umbilical vein endothelial cells (HUVEC). Treatment with levosimendan strongly attenuated IL-1β-induced expression of IL-6 and IL-8 in HACM as well as E-selectin and ICAM-1 in ECs. Levosimendan treatment further reduced adhesion of PMN to activated endothelial cells under both static and flow conditions by approximately 50 %. Incubation with 5-hydroxydecanoic acid, a selective blocker of mitochondrial ATP-dependent potassium channels, partly abolished the above seen anti-inflammatory effects. Additionally, levosimendan strongly diminished IL-1β-induced reactive oxygen species and nuclear factor-κB (NF-κB) activity through inhibition of S536 phosphorylation. In conclusion, levosimendan exhibits anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. These findings could explain, at least in part, the beneficial effects of levosimendan after myocardial infarction.

Topics: Anti-Inflammatory Agents; Cell Adhesion; Cells, Cultured; Decanoic Acids; E-Selectin; Enzyme-Linked Immunosorbent Assay; Heart Failure; Human Umbilical Vein Endothelial Cells; Humans; Hydrazones; Hydroxy Acids; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Interleukin-8; Microcirculation; Microscopy, Fluorescence; Muscle Cells; Myocardial Infarction; Myocytes, Cardiac; Necrosis; Neutrophils; NF-kappa B; Phosphorylation; Pyridazines; Reactive Oxygen Species; Simendan; Vasodilator Agents

Cardiovascular disease is the leading cause of death globally, and stem cell therapy remains one of the most promising strategies for regeneration or repair of the damaged heart. We report that human placenta-derived multipotent cells (hPDMCs) can modulate cardiac injury in small and large animal models of myocardial ischemia (MI) and elucidate the mechanisms involved. We found that hPDMCs can undergo in vitro cardiomyogenic differentiation when cocultured with mouse neonatal cardiomyocytes. Moreover, hPDMCs exert strong proangiogenic responses in vitro toward human endothelial cells mediated by secretion of hepatocyte growth factor, growth-regulated oncogene-α, and interleukin-8. To test the in vivo relevance of these results, small and large animal models of acute MI were induced in mice and minipigs, respectively, by permanent left anterior descending (LAD) artery ligation, followed by hPDMC or culture medium-only implantation with follow-up for up to 8 weeks. Transplantation of hPDMCs into mouse heart post-acute MI induction improved left ventricular function, with significantly enhanced vascularity in the cell-treated group. Furthermore, in minipigs post-acute MI induction, hPDMC transplantation significantly improved myocardial contractility compared to the control group (p = 0.016) at 8 weeks postinjury. In addition, tissue analysis confirmed that hPDMC transplantation induced increased vascularity, cardiomyogenic differentiation, and antiapoptotic effects. Our findings offer evidence that hPDMCs can modulate cardiac injury in both small and large animal models, possibly through proangiogenesis, cardiomyogenesis, and suppression of cardiomyocyte apoptosis. Our study offers mechanistic insights and preclinical evidence on using hPDMCs as a therapeutic strategy to treat severe cardiovascular diseases.

Topics: Animals; Apoptosis; Cell Differentiation; Cell- and Tissue-Based Therapy; Cells, Cultured; Chemokine CXCL1; Coculture Techniques; Disease Models, Animal; Endothelial Cells; Female; Hepatocyte Growth Factor; Humans; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Multipotent Stem Cells; Muscle Development; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocytes, Cardiac; Neovascularization, Physiologic; Placenta; Pregnancy; Swine; Swine, Miniature; Ventricular Function, Left

Left ventricular (LV) function and prognosis in patients after myocardial infarction are associated with some angiographic parameters.. The aim of the study was to assess the associations between the TIMI score in the infarct-related artery (IRA) before percutaneous coronary intervention (PCI), myocardial blush grade (MBG) following effective PCI, and the extent of collaterals measured using the Rentrop scale and plasma levels of vascular endothelial growth factor (VEGF) and angiogenin, number of CD34⁺ cells, as well as LV ejection fraction (LVEF) and wall motion score index (WMSI).. In 62 patients with the first ST-segment elevation myocardial infarction (STEMI) treated with PCI and bare metal stent implantation, plasma VEGF and angiogenin levels as well as the number of CD34⁺ cells were assessed before PCI, 24 hours after PCI, at discharge, and at 30 days following STEMI. LVEF and WMSI were evaluated by echocardiography at discharge and at 1 and 6 months after STEMI.. Patients with TIMI 0-1 flow in the IRA before PCI (64.6% of the patients) had significantly higher troponin I and VEGF levels as well as a higher number of CD34⁺ cells than patients with TIMI 3 flow. Patients with TIMI 0-1 flow also had worse LV systolic function at 1 and 6 months following STEMI. Neither the MBG grade nor the Rentrop score showed associations with the mobilization of CD34⁺ cells, VEGF and angiogenin levels, and parameters of L V systolic function.. Early patency of the IRA and lower myocardial necrosis seem to be more important for LV function assessed in patients 6 months after STEMI than mobilization of CD34⁺ cells and levels of angiogenic factors.

Topics: Antigens, CD34; Coronary Angiography; Female; Follow-Up Studies; Humans; Interleukin-6; Interleukin-8; Male; Myocardial Infarction; Percutaneous Coronary Intervention; Prognosis; Severity of Illness Index; Vascular Endothelial Growth Factor A

Vascular disease is promoted by systemic inflammation that can arise from sites distal to the affected vessels. We sought to characterize the net inflammatory potential of serum from patients with coronary artery disease (CAD) using cultured endothelial cells as a cumulative biosensor.. Serum samples from CAD patients (N = 45) and healthy control subjects (N = 48) were incubated with primary human coronary artery endothelial cells at a 1:10 dilution for 4 h, followed by isolation of the cellular RNA. Alteration of inflammation-responsive elements (adhesion molecules and cytokines) was assessed by gene expression. Specific indicators included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-8 (IL-8). Additionally, the cytokine levels in serum samples from all subjects were quantified. Serum from CAD subjects induced greater endothelial ICAM-1, VCAM-1, and IL-8 expression compared to healthy control serum (p < 0.001 for each analysis). The three indicators of inflammatory potential (ICAM-1, VCAM-1, and IL-8 mRNA) trended independently of each other and also of serum inflammatory biomarkers. IL-8 expression correlated negatively with serum HDL levels but positively correlated with VLDL, plasminogen activator inhibitor-1 and C-reactive protein. Interestingly, serum levels of cytokines in CAD patients were not statistically different from healthy control subjects. A year of follow-up in a sub-group of CAD subjects revealed relatively stable measures.. As yet unidentified circulating factors in the serum of CAD patients appear to activate endothelial cells, leading to upregulation of adhesion molecules and chemokines. This cumulative assay performed well in terms of discriminating patients with CAD compared to healthy subjects, with greater range and specificity than specific inflammatory markers.

Topics: Adolescent; Adult; Age Factors; Aged; Biological Assay; Biosensing Techniques; Body Mass Index; Case-Control Studies; Cohort Studies; Coronary Artery Disease; Coronary Vessels; Demography; Endothelial Cells; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Linear Models; Luminescent Measurements; Male; Middle Aged; Myocardial Infarction; Sex Characteristics; Time Factors; Vascular Cell Adhesion Molecule-1; Young Adult

Inflammation is now believed to be responsible for coronary heart disease (CHD). This belief has stimulated the evaluation of various inflammatory markers for predicting CHD. This study was designed to investigate the association between four inflammatory cytokines (CD121a, interleukin [IL]-1β, IL-8, and IL-11) and CHD. Here, we evaluated 443 patients with CHD and 160 CHD-free controls who underwent coronary angiography. Cytokines were evaluated using flow cytometry, and statistical analyses were performed to investigate the association between cytokine levels and the risk of CHD. Patients with CHD had significantly higher levels of CD121a. The odds ratios for CHD according to increasing CD121a quartiles were 1.00, 1.47 [95% confidence interval (CI): 0.79-2.72], 2.67 (95% CI: 1.47-4.84), and 4.71 (95% CI: 2.65-8.37) in an age- and sex-adjusted model, compared to 1.00, 1.48 (95% CI: 0.70-3.14), 2.25 (95% CI: 1.10-4.62), and 4.39 (95% CI: 2.19-8.79) in a model that was adjusted for multiple covariates. A comparison of the stable angina, unstable angina, and acute myocardial infarction (AMI) subgroups revealed that patients with AMI had the highest CD121a levels, although IL-1β levels were similar across all groups. IL-8 levels were also increased in AMI patients, and IL-11 levels were higher in CHD patients than in non-CHD patients. Correlation analysis revealed a positive association between CD121a, IL-8, and the Gensini score. Together, the significant increase in CD121a levels among CHD patients suggests that it may be a novel inflammatory marker for predicting CHD.

Topics: Adult; Aged; Aged, 80 and over; Angina, Stable; Angina, Unstable; Biomarkers; Case-Control Studies; Coronary Disease; Female; Humans; Inflammation Mediators; Interleukin-11; Interleukin-1beta; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Receptors, Interleukin-1 Type I

To investigate the long-term prognostic significance of baseline plasma IL-8 levels in a group of well-characterized male patients presenting with acute coronary syndrome.. IL-8 is a cytokine that has been implicated in the pathogenesis of atherosclerosis and acute coronary syndrome. Elevated plasma levels have been reported in patients with acute coronary syndrome.. Baseline plasma IL-8 levels were measured in 180 male patients with acute coronary syndrome who were referred for coronary angiography and followed prospectively for the development of all-cause mortality for 5 years.. In a multivariate model that included a wide variety of baseline clinical, laboratory and angiographic parameters in the selection process, baseline plasma IL-8 levels (analyzed as a continuous variable) emerged as a significant predictor of all-cause mortality at 5 years (HR, 1.43; 95% CI, 1.08-1.88; p = 0.0123). Furthermore, in 3 additional multivariate models that also included in the selection process a number of contemporary biomarkers with established prognostic efficacy in ACS (i.e., NT-proBNP, hs-CRP, hemoglobin and RDW), IL-8 remained an independent predictor of all-cause mortality at 5 years.. Elevated baseline plasma levels of IL-8 are associated with an increased risk of long-term all-cause mortality in patients with acute coronary syndrome. Furthermore, this association is independent of a variety of clinical, laboratory and angiographic variables, including contemporary biomarkers with established prognostic efficacy in acute coronary syndrome.

Topics: Acute Coronary Syndrome; Age Factors; Aged; Atherosclerosis; Biomarkers; C-Reactive Protein; Coronary Angiography; Coronary Artery Disease; Erythrocytes; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Hemoglobins; Humans; Interleukin-8; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Multivariate Analysis; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Renal Insufficiency

Restoration of coronary blood flow is crucial in the treatment of acute myocardial infarction. Reperfusion, however, induces ischaemia-reperfusion (IR) injury, which further deteriorates myocardial function. The innate immune system plays an important role in this process, mediating rapid influx of immune cells into the reperfused myocardium. Leukotriene B4 is an important leucocyte chemoattractant, performing its actions through binding to its specific receptor BLT1. We hypothesized that treatment with LSN2792613, a selective BLT1 antagonist, reduces infarct size (IS) in a mouse model of myocardial IR injury.. Male C57Bl/6J mice were subjected to myocardial ischaemia for 30 min by surgical coronary artery ligation, followed by reperfusion. Mice received either LSN2792613 or vehicle, three times daily (orally) for up to 72 h after reperfusion. BLT1 inhibition with LSN2792613 reduced IS compared with vehicle treatment (26.9 ± 2.7 vs. 34.9 ± 2.2%, P = 0.030) at 24 h after reperfusion. The levels of IL-6 and keratinocyte chemoattractant were reduced in the infarcted tissue of LSN2792613-treated mice. Reduced apoptosis in LSN2792613-treated mice was suggested by increased levels of phosphorylated JNK and GSK3α/β, and confirmed by flow cytometric analysis showing less apoptotic and necrotic cardiomyocytes in the infarcted myocardium. Echocardiography at 4 weeks after myocardial IR showed a slightly higher ejection fraction and stroke volume in mice treated with LSN2792613 compared with vehicle-treated mice, whereas left ventricular volumes were comparable.. Selective BLT1 inhibition with LSN2792613 reduces inflammation and apoptosis following IR, resulting in reduced IS, and therefore might be a promising strategy to prevent myocardial IR injury.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cardiotonic Agents; Collagen; Cytoprotection; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Interleukin-6; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Leukotriene Antagonists; Male; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Necrosis; Phosphorylation; Receptors, Leukotriene B4; Signal Transduction; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Remodeling

To explore the cardioprotective effect and its mechanism of total saponins of Panacis Majoris Rhizoma in myocardial infarction (MI) rats.. The MI model rats induced by ligating anterior descending branch of coronary artery were randomly divided into four group:model group, total saponins of Panacis Majoris Rhizoma (100 and 200 mg/kg) groups and compound Danshen dripping pills group. The rats were orally administrated with drugs once a day for four weeks. Another rats were selected as sham operation group. After four weeks intervention, cardiac function was examined, the serum levels of TNF-α, IL-1β, IL-6 and IL-8 were measured by using ELISA, respectively. The myocardial hypertrophy index was investigated, the myocardial infarct size, degree of ventricular dilatation, myocardial interstitial collagen volume fraction and tissue morphology were investigated by HE, Masson, picric acid-sirius red staining and observing with alight microscope and electron microscope. Protein expressions of phosphorylation IκB-α( pIκB-α) and NF-κB p65 in heart tissue were detected by Western blotting.. Total saponins of Panacis Majoris Rhizoma might significantly decrease the levels of serum TNF-α, IL-1β, IL-6 and IL-8; decrease myocardial hypertrophy indexes, myocardial infarct size, degree of ventricular dilatation and myocardial interstitial collagen volume fraction; improve heart tissue morphology and cardiac function; downregulate protein expression of pIκB-α and NF-κBp65; and upregulate protein expression of SIRT1. The aforementioned action effects of total saponins of Panacis Majoris Rhizoma (200 mg/kg) were similar with compound Danshen dripping pills.. Total saponins of Panacis Majoris Rhizoma possesses cardioprotective effect against ligating left anterior descending branch induced MI in rats. The mechanism may be related to strengthening SIRT1 expression, inhibiting the phosphorylation of IκB-α, and finally inhibiting the activation of NF-κB and proinflammatory production.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Drugs, Chinese Herbal; Heart; I-kappa B Proteins; Interleukin-1beta; Interleukin-6; Interleukin-8; Myocardial Infarction; Myocardium; NF-kappa B; NF-KappaB Inhibitor alpha; Panax; Rats; Rhizome; Salvia miltiorrhiza; Saponins; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Interleukin 8 (IL8) has been contradictorily associated with the risk of myocardial infarction (MI).. To investigate the association of IL8 serum levels with the risk of MI and the association of the IL8 (IL8) and IL8 receptors (CXCR1 and CXCR2) genetic variants with IL8 levels and MI risk in a large case control study, the Stockholm Heart Epidemiology Program.. IL8 levels (pg/mL) were divided into quartiles and the MI risk was calculated by logistic regression and expressed as odds ratio (OR) and 95% CI. Two IL8 SNPs (rs4073A/T, rs2227306C/T) and three SNPs tagging CXCR1 and CXCR2 (rs4674258C/T, rs1008563C/T, rs6723449T/C) were analyzed for association with IL8 levels and with MI risk. Multivariate adjusted ORs for MI risk by IL8 levels in the highest quartiles indicated reduced point estimates in both women (OR 0.37; 95% CI 0.2-0.8) and men when compared to the lowest quartile. In female cases, IL8 levels decreased progressively in the six months after MI (p=0.03). IL8, CXCR1 and CXCR2 genetic variants were not associated with IL8 levels. In men, the T allele at the IL8 SNP rs4073 was associated with a slight increase in the MI risk under an additive and a recessive model of inheritance.. IL8 serum levels were associated with a reduced occurrence of MI among women, whereas IL8 was associated with a slightly increased risk among men, possibly through different mechanisms. These data suggest that the biological effects of IL8 on MI risk may vary over time and warrant further cohort studies with repetitive IL8 measurements.

Topics: Aged; Case-Control Studies; Coronary Artery Disease; Female; Genetic Predisposition to Disease; HapMap Project; Humans; Interleukin-8; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Risk Factors; Sweden

We and others have previously demonstrated that adipose-derived stem cells (ASCs) transplantation improve cardiac dysfunction post-myocardium infarction (MI) under hemodynamic stress in rats. The beneficial effects appear to be associated with pleiotropic factors due to a complex interplay between the transplanted ASCs and the microenvironment in the absence of cell transdifferentiation. In the present work, we tested the hypothesis that mechanical stretch per se could change human ASCs (hASCs) into cardiovascular cell phenotypes that might influence post-MI outcomes.. Human ASCs were obtained from patients undergoing liposuction procedures. These cells were stretched 12%, 1Hz up to 96 hours by using Flexercell 4000 system. Protein and gene expression were evaluated to identify cardiovascular cell markers. Culture medium was analyzed to determine cell releasing factors, and contraction potential was also evaluated.. Mechanical stretch, which is associated with extracellular signal-regulated kinase (ERK) phosphorylation, failed to induce the expression of cardiovascular cell markers in human ASCs, and mesenchymal cell surface markers (CD29; CD90) remained unchanged. hASCs and smooth muscle cells (SMCs) displayed comparable contraction ability. In addition, these cells demonstrated a profound ability to secrete an array of cytokines. These two properties of human ASCs were not influenced by mechanical stretch.. Altogether, our findings demonstrate that hASCs secrete an array of cytokines and display contraction ability even in the absence of induction of cardiovascular cell markers or the loss of mesenchymal surface markers when exposed to mechanical stretch. These properties may contribute to beneficial post-MI cardiovascular outcomes and deserve to be further explored under the controlled influence of other microenvironment components associated with myocardial infarction, such as tissue hypoxia.

Topics: Adipose Tissue; Biomarkers; Cardiovascular System; Cell Differentiation; Gene Expression Regulation; Humans; Interleukin-10; Interleukin-8; Mechanical Phenomena; Myocardial Infarction; Phenotype; Stem Cell Transplantation; Stem Cells; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A

Between the pro- and antiinflammatory components of the immune system there is a dynamic balance, violation of which is an important mechanism of development of many pathological states, in particular, cardiac insufficiency. The purpose of the work was a study of secretion of cytokines by mononuclears in patients under myocardial infarction, uncomplicated (1 group) and complicated (2 group) acute cardiac insufficiency, and determination of balance between pro-(TNF-alpha, IL-6, IL-8) and antiinflammatory (1L-10) factors in development of acute cardiac insufficiency in patients with myocardial infarction. The results indicate that in patients of group 1 there is initially a high level of both proinflammatory and antiinflammatory cytokines. After 10 days, we observed a decline in the IL-6 level and an increase in the TNF-alpha and IL-10 levels. In patients of group 2 we observed initially high levels of TNF-alpha and IL-6 and a reduced levels of IL-8 and 1L-10, as compared to patients of group 1. In dynamics of supervision of this group, further increase of all proinflammatory cytokines and a decline of IL-10 was registered. Balance between the pro- and antiinflammatory cytokines reflects the index of inflammatory activity, determined by formula (TNFalpha+IL-6+IL-8)/IL-10 and testifying that in patients of group 1 in the dynamics of treatment there is normalization of cytokin's balance, accompanied by decline of the index, while in patients of group 2 the index rose at 10th day.

Topics: Case-Control Studies; Cells, Cultured; Female; Heart Failure; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Male; Myocardial Infarction; Severity of Illness Index; Th1-Th2 Balance; Tumor Necrosis Factor-alpha

Several lines of evidence indicate that increased inflammatory cytokine levels can be used for risk prediction in patients with acute coronary syndrome (ACS). This study therefore aimed to evaluate correlations between levels of soluble interleukin (IL)-2 receptor (sIL-2r), IL-6, and IL-8 and in-hospital incidence of acute heart failure (AHF) and left ventricular (LV) systolic dysfunction in the subacute phase of ACS. In 48 consecutive patients with ACS, circulating levels of sIL-2r, IL-6, and IL-8 were ascertained 72-96 h after onset of symptoms. Clinical data, LV function, and in-hospital incidence of AHF were also evaluated. IL-8 levels were significantly higher in patients with pulmonary edema (1,829 ± 2,496 vs 456 ± 624 pg/ml, p < 0.05); sIL-2r, IL-6, and IL-8 levels were increased proportionally to Killip class (r = 0.35, p < 0.05; r = 0.48, r = 0.47, p < 0.01) and in patients with LV ejection fraction (LVEF) < 30%. Levels of sIL-2r were inversely related to LVEF in subjects with acute myocardial infarction (r = -0.51, p < 0.05). Soluble IL-2r and IL-8 levels were related to mitral regurgitation severity (r = 0.34, p < 0.05; r = 0.37, p < 0.05). Levels of sIL-2 were proportional to LV end-diastolic diameter (r = 0.49, p < 0.001) and LV end-systolic diameter (r = 0.58, p < 0.001). Number of cytokines with circulating values above upper level of normal was significantly correlated with Killip class and LVEF (r = 0.40, r = -0.38, p < 0.05). sIL-2r, IL-6, and IL-8 are increased in patients with ACS and systolic dysfunction or AHF. These data suggest that inflammatory cytokine activity detectable in peripheral blood may be useful in identifying subjects with a worse clinical course.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Female; Heart Failure; Humans; Interleukin-2; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Pulmonary Edema; Receptors, Interleukin-2; Ventricular Dysfunction, Left

The IABP-SHOCK-trial was a morbidity-based randomized controlled trial in patients with infarction-related cardiogenic shock (CS), which used the change of the quantified degree of multiorgan failure as determined by APACHE II score over a 4-day period as primary outcome measure. The prospective hypothesis was that adding IABP therapy to "standard care" would improve CS-triggered multi organ dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with IABP support. In an inflammatory marker substudy, we analysed the prognostic value of interleukin (IL)-1β, -6, -7, -8, and -10 in patients with acute myocardial infarction complicated by cardiogenic shock.. Inflammatory marker substudy of the prospective, randomized, controlled, open label IABP-SHOCK-trial (ClinicalTrials.gov ID-NCT00469248).. A single-center study was performed in a 12-bed Intensive-Care-Unit in an university hospital in which 40 consecutive patients were enrolled with an observational period of 96 h.. The pro- and anti-inflammatory markers IL-6, -7, -8 and -10 showed a predictive power for mortality of infarct-related CS patients, while IL-1β did not discriminate. The maximal values during the observational period, in case of IL-7 the minimal value, showed the best power to predict mortality. Both, ROC and multivariate analyses confirmed these suggestions (area under the curve: IL-8, 0.80 ± 0.08; IL-6, 0.79 ± 0.08; IL-10, 0.76 ± 0.08; IL-7, 0.69 ± 0.08). Inflammatory markers were not affected by the presence of IABP support.. The inflammatory response in patients with myocardial infarction complicated by cardiogenic shock, as reflected by the inflammatory markers IL-6, IL-7, IL-8 and IL-10, demonstrates a clinically relevant prognostic contribution to clinical outcome.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Coronary Angiography; Female; Humans; Intensive Care Units; Interleukin-10; Interleukin-6; Interleukin-7; Interleukin-8; Interleukins; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Reperfusion; Prognosis; Shock, Cardiogenic

Clinical results from acute myocardial infarction (AMI) patients treated with MultiStem®, a large-scale expanded adherent multipotent progenitor cell population (MAPC), have demonstrated a strong safety and benefit profile for these cells. The mechanism of benefit with MAPC treatment is a result, in part, of its ability to induce neovascularization through trophic support. Production of clinical-grade stem cell products requires the development of lot-release criteria based on potency assays that directly reflect the fundamental mechanistic pathway underlying the therapeutic response to verify manufacturing process consistency and product potency.. Using an in vitro endothelial tube formation assay, a potency assay has been developed that reflects MAPC pro-angiogenic activity. Serum-free conditioned media collected from MAPC culture induced endothelial tube formation. A proteomic survey of angiogenic factors produced by the cells in vitro revealed candidate factors linked to angiogenic potency. Three cytokines, chemokine (C-X-C motif) ligand 5 (CXCL5), interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF), were required for this angiogenic activity. Depletion of any of these factors from the media prevented tube formation, while adding back increasing amounts of these cytokines into the depleted serum-free conditioned media established the lower limits of each of the cytokines required to induce angiogenesis.. A necessary threshold of angiogenic factor expression was established using an in vitro angiogenesis assay. By correlating the levels of the cytokines required to induce tube formation in vitro with levels of the factors found in the spent media from manufacturing production runs, detection of these factors was identified as a surrogate potency assay with defined pass/fail criteria.

Topics: Bone Marrow Cells; Cell Culture Techniques; Cell Differentiation; Cell- and Tissue-Based Therapy; Culture Media, Conditioned; Culture Media, Serum-Free; Cytokines; Endothelial Cells; Gene Expression; Humans; Interleukin-8; Multipotent Stem Cells; Myocardial Infarction; Neovascularization, Physiologic; Receptors, G-Protein-Coupled; Vascular Endothelial Growth Factor A

Some inflammatory cytokines and parameters of low density lipoproteins (LDL) oxidative modification were studied in blood of 250 acute coronary syndrome (ACS) patients--Siberian inhabitants, men and women with myocardial infarction (MI) or unstable angina on first, tenth and thirtieth days of disease. The inflammatory biomarkers in men and women with MI are: increased concentrations of interleukin (IL)-6, IL-8 and C-reactive protein (CRP), especially on the first day of disease. The most significant inflammatory biomarker of ACS is increased CRP level, especially in women. Oxidative biomarkers in men with ACS are increased basal level of LDL lipid peroxidation (LPO) products and decreased LDL resistance to oxidation. Inflammatory-oxidative biomarkers IL-6, IL-8, CRP and basal level of LDL LPO products are correlated and independently associated with MI.

Topics: Aged; Angina, Unstable; Biomarkers; C-Reactive Protein; Female; Humans; Interleukin-6; Interleukin-8; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Myocardial Infarction; Risk Factors; Sex Factors; Siberia; Time Factors

In this study, our aim was to evaluate the angio-vasculogenic properties of human adipose tissue-derived mesenchymal stem cells overexpressing the granulocyte chemotactic protein (GCP)-2 (hASCs/GCP-2) and to determine possible therapeutic effects in an experimental ischaemic heart model.. Quantitative real-time (qRT)-PCR results revealed that hASCs/GCP-2 expressed significantly higher levels of pro-angiogenic genes, including vascular endothelial growth factor (VEGF)-A, hepatocyte growth factor (HGF), and interleukin (IL)-8, when compared with control-vector transduced hASCs or human umbilical vascular endothelial cells (HUVECs). In addition, the anti-apoptotic insulin-like growth factor (IGF)-1 and Akt-1 were also highly up-regulated in the hASCs/GCP-2 cells. In vitro cell migration and proliferation assays showed that hASCs/GCP-2-derived conditioned media (CM) significantly accelerated the migration and proliferation of fibroblast cells. Examination of in vitro endothelial differentiation showed that hASCs/GCP-2 cells spontaneously formed vascular-like structures and highly expressed endothelial-specific genes and proteins. In vivo study results of our mouse myocardial infarction (MI) model revealed that hASCs/GCP-2 implantation improved the cardiac function and reduced the infarct size. Finally, transplanted hASCs/GCP-2 cells unexpectedly differentiated into endothelial cells and the engraftment rate was significantly higher than control groups.. We suggest that overexpression of GCP-2 in stem cells has the potential to enhance their angiogenic and survival properties.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Line; Cell Movement; Cell Proliferation; Cell Survival; Chemokine CXCL6; Culture Media, Conditioned; Disease Models, Animal; Endothelial Cells; Fibroblasts; Genetic Therapy; Hepatocyte Growth Factor; Humans; Insulin-Like Growth Factor I; Interleukin-8; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Mice, SCID; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Recovery of Function; Time Factors; Transfection; Up-Regulation; Vascular Endothelial Growth Factor A

To investigate the temporal changes of serum cytokines IL-6, IL-8, MCP-1 and IL-10 immediately before and after primary PCI (percutaneous coronary intervention) in patients with ST-segment elevation myocardial infarction (STEMI) and explore the interaction of these cytokines.. A total of 59 STEMI patients were recruited. And their serum concentrations of IL-6, IL-8, MCP-1 and IL-10 were measured by ELISA before primary PCI and 4-6 hours, 12 hours, 24 hours and 7 days post-intervention. For each cytokine, the level at each time-point post-PCI was compared to that at pre-PCI. Correlation coefficient test was used to analyze the interactions of these four cytokines.. At 12 hours post-PCI, the median serum levels of IL-6 and IL-8 were higher than those before PCI (IL-6: 8.51 ng/L vs 6.76 ng/L, IL-8: 4.67 ng/L vs 2.95 ng/L, both P < 0.05). At 4-6 hours and 12 hours post-PCI, the median values of MCP-1 were increasing significantly compared to those at pre-PCI (35.04 ng/L, 34.24 ng/L vs 30.45 ng/L, both P < 0.05) while those of IL-10 decreased (18.15 ng/L, 18.82 ng/L vs 20.95 ng/L, both P < 0.05). The levels of IL-6 and IL-10 at pre-PCI were associated with the Killip classification on admission (IL-6: r = 0.293, P < 0.05; IL-10: r = -0.287, both P < 0.05). Except for IL-8, other cytokines had no significant relation with the time length from onset to admission (P > 0.05). Additionally, these four cytokines were not found to be related with the location and extension of myocardial infarction, ejection fraction and NT-proBNP. At each time-point, there were a positive relationship among the natural logarithms of the concentrations of IL-6, IL-8 and MCP-1 (P < 0.01), all of which were inverse to the natural logarithm of the concentration of IL-10 (P < 0.01).. The pro-inflammatory cytokines increase while the anti-inflammatory cytokines decrease after myocardial ischemia/reperfusion. An imbalance of inflammatory cytokines may be present.

Topics: Aged; Angioplasty, Balloon, Coronary; Chemokine CCL2; Cytokines; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion Injury; Natriuretic Peptide, Brain; Peptide Fragments

Angiogenesis factors are produced in response to hypoxic or ischemic insult at the site of pathology, which will cause neovascularization. Insulin like growth factor-1 (IGF-1) exerts potent proliferative, angiogenic and anti-apoptotic effects in target tissues. The present study was aimed to evaluate the effects of IGF-1 on circulating level of angiogenic cytokine interleukin-8 (IL-8), in experimentally-induced myocardial ischemia in rats. Male Sprague-Dawley rats were divided into control, IGF-1 treated (2 μg/kg/day subcutaneously, for 5 and 10 days), isoproterenol (ISO) treated (85 mg/kg, subcutaneously for two days) and ISO with IGF-1 treated (for 5 and 10 days). Heart weight, serum IGF-1, IL-8 and cardiac marker enzymes (CK-MB and LDH) were recorded after 5 and 10 days of treatment. Histopathological analyses of the myocardium were also done. There was a significant increase in serum cardiac markers with ISO treatment indicating myocardial infarction in rats. IGF-1 level increased significantly in ISO treated groups and the level of IGF-1 was significantly higher after 10 days of treatment. IL-8 level increased significantly after ISO treatment after 5 and 10 days and IGF-1 concurrent treatment to ISO rats had significantly increased IL-8 levels. Histopathologically, myocyte necrosis and nuclear pyknosis were reduced significantly in IGF-1 treated group and there were numerous areas of capillary sprouting suggestive of neovascularization in the myocardium. Thus, IGF-1 protects the ischemic myocardium with increased production of circulating angiogenic cytokine, IL-8 and increased angiogenesis.

Topics: Animals; Insulin-Like Growth Factor I; Interleukin-8; Isoproterenol; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley

The no-reflow phenomenon is a deteriorating factor for prognosis of acute myocardial infarction (AMI). Leukocyte enzymes may be involved in developing the no-reflow phenomenon. The aim of this study was to clarify the association of myeloperoxidase, a leukocyte enzyme, with the no-reflow phenomenon in patients with AMI after percutaneous coronary inetervention (PCI).. We enrolled 50 patients with AMI whose infarct-related coronary arteries were rescued by thrombectomy devices. Blood samples were collected from peripheral vein (PV), ostium and culprit lesion of infarct-related coronary artery. Myeloperoxidase, elastase and interleukin (IL)-8 were measured by ELISA. Antegrade blood flow in the infarct-related coronary artery and myocardial perfusion were evaluated according to the corrected TIMI frame counts (cTFC) and the myocardial blush grade (MBG).. Plasma myeloperoxidase and IL-8 levels at the ostium and the culprit lesion of infarct-related coronary artery were significantly greater than those in PV. No-reflow was found in 10 patients (20%). Plasma levels of myeloperoxidase at the culprit lesion of infarct-related coronary artery were significantly greater in the patients with no-reflow than those without no-reflow. Plasma myeloperoxidase levels at the culprit lesion of infarct-related coronary artery positively correlated with the cTFC. Also, plasma myeloperoxidase levels were significantly higher in the patients with MBG 0-1 than those with MBG 2-3.. The present findings indicate that local myeloperoxidase levels in the culprit coronary artery may contribute to the no-reflow phenomenon in the patients with AMI.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Circulation; Female; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Pancreatic Elastase; Peroxidase; Treatment Failure

The therapeutic mechanism of mesenchymal stromal/stem cells (MSC) for the treatment of acute myocardial infarction is not well understood. Our goal was to get insights into this mechanism by analyzing the survival kinetics of allogeneic and syngeneic cell transplants under different tissue conditions. Two MSC cell banks, stably and equally expressing the luciferase reporter construct, were developed for these studies and injected directly to the myocardium of Lewis rat recipients under syngeneic or allogeneic transplantation conditions. Cell survival was monitored by real-time fashion for up to 2 weeks, using optical imaging device (IVIS, Xenogen Corp.). We found that both syngeneic and allogeneic grafts reduced significantly in size during the first week of transplantation, either in the normal or in the late infarcted heart (5 days after MI) and allotransplants became always smaller than syngeneic grafts during this period. Low dose of cyclosporine A treatment had a benefit on both allo- and syngeneic graft sizes, suggesting that multiple mechanisms play a role in early graft reduction. The MSC characteristic factors IL-6, IL-8, MCP-1, and VEGF were well above the control level in the heart tissue at 4 days after cell injection, suggesting that the peak therapeutic effect of MSC can be expected during the first week of the administration. Although allogeneic cells induced immunoglobulin production, their biological effects (cell survival, factor productions) are very similar to the syngeneic transplants and therefore they could deliver the same therapeutic effect as the syngeneic cells. Finally, freshly infarcted tissue (30 min) supported better the survival of MSC than late postischemic tissue (5 days) but only "off the shelf" allogeneic cell transplants fits with this treatment strategy.

Topics: Animals; Cell Survival; Chemokine CCL2; Cyclosporine; Genes, Reporter; Imaging, Three-Dimensional; Injections; Interleukin-6; Interleukin-8; Luciferases, Firefly; Male; Mesenchymal Stem Cell Transplantation; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Lew; Time Factors; Transplantation, Homologous; Transplantation, Isogeneic; Vascular Endothelial Growth Factors

Effects of ischaemic preconditioning (IP) on the mobilisation and recruitment of haematopoietic (HSCs) and mesenchymal stem (MSC) cells were determined in porcine coronary occlusion/reperfusion. Thirty-three pigs underwent percutaneous occlusion of the left anterior descending coronary artery (LAD) for 90 minutes (min), followed by 120 min reperfusion. IP was performed in 16 of the 33 pigs by two cycles of 5 min balloon occlusion/reperfusion prior to the 90 min occlusion (group IP vs. group C). Peripheral blood and myocardial tissue concentration of bone marrow origin HSCs (characterised by coexpression of CD31+, CD90+, CD45+) and MSCs (characterised by coexpression of CD44+, CD90+, CD45-) were measured by flow cytometry in the early phase of IP. Plasma/serum levels of stem cell mobilisation factors (stromal cell-derived factor-1a [SDF-1a], vascular endothelial growth factor [VEGF], tumour necrosis factor a[TNF-a] and interleukin-8 [IL-8]) were measured. IP led to a significant increase in circulating HSCs as compared with the group C (475 +/- 233 vs. 281 +/- 264 /ml, p=0.032) in the early phase of IP. In contrast, a rapid and prolonged decrease in level of circulating MSCs was observed in group IP as compared with group C (19 +/- 12 vs. 32 +/- 17 /ml, p=0.015). The recruitment of HSCs and MSCs in infarct and border zone was significantly greater in IP group, indicating a faster homing of MSCs as compared with the rate of mobilisation. Rapid increase in VEGF, TNF-a and IL-8 levels was induced by IP, which, however, was not correlated with the levels of circulating SCs. In conclusion, IP resulted in differential mobilisation and recruitment of HSCs and MSCs in the early phase of cardioprotection.

Topics: Animals; Apoptosis; Chemokine CXCL12; Chemotaxis; Disease Models, Animal; Flow Cytometry; Hematopoietic Stem Cells; Hyaluronan Receptors; Interleukin-8; Ischemic Preconditioning, Myocardial; Leukocyte Common Antigens; Mesenchymal Stem Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Platelet Endothelial Cell Adhesion Molecule-1; Sus scrofa; Thy-1 Antigens; Time Factors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Ventricular Function, Left

Raised levels of inflammation markers are associated with worse prognosis in patients with coronary artery disease. It is generally believed, although it has never been proven, that inflammation markers are released from (un)stable plaques in coronary arteries. We investigated this issue by directly comparing levels of inflammation markers in coronary and systemic blood.. Patients with acute coronary syndrome (N = 11), stable angina pectoris (N = 10) and controls with noncoronary origin of chest pain (N = 9) were included in the study. Intracoronary blood samples were taken at the culprit lesion in the coronary artery in patients with acute coronary syndrome and from any coronary artery in the other two groups, together with systemic blood samples from the femoral vein and artery. Levels of high-sensitivity C reactive protein (hsCRP), interleukin 6, interleukin 8, interleukin 10, soluble receptor for interleukin 2 (tR IL-2) and myeloperoxidase were measured in all samples.. We found significantly elevated levels of hsCRP and interleukin 10 in patients with acute coronary syndrome compared with patients with stable angina and the control patients. Notably, we did not find any difference between intracoronary and systemic levels of any inflammatory marker in patients with acute coronary syndrome. Furthermore, no difference between intracoronary and systemic levels of markers was present in patients with stable angina or in the control group.. We observed that excess circulating inflammation markers, being characteristic of unstable coronary artery disease, are released from noncoronary sources. Thus, it may be speculated that systemic inflammation precedes local inflammation at the plaques, thereby transforming coronary disease from a stable to an unstable form.

Topics: Acute Coronary Syndrome; Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; C-Reactive Protein; Cardiac Catheterization; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Female; Humans; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Peroxidase; Prognosis; Receptors, Interleukin-2; Reference Values

Atherothrombotic disease in the coronary arteries leads to myocardial infarction (MI) through plaque rupture or erosion of the endothelium, the former mechanism predominating in men and the latter in women. Inflammation is a key feature of these processes, and the interplay between inflammation and matrix metalloproteinases (MMPs) in this context is not fully understood. In this study, we investigated the association between inflammatory markers and MMPs in men and women.. Blood samples were drawn 3 months after a first MI in 387 patients and 387 sex- and age-matched controls (82% men). C-reactive protein (CRP), interleukin-6 (IL-6), IL-8, -18, tumour necrosis factor-alpha (TNF-alpha), macrophage chemoattractant protein-1 (MCP-1), MMP-1, -3 and -9 were measured. Coronary angiography was performed in 243 of the patients, and they were classified into 0-, 1-, 2- or 3-vessel disease groups.. CRP, IL-6, -8, -18 and TNF-alpha were higher, and MMP-3 and -9 were lower, in patients than in controls. A greater proportion of women (49%) had 0-vessel disease than men (16%, p<0.0001). A gender specific pattern of associations between inflammatory markers and MMPs was found as IL-6 (r(S)=0.29, p<0.05), IL-18 (r(S)=0.34, p<0.01) and MCP-1 (r(S)=0.35, p<0.01) correlated with MMP-3 in female patients, whereas CRP (r(S)=0.23, p<0.0001), IL-6 (r(S)=0.13, p<0.05) and IL-8 (r(S)=-0.21, p<0.01) correlated with MMP-9 in male patients.. The present study demonstrates different patterns of association between inflammatory markers and MMPs in men and women, strengthening the hypothesis of gender specific differences in pathophysiological mechanisms of MI.

Topics: Biomarkers; C-Reactive Protein; Chemokine CCL2; Coronary Artery Disease; Female; Humans; Interleukin-18; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Myocardial Infarction; Sex Characteristics; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the influence of intracoronary injection of mononuclear BM cells (mBMCs) on inflammatory mediators in swine with acute myocardial infarction (AMI) in two groups. Group 1 received the therapy immediately after AMI, but group 2 received it after 3 weeks. The levels of cytokines and heart functions, respectively, were examined 3 weeks after cell therapy. The serum levels of TNF-alpha and IL-8 were significantly lower than in the control group: in contrast, IL-10 was significantly elevated in the cell recipients, especially in group 1. TNF-alpha correlated with IL-8 between groups. The ventricular functions were significantly improved. These results show that although the intracoronary injection of mBMCs induces a marked short-term inflammatory response in the acute stage, mBMCs may play an anti-inflammatory role topically and systematically and early cell therapy may be preferable.

Topics: Animals; Bone Marrow Transplantation; Cell Separation; Disease Models, Animal; Heart; Inflammation Mediators; Infusions, Parenteral; Interleukin-10; Interleukin-8; Myocardial Infarction; Regeneration; Swine; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Function, Left

The study was undertaken to search for additional diagnostic criteria allowing the depth of myocardial damage to be estimated in males aged 57.2 +/- 9.6 years. Few interrelated acute phase reaction indices, including the levels of interleukin-8 (IL-8), lactoferrin (LF), alpha2-macroglobulin (alpha2-MG), plasmin (PL) and alpha2-MG-PL circulating complexes, were studied in serum on days 1, 7, and 17 of the onset of the disease. In small-focal myocardial infarction, the levels of alpha2-MG and PL were decreased on day 1 and those of LF and IL-8 were increased on day 14. On the contrary, in large-focal myocardial infarction, the concentrations of IL-8 and LF rose just on day 1 while those of alpha2-MG and PL remained unchanged. The detected differences may be used as additional criteria in differential diagnosis, particularly when ECG was of no informative value. Further, the concurrent elevation of alpha2-MG, PL, and PL-alpha2MG concentrations in large-focal myocardial infarction is indicative of poor prognosis.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Aged; alpha-Macroglobulins; Electrocardiography; Humans; Interleukin-8; Lactoferrin; Male; Middle Aged; Myocardial Infarction

Variations in candidate genes participating in oxidative stress, inflammation, and their interactions are potentially associated with diseases of atherosclerotic origin. We investigated independent and joint associations of variations in cholesterol ester transfer protein (CETP), interleukin-8 (IL8), peroxisome proliferator activator receptor-alpha (PPARA), and Toll-like receptor 4 (TLR4) genes with incident nonfatal myocardial infarction (MI) or ischemic stroke. In a population-based case-control study, patients (848 with MI and 368 with ischemic stroke) and controls (2,682) were recruited from postmenopausal women and hypertensive men/women who were members of Group Health in western Washington State. Common tag single-nucleotide polymorphisms (SNPs; n=34) representing gene-wide variations were selected from gene sequencing data using pairwise linkage disequilibrium. Haplotypes were inferred using a modified expectation maximization algorithm. Multivariate logistic regression evaluated individual haplotype and SNP-disease associations in log-additive models. Global haplotype tests assessed overall gene-disease associations. Logic regression was used to evaluate gene-gene interactions. False discovery rates and permutation tests were used for multiple testing adjustment in evaluating independent associations and interactions, respectively. Overall, gene-wide variations in PPARA and TLR4 genes were associated with MI. The minor allele of the PPARA SNP, rs4253623, was associated with a higher risk of MI (odds ratio 1.25, 95% confidence interval 1.08 to 1.46), whereas the minor allele of the TLR4 SNP, rs1927911, was associated with a lower risk of MI (odds ratio 0.88, 95% confidence interval 0.77 to 0.99). No within-gene or gene-gene interaction was associated with MI or ischemic stroke risk. In conclusion, potential SNP-disease associations identified in the present study are novel and need further investigation.

Topics: Adult; Aged; Alleles; Brain Ischemia; Cholesterol Ester Transfer Proteins; Confidence Intervals; Dementia; DNA; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Incidence; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Polymorphism, Single Nucleotide; PPAR alpha; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; Toll-Like Receptor 4; Washington

We examined the effects of bone marrow-derived mononuclear cells (BMDMNCs) on preventing viable myocardium damage from myocardial infarction (MI) in a rat MI model.. Saline (group 1) or BMDMNCs (group 2) were implanted into the infarct area (IA) of 1-week-old anterior wall MI Sprague-Dawley (SD) rats. Twenty SD rats without MI served as the controls (group 3). The results demonstrated that in remote viable myocardium, the integrated area (microm2) of connexin43 spots was lower, whereas the number of apoptotic nuclei were higher in group 1 than in groups 2 and 3 on day 90 following BMDMNC implantation (all p<0.001). Additionally, the number of vessels and survival myocardium in the IA was lower in group 1 than in groups 2 and 3 (all p<0.005). Furthermore, the mRNA expressions of nitric oxide synthase, interleukin-8/Gro-alpha, interleukin-10 and matrix metalloproteinase-9 were higher in group 2 than in groups 1 and 3 in peri-IA (all p<0.05). On days 42 and 90, the left ventricular (LV) function was lower in group 1 than in groups 2 and 3 (p<0.001).. Autologous BMDMNC therapy improves LV function, and mitigates molecular and cellular perturbation following MI.

Topics: Animals; Apoptosis; Blotting, Western; Bone Marrow Transplantation; Cell Movement; Connexin 43; Coronary Vessels; Disease Models, Animal; Echocardiography; Flow Cytometry; Fluorescent Antibody Technique; Interleukin-10; Interleukin-8; Male; Matrix Metalloproteinase 9; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Survival; Transplantation, Autologous; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

To investigate whether patients with acute coronary syndrome (ACS) possessed high levels of platelet-monocyte aggregates (PMAs) and related circulating biomarkers.. 74 ACS patients, 58 stable angina pectoris (SAP) patients and 46 control patients without coronary artery disease were selected and their PMAs were measured by flow cytometry. Their plasma IL-6, IL-8, MCP-1, soluble CD40L and soluble P-selectin were also measured simultaneously by flow cytometry.. Patients with ACS exhibited higher level of PMAs compared with SAP patients and the control. Furthermore, the levels of IL-6, IL-8, MCP-1, soluble CD40L, soluble P-selectin and CRP were also significantly higher in ACS patients than in SAP patients and the control group. However, there were no significant difference in the levels of IL-8, sCD40L, sP-selectin and CRP between SAP patients and the control group. Correlation analysis showed that high levels of IL-6 and sP-selectin were significantly correlated with PMAs. Logistic analysis further demonstrated that the presence of elevated CRP, IL-6 and PMAs level each confers an increased risk of ACS.. Elevated levels of PMAs and related circulating biomarkers might indicate the unstable coronary syndrome in ACS patients, and the levels of PMAs, CRP and IL-6 could be used for monitoring and guiding the early intervention of ACS patients.

Topics: Aged; Analysis of Variance; Biomarkers; C-Reactive Protein; CD40 Ligand; Coronary Angiography; Cross-Sectional Studies; Female; Humans; Interleukin-6; Interleukin-8; Logistic Models; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activating Factor; Probability; Prognosis; Reference Values; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

Clinical experimental stem cell therapy after myocardial infarction appears feasible, but its use has preceded the understanding of the working mechanism. The ischemic recipient cardiac environment is determinative for the attraction and subsequent fate of stem cells. Here, we studied expression levels of genes that are anticipated to be essential for adequate stem cell-based cardiac repair at various time-points during the 1 month period following myocardial infarction (MI).. Gene expression in the hearts of mice that underwent MI by permanent or transient (30 min) ligation of the coronary artery was monitored using quantitative RT-PCR analysis of mRNA isolated from whole heart sections as well as from specific, laser micro-dissected, regions of sections. Protein expression was performed by immunohistochemical stainings and Western blot analysis.. Many inflammatory genes were highly expressed for at least 1 week after MI. The expression of pro-angiogenic genes such as bFGF, VEGF-A and VEGF-R2 changed only marginally post-MI. Markers used to test stem cell gene expression remained unchanged post-MI with the exception of G-CSF and GM-CSF, which are genes that are also known to enhance the inflammatory response. Analysis of micro-dissected regions revealed that SDF-1, SCF (both stem cell attractants) and VEGF-R2 (involved in angiogenesis) gene expression was slightly decreased especially in the infarcted region.. Genes that are generally considered to participate in stem cell-related processes and angiogenesis were not upregulated after MI, whereas the inflammatory gene expression dominated. Modulation of this imbalance might be of value for stem cell-mediated therapy.

Topics: Animals; Blotting, Western; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokines, CC; Cytokines; Gene Expression; Gene Expression Profiling; Granulocyte-Macrophage Colony-Stimulating Factor; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Ligation; Macrophage Inflammatory Proteins; Male; Mice; Mice, Inbred C57BL; Microdissection; Microscopy, Confocal; Models, Animal; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stem Cell Transplantation; Stem Cells; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Emerging research suggests that oxidant-driven transcription of key cytokine/chemokine networks within the myocardium plays a crucial role in producing ischemia-reperfusion (I/R) injury. We recently showed that activation of hypoxia-inducible factor-1 (HIF-1) attenuated cardiac I/R injury. Diminished injury in these prior studies was associated with significant reductions in circulating interleukin-8 levels, suggesting that HIF-1 may play an important role in modulating postischemic cardiac inflammation. In the current study, we examined the role of HIF-1 activation in modulating proinflammatory chemokine [macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant factor (KC), and lipopolysaccharide-induced CXC chemokine (LIX)] and adhesion molecule [intercellular adhesion molecule (ICAM)-1] expression in murine cardiomyocytes in vitro (HL-1 cell line) and in intact murine hearts following in vivo I/R injury. Our results show that HIF-1 activation induced both pharmacologically by the prolyl hydroxylase inhibitor dimethyloxallyl glycine and via small-interfering RNA (siRNA)-mediated prolyl-4 hydroxylase-2 (P4HA2) gene silencing significantly attenuated tumor necrosis factor-alpha-induced chemokine (KC and LIX) and ICAM-1 expression in cardiomyocytes. In vivo, postischemic hearts obtained from animals receiving the P4HA2 siRNA (HIF-1 activation) exhibited significantly reduced CXC chemokine (MIP-2, KC, and LIX), CC chemokine (monocyte chemoattractant protein-1), and ICAM-1 expression when compared with postischemic hearts from either saline I/R controls or postischemic hearts from animals receiving a nontargeting control siRNA (no HIF-1 activation). Diminished chemokine and adhesion molecule expression in HIF-1-activated postischemic hearts was associated with significantly reduced polymorphonuclear leukocyte infiltration and myocardial infarct size (>60% reduction P4HA2 siRNA I/R vs. saline I/R, P < 0.001, n = 6). In conclusion, these results demonstrate for the first time that HIF-1 activation following infusion of siRNA to P4HA2 plays a key role in modulating I/R-associated cardiac inflammatory responses.

Topics: Animals; Cell Line; Chemokine CXCL2; Chemokine CXCL5; Chemokines; Chemokines, CXC; Gene Silencing; Heme Oxygenase-1; Hypoxia; Hypoxia-Inducible Factor 1; Intercellular Adhesion Molecule-1; Interleukin-8; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type II; Procollagen-Proline Dioxygenase; RNA, Small Interfering

Recent findings indicate that atherosclerosis, a chronic inflammatory process, might start during childhood. Nevertheless, the expression of inflammation-related molecules of endothelial cell isolated from healthy neonates with a strong family history of myocardial infarction (SFHMI) has been rarely analyzed.. Human umbilical vein endothelial cells (HUVECs) from children with SFHMI were assessed for the expression of CD40 and CD40L, in the presence of TNF-alpha and oxLDL. The intracellular content of CD80, CXCL8 and tissue factor by HUVECs stimulated with a CD40 agonist monoclonal antibody as well as monocytes/lymphocyte adhesion to TNF-alpha-stimulated HUVECs was also evaluated.. The basal expression of CD40 and CD40L was higher in SFHMI-positive HUVECs in comparison to controls. TNF-alpha and oxLDL upregulated the expression of CD40 and CD40L in SFHMI versus control HUVECs (p<0.001). The intracellular expression of CXCL8, tissue factor and CD80 was also higher than in controls, and the adhesion of lymphocyte- and monocyte-like cells augmented upon TNF-alpha stimulation.. It is possible that the modifications observed in the SFHMI-positive HUVECs, all of them relevant to the atherosclerosis process, may lead to early inflammatory reactions, thus contributing to the premature initiation of atherosclerotic lesions in these children.

Topics: CD40 Antigens; CD40 Ligand; Cell Adhesion; Endothelial Cells; Humans; Infant, Newborn; Inflammation; Interleukin-8; Lipoproteins, LDL; Lymphocytes; Monocytes; Myocardial Infarction; Thromboplastin; Tumor Necrosis Factor-alpha; Umbilical Veins

Atherosclerotic plaques prone to cause thrombotic complications and plaque rupture account for the majority of fatal myocardial infarctions (MI), which may be complicated by ventricular fibrillation (VF). Matrix-degrading metalloproteinases (MMPs) and their inhibitors (TIMPs) are expressed in atherosclerotic lesions and contribute to plaque vulnerability. Interleukin-8 (IL-8) is one of the predominant chemokines interacting with MMPs and TIMPs and the coagulation system. The aim of the present study was to assess potential differences of levels of MMP-9, TIMP-1 and IL-8 in postmyocardial infarction patients with or without VF complicating acute MI.. Blood samples were taken from 45 patients with VF complicating acute MI and from 88 patients without VF. All samples were collected during a symptom-free interval remote from the acute ischemic event with a median of 556 days. The markers of interest were TIMP-1, MMP-9 and IL-8.. IL-8 and TIMP-1 levels were significantly higher among patients with VF than among patients without VF (p<0.001). In a logistic regression approach IL-8 was an independent indicator of patients prone to VF during MI (p=0.03). High levels of TIMP-1 (p=0.05), MMP-9 (p=0.03), the MMP-9/TIMP-1 ratio (p=0.049) and hypertension (p=0.02) were found to be indicators in patients with reinfarction or unstable angina pectoris during follow-up. Hypertension (p=0.02) and MMP-9 (p=0.03) were the only significant indicators characterizing patients undergoing coronary reinterventions, such as percutaneous coronary interventions and coronary bypass surgery.. Higher TIMP-1 and IL-8 levels are present in patients with VF complicating MI. High TIMP-levels may be related to the degree of fibrosis which is a substrate for electrical instability and may contribute to the occurrence of VF. Patients prone to develop VF during MI seem to have an increased proinflammatory condition compared to patients without VF.

Topics: Aged; Biomarkers; Humans; Hypertension; Interleukin-8; Matrix Metalloproteinase 9; Middle Aged; Myocardial Infarction; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Ventricular Fibrillation

Recent studies have shown that pro-inflammatory cytokines play a significant contributory role in the pathogenesis of the acute heart failure. The purpose of this study was to determine whether the serum IL-8 concentration in patients with acute myocardial infarction (AMI), who were undergoing percutaneous coronary intervention (PCI) was related to the subsequent presence or absence of heart failure.. The study included 50 patients who underwent successful PCI. During their subsequent stay in the coronary care unit, their maximum degree of heart failure was recorded. Patients were then divided into two groups: group A (Killip I) and group B (Killip class > I). The serum IL-8 concentration was measured during the 24 h following admission to the coronary care unit.. Serum levels of IL-8 in the group B were significantly higher than those of group A (P < 0.001). By multivariante analysis a higher level of IL-8 was a significant predictor of heart failure after PCI.. Serum levels of IL-8 after PCI appear to be a predictor for the development of heart failure in patients with AMI.

Topics: Angioplasty, Balloon, Coronary; Female; Humans; Interleukin-8; Male; Myocardial Infarction; Predictive Value of Tests; Prognosis

Release of progenitor cells is observed during inflammatory conditions and contributes to neovascularization. We, therefore, sought to investigate the relationship of circulating progenitor cells and interleukin (IL)-8 in acute myocardial infarction (AMI).. From patients with stable angina and AMI, serial venous blood samples were obtained. The number of circulating CD133+CD45- progenitor cells, endothelial progenitor cells (EPCs), and circulating endothelial P1H12+CD45- cells was analyzed by flow cytometry. After stenting in patients with AMI, an increase in plasma IL-8 and vascular endothelial growth factor (VEGF) concentrations was observed, which was only minimal in patients with stable angina. Only in patients with AMI, this was followed by an increase in circulating CD133+CD45- progenitor cells. In contrast, circulating endothelial P1H12+CD45- cells and E-selectin RNA expression in peripheral blood were only elevated early in AMI, indicating shedding of activated endothelial cells. Multivariable analysis revealed an association of IL-8 and circulating CD133+CD45- progenitor cells in AMI, in addition to statin therapy and risk factor profile.. In AMI, IL-8 is associated with circulating progenitor cells. In addition to the pro-angiogenic functions of IL-8 and VEGF, this mechanism may contribute to new vessel generation and, thereby, improve myocardial function.

Topics: AC133 Antigen; Angina Pectoris; Antigens, CD; Endothelial Cells; Flow Cytometry; Glycoproteins; Humans; Interleukin-8; Myocardial Infarction; Peptides; Stem Cells; Vascular Endothelial Growth Factor A

To clarify the role of myocardial apoptosis associated with the expression of proinflammatory cytokines in human myocardial infarction (MI), we have analyzed the expression of apoptosis positive for single-stranded DNA (ss-DNA) antibody, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-8 in 147 samples of infarcted myocardial tissue from 65 patients. ss-DNA-positive apoptotic nuclei were found mainly in cardiomyocytes in the border zones and granulation tissue cells in the infarct foci. The ss-DNA index (SI) of cardiomyocytes (average 0.13%) peaked at stage II (established myocardial necrosis), the value being significantly higher than at stages III (macrophage infiltration), IV (granulation formation), and V (scar formation) (P<0.05), whereas the SI of granulation tissue (average 0.08%) at stages III, IV, and V showed no significant differences between the three stages. These results suggest that cardiomyocyte apoptosis in the border zone is responsible for cellular loss in the acute stage of MI, whereas granulation tissue apoptosis may not be involved in the process of ventricular remodeling. TNF-alpha was expressed in cardiomyocytes in the border zones of infarct foci, but no significant positive correlation was found between SI and TNF-alpha index in cardiomyocytes (r=0.08, P = 0.37), suggesting that TNF-alpha does not serve as a direct trigger of cardiomyocyte apoptosis in vivo. The number of IL-8-positive cells peaked at stage II, and IL-8-myeloperoxidase-double-positive neutrophils were frequently detected, indicating that infiltrating neutrophils are the predominant source of IL-8 in the infarcted myocardium. These results suggest that, in human MI, TNF-alpha produced by cardiomyocytes does not play a critical role in their apoptosis, and that IL-8 produced by neutrophils is responsible for the subsequent accumulation and activation of neutrophils, thus increasing the degree of myocardial damage.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Cytokines; Female; Humans; Immunohistochemistry; Interleukin-10; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myocytes, Cardiac; Severity of Illness Index; Tumor Necrosis Factor-alpha

Topics: AC133 Antigen; Antigens, CD; Glycoproteins; Hematopoietic Stem Cell Mobilization; Interleukin-8; Myocardial Infarction; Peptides; Stem Cells

In an animal model of acute myocardial infarction (AMI), deletion of matrix metalloproteinase (MMP)-9 results in suppression of the development of cardiac rupture. The present study sought to clarify how myocardial MMP-9 activity is related to the pathophysiologies of AMI and cardiac rupture in humans.. Levels of interleukin-8 (IL-8), polymorphonuclear leukocyte (PMN) elastase, monocyte chemotactic protein-1 (MCP-1) and MMP activity were measured in the pericardial fluid obtained from 28 patients with angina pectoris (AP group) and 16 patients with AMI (AMI group) undergoing cardiac surgery. In the AMI group, 5 were complicated with ventricular septal perforation (VSP) and the remaining 11 were not (non-VSP). Levels of IL-8, PMN elastase, MMP-2 and MMP-9 activity were all higher in the AMI group than in the AP group. In the AMI group, all levels other than MMP-2 activity were further elevated in cases with VSP compared with those in the non-VSP group. There was no significant difference in MCP-1 among the groups. Markers of neutrophil activation in the infarcted cardiac tissue seem to be elevated in AMI. Highly elevated levels of MMP-9 activity, which may be derived from neutrophils, and PMN elastase may be related to the pathophysiology of VSP or cardiac rupture in AMI.

Topics: Acute Disease; Aged; Animals; Biomarkers; Chemokine CCL2; Disease Models, Animal; Female; Gene Deletion; Humans; Interleukin-8; Leukocyte Elastase; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Myocardial Infarction; Neutrophil Activation; Neutrophils; Pericardium; Ventricular Septal Rupture

In acute myocardial infarction (AMI), proinflammatory plasma C-reactive protein values are strongly associated with postinfarction morbidity and mortality. So far, the cause of these inflammatory changes is not well understood. Therefore, we sought to investigate the relationship between the activation of coagulation and subsequent systemic inflammatory changes in AMI.. Factor Xa (FXa) bound to tissue factor pathway inhibitor and prothrombin fragments F1+2 (F1+2) were used as a measure for activated coagulation. To assess systemic inflammatory changes, plasma interleukin (IL)-6 and IL-8 concentrations were analyzed by immunoassay. Blood samples were taken from 21 patients with AMI and 20 patients with stable angina pectoris. In AMI, tissue factor pathway inhibitor FXa but not F1+2 plasma levels were associated with circulating IL-8 (P=0.01). In vitro experiments revealed that FXa stimulated IL-8 and monocyte chemoattractant protein-1 release and RNA expression in endothelial cells and mononuclear leukocytes by activation of protease-activated receptor-1.. Our data suggest that coagulation FXa may contribute to proinflammatory changes in AMI by stimulation of IL-8 release. Therapeutic inhibition of the proinflammatory effects of FXa may improve the clinical course in AMI. This study investigates the relationship between the activation of coagulation and systemic inflammatory changes in acute myocardial infarction. Tissue factor pathway inhibitor factor Xa but not F1+2 plasma levels were associated with circulating interleukin-8. In vitro factor Xa stimulated interleukin-8 and monocyte chemoattractant protein-1 release and RNA expression by activation of protease-activated receptor 1 as an underlying mechanism.

Topics: Adult; Aged; Angina Pectoris; Cells, Cultured; Chemokine CCL2; Endothelial Cells; Endothelium, Vascular; Factor Xa; Factor Xa Inhibitors; Female; Hirudins; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Oligopeptides; Peptide Fragments; Prothrombin; Recombinant Proteins; Umbilical Veins

To test the hypothesis that heat shock protein (Hsp) 70 may be released into the circulation after acute myocardial infarction (AMI) by exploring the kinetics of Hsp70 release and the relations between Hsp70 and markers of inflammation and myocardial damage in AMI.. Blood samples from 24 patients were prospectively collected through to the first day after AMI. Hsp70, interleukin (IL) 6, IL-8, and IL-10 in serum were measured by enzyme linked immunosorbent assay (ELISA).. Median Hsp70 concentrations in AMI patients measured at arrival, six hours thereafter, and the following morning were 686, 868, and 607 pg/ml, respectively. These concentrations were all significantly different from those of the control patients with angina with a median serum Hsp70 concentration of 306 pg/ml. Peak Hsp70 correlated with creatine kinase (CK) MB (r = 0.62, p < 0.01) and cardiac troponin T (r = 0.58, p < 0.01). Furthermore, serum Hsp70 correlated with IL-6 and IL-8 at six hours (r = 0.60, p < 0.01 and r = 0.59, p < 0.01, respectively).. In this study, Hsp70 was rapidly released into the circulation after AMI. Circulating Hsp70 is suggested as a marker of myocardial damage. In addition, Hsp70 may have a role in the inflammatory response after AMI.

Topics: Biomarkers; Creatine Kinase; Female; HSP70 Heat-Shock Proteins; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Prospective Studies; Troponin

The CXC chemokine IL-8, which promotes adhesion, activation, and transmigration of polymorphonuclear neutrophils (PMN), has been associated with production of tissue injury in reperfused myocardium. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric peptide that is a key regulator of genes such as heme oxygenase (HO)-1 expressed under hypoxic conditions. We hypothesized that HO-1 plays an important role in regulating proinflammatory mediator production under conditions of ischemia-reperfusion. HIF-1 was activated in the human microvascular endothelial cell line (HMEC-1) with the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). DMOG significantly attenuated cytokine-induced IL-8 promoter activity and protein secretion and cytokine-induced PMN migration across human microvascular endothelial cell line HMEC-1 monolayers. In vivo studies in a rabbit model of myocardial ischemia-reperfusion showed that rabbits pretreated with a 20 mg/kg DMOG infusion (n = 6) 24 h before study exhibited a 21.58 +/- 1.76% infarct size compared with 35.25 +/- 2.06% in saline-treated ischemia-reperfusion animals (n = 6, change in reduction = 39%; P < 0.001). In DMOG-pretreated (20 mg/kg) animals, plasma IL-8 levels at 3 h after onset of reperfusion were 405 +/- 40 pg/ml vs. 790 +/- 40 pg/ml in saline-treated ischemia-reperfusion animals (P < 0.001). DMOG pretreatment reduced myocardial myeloperoxidase activity, expressed as number of PMN per gram of myocardium, to 1.43 +/- 0.59 vs. 4.86 +/- 1.1 (P = 0.012) in saline-treated ischemia-reperfused hearts. Both in vitro and in vivo DMOG-attenuated IL-8 production was associated with robust HO-1 expression. Thus our data show that HIF-1 activation induces substantial HO-1 expression that is associated with attenuated proinflammatory chemokine production by microvascular endothelium in vitro and in vivo.

Topics: Amino Acids, Dicarboxylic; Blood Vessels; Cells, Cultured; Chemokines; DNA-Binding Proteins; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-8; Membrane Proteins; Microcirculation; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophil Infiltration; Nuclear Proteins; Procollagen-Proline Dioxygenase; Promoter Regions, Genetic; Transcription Factors

Long-term risk of mortality in patients with myocardial infarction is thought to be linked with plasma concentrations of proinflammatory cytokines and CRP (markers of inflammation). The aim of our study was to analyze plasma levels of interleukin (IL) 1, interleukin 6, interleukin 8 and C-reactive protein (CRP) in patients with myocardial infarction. One hundred and seven (107) patients with myocardial infarction hospitalized at the Cardiac Care Unit of St. Elizabeth's Sisters' Hospital in Warsaw and a control group of 10 subjects were enrolled in our study. The samples of peripheral venous blood were withdrawn from the patients on 2nd and 7th of infarction and plasma levels of IL-1, IL-6, IL-8 and CRP were determined. The patients were followed-up for a year. The analysis of survivals and deaths caused by acute coronary syndrome allowed to determine the predictive value of IL-1, IL-6, IL-8 and CRP in myocardial infarction. Twenty-two (22) of the total 107 patients died of acute coronary syndrome during one-year follow-up. Plasma IL-6 and CRP levels were higher in non-survivors as compared to the levels of IL-6 and CRP in living subjects, whereas plasma levels of IL-1 and IL-8 were comparable in both groups. IL-6 and CRP proved to be of predictive value in patients with myocardial infarction during one-year follow-up. It has also been found that plasma IL-6 level correlates with plasma CRP concentration and that there is a positive correlation between the former and CK-MB levels. IL-6 and CRP levels were higher in patients with Q wave infarction in comparison with non-Q wave infarction. Plasma levels of IL-1 and IL-8 have not been found to be good predictors of death during 12-month follow-up.

Topics: Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Death, Sudden, Cardiac; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Poland; Predictive Value of Tests; Risk Factors; Survival Analysis; Time Factors

The aim of the present study was to investigate the prognostic value of plasma interleukin-8 (IL-8) for early complications after percutaneous coronary intervention (PCI). The pre- and postprocedural plasma levels of IL-8 and serum C-reactive protein (CRP) were examined by immunoassay, and the expression of CD11b/CD18 on neutrophils was assessed by flow cytometry. Early complications (abrupt occlusion, threatened abrupt occlusion, early recurrence of ischemia, myocardial infarction, cardiac sudden death, and target vessel revascularization) occurred intra-procedure and 30 days after PCI and were observed in 121 consecutive patients with coronary heart disease. Sixteen patients with early complications had high preprocedural levels and high postprocedural differentials of IL-8, CRP, and CD11b/CD18 compared to those without complications (all P < 0.05). The occurrence of complications showed a significant increase in the patients according to the tertiles of IL-8, CRP, and CD11b/CD18. Preprocedural levels of IL-8 (RR = 5.864, CI = 1.658-20.734, P = 0.006) and diabetes (RR = 1.587, CI = 1.246-2.132, P = 0.038) were independent predictors of early complications. There were significant correlations in the postprocedural differential between IL-8 and CD11b/CD18 (r = 0.776, P = 0.002) in patients with complications. The results reveal that the early complications after PCI contribute to preprocedural inflammatory responses. Normal levels of IL-8 may be powerful negative predictors of early complications in patients with CHD following PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; C-Reactive Protein; CD11b Antigen; CD18 Antigens; Coronary Disease; Coronary Restenosis; Female; Forecasting; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia

To study several markers of myocardial injury in relation to aortic cross-clamping and cardiopulmonary bypass (CPB) after coronary artery bypass graft (CABG) surgery.. Prospective observational study.. University hospital.. Thirty adult patients who underwent elective CABG surgery with aortic cross-clamping and CPB.. Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), troponin-T (TnT), myosin light chain I (MLCI), and MB isoenzyme of creatine kinase (CK-MB), as markers of myocardial injury, were measured after induction of anesthesia for baseline values, then again at the end of surgery and on postoperative days 1, 3, and 5. IL-6, IL-8, and CK-MB levels were significantly elevated in the early postoperative stage. TnT significantly increased from the end of surgery to postoperative day 5. MLCI increased also but later than TnT. Aortic cross-clamping time correlated positively with peak TnT (r = 0.51, p < 0.05), TnT level on postoperative day 1 (r = 0.69, p < 0.01), and MLCI level on postoperative day 5 (r = 0.45, p < 0.05). CPB time was correlated only with peak TnT (r = 0.47, p < 0.05).. The increase in TnT level is strongly related to aortic cross-clamping.

Topics: Adult; Aged; Aorta; Biomarkers; Cardiopulmonary Bypass; Constriction; Coronary Artery Bypass; Creatine Kinase; Creatine Kinase, MB Form; Humans; Interleukin-6; Interleukin-8; Isoenzymes; Middle Aged; Myocardial Infarction; Myosin Light Chains; Prospective Studies; ROC Curve; Sensitivity and Specificity; Treatment Outcome; Troponin T

The aim of this study was to determine the effect of FR183998 (5-(2,5-dichlorothiophen-3-yl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoylguanidine dihydrochloride), an Na+/H+ exchange inhibitor, on myocardial interleukin-8 (IL-8) content and myocardial infarct size in a rat ischaemia and reperfusion model. Rats underwent 30 min of ischaemia followed by 1 to 24 h of reperfusion. IL-8 content rapidly increased in reperfused rat hearts. The maximum increase in IL-8 was obtained after 3 h of reperfusion. Intravenous administration of FR183998 at 1 and 3.2 mg kg(-1), 5 min before ischaemia, significantly reduced the IL-8 level after 3 h of reperfusion (122 +/- 16 and 149 +/- 23 pg mg(-1) protein, respectively), compared with that of the saline-treated group (258 +/- 27 pg mg(-1) protein). Myeloperoxidase activity after 3 h of reperfusion was also reduced by FR183998 (from 0.83+0.19 unit g(-1) weight of tissue in the saline-treated group to 0.36 +/- 0.09 and 0.33 +/- 0.06 unit g(-1) weight of tissue in FR183998-treated groups at 1.0 and 3.2 mg kg(-1), respectively). Myocardial infarction induced by 30 min of ischaemia and 24 h of reperfusion was significantly suppressed by the same doses of FR183998 (14.0 +/- 1.5,13.5 +/- 1.9% at 1.0 and 3.2 mg kg(-1)), compared with 22.2+2.7% in the saline-treated group. These results suggestthat IL-8 may contribute to the generation of myocardial infarction in an ischaemia and reperfusion model in rats.

Topics: Animals; Depression, Chemical; Disease Models, Animal; Guanidines; Interleukin-8; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Peroxidase; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Thiophenes

To quantify interleukin-8 (IL-8), interleukin-2 (IL-2) and soluble receptor of IL-2 (sIL-2r) in blood serum of patients with various forms of ischemic heart disease (IHD).. Levels of IL-8, IL-2 and sIL-2r were measured with enzyme immunoassay (EIA) in the serum of 75 patients with IHD: angina of effort (group 1), progressive angina (group 2) and acute myocardial infarction (group 3). The EIAs were performed at admission and 2 weeks later.. Baseline levels of IL-2 in group 1 and 2 patients were close (9.1 +/- 1.6 and 10.1 +/- 3.8 pg/ml) being significantly lower in group 3 (0.81 +/- 0.57 pg/ml, p < 0.01). 14 days of therapy did not change the values noticeably. IL-8 level was the highest in group 1 (94.2 +/- 27.6, 20.03 +/- 7.4, 22.47 +/- 4.8 pg/ml, respectively). sIL-2r in the three groups did not vary greatly (73.95 +/- 12.23, 89.46 +/- 18.17, 89.2 +/- 14.17 pg/ml, respectively). SIL-2r levels rose in 2 weeks in group 3 (to 147.67 +/- 18.17 pg/ml).. It is confirmed that IL-2, IL-8 and sIL-2r take part in pathogenesis of IHD. IL-2 and IL-8 levels are persistently high in anginal patients while in patients with acute myocardial infarction they are low. Low concentrations of IL-2 in the latter may be attributed to high levels of its soluble receptor.

Topics: Aged; Angina Pectoris; Female; Humans; Interleukin-2; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Receptors, Interleukin-2; Solubility

The novel glycolipid RC-552 shares common structural features with the natural products lipid A and the previously described cardioprotectant monophosphoryl lipid A. RC-552 administered to dogs as a bolus intravenous dose (35-70 microg/kg) either 24 h or 10 min prior to 60 min of regional myocardial ischemia and 3 h of reperfusion significantly (P<0.05 v control) reduced infarct size (IS) as assessed by triphenyltetrazolium staining from 27.0+/-2.3% of the area-at-risk (AAR) to 13.3+/-2.2% and 15.0+/-3.0%, respectively. Administration of the non-specific inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (30 mg/kg, subcutaneously) 1 h prior to ischemia blocked the ability of RC-552 (35 microg/kg, 24 h pretreatment) to reduce infarct size. Intravenous pretreatment with RC-552 (35 microg/kg) either 24 h or 10 min prior to five 5 min repetitive cycles of ischemia and reperfusion significantly improved regional myocardial segment shortening (percentage of control) at all time points during 2 h of reperfusion in dogs. These effects of RC-552 in either cardiac injury model occurred independent of differences in AAR, transmural blood flow during ischemia or hemodynamics throughout the experiment. In contrast with monophosphoryl lipid A (MLA), which has also been reported to be cardioprotective at similar doses in dogs, RC-552 was approximately 100 times less prone to cause fever in the USP rabbit pyrogen test. Likewise, RC-552 did not induce secretion of the proinflammatory cytokines TNF, IL-6 or IL-8 from THP-1 cells or alter the expression of adhesion molecules on human neutrophils at concentrations up to 10 microg/ml. MLA was active in these systems at concentrations in the range 0.1-1.0 microg/ml. In conclusion, RC-552 reduces myocardial infarct size and stunning in dogs in the absence of residual immunomodulatory activity.

Topics: Animals; Antibodies, Monoclonal; Blood Flow Velocity; Dogs; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Glycolipids; Hemodynamics; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; L-Selectin; Leukocytes, Mononuclear; Lipid A; Lipopolysaccharides; Male; Myocardial Infarction; Myocardial Stunning; Neutrophils; Rabbits; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

The ability of the heparin derivative, N-acetylheparin (NHEP) to protect the heart from regional ischemia/reperfusion injury was examined in vivo. NHEP (2 mg/kg i.v.) or vehicle was administered 2 h before occlusion of the left circumflex coronary (LCX) artery. Open-chest, anesthetized rabbits were subjected to 30 min of regional myocardial ischemia followed by 5 h of reperfusion. Myocardial myeloperoxidase activity, membrane attack complex (MAC) deposition and IL-8 generation were assessed in supernatant samples from the area at risk. Infarct size in rabbits pretreated with NHEP (32.5 +/- 3.8%, n = 10) decreased by 41% compared to infarct size in rabbits that received vehicle (55.3 +/- 4.9%, n = 10; p = 0.002). Accumulation of neutrophils within the ischemic region, as assessed by myeloperoxidase activity, declined by 45% (p < 0.05) in AAR from NHEP-treated animals compared to AAR from vehicle-treated animals. Levels of MAC and IL-8 obtained from AAR were less in NHEP-pretreated animals compared to controls. These results suggest that NHEP may protect the myocardium by inhibiting complement activation and subsequent neutrophil infiltration.

Topics: Animals; Calcium; Complement Membrane Attack Complex; Hemodynamics; Heparin; Interleukin-8; Leukocyte Count; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophil Activation; Peroxidase; Rabbits

To validate the hypothesis that artery sites occluded with thrombi release pro-inflammatory cytokines, we measured concentrations of interleukin (IL)-6 and IL-8 in infarct-related coronary artery thrombi and atherosclerotic plaque specimens obtained with a transluminal extraction catheter (TEC) from cases of acute myocardial infarction (MI). Fifteen patients (group I) were enrolled in the study and four sets of samples were obtained (taken from the right atrium both before and after angioplasty, from infarct-related coronary artery thrombi and atherosclerotic plaque aspirated with a TEC and from the thoracic aorta aspirated with a TEC). Ten patients undergoing elective TEC served as controls (group II). IL-6 and IL-8 were measured in all patients by means of an enzyme-linked immunosorbent assay. Both IL-6 and IL-8 levels of infarct-related coronary artery samples in group I were significantly higher than in group II (mean +/- SEM, 15.3+/-4.5 vs. 3.8+/-1.2 pg/ml; P<0.01 and 44.0+/-2.4 vs. 15.6+/-0.6 pg/ml; P<0.01, respectively). The results suggest that pro-inflammatory cytokines originate from occluded coronary arteries in acute MI.

Topics: Angioplasty, Balloon, Coronary; Atherectomy, Coronary; Biomarkers; Cardiac Catheterization; Coronary Angiography; Coronary Artery Disease; Coronary Thrombosis; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Suction

Neutrophil accumulation and activation of the complement system with subsequent deposition of the cytolytic membrane attack complex (MAC) have been implicated in the pathogenesis of myocardial ischemia/reperfusion injury. The MAC, when present in high concentrations, promotes target cell lysis. However, relatively little is known about the potential modulatory role of sublytic concentrations of the MAC on nucleated cell function in vivo. In vitro studies demonstrated that the MAC regulates cell function by promoting the expression of pro-inflammatory mediators, including adhesion molecules and pro-inflammatory cytokines. We examined, using C6-deficient and C6-sufficient rabbits, the regulatory role of the MAC in mediating IL-8 expression and subsequent neutrophil recruitment in the setting of myocardial ischemia/reperfusion injury. C6-deficient and C6-sufficient rabbits were subjected to 30 min of regional myocardial ischemia followed by a period of reperfusion. In addition to a significant reduction in myocardial infarct size in C6-deficient animals, analysis of myocardial tissue demonstrated a decrease in neutrophil influx into the infarcted region. The reduction in neutrophil influx correlated with the decreased expression of the neutrophil chemotactic cytokine IL-8, as determined by ELISA and immunohistochemical analysis. The results derived from this study provide evidence that the MAC has an important function in mediating the recruitment of neutrophils to the reperfused myocardium through the local induction of IL-8.

Topics: Animals; Cell Movement; Complement C6; Complement Membrane Attack Complex; Interleukin-8; Leukocyte Count; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Rabbits

Both the hemostatic and inflammatory system are thought to play a role in the pathogenesis of acute coronary syndromes. However, their respective contribution and interrelationship remain unclear, therefore, we studied the relationship between activation of the coagulation system and proinflammatory activity in ischemic coronary syndromes.. Thrombin-antithrombin III (TAT), prothrombin fragments F1 + 2, fibrinopeptide A (FPA), interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured in 50 patients with unstable angina (UA), 60 patients with acute myocardial infarction (AMI) and in 50 patients with stable angina (SA).. FPA levels were significantly higher in patients with UA and AMI than in patients with SA (p = 0.0015 and p < 0.0001), and were higher in patients with AMI than UA (p = 0.0013). Plasma IL-6 concentrations were significantly higher in patients with UA and AMI than in patients with SA (p = 0.0020 and p < 0.001), and again were higher in AMI than UA (p = 0.001). Interestingly, FPA or IL-6 elevations on admission were found in different patients. In contrast, TAT, F1 + 2 and IL-8 levels were not different between the three groups.. IL-6 and FPA were shown to be independent predictive markers with equal discriminative power to distinguish stable (SA) from unstable (UA + AMI) patients. Moreover, hemostatic and inflammatory markers can be elevated independently in the acute phase of ischemic coronary syndromes.

Topics: Angina, Unstable; Antithrombin III; Biomarkers; Female; Fibrinopeptide A; Humans; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Peptide Fragments; Prothrombin; Statistics, Nonparametric; Thrombin

Superoxide release in neutrophils and sera levels of interleukin 8 (IL-8) were determined in 15 patients with complicated acute myocardial infarction (MI) and 15 patients with uncomplicated MI. All patients showed increased superoxide release in unstimulated and stimulated neutrophils compared with healthy control subjects, indicating priming of these cells. Superoxide release of unstimulated or stimulated neutrophils was found to be significantly higher in patients with complicated MI than in patients with uncomplicated MI. Thrombolytic therapy did not affect the rates of superoxide release. The neutrophil chemoattractant/activator IL-8 was detected in the sera of all patients, with significantly higher levels in those with complicated MI. The highest levels of IL-8 were detected at admission to the Coronary Care Unit and significantly decreased thereafter, suggesting its contribution to neutrophil-mediated tissue injury. The high levels of IL-8 may be one of the major contributors to the priming of neutrophils in these patients.

Topics: Aged; Aged, 80 and over; Female; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Ozone; Streptokinase; Superoxides; Tetradecanoylphorbol Acetate

This study sought to investigate whether cytokine expression in leukocytes may be induced by plasma from the reperfused heart of patients with an acute myocardial infarction (MI).. Reperfusion in acute MI is associated with deleterious local and systemic inflammatory responses that are regulated by cytokines. Induction of cytokine expression in resident leukocytes could contribute to inflammatory responses of the ischemic and reperfused heart.. Blood samples of 10 patients with an acute MI were obtained simultaneously from the coronary sinus and the aorta before and 5 min after recanalization of the coronary occlusion. Ten patients with elective percutaneous transluminal coronary angioplasty served as a control group. We incubated leukocytes from healthy donors with plasma samples and analyzed mRNA expression of interleukin (IL)-1 beta, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) by Northern blot analysis.. In patients with an acute MI, plasma obtained from the coronary sinus after recanalization increased the mRNA expression of IL-1 beta and IL-8 compared with that of plasma before recanalization (median [quartiles] difference before vs. after recanalization: 34.5 [4, 137], p = 0.017, for IL-1 beta; 18.5 [4, 35], p = 0.032, for IL-8) and simultaneously obtained aortic plasma (median [quartiles] coronary sinus-aortic differences after recanalization: 45.5 [-3, 115], p = 0.021, for IL-1 beta; 16 [4, 52], p = 0.005, for IL-8). No induction of IL-6 and TNF-alpha expression could be observed. No changes found in the study patients were detectable in the control group.. Plasma from the ischemic and reperfused heart stimulates the expression of IL-1 beta and IL-8 in leukocytes. Therefore, leukocyte-derived cytokines may contribute to the regulation of cardiac inflammatory responses in patients with an acute MI.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Northern; Confounding Factors, Epidemiologic; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Leukocytes; Male; Middle Aged; Myocardial Infarction; RNA Processing, Post-Transcriptional; RNA, Messenger; Tumor Necrosis Factor-alpha

The present study provides evidence that interleukin (IL)-6 and IL-8 are the main endogenous mediators of acute phase response in patients with myocardial infarction. This conclusion was supported by the observation of a strict relation between IL-6 elevation and the extent of myocardial tissue damage and rise in body temperature.

Topics: Acute-Phase Reaction; Adult; Aged; Aged, 80 and over; Female; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Thrombolytic Therapy

To determine whether rapid clearance of interleukin 8 (IL-8) from plasma through binding to the erythrocyte chemokine receptor may be responsible for failure to detect IL-8 consistently after acute myocardial infarction.. Plasma concentrations of IL-8 were measured at frequent intervals in 43 consecutive patients. In 21 of these, erythrocyte bound IL-8 concentrations were also measured. The influence of infarct size, type of treatment, and the presence of early successful reperfusion on IL-8 release was assessed.. Peak IL-8 concentrations in plasma were raised in 31 of the 43 patients (68%). Median plasma IL-8 concentrations were 16.0 pg/ml (range 2.4 to 225.0 pg/ml) six hours after the onset of chest pain. Twelve hours after the onset of symptoms, plasma IL-8 concentrations had already returned to normal in 27 patients. In contrast, in 18 of 21 patients (86%), erythrocyte bound IL-8 concentrations were raised at between 6 and 30 hours, with a median peak value of 59.8 pg/ml (range 19 to 148 pg/ml). No correlation between peak creatine kinase MB and peak IL-8 (plasma or erythrocyte bound) was observed. There was a significant difference in peak plasma IL-8 concentrations between patients who underwent direct PTCA (19.4 pg/ml) and those who received conservative treatment (9.9 pg/ml; p = 0.0206), but no correlation with the presence of early successful reperfusion.. IL-8 is released in plasma after acute myocardial infarction and subsequently binds to red blood cells, resulting in only a transient rise of plasma IL-8 and a more prolonged increase of erythrocyte bound IL-8.

Topics: Biomarkers; Creatine Kinase; Erythrocytes; Female; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Protein Binding; Receptors, Interleukin; Statistics, Nonparametric

Three cases of patients with cardiac myxoma who had attacks of acute myocardial infarction are presented. Cineangiographic study showed normal coronary arteries. Immunohistochemical and serologic examination revealed that both interleukin-6 and interleukin-8 were secreted in cardiac myxoma. The authors discuss the relation between these cytokines and myocardial infarction with normal coronary arteries.

Topics: Adult; Aged; Cineangiography; Coronary Thrombosis; Coronary Vessels; Heart Neoplasms; Humans; Immunohistochemistry; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myxoma

Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8, and anti unflammatory cytokines, such as interleukin-10, may play an important role in patient responses to cardiopulmonary bypass. We sought to define whether the myocardium and the lungs serve as important sources of these cytokines under conditions of cardiopulmonary bypass. Ten patients (age 64 +/- 3 years, mean +/- standard error of the mean) undergoing elective coronary artery bypass grafting were monitored with an arterial catheter, a coronary sinus catheter, and pulmonary artery catheter. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured simultaneously in peripheral arterial blood, coronary sinus blood, and mixed venous blood before heparin administration, 1 minute before aortic crossclamping, 5 minutes after aortic declamping, and at 0.5, 1, 1.5 and 2 hours after aortic declamping. The durations of cardiopulmonary bypass and aortic crossclamping were 114 +/- 9 and 64 +/- 5 minutes, respectively. Levels of tumor necrosis factor-alpha and interleukin-6 were significantly higher in coronary sinus blood than in arterial blood after aortic declamping. Tumor necrosis factor-alpha and interleukin-6 levels were also higher in mixed venous blood than in arterial blood within 1 hour after declamping. There were no significant differences among the three sampling sites with respect to interleukin-8 and interleukin-10 levels. In one patient who had postoperative myocardial infarction, however, interleukin-8 levels were three times as high as in coronary sinus blood than in arterial blood. These data indicate that the myocardium is a major source of tumor necrosis factor-alpha and interleukin-6 in patients undergoing cardiopulmonary bypass. The lungs may consume rather than release proinflammatory cytokines in the early phase of reperfusion. The source under these conditions of the antünflammatory cytokine interleukin-10 remains to be determined.

Topics: Aged; Anticoagulants; Arteries; Cardiac Catheterization; Cardiopulmonary Bypass; Catheterization, Peripheral; Catheterization, Swan-Ganz; Coronary Artery Bypass; Coronary Vessels; Elective Surgical Procedures; Female; Heparin; Humans; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Interleukins; Lung; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Postoperative Complications; Tumor Necrosis Factor-alpha; Veins

Cytokines play a pathogenetic role in a variety of infective and inflammatory diseases. In the present study, we had two objectives: (a) to define the kinetics of tumor necrosis factor (TNF) in plasma after acute myocardial infarction (AMI) in patients treated with early thrombolysis, and (b) to measure other cytokines, interleukin-1 (IL-1) and TNF receptor antagonists, in plasma. TNF-alpha, but not IL-1 beta or IL-8, was present in plasma of 6 of 7 patients with severe AMI (Killip class 3 or 4). No TNF (< 50 pg/ml) was detected in a group of 11 patients with uncomplicated myocardial infarction (Killip class 1) or in control patients without AMI. Soluble TNF receptor type I and IL-1 receptor antagonist (IL-1Ra) were also significantly increased in the group with severe AMI compared with those with uncomplicated AMI. Circulating TNF is increased only in AMI complicated by heart failure at hospital admission. This finding may have diagnostic and therapeutic relevance.

Topics: Aged; Aged, 80 and over; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Sialoglycoproteins; Streptokinase; Tissue Plasminogen Activator; Tumor Necrosis Factor-alpha

Interventions that inhibit neutrophil infiltration into myocardial tissue after ischaemia and reperfusion are reported to reduce the size of the infarct. We examined whether administration of trimetazidine, which is reported to reduce myocardial infarct size, affects this process. [111In]Neutrophils and [125I]albumin were administered intravenously (i.v.) to anaesthetized rabbits to allow measurement of cell accumulation and changes in microvascular plasma protein leakage. A 30-min period of coronary artery occlusion followed by 3-h reperfusion was used, and the area at risk (AR) myocardium was defined by dye exclusion. Twelve rabbits received 2.5 mg/kg trimetazidine i.v., 10 min before coronary artery occlusion; the 13 controls received saline. In the control group, the number of [111In]neutrophils/g tissue in the AR (30,591 +/- 6,725) was significantly greater than in the normal zone (NZ, 11,519 +/- 1,605, p < 0.01). In the trimetazidine-treated group, the number of [111In]neutrophils in the AR was significantly lower than in the control group (12,717 +/- 1,958 [111In]neutrophils/g, p < 0.01). There was no significant difference in neutrophil content of the NZ (7,832 +/- 1,117 [111In]neutrophils/g) in treated animals as compared with that in control. Accumulation of [111In]neutrophils in response to intradermal administration of leukotriene B4, interleukin-8 (IL-8), or zymosan-activated plasma was not affected by the drug. The effect of trimetazidine on neutrophil accumulation into post-ischaemic reperfused myocardium therefore does not appear to result from a direct action on the neutrophil.

Topics: Animals; Blood Pressure; Capillary Permeability; Disease Models, Animal; Heart Rate; Interleukin-8; Leukotriene B4; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; Rabbits; Trimetazidine; Zymosan

To determine whether interleukin-8 (IL-8, a potent activator of neutrophils) is involved in tissue injury during ischaemia and reperfusion in patients with acute myocardial infarction.. Teaching hospital.. Five consecutive patients with acute Q-wave myocardial infarction, two patients with stable angina who underwent elective percutaneous transluminal coronary angioplasty, and 10 normal controls.. Serum IL-8 concentration measured by enzyme linked immunosorbent assay (ELISA) over time (every four, eight or 12 hours for 36-72 hours).. All five patients with acute myocardial infarction had a transient but significant rise in serum IL-8 concentration (13-1100 ng/l) within 22 hours after the onset of symptoms, whereas IL-8 was not detected in any of the samples from patients with angina pectoris or normal controls. One patient who died of pump failure and two patients who had mild congestive heart failure showed the highest values (1100, 920, and 190 ng/l respectively).. Serum IL-8 concentration showed a transient rise during the very early phase of acute myocardial infarction. In combination with several recent lines of evidence indicating the importance of injurious activities of neutrophils as a cause of tissue damage in acute myocardial infarction and the potent stimulation of neutrophils by IL-8, these results strongly suggest that IL-8 is important in the development of myocardial injury in acute myocardial infarction.

Topics: Adult; Aged; Creatine Kinase; Female; Humans; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Myocardium; Time Factors