Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors

OBJECTIVE:. To examine the hypothesis that patients with systemic lupus erythematosus (SLE) have increased concentrations of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) and that these cytokines are associated with coronary risk factors and atherosclerosis. METHODS: Plasma IL-6, MCP-1, and serum IL-8 (pg/ml) concentrations were measured in 74 patients with SLE and in 85 controls. Clinical characteristics, homocysteine, lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and coronary artery calcification as detected by electron beam computed tomography were measured. RESULTS: IL-6 (13.2 +/- 13.8 pg/ml vs 6.7 +/- 3.2 pg/ml, p < 0.001) and MCP-1 (264.2 +/- 581.8 pg/ml vs 131.0 +/- 63.7 pg/ml, p < 0.001) concentrations were higher in patients with lupus than in controls. IL-8 concentrations did not differ between patients and controls (p = 0.86). In patients, IL-6 concentrations were correlated with CRP (p < 0.001), ESR (p < 0.001), SLE disease activity index (SLEDAI, p = 0.003), and body mass index (BMI, p = 0.003). IL-6 concentrations were inversely correlated with HDL cholesterol (p = 0.01). MCP-1 concentrations were correlated with SLEDAI (p = 0.01), ESR (p = 0.04), and triglycerides (p = 0.03). After controlling for age, sex, disease activity, SLICC damage index, smoking status, and systolic blood pressure, IL-6 was associated with coronary calcification (odds ratio, OR = 1.07, p = 0.035). Similar models found no association between MCP-1 or IL-8 with coronary artery calcification. CONCLUSION: Patients with SLE have increased concentrations of IL-6 and MCP-1. These cytokines are associated with increased inflammation, BMI, and adverse lipid profiles. IL-6 is associated with burden of atherosclerosis in SLE.     

Increased serum concentrations of interleukin-1 beta in patients with coronary artery disease.

OBJECTIVE: To assess serum interleukin-1 beta (IL-1 beta) concentrations in patients with ischaemic heart disease, to characterise subgroups of patients with raised IL-1 beta concentrations, and to examine whether serum IL-1 beta concentrations correlate with non-specific indices of inflammation. DESIGN: Survey study of patients with ischaemic heart disease. SETTING: Cardiac catheterisation laboratory of a tertiary medical centre. PATIENTS: Consecutive patients with angina pectoris and patients recovering from uncomplicated acute myocardial infarction and undergoing elective coronary angiography. RESULTS: Mean(SD) serum IL-1 beta concentrations were higher (P < 0.001) in patients with angina and < 50% coronary artery stenosis (n = 11; 18.8(19.9) pg/ml), patients with angina > or = 50% stenosis (n = 23; 10.2(11.4) pg/ml), and patients 8(0.8) days post-infarction (n = 13; 4.4(5.8) pg/ml) than in 15 healthy, age-matched controls (0.3(0.5) pg/ml). Serum IL-1 beta concentrations did not correlate with total blood leucocyte counts (r = -0.07, P = NS), blood lymphocyte counts (r = -0.24, P = NS), and blood monocyte counts (r = -0.29, P = NS), or with fibrinogen (r = -0.16, P = NS) and C-reactive protein concentrations (9(10.5) mg/dl v 14.1(19) mg/dl for patients with undetectable and detectable concentrations, respectively, P = NS). CONCLUSION: Serum IL-1 beta concentrations are raised in patients with ischaemic heart disease, in particular in those with minimal coronary artery disease and angina. The precise role of IL-1 beta in coronary artery disease remains to be determined.     

Increased coronary arterial release of interleukin-1 receptor antagonist and soluble CD40 ligand indicative of inflammation associated with culprit coronary plaques

Blood taken from the coronary artery ostium reflects biochemical changes indicative of thrombosis in the culprit vessel. We sought to determine whether inflammation is manifested by increased concentrations of selected markers in ostial blood sampled from a culprit coronary artery proximal to an atherosclerotic plaque. The concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-1 receptor antagonist, and soluble CD40 ligand (sCD40L) were measured in blood drawn from 75 patients before percutaneous coronary intervention from the femoral artery and from a guide catheter after engagement of the culprit coronary artery. Results were compared using Student's t tests. An acute coronary syndrome was present in 88% of patients. The concentrations of CRP and IL-6 were similar in coronary ostial and peripheral blood. Concentrations of IL-1 receptor antagonist were consistently greater in coronary arterial compared with peripheral arterial blood (peripheral 545 +/- 378 vs coronary 595 +/- 388 pg/ml, p = 0.003). Concentrations of sCD40L were also greater in the coronary compared with peripheral blood (peripheral 0.80 +/- 0.46 vs coronary 2.12 +/- 2.77 ng/ml, p <0.0001). The increased concentration of IL-1 receptor antagonist and sCD40L in blood drawn from the culprit coronary artery compared with that taken from the peripheral artery suggests that these cytokines contribute directly to inflammation in response to coronary intervention and may potentiate a systemic inflammatory state.     

Impact of percutaneous coronary intervention on the levels of interleukin-6 and C-reactive protein in the coronary circulation of subjects with coronary artery disease

Many clinical studies have evaluated the inflammatory response (mainly interleukin [IL]-6 and C-reactive protein [CRP]) after percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD). The aim of this study was to verify the source of possible elevation of IL-6 and CRP after PCI using coronary sinus sampling. We studied 87 subjects who underwent coronary angiography for diagnostic, therapeutic, or follow-up purposes. Blood samples were taken by the PCI team during the catheterization study from the coronary sinus. We measured coronary IL-6 levels by sandwich enzyme-linked immunosorbent assay, and high-sensitivity CRP levels were measured by latex immunonephelometry. The subjects were then classified according to their coronary angiographic findings into non-CAD (no evidence of significant organic CAD), mild CAD (1 vessel narrowed), and severe CAD (>or=2 vessels narrowed) groups. PCI (including stent deployment) was performed in 16 patients with CAD. The mean coronary IL-6 value was higher in the severe than in the mild CAD group (3.67 +/- 2.48 vs 2.3 +/- 1.15 pg/ml, p = 0.027). The mean coronary IL-6 value was higher in the subjects who underwent PCI than in those who did not (2.9 +/- 1.23 vs 1.87 +/- 0.9 pg/ml, p = 0.037), and the same was found regarding CRP (1.244 +/- 0.72 vs 0.498 +/- 0.51 mg/L, p = 0.032). The coronary IL-6 values correlated positively with the coronary CRP values (r = 0.374, p = 0.017). In conclusion, the increase in coronary IL-6 and CRP levels after PCI in patients with CAD might be attributed to their release from the coronary atheroma secondary to the direct mechanical effect applied on the atheroma itself by balloon inflation and stent deployment.     

Inflammatory and vasoactive factors in the aspirate from the culprit coronary artery of patients with acute myocardial infarction

BACKGROUND: Besides distal embolization of thrombus and plaque debris, locally increased inflammatory markers at the site of ruptured plaque in acute myocardial infarction (AMI) are thought to have an adverse impact on myocardial reperfusion during primary percutaneous coronary intervention (PCI). However, there is lack of data on such factors. Therefore, we investigated the presence of locally increased inflammatory and vasoactive factors in culprit coronary artery. METHODS: We performed primary PCI with PercuSurge GuideWire system in 18 AMI patients. We collected blood samples from the femoral artery before PCI and from culprit coronary artery after first predilation while inflating the distal protection balloon and after completing PCI. We determined concentrations of C-reactive protein, soluble CD40 ligand, Interleukin (IL-6), serotonin, tissue factor, and factor VIIa. RESULTS: While the concentrations of soluble CD40 ligand (2.84+/-3.74 vs 0.98+/-0.63 ng/mL, p=0.004), IL-6 (33.67+/-32.63 vs 17.08+/-21.41 pg/mL, p<0.001), serotonin (2.05+/-0.76 vs 0.92+/-0.60 ng/mL, p<0.001), tissue factor (257.17+/-84.34 vs 154.60+/-87.99 pg/mL, p<0.001) and factor VIIa (34.30+/-27.30 vs 24.19+/-28.00 ng/mL, p=0.016) were significantly higher in the culprit coronary artery than in the femoral artery, CRP levels did not differ. The locally elevated concentrations of various factors were successfully reduced after multiple aspirations of blood using the PercuSurge GuideWire system. CONCLUSIONS: We found increased levels of soluble CD40 ligand, IL-6, serotonin, tissue factor and factor VII in the culprit coronary artery compared to those in peripheral blood. The clinical impact of such locally increased soluble factors in the culprit coronary artery needs to be investigated in further studies.     

Elevated preprocedural high-sensitivity C-reactive protein levels are associated with neointimal hyperplasia and restenosis development after successful coronary artery stenting.

BACKGROUND: Recent data indicate that an elevated serum level of high-sensitivity C-reactive protein (hs-CRP) predicts the risk of recurrent coronary events, and that statin therapy decreases the risk of coronary events. This study assessed the relationship between the pre-procedural hs-CRP level and in-stent neointimal hyperplasia (NIH) after stenting and the effects of statins on the relationship between restenosis after stenting and the serum hs-CRP levels of patients with coronary artery disease. METHODS AND RESULTS: This study included 100 patients who underwent stent implantation for angiographically significant stenosis. Patients were divided into a normal C-reactive protein (CRP) group (<0.5 mg/dl, n=59) and elevated CRP group (>or=0.5 mg/dl, n=41). All patients underwent angiographic and intravascular ultrasound follow-up at 6 months. The baseline CRP level was 0.29+/-0.08 mg/dl in the normal CRP group and 2.90+/-2.31 mg/dl in the elevated CRP group. The NIH cross-sectional area (CSA) in the minimal lumen CSA at follow-up was significantly larger in the elevated CRP group compared with the normal CRP group (1.9+/-1.3 mm2 vs 3.0+/-1.5 mm2, p=0.001). A significant positive correlation was found between pre-interventional CRP level and NIH area (r=0.52, p<0.001). In patients with normal CRP, an association between statin therapy and restenosis was not observed. However, when the analysis was confined to patients with elevated CRP, statin therapy significantly reduced the restenosis rate (20% vs 37.5%, p=0.031). In the normal CRP group, the intra-stent neointimal area at 6 months was not different between the non-statin and statin groups (2.2+/-1.4 mm2 vs 1.8+/-1.1 mm2). However, in the elevated CRP group, statin therapy significantly decreased the neointimal area at 6-month follow-up (3.6+/-1.7 mm2 vs 2.4+/-1.3 mm2, p<0.001). CONCLUSION: Measuring the pre-interventional hs-CRP level may help predict the development of restenosis after stenting and statin therapy will significantly reduce the restenosis rate in patients with an elevated hs-CRP.     

Exercise training modulates cytokines activity in coronary heart disease patients

BACKGROUND: Physical activity may lower the risk for coronary artery disease (CAD) by mitigating inflammation, which plays a key role in the pathophysiology of atherosclerosis. The purpose of this study was to determine the effect of aerobic exercise training on levels of pro- and anti-inflammatory cytokines, IL-1, IL-6, IL-10, INF-gamma, and C-reactive protein (CRP), in CAD patients participating in a cardiac rehabilitation program. METHODS AND RESULTS: Twenty-eight patients, age 64+/-7.1 years, participated in a 12-week aerobic exercise training program at 70-80% of individual maximal heart rate. Training resulted in a significant reduction of all pro-inflammatory cytokines, CRP from 7.5+/-4.2 to 3.9+/-3.5 mg/l, p<0.001, IL-1, 0.33+/-0.23 to 0.51+/-0.12 pg/ml, p=0.014, IL-6, 2.50+/-1.50 to 1.44+/-0.57 pg/ml, p=0.002, INF-gamma, 18.63+/-3.31 to 16.77+/-2.49 pg/ml, p<0.001, as well as a significant increase in the anti-inflammatory, cytokine IL-10, from 1.61+/-1.40 to 2.29+/-2.01 pg/ml, p=0.008. Baseline CRP levels were 36% (p=0.006) higher among diabetes mellitus patients and training was associated with a 40.5% CRP reduction in these patients compared to 19% reduction in non-diabetics, p<0.01. At baseline 72% of patients were in a high risk category (CRP>3 mg/l), 28% in an intermediate (CRP=1-3 mg/l), with none in a low risk category (<1 mg/l). Following exercise training, 11% were in the low risk, 50% in the intermediate and 39% in the high risk category, indicating 46% reduction in the number of subjects in the high risk category. CONCLUSIONS: Aerobic exercise training in CAD patients is an effective mean in inducing reduction in CRP, IL-1, IL-6, INF-gamma levels, and increase in IL-10, thus, possibly improving coronary risk profile.     

Comparison of interleukin-6 and C-reactive protein serum concentrations assessment in diagnosis of infective endocarditis

Serum interleukin-6 (IL-6) level might be used to aid in diagnosis of infective endocarditis (IE), especially when blood cultures are negative. One of typical acute phase proteins is C-reactive protein (CRP), often served as an additional inflammation maker. The aim of the study was to compare serum IL-6 and CRP concentrations assessment in diagnosis and monitoring of IE. The study group consisted of 40 patients with ongoing IE and valvular heart diseases. Two control groups consisted of patients with valvular heart diseases: 15 without infection and another 15 with urinary tract infection. The diagnosis of IE was established according to the Duke University criteria; in 34 patients positive blood cultures were found. Serum IL-6 and CRP were measured on three occasions after diagnosis of IE was established and during antimicrobial treatment (mean period 14 +/- 7 days) by ELISA. Usefulness of both parameters for IE diagnosis were described. Reference values were defined as 0-12.5 pg/ml for IL-6, and 0-10 mg/l for CRP. Mean concentrations of IL-6 and CRP in patients with IE (37 +/- 44.3 pg/ml and 27.1 +/- 23.9 mg/l) were significantly higher than in controls: with urinary tract infection (9.1 +/- 4.42 pg/ml and 6.95 +/- 4.39 mg/l) and without infection (3.95 +/- 1.4 pg/ml and 2.21 +/- 0.96 mg/l). CRP concentration was not significantly correlated with IL-6 (r = 0.51, p = 0.07). The significant tendency of consecutive IL-6 concentrations to decrease (from 37 +/- 44.3 to 8.7 +/- 5.7 pg/ml), without decrease of CRP (from 27.1 +/- 23.9 mg/l to 22 +/- 18.3 mg/l) was found. CONCLUSIONS: 1. Elevated serum IL-6 and CRP levels may suggest ongoing IE. 2. Sensitivity, specificity, positive and negative predictive value are nonsignificantly higher for IL-6 than CRP. 3. Combined assessment of serum IL-6 and CRP concentration has no higher value in diagnosis of IE. 4, IL-6 level decrease is faster than CRP during antimicrobial treatment, and it helps better and faster monitoring of treatment.     

Inflammatory markers and coronary interventions: a potentially useful follow-up modality after stenting.

Periprocedural levels of various inflammatory markers have been correlated with prognosis in patients undergoing percutaneous coronary interventions. However, long-term variations of interleukin-1 receptor antagonist (IL-1Ra) or C-reactive protein (CRP) during follow-up after coronary interventions were not previously investigated. The aim of our study was to perform serial evaluations of these markers before and after coronary stenting and to correlate them with clinical status. Plasma levels of IL-1Ra and CRP were measured at baseline and 3 and 6 months after the procedure in 31 patients with symptomatic coronary artery disease undergoing stent implantation, who had no evidence of myocardial ischemia at 6-month follow-up. While at 3 months there were no significant variations of baseline values, 6 months after the procedure a significant decrease from baseline was observed both in IL-1Ra and CRP levels (median -24 pg/ml, P = 0.048, and -0.13 mg/dl, P = 0.017, respectively). Six-month reduction in both IL-1Ra and CRP levels was significant in patients with unstable angina (n = 18; IL-1Ra: from 175 to 119 pg/ml, P = 0.001; CRP: from 0.52 to 0.18 mg/dl, P = 0.002) and nonsignificant in those with stable angina (n = 13) on admission (IL-1Ra: from 123 to 158 pg/ml, P = 0.22; CRP: from 0.19 to 0.10 mg/dl, P = 0.44). In conclusion, a significant reduction of IL-1Ra and CRP levels is observed 6 months after stent implantation in patients with preprocedural unstable angina who remain free of ischemia. This decrease suggests a stabilization of the inflammatory process and may be associated with a favorable prognosis after coronary interventions.     

Chios mastic treatment of patients with active Crohn＇s disease

AIM： To evaluate the effectiveness of mastic administration on the clinical course and plasma inflammatory mediators of patients with active Crohn＇s disease （CD）. METHODS： This pilot study was conducted in patients with established mild to moderately active CD, attending the outpatient clinics of the hospital, and in healthy controls. Ten patients and 8 controls were recruited for a 4-wk treatment with mastic caps （6 caps/d, 0.37 g/cap）. All patients successfully completed the protocol. CD Activity Index （CDAI）, Nutritional Risk Index （NRI）, C-reactive protein （CRP）, interleukin-6 （IL-6）, tumor necrosis factor-alpha （TNF-α）, monocyte chemotactic protein-1 （MCP-1）, and total antioxidant potential （TAP） were evaluated in the plasma at baseline and at the end of the treatment period. Results were expressed as mean values ± SE and P 〈 0.05 was considered to indicate statistical significance. RESULTS： Patients exhibited significant reduction of CDAI （222.9 ± 18.7 vs 136.3 ± 12.3, P = 0.05） as compared to pretreament values. Plasma IL-6 was significantly decreased （21.2 ± 9.3 pg/mL vs 7.2 ± 2.8 pg/ mL, P = 0.027）, and so did CRP （40.3 ± 13.1 mg/mL vs 19.7 ± 5.5, P = 0.028）. TAP was significantly increased （0.15 ± 0.09 vs 0.57 ± 0.15 mmol/L uric acid, P = 0.036）. No patient or control exhibited any kind of side effects. CONCLUSION： The results suggest that mastic significantly decreased the activity index and the plasma levels of IL-6 and CRP in patients with mildly to moderately active CD. Further double-blind, placebo-controlled studies in a larger number of patients are required to clarify the role of this natural PrOduct in the treatment of patients with CD.     

Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation

BACKGROUND: Interleukin (IL)-6 has recently been shown to have negative inotropic effects, and several studies have reported increases in circulating concentrations of this cytokine in patients with depressed left ventricular ejection fraction and chronic left heart failure. However, most previous clinical studies have measured cytokines in compensated chronic heart failure. HYPOTHESIS: The purpose of this study was to examine the temporal evolution of circulating concentrations of C-reactive protein (CRP) and cytokines in patients with cardiomyopathy and acute cardiac decompensation, free of infection and unstable angina. METHODS: The time course of circulating concentrations of CRP, an anti-inflammatory cytokine interleukin (IL)-4, and a proinflammatory cytokine IL-6 were studied in eight patients with cardiomyopathy and acute cardiac decompensation in the absence of infection or unstable angina. Control samples were obtained from eight age-matched asymptomatic subjects. RESULTS: Increased circulating concentrations of CRP (2.6 +/- 0.8 mg/dl), IL-4 (164.6 + 36.5 pg/ml), and IL-6 (17.1 +/- 5.1 pg/ml) were found in all eight patients during acute cardiac decompensation; these values decreased significantly with the resolution of symptoms of cardiac decompensation (0.5 +/- 0.1 mg/dl, 77.8 +/- 23.6 pg/ml, 2.3 +/- 0.1 pg/ml, respectively, p < 0.05 for both). There was a significant correlation between peak CRP and peak IL-6 (p < 0.05). CONCLUSIONS: In patients with acute left heart decompensation in the absence of infection or coronary events, CRP, IL-4, and IL-6 increased and returned toward normal levels as the symptoms of heart failure resolved. Since the changes in concentrations of CRP, IL-4, and IL-6 in patients with heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significance of acute reactive proteins or cytokines in the pathogenesis of heart failure.     

Dietary alpha-linolenic acid decreases C-reactive protein,serum amyloid A and interleukin-6 in dyslipidaemic patients

BACKGROUND: Inflammation plays an important role in the pathogenesis of coronary artery disease. We examined whether dietary supplementation with alpha-linolenic acid (ALA, 18:3n-3) affects the levels of inflammatory markers in dyslipidaemic patients. METHODS: We recruited 76 male dyslipidaemic patients (mean age=51+/-8 years) following a typical Greek diet. They were randomly assigned either to 15 ml of linseed oil (rich in ALA) per day (n=50) or to 15 ml of safflower oil (rich in linoleic acid (LA, 18:2n-6)) per day (n=26). The ratio of n-6:n-3 in linseed oil supplemented group was 1.3:1 and in safflower oil supplemented group 13.2:1. Dietary intervention lasted for 3 months. Blood lipids and C-reactive protein (CRP), serum amyloid A (SAA), and interleukin-6 (IL-6) levels were determined prior and after intervention. CRP and SAA were measured by nephelometry and IL-6 by immunoassay. RESULTS: Dietary supplementation with ALA decreased significantly CRP, SAA and IL-6 levels. The median decrease of CRP was 38% (1.24 vs. 0.93 mg/l, P=0.0008), of SAA 23.1% (3.24 vs. 2.39 mg/l, P=0.0001) and of IL-6 10.5% (2.18 vs. 1.7 pg/ml, P=0.01). The decrease of inflammatory markers was independent of lipid changes. Dietary supplementation with LA did not affect significantly CRP, SAA and IL-6 concentrations but decreased cholesterol levels. CONCLUSIONS: Dietary supplementation with ALA for 3 months decreases significantly CRP, SAA and IL-6 levels in dyslipidaemic patients. This anti-inflammatory effect may provide a possible additional mechanism for the beneficial effect of plant n-3 polyunsaturated fatty acids in primary and secondary prevention of coronary artery disease.     

Prognostic value of C-reactive protein,fibrinogen, interleukin-6, and macrophage colony stimulating factor in severe unstable angina

BACKGROUND: Inflammatory process plays an important role in the pathogenesis of acute coronary syndromes. HYPOTHESIS: The study was undertaken to evaluate whether admission levels of C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6). and macrophage colony stimulating factor (MCSF) can predict short-term prognosis in patients with unstable angina. METHODS: C-reactive protein, fibrinogen, IL-6, and MCSF were measured on admission in 141 consecutive patients, aged 59 +/- 10 years, with unstable angina (Braunwald class IIIb). Patients were divided into two groups according to their in-hospital outcome: Group 1 comprised 77 patients with a complicated course (2 died, 15 developed nonfatal myocardial infarction, and 60 had recurrence of angina), and Group 2 comprised 64 patients with an uneventful course. RESULTS: Admission median levels of CRP (8.8 vs. 3.1 mg/l, p = 0.0002). fibrinogen (392 vs. 340 mg/dl, p = 0.008), IL-6 (8.8 vs. 4.5 pg/ml, p = 0.03), and MCSF (434 vs. 307 pg/ml, p = 0.0001) were higher in Group I than in Group 2. The MCSF levels were an independent risk factor for in-hospital events, with an adjusted odds ratio for eventful in-hospital outcome of 3.3 (95% confidence interval 1-10.9, p = 0.04), and correlated with levels of IL-6 (r(s) = 0.52, p = 0.0001), CRP (r(s) = 0.43, p = 0.0001), and fibrinogen (r(s) = 0.25, p = 0.004). CONCLUSIONS: These findings suggest that among the studied inflammatory indices only increased admission levels of MCSF are strongly and independently related with adverse short-term prognosis in patients with severe unstable angina.     

Comparison of serum levels of inflammatory markers and allelic variant of interleukin-6 in patients with acute coronary syndrome and stable angina pectoris

OBJECTIVES: Although the relationship between atherosclerosis and inflammatory cells has been recognized in recent years, the effect of interleukin-6 (IL-6) genetic variants associated with atherosclerosis is still controversial. Therefore, we investigated the association between IL-6 polymorphism and levels of IL-6 in patients with coronary artery disease (CAD). METHODS: We conducted a case-control study on 294 unrelated participants who were referred to the cardiology department of the university hospital for coronary angiography because of suspected ischemic heart disease. Group I comprised patients with clinically acute coronary syndrome, and group II comprised patients (individuals matched for age and sex) with clinically stable angina pectoris; both groups were categorized, based on their angiographic findings, as either having angiographically documented less extensive CAD (1 vessel narrowed) or extensive CAD (> or =2 vessels narrowed). They were studied to examine effect of the IL-6 gene variants in CAD. Genotyping was determined by polymerase chain reaction. RESULTS: The IL-6 G/C-174 polymorphism was found in 19 of 106 (18%) in group I and in four of 188 (2%) in group II (P<0.001). Median IL-6 levels were significantly higher in group I (6.7+/-13.6 pg/ml) than in group II (4.1+/-3.8 pg/ml) (P<0.05). In addition, high sensitivity C-reactive protein levels were significantly higher in group I (8.2+/-6.2 mg/dl) than in group II (4.6+/-3.4 mg/dl) (P<0.001). CONCLUSION: These results demonstrated that the presence of the IL-6 G/C-174 polymorphism and increased IL-6 and high sensitivity C-reactive protein levels are strongly associated with the inflammatory system and the course of clinical and hemodynamically significant CAD.     

Interleukin-6 enhancement after direct autologous retransfusion of shed thoracic blood does not influence haemodynamic stability following coronary artery bypass grafting

BACKGROUND: Direct autologous retransfusion of shed thoracic blood is carried out to reduce homologous transfusion after cardiac surgery, but it contains high concentrations of inflammatory mediators. The purpose of the study was to investigate whether retransfusion of shed thoracic blood induces plasma interleukin-6 (IL-6) expression and influences haemodynamics. METHODS: Following uncomplicated coronary artery bypass graft surgery, forty-four patients were randomised in case postoperative blood loss via thoracic drains exceeded 350 ml. The course of plasma IL-6 levels and haemodynamics including cardiac output, extravascular lung water and intrathoracic blood volume were investigated prior to (T0), 30 minutes (T1), 1 (T2), 3 (T3) and 12 hours (T4) after retransfusion of 350 ml shed blood in comparison to 350 ml saline. RESULTS: Plasma IL-6 levels at T1 (1892 +/- 202 vs. 485 +/- 30 pg/ml) and T2 (1059 +/- 119 vs. 413 +/- 30 pg/ml) were significantly higher in the verum group (n = 20) compared to controls (n = 24) ( P < 0.01). Severe haemodynamic side effects were not detected. CONCLUSION: This study found significantly elevated plasma IL-6 levels following direct autologous retransfusion of shed thoracic blood but failed to show severe adverse effects affecting haemodynamic stability.     

Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide

BACKGROUND: The accumulating evidence suggests that C-reactive protein (CRP) may have direct inflammatory effects on the vascular wall and that statin therapy may have important non-lipid anti-inflammatory effects confirmed by decreasing serum inflammatory markers, such as CRP. However, the effect of simvastatin on interleukin-6 (IL-6) release in cultured human monocytes was not investigated.DESIGN A prospective, human monocyte culture, simvastatin intervention study. METHODS: Monocytes were isolated from blood of healthy volunteers by the Ficoll density gradient and stimulated by broad concentrations of CRP (1-20 microg/ml) and lipopolysaccharide (LPS, 1-10 ng/ml) at indicated time points (0, 2, 4, 8, 16 and 24 h). Also 10-8-10-6 mol/l simvastatin was coincubated with cells in the presence of CRP and LPS. Measurements of IL-6 were performed from supernatants of cultured medium in duplicate, using a commercial assay kit. RESULTS: CRP and LPS induced the rapid release of IL-6, with significantly elevated levels in cultured supernatants at 4 h in the CRP group and at 2 h in the LPS group. The effects of CRP and LPS on IL-6 release of monocytes were dose and time dependent. A greater than 11-fold increase of IL-6 in the CRP group (20 microg/ml) and a greater than 26-fold increase in the LPS group (10 ng/ml) were observed at 24 h compared with the control group (945.7+/-98.3 pg/ml compared with 94.3+/-12.4 pg/ml and 1720.4+/-690.1 pg/ml compared with 70.1+/-16.7 pg/ml, P<0.001, respectively). However, 10-8-10-6 mol/l simvastatin inhibited significantly the production of IL-6 in monocytes stimulated by CRP and LPS in a dose-dependent manner, with the maximal inhibiting effect at a concentration of 10-6 mol/l (945.7+/-98.3 pg/ml compared with 180.9+/-31.2 pg/ml and 1720.4+/-690.1 pg/ml compared with 824.0+/-206.2 pg/ml, P<0.001 respectively). CONCLUSIONS: CRP and LPS could induce IL-6 release in human monocytes and simvastatin could inhibit this response in a dose-dependent manner, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of simvastatin.     

Serum C-reactive protein elevation predicts poor clinical outcome in patients with distal type acute aortic dissection: association with the occurrence of oxygenation impairment

BACKGROUND: Acute aortic dissection (AAD) is sometimes complicated by respiratory failure due to severe lung oxygenation impairment. Systemic activation of inflammatory system after aortic injury may play some roles in the development of this complication. The aim of this study was to determine the significance of serum C-reactive protein (CRP) elevation in the development of oxygenation impairment and clinical outcome with distal type AAD. METHODS AND RESULTS: A total of 61 patients, who were admitted with distal type AAD within 24 h from the onset, were examined. Serum CRP levels, white blood cell (WBC) counts and body temperature were measured serially for at least 4 days. Oxygenation impairment, defined as the lowest PaO2/FIO2 ratio < or = 200 mmHg, was noted in 31 patients (51%). In patients with oxygenation impairment, peak CRP levels (20.7+/-7.9 vs. 12.7+/-3.8 mg/dl, P < 0.001), peak WBC counts (14,600+/-3600 vs. 11,800+/-4300/mm3, P = 0.008) and body temperature (38.4+/-0.5 vs. 38.0+/-0.6 degrees C, P = 0.004) were significantly higher than those without. Peak CRP level was inversely correlated with the lowest PaO2/FIO2 (P < 0.001). Patients who underwent urgent surgical treatment and/or died in the hospital had higher peak CRP levels (25.1+/-12.3 vs. 16.1+/-7.4 mg/dl, P = 0.010) than those who did not. Multivariate analysis revealed that a peak CRP level > or = 15 mg/dl (relative risk = 12.6, P < 0.001) was an independent determinant of the development of oxygenation impairment. CONCLUSION: The greater serum CRP elevation after distal type AAD was associated with a higher incidence of oxygenation impairment and poor clinical outcome. Systemic activation of the inflammatory system after aortic injury may play an important role in the development of oxygenation impairment.     

Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6

AIM: Interleukin-18 (IL-18) is a pro-inflammatory cytokine with a central role in the inflammatory cascade. In the present study, we investigated whether patients with precocious myocardial infarction have higher plasma IL-18 concentrations than matched controls. Furthermore, the relationships between plasma IL-18 concentrations and coronary atherosclerosis, C-reactive protein (CRP), interleukin-6 (IL-6) and traditional cardiovascular risk factors were examined. METHODS AND RESULTS: Three hundred eighty-seven unselected survivors of a first myocardial infarction aged less than 60 years and 387 sex and age matched controls were enrolled in the study. A subset of patients (n=236) was evaluated by quantitative coronary angiography. Postinfarction patients had significantly higher mean level of plasma IL-18 than controls (309.6+/-138.6 versus 285.4+/-115.7pg IL-18/mL). Furthermore, plasma IL-18 concentration was significantly associated with coronary plaque area (r=0.17, p=0.009). This relationship remained in a partial correlation analysis adjusting for CRP (r=0.15, p=0.02), for IL-6 (r=0.15, p=0.02) and for both CRP and IL-6 (r=0.15, p=0.02). In addition, IL-18 levels were significantly associated with other cardiovascular risk factors, namely age, low density lipoprotein (LDL) cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, insulin, proinsulin, body mass index (BMI), systolic and diastolic blood pressure. CONCLUSION: The present work provides evidence that plasma IL-18 is increased in postinfarction patients and is associated with coronary atherosclerosis.     

Effect of rosuvastatin therapy and myocardial revascularization on angiogenesis in coronary artery disease patients

We studied the influence of rosuvastatin therapy and myocardial revascularization on angiogenic growth factors in coronary artery disease (CAD) patients. Two main groups were examined: the first one consisted of patients passed through successful percutaneous coronary intervention (PCI), the second one consisted of patients on 3 months rosuvastatin therapy. Vascular endothelial growth factor (VEGF), VEGF receptor Flt-1 (sVEGF-Rl) and transforming growth factor-beta (TGF-bl) levels were measured in healthy volunteers and CAD patients before and 6 days after myocardial revascularization by PCI. VEGF and basic fibroblast growth factor (bFGF) levels were measured before and 3 month after rosuvastatin therapy, as well as total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), C-reactive protein (CRP), interleukin 6 (IL-6) and endothelium dependent vasodilation. VEGF levels did not differ, but TGF - b levels were significantly lower in CAD patients compared to healthy subjects (11.0 +/- 4.9 pg/ml and 120.0 +/- 32.4 pg/ml, respectively, p < 0.000l). Myocardial revascularization caused changes in VEGF levels from 192.4 +/- 166.1 pg/ml to 264.7 +/- 226.6 pg/ml (p=0.0066) without significant influence on TGF and VEGF-R1 levels in 6 days. There were positive changes in lipid levels, lowering of CRP and IL-6 concentrations, improvement of endothelial function and decrease of VEGF levels from 382 +/- 249 pg/ml to 297 +/- 220 pg/ml (p=0.006) 3 month after start of rosuvastatin treatment (no changes in bFGF levels were observed). Chronic insufficient myocardial blood supply leads to decreasing of TGF - b levels. The elevation of VEGF after myocardial revascularization reflects transient ischemia and potentially may provoke hemodynamic instability, caused by atherosclerotic plaque neovascularization. Strengthening of statin therapy early after myocardial revascularization may allow to stabilize the atherosclerotic plaque condition, also by means of VEGF lowering.     

Systemic inflammation in unstable angina is the result of myocardial necrosis

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