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July 2004

LE Magazine July 2004

C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: the PRIME Study.
OBJECTIVE: This study was undertaken to examine the association of plasma inflammatory markers such as C-reactive protein (CRP), interleukin-6, and fibrinogen with the incidence of coronary heart disease within the prospective cohort study on myocardial infarction (PRIME study). METHODS AND RESULTS: Multiple risk factors were recorded at baseline in 9758 men aged 50 to 59 years who were free of coronary heart disease (CHD) on entry. Nested case-control comparisons were carried out on 317 participants who suffered myocardial infarction (MI)-coronary death (n=163) or angina (n=158) as an initial CHD event during a follow-up for 5 years. After adjustment for traditional risk factors, incident MI-coronary death, but not angina, was significantly associated with CRP, interleukin-6, and fibrinogen, but only interleukin-6 remained significantly associated with MI-coronary death when the 3 inflammatory markers were included in the model. The different interleukin-6 levels in Northern Ireland and France partly explained the difference in risk between these countries. Interleukin-6 appeared as a risk marker of MI-coronary death, and it improved the definition of CHD risk beyond LDL cholesterol. CONCLUSIONS: This association may reflect the underlying inflammatory reaction located in the atherosclerotic plaque or a genetic susceptibility on the part of CHD subjects to answer a proinflammatory stimulus and subsequent increase in hepatic CRP gene expression.

Arterioscler Thromb Vasc Biol . 2003 Jul 1;23(7):1255-61. Epub 2003 May 29

Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy.
CONTEXT: Inflammatory activity is associated with high rates of long-term mortality in unstable coronary artery disease (CAD). Interleukin 6 (IL-6) induces C-reactive protein and fibrinogen, systemic markers of inflammation. OBJECTIVES: To determine whether plasma levels of IL-6 are predictive of mortality and to evaluate the interaction of IL-6 levels with the effects of invasive vs noninvasive treatment strategies in unstable CAD patients. DESIGN, SETTING, AND PATIENTS: The prospective, randomized Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II trial, conducted among 3,489 patients, 3,269 of whom had plasma samples analyzed for IL-6 levels, with diagnosed unstable CAD (67% male; median age, 67 years) at 58 Scandinavian hospitals between June 1996 and August 1998. INTERVENTIONS: Patients were randomly assigned to receive either an early invasive (n = 1222) or a noninvasive treatment strategy (n = 1235). The latter group, as well as 666 patients with contraindications to invasive therapy, were further randomized to 90-day treatment with low-molecular-weight heparin (dalteparin, 5000-7500 IU twice per day; n = 1140) or placebo (n = 1127). MAIN OUTCOME MEASURE: Mortality at 6 and 12 months in the medically and interventionally randomized cohorts, respectively, in relation to IL-6 levels, measured at randomization. RESULTS: Plasma levels of IL-6 that were at least 5 ng/L compared with levels lower than 5 ng/L were associated with greatly increased mortality in the noninvasive group (7.9% vs 2.3%; relative risk [RR], 3.47; 95% confidence interval [CI], 1.94-6.21) and in the placebo-treated group (7.9% vs 2.5%; RR, 3.19; 95% CI, 1.77-5.74). The association remained significant after adjustment for most established risk indicators. An early invasive treatment strategy strongly reduced 12-month mortality among those with elevated IL-6 levels (5.1% absolute reduction; P =.004) whereas mortality was not reduced among patients without elevated IL-6 concentrations. Those taking dalteparin with elevated IL-6 levels experienced lower 6-month mortality than those who did not take dalteparin (3.5% absolute reduction; P =.08). CONCLUSIONS: Circulating IL-6 is a strong independent marker of increased mortality in unstable CAD and identifies patients who benefit most from a strategy of early invasive management.

JAMA . 2001 Nov 7;286(17):2107-13

Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure.
Interleukin-6 (IL-6), the main circulating cytokine, is putatively a major mediator of the effects of the immune system on several endocrine axes and intermediate metabolism. We performed dose-response studies of recombinant human IL-6 on pituitary hormone secretion in 15 healthy male volunteers, using 5 single, escalating subcutaneous doses of IL-6 (0.1, 0.3, 1.0, 3.0 and 10.0 micrograms/kg body weight), each in 3 volunteers. We measured resting metabolic rate (RMR) with indirect calorimetry and plasma anterior pituitary hormones and vasopressin (AVP) at baseline and half-hourly over 4 hours after the injection. All doses examined were tolerated well and produced no significant adverse effects. Dose-dependent RMR increases were observed in response to the 3.0- and 10.0-microgram/kg doses of IL-6, beginning at 60 min and slowly peaking between 180 and 240 min. Plasma adrenocorticotropic-hormone concentrations increased dramatically and dose-dependently in all the patients who received the 3.0- and 10.0-microgram/kg doses of IL-6, respectively, peaking to 150 and 255 pg/ml at 60 min, and slowly returning to normal by 4 hours. Corresponding plasma cortisol levels peaked dose-dependently between 90 and 150 min, but remained elevated throughout the sampling period. In contrast, the growth hormone (GH) dose-response was bell-shaped, with maximum (approximately 100-fold) stimulation achieved by 3.0 micrograms/kg IL-6. Prolactin (PRL) showed a similar but less pronounced response pattern. Thyroid-stimulating hormone (TSH) dose-dependently and progressively decreased over the 240 min, while gonadotropins showed no clear-cut changes. In conclusion, subcutaneous IL-6 administration induced synchronized dose-dependent increases in the RMR and hypothalamic-pituitary-adrenal axis activity, suggesting that hypothalamic corticotropin-releasing hormone may mediate both of these functions in humans. IL-6 also acutely stimulated GH and PRL secretion and suppressed TSH secretion. The dose of 3.0 micrograms/kg could be used safely in the study of patients with disturbances of the hypothalamic-pituitary unit or of thermogenesis.

Neuroendocrinology. 1997 Jul;66(1):54-62

Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.
BACKGROUND: Both C-reactive protein and low-density lipoprotein (LDL) cholesterol levels are elevated in persons at risk for cardiovascular events. However, population-based data directly comparing these two biologic markers are not available. METHODS: C-reactive protein and LDL cholesterol were measured at base line in 27,939 apparently healthy American women, who were then followed for a mean of eight years for the occurrence of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. We assessed the value of these two measurements in predicting the risk of cardiovascular events in the study population. RESULTS: Although C-reactive protein and LDL cholesterol were minimally correlated (r=0.08), base-line levels of each had a strong linear relation with the incidence of cardiovascular events. After adjustment for age, smoking status, the presence or absence of diabetes mellitus, categorical levels of blood pressure, and use or nonuse of hormone-replacement therapy, the relative risks of first cardiovascular events according to increasing quintiles of C-reactive protein, as compared with the women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the corresponding relative risks in increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9, 1.1, 1.3, and 1.5 (P<0.001). Similar effects were observed in separate analyses of each component of the composite end point and among users and nonusers of hormone-replacement therapy. Overall, 77% of all events occurred among women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per liter), and 46% occurred among those with LDL cholesterol levels below 130 mg per deciliter (3.36 mmol per liter). By contrast, because C-reactive protein and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biologic markers provided better prognostic information than screening for either alone. Independent effects were also observed for C-reactive protein in analyses adjusted for all components of the Framingham risk score. CONCLUSIONS: These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.

N Engl J Med . 2002 Nov 14;347(20):1557-65

The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis.
OBJECTIVE: Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappa B. Inhibition of nuclear factor-kappa B activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappa B activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappa B activation and circulating cytokine and adhesion molecules in patients with sepsis. DESIGN: Prospective, randomized, double blind, placebo-controlled pilot trial. SETTING: Eight-bed intensive care unit in a university teaching hospital. PATIENTS: Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis. INTERVENTIONS: A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hours as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hours, or an equivalent volume of saline. MEASUREMENTS AND MAIN RESULTS: Nuclear factor-kappa B activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hours later. Activation decreased significantly in patients treated with N-acetylcysteine (p =.016) but not placebo and was significantly reduced at 72 hours compared with both preinfusion values (p =.028) and patients receiving placebo (p =.01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interleukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p =.0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients. CONCLUSIONS: Administration of N-acetylcysteine results in decreased nuclear factor-kappa B activation in patients with sepsis, associated with decreases in interleukin-8 but not interleukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

Crit Care Med . 2003 Nov;31(11):2574-8