Thursday, December 04, 2014 2:08:44 PM
Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction Among Apparently Healthy Men
Paul M. Ridker, MD; Nader Rifai, MD; Meir J. Stampfer, MD; Charles H. Hennekens, MD
+ Author Affiliations
From the Center for Cardiovascular Disease Prevention (P.M.R.) and the Divisions of Preventive Medicine (P.M.R., C.H.H.), Cardiovascular Diseases (P.M.R.), and the Channing Laboratory (M.J.S.), Brigham and Women’s Hospital; the Department of Ambulatory Care and Prevention (C.H.H.); and the Children’s Hospital Medical Center (N.R.), all at the Harvard Medical School, Boston, Mass.
Correspondence to Paul M. Ridker, MD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail pridker@partners.org
Next SectionAbstract
Background—Interleukin-6 (IL-6) plays a central role in inflammation and tissue injury. However, epidemiological data evaluating the role of IL-6 in atherogenesis are sparse.
Methods and Results—In a prospective study involving 14 916 apparently healthy men, we measured baseline plasma concentration of IL-6 in 202 participants who subsequently developed myocardial infarction (MI) and in 202 study participants matched for age and smoking status who did not report vascular disease during a 6-year follow-up. Median concentrations of IL-6 at baseline were higher among men who subsequently had an MI than among those who did not (1.81 versus 1.46 pg/mL; P=0.002). The risk of future MI increased with increasing quartiles of baseline IL-6 concentration (P for trend <0.001) such that men in the highest quartile at entry had a relative risk 2.3 times higher than those in the lowest quartile (95% CI 1.3 to 4.3, P=0.005); for each quartile increase in IL-6, there was a 38% increase in risk (P=0.001).This relationship remained significant after adjustment for other cardiovascular risk factors, was stable over long periods of follow-up, and was present in all low-risk subgroups, including nonsmokers. Although the strongest correlate of IL-6 in these data was C-reactive protein (r=0.43, P<0.001), the relationship of IL-6 with subsequent risk remained after control for this factor (P<0.001).
Conclusions—In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis.
Discussion
These data indicate that baseline levels of the inflammatory cytokine IL-6 are significantly elevated among apparently healthy men at risk for future myocardial infarction. The relationship between IL-6 level and risk was not altered in analyses that adjusted for baseline differences in total cholesterol, HDL cholesterol, body mass index, blood pressure, diabetes, a family history of premature coronary artery disease, alcohol use, or exercise frequency; it was stable over the 6-year follow-up period and was present even among all low-risk subgroups evaluated, including nonsmokers.
Prior data evaluating the role of IL-6 among healthy individuals at risk for future coronary events are sparse. In the setting of acute ischemia, however, it has recently been shown that IL-6 levels increase with the acute-phase response and that these elevations may be a marker for plaque instability.24 25 26 However, because blood samples in the present study were collected at baseline, we can exclude the possibility that acute ischemia was a cause of IL-6 elevation in these data. Thus, if an enhanced inflammatory response is present among individuals with a propensity for acute plaque rupture,33 then our data indicate that such effects are present and can be clinically detected many years in advance of first myocardial infarction.
Elevated levels of IL-6 have previously been observed in several autoimmune disorders, including arthritis, Castleman syndrome, psoriasis, mesangial proliferative glomerulonephritis, and inflammatory bowel disease.2 In this regard, the current data provide support for the hypothesis that atherosclerosis represents, at least in part, a fundamentally inflammatory condition.27
The strongest correlates of IL-6 in these data were C-reactive protein and fibrinogen, a finding that would be expected because IL-6 is a primary stimulant for hepatic production of acute-phase proteins.6 7 In our data, the effects of IL-6 on subsequent risk remained statistically significant after we controlled for these latter factors. Thus, the current data also help to explain why several acute-phase proteins, such as C-reactive protein, serum amyloid A, albumin, and fibrinogen, have been associated with increased vascular risk.34
Limitations of these data should be considered. We relied on a single baseline blood sample and thus cannot take into account any variation of IL-6 that may occur over time. Furthermore, because our baseline blood samples were not obtained at a uniform time of day, our data may be limited by any diurnal variation in IL-6 that might exist, a potential issue because both glucocorticoids and catecholamines increase IL-6 levels, and the plasma half-life of IL-6 is <6 hours. It is important to recognize, however, that both of these potential limitations would tend to increase random misclassification in our data, an effect that, if anything, would lead to an underestimation of true effects. Finally, because our samples were stored at -80°C, we cannot exclude the possibility of protein degradation. Such an effect is unlikely, however, because the distribution of IL-6 in our study was quite similar to that observed in studies that used fresh blood samples. Furthermore, even if such an effect were present, it would not affect the validity of our results, because both case and control samples were handled identically and in a blinded fashion throughout the study. In addition, because all our study participants were taking oral aspirin at the time of blood sampling, any effect of this agent on IL-6 levels could not have affected our main results.35
Stimuli underlying IL-6 production in apparently healthy men at risk for future myocardial infarction are uncertain. It is possible, for example, that preclinical atherosclerosis is itself an inflammatory stimulus and that IL-6 is a marker rather than a cause of disease. On the other hand, because monocyte-derived macrophages are abundant in atherosclerotic plaque and IL-6 gene transcripts are expressed in human atheroma, it is also possible that increased IL-6 production from endothelium and vascular smooth muscle has direct effects on plaque proliferation and stability.27 28 IL-6 levels also increase with infection,1 2 36 and it has been hypothesized that infection might aggravate atherogenesis.37 In this cohort, however, baseline IgG titers directed against Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, and cytomegalovirus were not associated with increased vascular risk or with increased levels of inflammatory markers.38 39
Together, these prospective epidemiological data support a fundamental role for cytokine-mediated inflammation in the early stages of atherogenesis, data that corroborate and extend the recent finding that IL-6 levels are associated with increased mortality in the elderly.40 As such, we believe these data support the possibility that anti-inflammatory therapies might provide a new approach to cardiovascular disease treatment and prevention.
http://circ.ahajournals.org/content/101/15/1767.full
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