(Circulation. 2000;101:1767.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction Among Apparently Healthy Men
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{at}partners.org
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Abstract |
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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.
Key Words: myocardial infarction • risk factors • inflammation • epidemiology • cytokines
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Introduction |
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Interleukin (IL)-6 is a pleiotropic cytokine with a broad range of humoral and cellular immune effects relating to inflammation, host defense, and tissue injury.1 2 Produced in response to several factors, including infection, IL-1, interferon-
, and tumor necrosis factor,3 4 5 IL-6 is a
central mediator of the acute-phase response and a primary determinant
of hepatic production of C-reactive
protein.6 7 Although elevated levels of IL-6 have been reported in some chronic inflammatory conditions,2 epidemiological data evaluating the potential role of IL-6 in early atherogenesis are sparse. However, experimental studies indicate that vascular endothelial and smooth muscle cells from normal and aneurysmal arteries produce IL-6,8 9 10 that IL-6 gene transcripts are expressed in human atherosclerotic lesions,11 12 and that IL-6 may have procoagulant effects.13 14 15 Furthermore, prospective studies of apparently healthy16 17 as well as high-risk18 19 20 individuals indicate that elevated levels of C-reactive protein, a potential surrogate for IL-6 activity,21 are associated with first coronary and cerebrovascular events. Finally, elevated levels of IL-6 and other acute-phase proteins have been reported among patients with acute coronary syndromes,22 23 24 25 even among those without overt plaque rupture or acute tissue trauma.26
On the basis of these data and the hypothesis that atherosclerosis fundamentally represents a chronic inflammatory disorder,27 28 we sought to determine whether plasma levels of IL-6 might be elevated among apparently healthy individuals at risk for future myocardial infarction. We further sought to determine whether any relationship between IL-6 and subsequent vascular risk was modified by other cardiovascular risk factors, including markers of chronic inflammation.
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Methods |
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We performed a prospective, nested, case-control study of IL-6 as a potential marker for future myocardial infarction among participants in the Physicians’ Health Study, a randomized, double-blind, placebo-controlled trial of aspirin (325 mg PO every other day) and ß-carotene (50 mg PO every other day) in the primary prevention of cardiovascular disease and cancer conducted among 22 071 US male physicians 40 to 84 years of age with no prior history of myocardial infarction, stroke, transient ischemic attack, or cancer.29 Before randomization, between August 1982 and December 1984, potential participants were asked to provide baseline blood samples, which were collected in EDTA and processed for long-term storage at -80°C. Of randomized study participants, 14 916 (68%) provided baseline plasma samples. At the time of blood collection, all study participants were taking active oral aspirin.
For cases of incident myocardial infarction reported during study follow-up, hospital records, death certificates, and autopsy reports were reviewed by a committee of physicians using standardized criteria to confirm or refute reported events. Reported myocardial infarction was confirmed if symptoms met World Health Organization criteria and the event was associated with increased concentrations of diagnostic cardiac enzymes or characteristic ECG changes. Deaths due to coronary disease were confirmed on the basis of autopsy reports, circumstances of death, symptom patterns, and a history of coronary disease. Silent myocardial infarctions were not included, because they could not be dated accurately.
Study participants who provided an adequate baseline plasma sample for analysis and who had a confirmed myocardial infarction during follow-up (cases) were each matched with 1 control subject. Controls were study participants who also provided adequate baseline plasma samples and who remained free of reported vascular disease during follow-up. Controls were randomly selected from study participants who met the matching criteria of age (±1 year), length of study follow-up (6-month intervals), and smoking status (past smoker, current smoker, or never smoked). With these criteria, 202 cases and 202 matched controls were evaluated in this analysis.
Stored plasma obtained at baseline from each case and control subject was thawed and assayed for IL-6 by use of a commercially available ELISA (R&D Systems). In pilot data based on these frozen plasma samples, coefficients of variation ranged between 5% and 11%, and repeat determinations on the same plasma sample were highly correlated (r=0.93, P<0.001). Blood specimens were analyzed in blinded pairs, with the position of the case specimen varied at random within pairs to reduce the possibility of systematic bias and minimize interassay variability. Methods used to evaluate baseline lipid parameters, homocysteine, fibrinogen, C-reactive protein, and tissue-type plasminogen activator have been described elsewhere.16 30 31 32
Because IL-6 levels were skewed, median concentrations were computed, and the significance of any differences in median values between cases and controls was assessed by Wilcoxon rank-sum test. We used logistic regression analysis, conditioned on the matching variables of age and smoking, to determine relative risks of future myocardial infarction after dividing the study sample into quartiles of IL-6 based on the distribution of the control values. Adjusted estimates of risk were obtained with multivariate models that additionally controlled for body-mass index; history of diabetes, hypertension, or hyperlipidemia; parental history of premature atherosclerosis; and randomized treatment assignment. Stratified analyses were performed in low-risk subgroups and by duration of follow-up. All probability values are 2-tailed, and all CIs were computed at the 95% level.
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Results |
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Baseline characteristics of the study participants are shown in Table 1
. Owing to matching, the
distribution of age and smoking was identical for cases and controls.
As expected in a prospective study of myocardial infarction, cases had
higher baseline levels of total cholesterol and
triglycerides, lower levels of HDL cholesterol,
and a greater prevalence of hypertension and obesity than controls.
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The overall frequency distribution of baseline IL-6 levels is
presented in Figure 1. As shown,
IL-6 levels ranged between 0.015 and 10.01 pg/mL in a pattern virtually
identical to that expected from fresh blood samples obtained in
otherwise healthy populations (0.01 to 11.5 pg/mL; data on file, R&D
Systems, Minneapolis, Minn).
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Median plasma concentrations of IL-6 at baseline were significantly
higher among men who went on to experience a first myocardial
infarction than among men who remained free of reported
cardiovascular disease during follow-up (1.81 versus
1.46 pg/mL; P=0.002). As shown in Table 2, these differences were present in
the total cohort as well as in the low-risk subgroups of nonsmokers and
those with no history of hypertension, hyperlipidemia,
diabetes, or obesity or a family history of premature myocardial
infarction (all P
0.001).
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As shown in Table 3, the relative risk of
first myocardial infarction increased with increasing quartiles of
baseline IL-6 concentration (P for trend <0.001) such that
men in the highest quartile at baseline had a relative risk 2.3 times
higher than those in the lowest quartile (95% CI 1.3 to 4.3,
P=0.005); overall, each quartile increase in baseline plasma
concentration of IL-6 was associated with a statistically significant
38% increase in risk of future myocardial infarction (95% CI 15% to
66%, P=0.001).The relationship between baseline IL-6 level
and risk of future myocardial infarction 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, and exercise frequency
(Table 3).
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Smokers had significantly higher median concentrations of IL-6 than did
nonsmokers (2.23 versus 1.58 pg/mL; P<0.001). However,
because we matched case and control subjects on smoking status,
confounding by this factor was minimized. Moreover, in analyses
limited to nonsmokers, the relationship between baseline level of IL-6
and subsequent risk remained highly significant such that the relative
risks of future myocardial infarction from lowest to highest quartiles
of IL-6 among nonsmokers were 1.0, 1.4, 2.5, and 2.6 (P for
trend 0.001). As in the total cohort, these effects were minimally
altered in analyses that adjusted for lipid and nonlipid risk
factors (Table 3
).
To assess whether the effect of baseline IL-6 levels on risk of future
myocardial infarction varied over time, we stratified our
analyses by months of follow-up. Statistically significant
increases in risk were found to be associated with elevations of IL-6
in the first 2 years of follow-up (P=0.04), in years 2 to 4
(P=0.006), and in years 4 to 6 (P=0.02). As shown
in Figure 2, the relative risk associated
with each increasing quartile of baseline IL-6 level was stable over
long periods of time, with no significant time trends noted.
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Log-normalized concentration of IL-6 was not correlated with total cholesterol (r=-0.01, P=0.9) or triglycerides (r=0.03, P=0.5) and was modestly correlated with HDL cholesterol (r=0.15, P=0.003). Modest correlations were also found between IL-6 and several nontraditional markers of vascular risk, including antigen level for tissue-type plasminogen activator (r=0.21, P=0.004), total plasma homocysteine (r=0.15, P=0.003), fibrinogen (r=0.24, P=0.002), and soluble intercellular adhesion molecule-1 (r=0.19, P=0.001). The strongest correlate of IL-6 in these data was log-normalized plasma concentration of C-reactive protein (r=0.43, P=0.001). However, the relationship between IL-6 and myocardial infarction remained statistically significant after controlling for this inflammatory marker. Specifically, in analyses that adjusted for baseline plasma concentration of C-reactive protein, a 44% increase in relative risk of future myocardial infarction was associated with each increasing quartile of IL-6 (95% CI 12% to 86%, P=0.005).
Nonlipid cardiovascular risk factors that correlated
with IL-6 levels included age (r=0.15, P=0.002),
systolic (r=0.27, P=0.001) and
diastolic (r=0.21, P=0.001) blood
pressure, and body mass index (r=0.26, P=0.001).
As shown in Figure 3, median levels of
IL-6 increased with increasing number of traditional risk factors
(hypertension, hyperlipidemia, smoking, diabetes, age
>60 years, family history, and body mass index >27.3
kg/m2) (P for trend 0.001). However,
as shown in Tables 2 and 3, adjustment for these factors
had a minimal effect on the relationship between IL-6 levels and future
risk of myocardial infarction. Alcohol consumption also appeared to
affect IL-6 such that daily drinkers had significantly higher plasma
levels than those who consumed alcohol on a less frequent basis (2.7
versus 2.9 pg/mL; P=0.001). By contrast, daily exercisers
tended to have lower levels of IL-6 than those who exercised less
frequently, although this association was not statistically significant
(2.1 versus 2.3 pg/mL; P=0.2). As shown in our
multivariate analyses, additional control for
these factors had no effect on our overall results.
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We repeated these analyses for events that occurred before the termination of the randomized aspirin component of the Physicians’ Health Study. In this subgroup, as in the cohort as a whole, each increasing quartile of IL-6 was associated with an increased risk of subsequent myocardial infarction (P for trend 0.001) such that those with the highest levels at baseline had a relative risk 4.1 times higher than those with the lowest levels (95% CI 1.7 to 9.5, P=0.001). The highest risk was observed among those with elevated levels of IL-6 who were randomly assigned to placebo (relative risk 7.3, P=0.001). The reduction in risk of first myocardial infarction attributable to aspirin was similar for those with and without elevated levels of IL-6.
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Discussion |
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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.
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Acknowledgments |
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This study was supported by funding from the National Heart, Lung, and Blood Institute (HL58755) and by an Established Investigator Award from the American Heart Association (Dr Ridker).
Received September 23, 1999; revision received November 3, 1999; accepted November 15, 1999.
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C. J. Pemberton, S. D. Raudsepp, T. G. Yandle, V. A. Cameron, and A. M. Richards Plasma cardiotrophin-1 is elevated in human hypertension and stimulated by ventricular stretch Cardiovasc Res, October 1, 2005; 68(1): 109 - 117. [Abstract] [Full Text] [PDF]
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 M Rattazzi, E Faggin, B Bertipaglia, and P Pauletto Innate immunity and atherogenesis Lupus, September 1, 2005; 14(9): 747 - 751. [Abstract] [PDF]
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K. Minoguchi, T. Yokoe, T. Tazaki, H. Minoguchi, A. Tanaka, N. Oda, S. Okada, S. Ohta, H. Naito, and M. Adachi Increased Carotid Intima-Media Thickness and Serum Inflammatory Markers in Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 625 - 630. [Abstract] [Full Text] [PDF]
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W. M. Clark Adiponectin: Spectator or Player? Stroke, September 1, 2005; 36(9): 1919 - 1920. [Full Text] [PDF]
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J. Hetzel, B. Balletshofer, K. Rittig, D. Walcher, W. Kratzer, V. Hombach, H.-U. Haring, W. Koenig, and N. Marx Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1804 - 1809. [Abstract] [Full Text] [PDF]
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C. Zoccali, G. Tripepi, S. Cutrupi, P. Pizzini, and F. Mallamaci Low Triiodothyronine: A New Facet of Inflammation in End-Stage Renal Disease J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2789 - 2795. [Abstract] [Full Text] [PDF]
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I. Tzoulaki, G. D. Murray, A. J. Lee, A. Rumley, G. D.O. Lowe, and F. G. R. Fowkes C-Reactive Protein, Interleukin-6, and Soluble Adhesion Molecules as Predictors of Progressive Peripheral Atherosclerosis in the General Population: Edinburgh Artery Study Circulation, August 16, 2005; 112(7): 976 - 983. [Abstract] [Full Text] [PDF]
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A. M. Gori, A. M. Corsi, S. Fedi, A. Gazzini, F. Sofi, B. Bartali, S. Bandinelli, G. F. Gensini, R. Abbate, and L. Ferrucci A proinflammatory state is associated with hyperhomocysteinemia in the elderly Am. J. Clinical Nutrition, August 1, 2005; 82(2): 335 - 341. [Abstract] [Full Text] [PDF]
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 P Danielsson, L Truedsson, K-F Eriksson, and L Norgren Inflammatory markers and IL-6 polymorphism in peripheral arterial disease with and without diabetes mellitus Vascular Medicine, August 1, 2005; 10(3): 191 - 198. [Abstract] [PDF]
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H. Yamagami, K. Kitagawa, T. Hoshi, S. Furukado, H. Hougaku, Y. Nagai, and M. Hori Associations of Serum IL-18 Levels With Carotid Intima-Media Thickness Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1458 - 1462. [Abstract] [Full Text] [PDF]
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