This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Volpato, S. Articles by Harris, T. B. Search for Related Content PubMed PubMed Citation Articles by Volpato, S. Articles by Harris, T. B. Related Collections Risk Factors Epidemiology

(Circulation. 2001;103:947.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Cardiovascular Disease, Interleukin-6, and Risk of Mortality in Older Women

The Women’s Health and Aging Study

Stefano Volpato, MD, MPH; Jack M. Guralnik, MD, PhD; Luigi Ferrucci, MD, PhD; Jennifer Balfour, PhD; Paulo Chaves, MD; Linda P. Fried, MD, MPH; Tamara B. Harris, MD, MS

From the Epidemiology, Demography, and Biometry Program, National Institute on Aging, Bethesda, Md (S.V., J.M.G., L.F., J.B., T.B.H.); the Geriatric Department, I Fraticini, Italian National Institute for Research and Care on Aging (INRCA), Florence, Italy (L.F.); and the Departments of Medicine and Epidemiology, The Johns Hopkins Medical Institutions, Baltimore, Md (P.C., L.P.F.).

Correspondence to Stefano Volpato, MD, MPH, National Institute on Aging, 7201 Wisconsin Ave, Room 3C-309, Bethesda, MD 20892. E-mail volpatos{at}nia.nih.gov

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Systemic chronic inflammation has been found to be related to all-cause mortality risk in older persons. We investigated whether specific chronic conditions, particularly cardiovascular disease (CVD), affect the association between high interleukin (IL)-6 level and mortality in a sample of disabled older women.

Methods and Results—IL-6 serum level was measured at baseline in 620 women 65 years old. The presence and severity of medical conditions was ascertained by standard criteria that used multiple sources of information. The sample was surveyed over the 3-year follow-up. After adjustment for potential confounders, compared with those in the lowest tertile, women in the highest IL-6 tertile were at higher risk of all-cause mortality. The presence of CVD, however, strongly affected the risk of mortality associated with high IL-6. Among women with prevalent CVD, those with high IL-6 levels had >4-fold risk of death (RR 4.6; 95% CI 2.0 to 10.5) compared with women in the lowest tertile, whereas the relative risk associated with high IL-6 among those without CVD was much lower and not significant (RR 1.8; 95% CI 0.7 to 4.2). Adjustment for all chronic diseases and disease severity measures, including ankle-brachial index, forced expiratory volume, and exercise tolerance, did not change the results.

Conclusions—IL-6 level is helpful in identifying a subgroup of older CVD patients with high risk of death over a period of 3 years. Systemic inflammation, as measured by IL-6, may be related to the clinical evolution of older patients with CVD.

Key Words: interleukins • cardiovascular diseases • mortality • women • aging

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Circulating levels of acute-phase proteins have been shown to be associated with and to predict the onset of cardiovascular events.^{1 2 3 4} The predictive value of these markers, including C-reactive protein (CRP), has been demonstrated for subjects with preexisting coronary heart disease (CHD) as well as for apparently healthy subjects.^{3 4} More recently, increased levels of interleukin-6 (IL-6) and CRP have been also associated with high risk of all-cause mortality in older people.^{5 6 7}

A persistent inflammatory state has been proposed to be involved in the causal pathway of certain age-related chronic conditions.⁸ In particular, there is strong evidence of a substantial role for inflammation in the development and progression of atherosclerosis.¹ Increased levels of CRP and IL-6 are associated with acute ischemic conditions, and CRP is a predictor of recurrent events in patients with coronary heart disease.^{4 9 10} The serum level of IL-6, along with other cytokines, has also been associated with unfavorable clinical outcomes in patients hospitalized for unstable angina.¹¹ Furthermore, many chronic conditions that are common causes of death in older persons may stimulate and sustain a systemic inflammatory state, which can be measured as increased levels of CRP, IL-6, or other proinflammatory cytokines. Secretion of IL-6, which is a major determinant of the production of acute-phase proteins, is increased in clinical situations characterized by tissue injury, including infections, malignant neoplasms, ischemic diseases, and trauma.^{12 13} This pathophysiological mechanism could also explain the excess risk of mortality associated with increased circulating levels of inflammatory markers.

Only a few population-based studies have investigated the association between circulating levels of IL-6 or CRP and the risk of all-cause mortality.^{5 6 7} Results from these studies suggest that markers of inflammation may be helpful in identifying high-risk subjects. The influence of clinical and subclinical chronic diseases on this association, however, has not been fully investigated, and consequently, the prognostic value of these markers of inflammation, independent of disease status, remains uncertain. The Women’s Health and Aging Study (WHAS) is a prospective study of older disabled women that has detailed information on the prevalence of the major chronic diseases along with objective measures of disease severity. Thus, this data set gave us the opportunity to investigate the value of IL-6 as an independent predictor of 3-year risk of mortality, taking into account the presence and severity of chronic conditions, in particular cardiovascular diseases.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
The WHAS is a study of the causes and course of disability among moderately to severely disabled older women living in the community. The study design is described in detail elsewhere.¹⁴ Briefly, a random sample of 6521 community-dwelling women 65 years old was selected from the Health Care Financing Administration’s Medicare Eligibility list for Baltimore, Md. Women who reported difficulty with 1 task in 2 of 4 domains of functioning (mobility/exercise tolerance, upper extremity activities, basic self-care, and higher functioning tasks of independent living) and who had a Mini Mental State score 18 were considered eligible for the study. Seventy-one percent (1002) of those eligible (1049) agreed to participate. Blood samples were obtained within 180 days from the baseline examination in 634 subjects, processed, placed on ice, and sent the same day to the Quest Diagnostic Laboratories in Teterboro, NJ. Samples were also processed to obtain aliquots of serum or plasma that were stored at -80°C. Participants who did not provide blood samples were older and had more disability in activities of daily living but were not different in body mass index (BMI) or number of chronic diseases.

Biochemical Measures
IL-6 was measured in duplicate by ELISA from the frozen specimens with a commercial kit (High Sensitivity Quantikine kit, R&D Systems), and the average of the 2 measurements was used in the analysis. CRP was measured by nephelometry from fresh serum, according to the method of Behring Diagnostic. Albumin was measured with dye-binding bromocresol green.

Mortality Follow-Up
Vital status was ascertained through follow-up interviews with proxies, obituaries, and matching with the National Death Index over the 3-year follow-up period. Death certificates were obtained for all but 6 of the women who died. Cause-specific mortality was based on underlying cause of death coded according to the International Classification of Diseases as any cardiovascular mortality (codes 390 to 459; 41 deaths) or all other mortality (48 deaths).

Other Measures
Seventeen chronic diseases were ascertained at baseline with disease-specific standardized algorithms.¹⁴ The algorithms used data from the baseline interview, the nurse’s examination (including ECG, the ankle-brachial index [ABI], and spirometry), and the participant’s current medication list. Additional information was collected from medical records, blood test results, and a questionnaire sent to the participant’s primary care physicians. Disease categories used in this analysis were coronary heart disease (CHD; angina or myocardial infarction), peripheral arterial diseases (PAD), stroke, congestive heart failure (CHF), hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and malignant neoplasms. History of CVD was defined as the presence of 1 of the following: CHD, CHF, PAD, and stroke.

The ABI, measured with a Doppler stethoscope (Parks model 841-A), was used as an indicator of severity of atherosclerosis.¹⁵ The ABI was categorized with the cutoff points of 1.5, 1, and 0.9; 2 subjects with ABI values >1.5 were excluded. Forced expiratory volume at the first second (FEV₁) served as a marker of pulmonary function and was measured with a PJ5 Spirometer with a pneumotachograph (Tamarac Co). Sixty-five percent of participants had a valid result on spirometry examination. For women without spirometric measurements, a missing-value category was created and included in all models. Cardiovascular functional class was assessed from self-reported exercise tolerance, estimated from a modified version of the Specific Activity Scale.¹⁶ This scale consists of 18 activities grouped into 6 categories according to the estimated metabolic equivalents (METs) required to perform the activity. Three levels of exercise tolerance were defined according to the type of physical task the participants were able to perform without symptoms: (1) low (<2.5 METs), (2) middle (2.5 to 5 METs), and (3) high (>5 METs). Presence of orthopnea, exertional chest pain, and ankle edema was assessed from baseline assessment. BMI (kg/m²), computed by objective measures, was categorized in a 3-level variable using the cutoff points of 21.44 and 31.58 (15th and 85th percentiles, respectively, for a nationally representative sample of older women).¹⁷ Sociodemographic characteristics included age, race, and self-reported household income. History of smoking and medication use was ascertained from baseline interview.

Statistical Analysis
Baseline characteristics were compared across tertiles of IL-6 (1.78 pg/mL, n=214; 1.79 to 3.10 pg/mL, n=204; >3.10 pg/mL, n=202) by use of age-adjusted logistic regression models for binary outcomes and age-adjusted general linear models for continuous dependent variables. Death rates per 1000 person-years were calculated. Cox proportional-hazard regression models were then used to compare survival function according to baseline IL-6 tertiles, adjusting for several potential confounders. Tests for trends were ascertained from models with tertiles of IL-6 concentration entered as an ordinal variable.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The mean age of participants was 77.8 years (65 to 100 years), and 50% had a history of any cardiovascular disease. History of smoking, BMI, CHD, PAD, CHF, diabetes, and COPD were all associated with greater levels of IL-6 (Table 1). Women in the highest tertile of IL-6 also had lower ABI, FEV₁, and exercise tolerance, whereas the prevalence of functional limitation was higher in women with high IL-6. No association was found between stroke, hypertension, and cancer and IL-6 level.

View this table: [in this window] [in a new window]   Table 1. Demographic and Health-Related Characteristics of Subjects by Tertile of Interleukin-6

After 3 years, 95 of 620 women had died (Table 2). In the unadjusted analysis, women in the highest tertile of IL-6 had an almost 4-fold risk of mortality (RR 3.8; 95% CI 2.2 to 6.6) compared with women in the lowest tertile. The point estimate remained almost unchanged after adjustment for age, smoking history, and BMI (RR 3.5; 95% 2.1 to 6.2), but there was a more pronounced reduction after chronic disease, and measures of disease severity were included into the model (RR 2.6; 95% CI 1.5 to 4.7). The risk associated with the highest level of IL-6 was still substantial and statistically significant after further adjustment for other markers of inflammation, including CRP and albumin (model 4).

View this table: [in this window] [in a new window]   Table 2. Crude and Adjusted Relative Risks of All-Cause Mortality by Baseline IL-6 Tertile

We found an interaction between CVD status and IL-6 concentration (P value for the interaction term =0.09 in fully adjusted model), suggesting that the excess risk of mortality associated with high IL-6 was larger in women with CVD than in those without; therefore, the analyses were stratified according to history of CVD (Table 3). Among participants with CVD, the unadjusted risk of mortality increased progressively according to IL-6 level. Adjustment for confounders did not change the results. Conversely, among women without CVD, the crude relative risk for those in the highest tertile of IL-6 was 2.5 (95% CI 1.1 to 5.7), but the inclusion into the model of potential confounders, particularly disease history and severity, progressively reduced the size of the relative risk, which became no longer statistically significant.

View this table: [in this window] [in a new window]   Table 3. Crude and Adjusted Relative Risks of All-Cause Mortality by Baseline IL-6 Tertile and History of CVD

In analyses that evaluated risk for specific cause of death, high IL-6 levels were associated with both cardiovascular and noncardiovascular mortality. The association was somewhat stronger for mortality not related to CVD (Table 4).

View this table: [in this window] [in a new window]   Table 4. Association Between Baseline IL-6 and Cause-Specific Mortality

To assess the hypothesis of the effect of preexisting diseases on IL-6 level, we also examined the relation between IL-6 and mortality by 2 different follow-up periods. The increased mortality associated with high IL-6 level was very high in the first 18 months (RR 5.7; 95% CI 1.9 to 16.5) and tended to attenuate in the following months (Table 5). In the second part of the follow-up, women with high IL-6 had a 2-fold risk of mortality (RR 2.2; 95% CI 1.1 to 4.4) compared with those in the first tertile, and after full adjustment, the risk was reduced to 1.6 (95% CI 0.8 to 3.3). In light of these findings, we estimated the mortality risk according to history of CVD separately in the 2 follow-up periods (Figure). In the first 18 months, women in the highest tertile of IL-6 had high mortality rates regardless of the presence of CVD. In contrast, during the second half of the follow-up, for women with preexisting CVD, we found a stepwise dose-response relationship between IL-6 concentration and the risk of death. In a separate fully adjusted model, women in the middle and highest tertiles had a relative risk of death of 1.8 (95% CI 0.6 to 4.9) and 2.8 (95% CI 1.01 to 7.03; P for linear trend =0.030), respectively, compared with those in the lowest tertile.

View this table: [in this window] [in a new window]   Table 5. Crude and Adjusted Relative Risks of All-Cause Mortality by Baseline IL-6 Tertile and Follow-Up Period

View larger version (28K): [in this window] [in a new window]   Figure 1. Age-adjusted all-cause mortality rates/1000 person-years by IL-6 levels, history of CVD, and follow-up period. Figures on bars are numbers of deaths and subjects at risk.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The findings of this study demonstrated a strong, nonspecific association between IL-6 levels and subsequent risk of mortality among older women with preexisting CVD. Using data from a sample of randomly selected disabled women, we demonstrated that the risk of death associated with high levels of IL-6 is dependent on history of CVD. Indeed, the association was substantial and consistent during the entire study for women with CVD, whereas for those without CVD, the risk was relevant in the unadjusted analysis but completely disappeared after adjustment for potential confounders. Several chronic conditions were associated with IL-6 level; nevertheless, in multivariate analyses including prevalent chronic conditions and indicators of severity of disease, the association between IL-6 and risk of death in women with CVD was not substantially reduced, suggesting a possible pathophysiological role of this proinflammatory cytokine in the process leading to death.

Our results confirm, at a population level, the findings of previous clinical studies on the potential role of inflammation in the progression of CVD. Increased levels of inflammatory markers, including CRP and IL-6, have been demonstrated in patients with myocardial infarction and unstable and chronic stable angina^{3 10 11} ; levels of IL-6 not only are associated with the severity of the conditions but also are very strong predictors of subsequent outcomes. For example, Biasucci et al¹¹ demonstrated that patients with unstable angina and complicated in-hospital course have higher IL-6 concentrations than subjects without complications. Furthermore, they demonstrated that despite being treated with the same therapy, patients with a fall in IL-6 levels 48 hours after hospital admission had better outcomes than patients without decreases in IL-6 concentration. The presence of a procoagulant effect of inflammation may explain the association between IL-6 level and mortality among subjects with preexisting CVD. CRP, whose secretion is induced by IL-6, may promote thrombosis by activating the complement pathway,¹⁸ and it has been demonstrated that CRP induces circulating monocytes to express tissue factor, a potent procoagulant factor.¹⁹ In addition, proinflammatory cytokines may be involved in destabilizing and disrupting atherosclerotic plaque. The presence of an inflammatory process characterizes the site of plaque rupture or erosion,²⁰ and proinflammatory cytokines upregulate the expression of matrix metalloproteinases, which are known to be involved in the vascular remodeling and plaque disruption.²¹

Elevated circulating levels of cytokines have also been demonstrated in patients with CHF. In particular, tumor necrosis factor²² and IL-6²³ were associated with the severity of left ventricular dysfunction and with the degree of activation of the sympathetic and renin-angiotensin systems. It is not clear whether this increase of circulating cytokines is mainly an epiphenomenon of the severity of the underlying cardiac impairment,¹³ but in vitro and in vivo studies suggest that proinflammatory cytokines might depress myocardial contractility.^{24 25} From this point of view, our results may support such an independent effect of IL-6. Indeed, in a separate analysis among the 63 women with CHF, after full adjustment, we found a significant and graded relationship between IL-6 level and risk of death (data not shown).

Nevertheless, we found that the association between IL-6 and mortality risk was not limited to CVD mortality, and it was even stronger for cause of death unrelated to CVD. These findings are in agreement with recent studies in older populations,^{5 7} and they suggest that chronic inflammation is probably involved in the pathophysiology of many conditions, as already suggested by others.¹² In addition, it is possible that in older patients, the presence of CVD strongly interacted with other conditions, including cancer and pneumonia, in the process leading to death. Indeed, 30 of 48 patients with non-CVD mortality either had CVD as first-listed contributing cause of death in the death certificate or had prevalent CVD.

Few population-based studies have investigated the association between inflammation and health outcomes in subjects without CVD. Ridker et al,²⁶ in a cohort of apparently healthy women, showed that baseline CRP level was a strong predictor of the incidence of cardiovascular events during a 3-year follow-up period; nevertheless, this study did not evaluate the mortality risk. Using data from the Multiple Risk Factor Intervention Trial, Kuller and coauthors²⁷ demonstrated a strong association between CRP and the risk of CHD death. Men without clinical CVD composed the study population, but they were smokers and had other CVD risk factors, and the possibility of preexisting subclinical CVD cannot be ruled out. Harris et al⁵ recently reported that in older persons, the relation between IL-6, CRP, and the risk of mortality was similar for those with and without CVD. Nevertheless, disease status was classified from only self-reported data, and CHF was not included in the CVD classification. These methodological differences might partially explain the inconsistency between the results of the above-mentioned population-based studies and ours. Conversely, some characteristics of our study could explain the lack of association in women without baseline CVD. First, a 3-year follow-up period may not be long enough to demonstrate the effects of inflammation on risk of death in women without preexisting CVD. Indeed, the number of deaths in the subgroup without CVD (n=31) was relatively small compared with the number in women with CVD (n=64). Second, our cohort includes disabled women affected, on average, by a high level of comorbidity. It is possible that in this group of participants, the effect of IL-6 was obscured by the presence of other conditions not related to inflammation. Other studies, with different study design, are needed to clarify the association between IL-6 and mortality in older persons without CVD. Our findings seem to be consistent with a previous observation of the Cardiovascular Health Study, however, showing that in older women, the relationship between CRP and incident CVD events is limited to subjects with subclinical disease.²⁸

Our analysis is based on a double approach for taking into account the baseline severity of disease by adjusting for measure of disease severity in multivariate analyses and by stratifying for early and late follow-up period. The results of both analyses indicated an independent relationship of IL-6 level with the risk of death in women with CVD; nevertheless, a residual confounding effect of baseline disease status cannot be completely ruled out. Indeed, other measures that were not available for this study, including carotid ultrasound, ejection fraction determination, objective exercise tolerance testing, and assessment of diabetes complications, could have provided more precise and appropriate information.

In conclusion, our findings confirm that IL-6 is helpful in identifying a subgroup of older CVD patients with high risk of death over a period of 3 years. Although IL-6 was not specifically related to cardiovascular mortality, these results suggest that the relation with mortality is not explained simply by the severity of concomitant diseases and that systemic inflammation may be related to a poorer clinical course in subjects with CVD.

	Acknowledgments

 
This study was supported by contract NO1-AG-1-2112 from the National Institute on Aging.

Received September 6, 2000; revision received October 19, 2000; accepted October 19, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126.[Free Full Text]
   
2. Biasucci LM, Vitelli A, Liuzzo G, et al. Elevated levels of interleukin-6 in unstable angina. Circulation. 1996;94:874–877.[Abstract/Free Full Text]
   
3. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424.[Abstract/Free Full Text]
   
4. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.[Abstract/Free Full Text]
   
5. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506–512.[Medline] [Order article via Infotrieve]
   
6. Jager A, van Hinsbergh VW, Kostense PJ, et al. von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler Thromb Vasc Biol. 1999;19:3071–3078.[Abstract/Free Full Text]
   
7. Gussekloo J, Schaap MC, Frolich M, et al. C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol. 2000;20:1047–1051.[Abstract/Free Full Text]
   
8. Ershler WB, Sun WH, Binkley N. The role of interleukin-6 in certain age-related diseases. Drugs Aging. 1994;5:358–365.[Medline] [Order article via Infotrieve]
   
9. Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100:793–798.[Abstract/Free Full Text]
   
10. Liuzzo G, Baisucci LM, Gallimore JR, et al. Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol. 1999;34:1696–1703.[Abstract/Free Full Text]
    
11. Biasucci LM, Liuzzo G, Fantuzzi G, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999;99:2079–2084.[Abstract/Free Full Text]
    
12. Papanicolaou DA, Wilder RL, Manolagas SC, et al. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 1998;128:127–137.[Abstract/Free Full Text]
    
13. Aukrust P, Ueland T, Lien E, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;83:376–382.[Medline] [Order article via Infotrieve]
    
14. Guralnik JM, Fried LP, Simonsick EM, et al, eds. The Women’s Health and Aging Study. Health and Social Characteristics of Older Women with Disability. Bethesda, MD: National Institute on Aging; 1995: NIH publication No. 95-4009.
    
15. Newman AB, Siscovick DS, Manolio TA, et al, Cardiovascular Heart Study (CHS) Collaborative Research Group. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation. 1993;88:837–845.[Abstract/Free Full Text]
    
16. Goldman L, Hashimoto B, Cook EF, et al. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation. 1981;64:1227–1234.[Abstract/Free Full Text]
    
17. Must A, Dallal GE, Dietz WH. Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht²) and triceps skinfold thickness. Am J Clin Nutr. 1991;53:839–846.[Abstract/Free Full Text]
    
18. Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol. 1983;34:141–212.[Medline] [Order article via Infotrieve]
    
19. Cermak J, Key NS, Bach RR, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993;82:513–520.[Abstract/Free Full Text]
    
20. van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36–44.[Abstract/Free Full Text]
    
21. Rajavashisth TB, Xu XP, Jovinge S, et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation. 1999;99:3103–3109.[Abstract/Free Full Text]
    
22. Levine B, Kalman J, Mayer L, Fillit HM, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–241.[Abstract]
    
23. Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol. 1998;31:391–398.[Abstract/Free Full Text]
    
24. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257:387–389.[Abstract/Free Full Text]
    
25. Blum A, Miller H. Role of cytokines in heart failure. Am Heart J. 1998;135:181–186.[Medline] [Order article via Infotrieve]
    
26. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843.[Abstract/Free Full Text]
    
27. Kuller LH, Tracy RP, Shaten J, et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;144:537–547.[Abstract/Free Full Text]
    
28. Tracy RP, Psaty BM, Macy E, Bovill EG, Cushman M, Cornell ES, Kuller LH. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997;17:2167–2176. [Abstract/Free Full Text]
    

This article has been cited by other articles:

				L. Gallicchio, H. Chang, D. K. Christo, L. Thuita, H.-Y. Huang, P. Strickland, I. Ruczinski, S. C. Hoffman, and K. J. Helzlsouer Single Nucleotide Polymorphisms in Inflammation-related Genes and Mortality in a Community-based Cohort in Washington County, Maryland Am. J. Epidemiol., April 1, 2008; 167(7): 807 - 813. [Abstract] [Full Text] [PDF]

				W. Koenig, N. Khuseyinova, J. Baumert, and C. Meisinger Prospective Study of High-Sensitivity C-Reactive Protein as a Determinant of Mortality: Results from the MONICA/KORA Augsburg Cohort Study, 1984-1998 Clin. Chem., February 1, 2008; 54(2): 335 - 342. [Abstract] [Full Text] [PDF]

				S. Shinkai, P. H. M. Chaves, Y. Fujiwara, S. Watanabe, H. Shibata, H. Yoshida, and T. Suzuki {beta}2-Microglobulin for Risk Stratification of Total Mortality in the Elderly Population: Comparison With Cystatin C and C-Reactive Protein Arch Intern Med, January 28, 2008; 168(2): 200 - 206. [Abstract] [Full Text] [PDF]

				A. Cvoro, D. Tatomer, M.-K. Tee, T. Zogovic, H. A. Harris, and D. C. Leitman Selective Estrogen Receptor- Agonists Repress Transcription of Proinflammatory Genes J. Immunol., January 1, 2008; 180(1): 630 - 636. [Abstract] [Full Text] [PDF]

				D. Adamis, A. Treloar, F.-Z. Darwiche, N. Gregson, A. J. D. Macdonald, and F. C. Martin Associations of delirium with in-hospital and in 6-months mortality in elderly medical inpatients Age Ageing, November 1, 2007; 36(6): 644 - 649. [Abstract] [Full Text] [PDF]

				M. Jylha, P. Paavilainen, T. Lehtimaki, S. Goebeler, P. J. Karhunen, A. Hervonen, and M. Hurme Interleukin-1 Receptor Antagonist, Interleukin-6, and C-Reactive Protein as Predictors of Mortality in Nonagenarians: The Vitality 90+ Study J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2007; 62(9): 1016 - 1021. [Abstract] [Full Text] [PDF]

				E. I. Boesen and D. M. Pollock Effect of chronic IL-6 infusion on acute pressor responses to vasoconstrictors in mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1745 - H1749. [Abstract] [Full Text] [PDF]

				W. Koenig and N. Khuseyinova Biomarkers of Atherosclerotic Plaque Instability and Rupture Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]

				M. R. Irwin, M. Wang, C. O. Campomayor, A. Collado-Hidalgo, and S. Cole Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med, September 18, 2006; 166(16): 1756 - 1762. [Abstract] [Full Text] [PDF]

				M. K. Figaro, S. B. Kritchevsky, H. E. Resnick, R. I. Shorr, J. Butler, A. Shintani, B. W. Penninx, E. M. Simonsick, B. H. Goodpaster, A. B. Newman, et al. Diabetes, Inflammation, and Functional Decline in Older Adults: Findings from the Health, Aging and Body Composition (ABC) study. Diabetes Care, September 1, 2006; 29(9): 2039 - 2045. [Abstract] [Full Text] [PDF]

				C. Maraldi, S. Volpato, S. B. Kritchevsky, M. Cesari, E. Andresen, C. Leeuwenburgh, T. B. Harris, A. B. Newman, A. Kanaya, K. C. Johnson, et al. Impact of inflammation on the relationship among alcohol consumption, mortality, and cardiac events: the health, aging, and body composition study. Arch Intern Med, July 24, 2006; 166(14): 1490 - 1497. [Abstract] [Full Text] [PDF]

				T. T. Antunes, A. Gagnon, B. Chen, F. Pacini, T. J. Smith, and A. Sorisky Interleukin-6 release from human abdominal adipose cells is regulated by thyroid-stimulating hormone: effect of adipocyte differentiation and anatomic depot Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1140 - E1144. [Abstract] [Full Text] [PDF]

				R. S. Vasan Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations Circulation, May 16, 2006; 113(19): 2335 - 2362. [Full Text] [PDF]

				M. Maggio, S. Basaria, A. Ble, F. Lauretani, S. Bandinelli, G. P. Ceda, G. Valenti, S. M. Ling, and L. Ferrucci Correlation between Testosterone and the Inflammatory Marker Soluble Interleukin-6 Receptor in Older Men J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 345 - 347. [Abstract] [Full Text] [PDF]

				J. Walston, Q. Xue, R. D. Semba, L. Ferrucci, A. R. Cappola, M. Ricks, J. Guralnik, and L. P. Fried Serum Antioxidants, Inflammation, and Total Mortality in Older Women Am. J. Epidemiol., January 1, 2006; 163(1): 18 - 26. [Abstract] [Full Text] [PDF]

				E. M. Friedman, M. S. Hayney, G. D. Love, H. L. Urry, M. A. Rosenkranz, R. J. Davidson, B. H. Singer, and C. D. Ryff Social relationships, sleep quality, and interleukin-6 in aging women PNAS, December 20, 2005; 102(51): 18757 - 18762. [Abstract] [Full Text] [PDF]

				H. Bruunsgaard Physical activity and modulation of systemic low-level inflammation J. Leukoc. Biol., October 1, 2005; 78(4): 819 - 835. [Abstract] [Full Text] [PDF]

				P. Plomgaard, P. Keller, C. Keller, and B. K. Pedersen TNF-{alpha}, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue J Appl Physiol, June 1, 2005; 98(6): 2019 - 2023. [Abstract] [Full Text] [PDF]

				A. M. W. Petersen and B. K. Pedersen The anti-inflammatory effect of exercise J Appl Physiol, April 1, 2005; 98(4): 1154 - 1162. [Abstract] [Full Text] [PDF]

				T. Hoshi, K. Kitagawa, H. Yamagami, S. Furukado, H. Hougaku, and M. Hori Relations of Serum High-Sensitivity C-Reactive Protein and Interleukin-6 Levels With Silent Brain Infarction Stroke, April 1, 2005; 36(4): 768 - 772. [Abstract] [Full Text] [PDF]

				L. Ferrucci, A. Corsi, F. Lauretani, S. Bandinelli, B. Bartali, D. D. Taub, J. M. Guralnik, and D. L. Longo The origins of age-related proinflammatory state Blood, March 15, 2005; 105(6): 2294 - 2299. [Abstract] [Full Text] [PDF]

				E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw Biochemical risk markers: a novel area for better prediction of renal risk? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508. [Full Text] [PDF]

				S. Leng, Q.-L. Xue, Y. Huang, R. Semba, P. Chaves, K. Bandeen-Roche, L. Fried, and J. Walston Total and Differential White Blood Cell Counts and Their Associations With Circulating Interleukin-6 Levels in Community-Dwelling Older Women J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2005; 60(2): 195 - 199. [Abstract] [Full Text] [PDF]

				J. A Joseph, B. Shukitt-Hale, and G. Casadesus Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds Am. J. Clinical Nutrition, January 1, 2005; 81(1): 313S - 316S. [Abstract] [Full Text] [PDF]

				J. A. McKenzie, E. P. Weiss, I. A. Ghiu, O. Kulaputana, D. A. Phares, R. E. Ferrell, and J. M. Hagberg Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes J Appl Physiol, October 1, 2004; 97(4): 1338 - 1342. [Abstract] [Full Text] [PDF]

				R. D. Brook, B. Franklin, W. Cascio, Y. Hong, G. Howard, M. Lipsett, R. Luepker, M. Mittleman, J. Samet, S. C. Smith Jr, et al. Air Pollution and Cardiovascular Disease: A Statement for Healthcare Professionals From the Expert Panel on Population and Prevention Science of the American Heart Association Circulation, June 1, 2004; 109(21): 2655 - 2671. [Abstract] [Full Text] [PDF]

				S. Volpato, M. Pahor, L. Ferrucci, E. M. Simonsick, J. M. Guralnik, S. B. Kritchevsky, R. Fellin, and T. B. Harris Relationship of Alcohol Intake With Inflammatory Markers and Plasminogen Activator Inhibitior-1 in Well-Functioning Older Adults: The Health, Aging, and Body Composition Study Circulation, February 10, 2004; 109(5): 607 - 612. [Abstract] [Full Text] [PDF]

</

				A. Silvestro, F. Scopacasa, A. Ruocco, G. Oliva, V. Schiano, C. Zincarelli, and G. Brevetti Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease Vascular Medicine, November 1, 2003; 8(4): 225 - 232. [Abstract] [PDF]