Inflammation in Cardiovascular Disease

HomeCirculationVol. 97, No. 20Inflammation in Cardiovascular Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBInflammation in Cardiovascular Disease Cart, Horse, or Both? Russell P. Tracy Russell P. TracyRussell P. Tracy Search for more papers by this author Originally published26 May 1998https://doi.org/10.1161/01.CIR.97.20.2000Circulation. 1998;97:2000–2002In this issue of Circulation, Ridker and colleagues1 discuss the incremental value of CRP as a predictor of future CVD events. Their conclusion is that CRP is at least additive to HDL and total cholesterol with respect to risk prediction. In fact, there is some evidence that lipids and CRP are better predictors jointly than would be expected by adding up their individual predictive powers. CRP appeared to predict events in those at low risk on the basis of lipids, and CRP-lipid relationships to events were minimally altered by adjustment for other known CVD risk factors. These findings have important implications for CVD risk assessment and risk management.CRP is an acute-phase reactant, the levels of which increase dramatically (100-fold or more) in response to severe bacterial infection, physical trauma, and other inflammatory conditions.2 Several roles have been postulated for CRP, including that of an opsonin, promoting the phagocytic uptake of invading microorganisms, and that of a procoagulant, promoting the expression of tissue factor on the monocyte surface. As a marker of inflammation, CRP is unique among the major plasma proteins in the fold increase that is observed and in that its levels appear to be unaffected by hormones and anti-inflammatory drugs but are regulated primarily by the proinflammatory cytokines, especially IL-6.23 Traditionally, 10 mg/L has been used as the cut point to signify clinically important levels, with values in the healthy reference range at or below the lower limit of sensitivity of most assays.Recently, elevated levels of CRP, although still for the most part in the healthy reference range, have been associated with increased risk of future CVD events. Initially, Liuzzo et al4 and Haverkate et al5 established the prognostic usefulness of CRP in the setting of angina. This was followed by studies in otherwise healthy individuals. With the use of new, sensitive CRP assays, CRP was identified as an independent, prospective CVD risk factor in the higher-risk middle-aged men of MRFIT,6 the healthy middle-aged men of the PHS7 and the MONICA-Augsburg cohort,8 and the healthy elderly men and women of the CHS and the Rural Health Promotion Project.9CRP is known to be related to smoking,10 and the MRFIT data indicated that although there was no confounding effect, there was an interaction of smoking with CRP: CRP better predicted events in smokers than in nonsmokers, independently of smoking cessation.6 Consistent with this finding, CRP levels were associated with lifetime exposure to cigarette smoke, independently of cessation, in cross-sectional analyses in the elderly.11 Interestingly, Howard et al12 have recently shown an association of carotid wall thickness with lifetime exposure to cigarette smoke. Taken together, these findings raise the speculation that CRP, at least in some people, may mark permanent underlying endothelial damage due in part to smoking. It is important to note that in the PHS, CRP predicted future events just as well in nonsmokers as in smokers. However, smoking levels were relatively low in the PHS, and event follow-up was from 1 to 7 years, whereas in MRFIT it was from 6 to 17 years.Other important independent correlates of CRP are obesity, markers of fibrinolytic activity, and subclinical atherosclerosis.11 The association of CRP with markers of fibrinolytic activity such as plasmin-α2-antiplasmin complex provides an important link between coagulant/fibrinolytic activity and inflammation. The nature of the link to obesity remains unclear. A possible mechanism may involve the association of adipose tissue with fibrinolysis inhibition.13Taken together, these data strongly support the position that CRP, as a marker of low-level inflammation, indicates increased risk of myocardial infarction and stroke in otherwise healthy individuals. Other acute-phase reactants have been used to indicate increased risk of CVD events.14 Fibrinogen has been shown in a wide variety of studies to consistently predict future CVD events in an independent manner.15 Factor VIII has recently been shown to predict events in middle-aged and older healthy adults.1617 Plasminogen activator inhibitor-1 predicts second myocardial infarctions in survivors of a first infarct18 and, owing to specificity issues of the assays involved, is probably the reason for the important observed association between tissue plasminogen activator antigen and future events in PHS.19 Markers used to estimate serum iron (ferritin) and serum copper (ceruloplasmin) are also acute-phase reactants and have been identified as risk factors in recent studies.2021 During the acute-phase reaction, albumin levels go down, and low levels of albumin predict future events,22 as do low levels of bilirubin (most of which is bound to albumin).23 Even plasma lipids are associated with inflammation, with levels of HDL cholesterol dropping and triglycerides rising,24 both consistent with CVD event prediction. The only “outlier” is total cholesterol, which also drops with inflammation. Finally, the cytokine mediators of inflammation themselves, specifically IL-6, are risk factors.25This raises several questions. First, are all of these measures equivalent with respect to risk prediction? Although there are few head-to-head comparisons, the answer is likely to be no, because although they all respond to inflammation, the factors that regulate many of these proteins are not identical.26 Some respond to both the more “immediate” IL-1/tumor necrosis factor cytokines as well as the more “secondary” IL-6/IL-6–like cytokines, whereas others respond only to the latter. Some are under major hormonal regulation, whereas other are not. Technically, the assays for some are much better than for others, and some factors exhibit much larger within-subject variation than do others. It is unclear which of these is the best assay from the standpoint of prediction, or which group would make the best panel of assays.The report of Ridker and coworkers1 in part addresses this issue. In the PHS, at least, CRP appears to give added information when lipids are considered and is statistically independent of other CVD risk factors. Similar results have been shown for fibrinogen.5Second, is the inflammation that these measures reflect an epiphenomenon of atherosclerotic disease or is it in the CVD-event causal pathway? The best current answer to this question is probably both. Many cross-sectional studies have determined that markers such as fibrinogen, CRP, and others have strong associations with underlying atherosclerotic disease and, given their status as acute-phase proteins that respond to tissue damage, probably reflect atherosclerotic damage. However, there are many plausible mechanistic links between all the above-mentioned variables, including increased clot formation, lipid oxidation, and cell activation and proliferation. Taken together, these data support the position that inflammation is not only a response to the underlying disease process but also an integral part of it.Third, are these markers independent of other estimates of subclinical CVD? Studies in the CHS were characterized by a design that matched cases and controls on the degree of subclinical disease as assessed by carotid wall thickness and several other variables.9 The results suggested that although CRP levels in part reflect underlying atherosclerosis, prediction was not confounded by subclinical CVD. Rather, there appeared to be effect modification, because prediction was stronger in those with subclinical disease than in those without it in the elderly group. This suggests there is added benefit to measuring CRP even if noninvasive measures of atherosclerotic burden are used as well.Fourth, should anti-inflammatory intervention strategies use CRP levels? Although we have limited data on this issue, the original results from the PHS indicated that although aspirin, with respect to incident myocardial infarction, had a protective effect in all CRP strata, this effect was greatest in those with the highest CRP levels at baseline.7 Although this is suggestive, we do not known if long-term aspirin use affects CRP levels. More work is needed on this issue.What may we conclude from these studies? Taken together, these data suggest that it may be time to add a marker of inflammation to the list of CVD risk factors commonly used to assess risk in otherwise-healthy middle-aged men. CRP is a good candidate because (1) levels appear reasonably stable over time,27 (2) levels are affected by little other than inflammation,23 (3) prediction is independent of other known CVD risk factors including lipids,1 (4) prediction appears additive to other noninvasive measures of subclinical atherosclerotic disease,9 (5) CRP predicts future events in both middle-aged and elderly healthy individuals,679 and (6) sensitive, inexpensive assays are becoming available,27 with WHO reference material available for assay standardization.Before it can be put into general use, however, there are several outstanding issues remaining. CRP levels predicted events in middle-aged men, with no indication of an interaction with time to event. However, in the elderly, there was a strong time-to-event dependency, with CRP predicting events <1 year after blood collection better than events >1 year later.9 Therefore, more work is needed to better understand the chronological relationship of CRP to future events in different age groups. In addition, we have little information about CRP and middle-aged women. Other inflammatory factors such as fibrinogen predict events in women as well as men,28 but studies are needed of CRP in middle-aged women, especially because in the elderly, CRP was a better predictor of events in women than in men.9Selected Abbreviations and AcronymsCHS=Cardiovascular Health StudyCRP=C-reactive proteinCVD=cardiovascular diseaseIL=interleukinMRFIT=Multiple Risk Factor Intervention TrialPHS=Physician’s Health StudyThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. References 1 Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation.1998; 97:2007–2011.CrossrefMedlineGoogle Scholar2 Pepys M. C-reactive protein fifty years on. Lancet. 1981;i:653–656.Google Scholar3 Kindmark C. The concentration of C-reactive protein in sera from healthy individuals. Scand J Clin Lab Invest.1972; 29:407–411.CrossrefMedlineGoogle Scholar4 Liuzzo G, Biasucci L, Gallimore J, Grillo R, Rebuzzi A, Pepys M, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med.1994; 331:417–424.CrossrefMedlineGoogle Scholar5 Haverkate F, Thompson S, Duckert F. Haemostasis factors in angina pectoris: relation to gender, age and acute-phase reaction. Thromb Haemost.1995; 73:561–567.CrossrefMedlineGoogle Scholar6 Kuller L, Tracy R, Shaten J, Meilahn E, for the MRFIT Research Group. Relationship of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol.1996; 144:537–547.CrossrefMedlineGoogle Scholar7 Ridker P, Cushman M, Stampfer M, Tracy R, Hennekens C. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.1997; 336:973–979.CrossrefMedlineGoogle Scholar8 Koenig W, Froehlich M, Sund M, Doering A, Fischer H, Loewel H, Hutchinson W, Pepys M. C-reactive protein (CRP) predicts risk of coronary heart disease (CHD) in healthy middle-aged men: results from the MONICA-Augsburg cohort study, 1984/85–1992. Circulation. 1997;96(suppl I):I-99. Abstract.Google Scholar9 Tracy R, Lemaitre R, Psaty B, Ives D, Evans R, Cushman M, Meilahn E, Kuller L. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol.1997; 17:1121–1127.CrossrefMedlineGoogle Scholar10 Das I. Raised C-reactive protein levels in serum from smokers. Clin Chim Acta.1985; 153:9–13.CrossrefMedlineGoogle Scholar11 Tracy R, Macy E, Bovill E, Cushman M, Psaty B, Cornell E, Kuller L. 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.CrossrefMedlineGoogle Scholar12 Howard G, Wagenknecht L, Burke G, Diez-Roux A, Evans G, McGovern P, Nieto F, Tell G, for the ARIC Investigators. Cigarette smoking and progression of atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) study. JAMA.1998; 279:119–124.CrossrefMedlineGoogle Scholar13 Lundgren C, Brown S, Nordt T, Sobel B, Fujii S. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. Circulation.1996; 93:106–110.CrossrefMedlineGoogle Scholar14 Tracy R. Atherosclerosis, thrombosis and inflammation: a question of linkage. Fibrinolysis and Proteolysis. 1997;11(suppl 1):137–142.Google Scholar15 Ernst E, Resch K. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med.1993; 118:956–963.CrossrefMedlineGoogle Scholar16 Folsom A, Wu K, Rosamond W, Sharrett A, Chambless L. Hemostatic factors and incidence of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study. Circulation.1996; 93:622. Abstract.Google Scholar17 Tracy R, Arnold A, Ettinger W, Freid L, Meilahn E, Savage P. Coagulation factor VIII is associated with incident cardiovascular disease and death in the elderly: the Cardiovascular Health Study. Circulation. 1996;94(suppl I):I-457. Abstract.Google Scholar18 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. 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Variability in the measurement of C-reactive protein in healthy subjects: implications for reference interval and epidemiological applications. Clin Chem.1997; 43:52–58.CrossrefMedlineGoogle Scholar28 Kannel W, Wolf P, Castelli W, D’Agostino R. Fibrinogen and risk of cardiovascular disease: the Framingham study. JAMA. 1987;258: 1183–1186.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 26, 1998Vol 97, Issue 20Article InformationMetrics Download: 210 Copyright © 1998 by American Heart Associationhttps://doi.org/10.1161/01.CIR.97.20.2000 Originally publishedMay 26, 1998 KeywordscholesterolC-reactive proteincoagulationrisk factorsfibrinolysisEditorialsPDF download