ORIGINAL ARTICLE Original Article C-Reactive Protein and Interleukin-18 Levels in Relation to Coronary Heart Disease: Prospective Cohort Study from Busselton Western Australia Joseph Hung, FRACP a,∗ , Matthew W. Knuiman, PhD b , Mark L. Divitini, B Appl Sc b , Paul E. Langton, FRACP a , Caroline L. Chapman, PhD c and John P. Beilby, PhD c,d a School of Medicine & Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, Western Australia, Australia b School of Population Health, University of Western Australia, Crawley,Western Australia, Australia c Clinical Biochemistry, PathWest Laboratory Medicine, Perth, Western Australia, Australia d School of Surgery & Pathology, University of Western Australia, Nedlands, Western Australia, Australia Background: Elevated levels of inflammatory markers are associated with incident coronary heart disease (CHD), but it remains controversial whether these markers provide incremental predictive value to conventional risk factors. We investigated the relationship between C-reactive protein (CRP) and interleukin-18 (IL-18) levels and risk of CHD in men and women without initial cardiovascular disease. Methods: A prospective case-cohort design over the period 1981–2001 involving 253 incident CHD cases and a random sub-cohort of 441 subjects was used. Cox proportional hazards regression was used to estimate the relative risks (RRs) of CHD for continuous and tertiles of CRP and IL-18 after controlling for conventional risk factors. Results: The multivariate-adjusted RR of CHD associated with one unit increase in log CRP in the overall population was 1.29 (1.07, 1.55; trend P = 0.008). Men and women in the top compared to bottom third of CRP distribution had an adjusted RR for CHD of 1.65 (1.03–2.65; P = 0.036). The multivariate RR for continuous log IL-18 was 1.34 in men, 1.63 in women and 1.36 overall, and none reached statistical significance. Conclusions: Baseline CRP but not IL-18 levels are independently predictive of future CHD. However CRP provides only modest additional predictive value over conventional risk factors and the benefit of a prevention strategy based on CRP still needs to be established. (Heart, Lung and Circulation 2008;17:90–95) © 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. C-reactive protein; Interleukin-18; Inflammation; Coronary heart disease; Prognosis Introduction I nflammation is involved throughout the process of atherosclerosis leading to coronary heart disease (CHD), and elevated levels of inflammatory markers such as C-reactive protein (CRP) have been found to predict future CHD. 1–4 A consensus panel concluded that CRP measurement may add to global risk assessment for pri- mary prevention, although its clinical utility in this setting remains controversial. 3,5,6 The Reykjavik study, the largest prospective study to assess CRP in the community set- ting, found that CRP was a relatively moderate predictor Received 13 March 2007; received in revised form 14 June 2007; accepted 9 July 2007; available online 11 September 2007 ∗ Corresponding author at: School of Medicine & Pharmacol- ogy, M503, Sir Charles Gairdner Hospital Unit, Verdun Street, Nedlands, WA 6009, Australia. Tel.: +61 8 9346 3483; fax: +61 8 9346 2816. E-mail address: jhung@cyllene.uwa.edu.au (J. Hung). of CHD, and was weaker than such traditional risk factors as total cholesterol, current smoking and systolic blood pressure. 4 They felt that recommendations regarding use of CRP for predicting the likelihood of CHD should be reviewed. 4 The Busselton Health Study (BHS; http://bsn.uwa. edu.au/), with comprehensive cardiovascular risk factor and disease data, stored serum collection, and hospi- tal admission and mortality follow-up of representative community cohorts, provided an opportunity to investi- gate prospectively the relationship between inflammatory markers and incident CHD. In addition to high sensi- tive CRP, we also assessed interleukin-18 (IL-18), a likely inflammatory candidate in CHD because it is a key pro-inflammatory cytokine that appears to play a role in atherosclerotic plaque development and instability. 7–9 Further, IL-18 levels were found to be independently predictive of coronary events in two separate population- based cohorts of initially healthy individuals. 10,11 Smok- © 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. 1443-9506/04/$30.00 doi:10.1016/j.hlc.2007.07.002