Abstract
Background Evidence suggests a critical role for inflammation in the pathogenesis of coronary artery/heart disease (CAD/CHD), implicating inflammatory molecules as central mediators of chronic inflammatory processes within the vascular wall. In this regard, patients with chronic inflammatory disease such as RA and SLE are at increased risk, which was attributed to the high levels of inflammatory mediators. However, less is known about the association of low-grade systemic inflammation with the cardiovascular risk. Objectives The aim of the present study was therefore to evaluate biomarkers representing low-grade systemic inflammation and their association with mortality in a large cohort of patients. Methods The Ludwigshafen Risk and Cardiovascular Health (LURIC) study included 3316 consecutive patients undergoing coronary angiography between June 1997 and May 2001 with a median follow-up of 9.9 years. Before coronary angiography fasting blood samples were collected and plasma levels of interleukin-6 (IL-6), C-reactive protein (CRP) and serum amyloid A (SAA) were measured by immunonephelometry. IL-6 and SAA polymorphisms were genotyped. Results During a median observation time of 9.9 years 949 deaths (30.3%) occurred, of these 597 (19.2%) died from cardiovascular events. Plasma levels of IL-6, CRP and SAA were associated with unstable CAD as well as established risk factors including type 2 diabetes, smoking, lower eGFR, lower triglycerides and lower HDL-C. In addition, IL-6 correlated with age, use of lipid lowering therapy and hypertension, SAA correlated with female gender and hypertension, and CRP correlated with female gender, lipid-lowering therapy and BMI. After adjustment for established cardiovascular risk markers and the other two inflammatory markers, SAA was found an independent risk factor for cardiovascular mortality after a short-term follow-up (1 year) with a HR of 1.41 (1.03-1.93, p=0.030), whereas IL-6 was identified as an independent risk factor for long-term follow-up (3, 5-9.9 years) with HRs of 1.21 (1.02-1.43, p=0.006), 1.22 (1.06-1.40, p=0.006) and 1.18 (1.07-1.31, p=0.001), respectively. Although 6 SNPs in the SAA gene were significantly associated with SAA plasma concentrations (none of the IL-6 SNPs associated with IL-6 levels), the genetic risk score was not associated with mortality. Conclusion In our large, long-term LURIC cohort study we demonstrate for the first time prospectively that plasma levels of IL-6 and SAA are not only associated with cardiovascular risk factors and the prevalence of CAD but also independently predicted cardiovascular mortality. These findings underline the importance of low-grade systemic inflammation for the cardiovascular risk and the prognostic relevance of inflammatory biomarkers, independently predicting cardiovascular mortality. Although it was not the focus of this study, our findings might suggest that even low-grade inflammation is unfavourable in chronic rheumatic disease. Disclosure of Interests None declared
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