title: The alternative complement pathway is longitudinally associated with adverse cardiovascular outcomes. The CODAM study.
abstract: The alternative pathway of complement activation is highly reactive and can be activated spontaneously in the vasculature. Activation may contribute to vascular damage and development of cardiovascular disease (CVD). We aimed to investigate functional components of the alternative pathway in cardiovascular risk. We studied 573 individuals who were followed-up for seven years. At baseline, we measured the enhancer properdin; the rate-limiting protease factor D (FD); and a marker of systemic activation, Bb. Using generalised estimating equations, we investigated their longitudinal associations with cardiovascular events (CVE, N=89), CVD (N=159), low-grade inflammation (LGI), endothelial dysfunction (ED) and carotid intima-media thickness (cIMT). Furthermore, we investigated associations with incident CVE (N=39) and CVD (N=73) in 342 participants free of CVD at baseline. CVE included myocardial infarction, stroke, cardiac angioplasty and/or cardiac bypass. CVD additionally included ischaemia on an electrocardiogram and/or ankle-brachial index < 0.9. In adjusted analyses, properdin was positively associated with CVE (per 1SD, longitudinal OR=1.36 [1.07; 1.74], OR for incident CVE=1.53 [1.06; 2.20]), but not with CVD. Properdin was also positively associated with ED (β=0.13 [95%CI 0.06; 0.20]), but not with LGI or cIMT. FD and Bb were positively associated with LGI (per 1SD, FD: β=0.21 [0.12; 0.29], Bb: β=0.14 [0.07; 0.21]), and ED (FD: β=0.20 [0.11; 0.29], Bb: β=0.10 [0.03; 0.18]), but not with cIMT, CVE or CVD. Taken together, this suggests that the alternative complement pathway contributes to processes of vascular damage, and that in particular a high potential to enhance alternative pathway activation may promote unfavourable cardiovascular outcomes in humans.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hertle
authors.forename: Ilja C W
authors.initials: IC
authors.lastname: Arts
authors.forename: Carla J H
authors.initials: CJ
authors.lastname: van der Kallen
authors.forename: Edith J M
authors.initials: EJ
authors.lastname: Feskens
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Marleen van Greevenbroek, PhD, Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands, Universiteitssingel 50, P. O. Box 616, 6200 MD Maastricht, The Netherlands, Tel.: ++31 43 3882135, Email: m.vangreevenbroek@maastrichtuniversity.nl.
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
mesh_terms: D000328:Adult; D000368:Aged; D055109:Ankle Brachial Index; D015415:Biomarkers / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood* / Q000378:metabolism; D002319:Cardiovascular System; D059168:Carotid Intima-Media Thickness; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism; D011416:Complement Factor D / Q000378:metabolism; D003170:Complement Pathway, Alternative; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007249:Inflammation; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood; D012307:Risk Factors; D020521:Stroke / Q000097:blood
chemical_list: D015415:Biomarkers; D003176:Complement C3; D011416:Complement Factor D
keywords: Alternative complement pathway; cardiovascular events; endothelial dysfunction; properdin