Thromb Haemost 2016; 115(02): 446-457
DOI: 10.1160/th15-05-0439
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

The alternative complement pathway is longitudinally associated with adverse cardiovascular outcomes

The CODAM study
Elisabeth Hertle
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Ilja C. W. Arts
2   Department of Epidemiology and School for Public Health and Primary Care (CAPHRI) and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Carla J. H. van der Kallen
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Edith J. M. Feskens
3   Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands
,
Casper G. Schalkwijk
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Coen D. A. Stehouwer
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Marleen M. J. van Greevenbroek
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
› Author Affiliations
Financial support: Part of this work was supported by grants of the Netherlands Organization for Scientific Research (940-35–034) and the Dutch Diabetes Research Foundation (98.901). The PhD fellowship of E. Hertle was supported by the Dutch Heart Foundation (NHS2010B194).
Further Information

Publication History

Received: 29 May 2015

Accepted after major revision: 08 September 2015

Publication Date:
22 November 2017 (online)

Summary

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.

Supplementary Material to this article is available online at www.thrombosis-online.com.

 
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