Association of systemic inflammation markers with the presence and extent of coronary artery calcification Dorette Raaz-Schrauder a,⇑ , Lutz Klinghammer a , Christina Baum a , Thomas Frank a , Piotr Lewczuk b , Stephan Achenbach a , Iwona Cicha a , Christian Stumpf a , Jens Wiltfang b , Johannes Kornhuber b , Werner G. Daniel a , Christoph D. Garlichs a a Department of Cardiology, University Hospital Erlangen, Erlangen, Germany b Department of Psychiatry, University Hospital Erlangen, Erlangen, Germany article info Article history: Received 4 April 2011 Received in revised form 15 November 2011 Accepted 20 November 2011 Available online 14 December 2011 Keywords: Atherosclerosis Coronary calcification Cytokines Inflammation Cardiac computed tomography abstract Background: Coronary artery calcification (CAC) is a marker for the presence and extent of coronary ath- erosclerotic plaques and can be detected non-invasively by multi-detector row CT (MDCT). Well known predictors of CAC are age, gender, and the classical atherogenic risk factors. CAC is associated with ath- erosclerotic plaque burden, but it is still elusive if atherosclerosis-relevant cytokines and chemokines are also associated with CAC. Methods: We conducted a clinical study among 455 consecutive individuals who underwent coronary calcium assessment performed by MDCT. Before MDCT, blood was drawn and subsequently analyzed for 20 different atherosclerosis-relevant cytokines and chemokines using a Luminex-laser-based fluores- cence analysis. Results: Using univariate analyses, CAC patients revealed significantly higher levels of the chemokines IP- 10 (P = 0.047) and eotaxin (P = 0.031) as compared to non-CAC patients. In multivariate analyses using common thresholds for calcium burden, the three cytokines interleukin-6 (P = 0.028), interleukin-8 (P = 0.009), and interleukin-13 (P = 0.024) were associated with high coronary calcium levels after adjust- ment for classical variables and risk factors. Conclusions: In a large group of individuals with atypical chest pain and a low to intermediate likelihood for coronary artery disease elevated plasma levels of IL-6 and reduced levels of IL-8 and IL-13 were pre- dictive for distinct coronary artery calcification. These findings support a specific role of these cytokines in coronary calcification. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Atherosclerosis is the major cause for coronary artery disease, and a better understanding of its pathophysiology would ease diagnosis and improve treatment. Atherosclerosis, by nature, is a chronic inflammatory disease [1]. It is well established that the development from early lesions to vulnerable plaque formation is driven by numerous cellular and molecular inflammatory compo- nents. Dendritic cells, T-lymphocytes, and monocyte-derived mac- rophages are the most prominent cells that accumulate in evolving lesions. These cell types produce a wide array of soluble inflamma- tory mediators (i.e. cytokines, chemokines) which are critically important in the initiation and perpetuation of the disease. Finally, this local atherogenic process within the vasculature is accompa- nied and modulated by systemic inflammation. Besides inflammation, atherosclerotic lesions reveal frequently extensive calcifications. Pathophysiologically, vascular calcification is a generalized active process arising in areas of chronic inflamma- tion in the intima, where atherosclerosis develops. While the exact pathogenesis of vascular calcification is currently still unknown, some authors see the causal factor in a lack of specific inhibitors for vascular calcification, such as fetuin [2]. Other studies detected products of bone metabolisms in atherosclerotic plaques, which are known to be strongly influenced by systemic inflammation. From a clinical point of view, the amount of coronary artery cal- cification (CAC) is associated with the amount of total atheroscle- rotic plaque burden and therefore can serve as a measure of subclinical atherosclerosis [3]. Furthermore, CAC is strongly pre- dictive of cardiovascular (CV) events, including individuals pre- sumably at low risk based on traditional risk factors [4,5]. Even low coronary calcium scores may double the risk of coronary events compared to non-CAC patients. Its predictive value has been found to be independent of and higher than that of traditionally used risk factors [4,6]. CAC can be detected and quantified non- 1043-4666/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2011.11.015 ⇑ Corresponding author. Address: Department of Cardiology, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany. E-mail address: Dorette.Raaz@uk-erlangen.de (D. Raaz-Schrauder). Cytokine 57 (2012) 251–257 Contents lists available at SciVerse ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/issn/10434666