Atherosclerosis 205 (2009) 590–594 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Increased serum levels of methylglyoxal-derived hydroimidazolone-AGE are associated with increased cardiovascular disease mortality in nondiabetic women Bente K. Kilhovd a,b , Auni Juutilainen c,d , Seppo Lehto c,d , Tapani Rönnemaa e,f , Peter A. Torjesen a,g , Kristian F. Hanssen a,b , Markku Laakso c,d,∗ a Aker and Ullevål Diabetes Research Centre, Oslo, Norway b Department of Endocrinology, Aker University Hospital, Faculty of Medicine, University of Oslo, Oslo, Norway c Kuopio University Hospital, Kuopio, Finland d Department of Medicine, University of Kuopio, Kuopio, Finland e Turku University Central Hospital, Turku, Finland f Department of Medicine, University of Turku, Turku, Finland g Hormone Laboratory, Aker University Hospital, Faculty of Medicine, University of Oslo, Oslo, Norway article info Article history: Received 26 May 2008 Received in revised form 20 December 2008 Accepted 28 December 2008 Available online 9 January 2009 Keywords: Advanced glycation end products Hydroimidazolone Cardiovascular disease Type 2 diabetes mellitus Cardiovascular disease mortality abstract Objective: To investigate the association of the levels of methylglyoxal-derived hydroimidazolone AGE modified proteins (MG-H1-AGE) with cardiovascular disease (CVD) mortality in an 18-year follow-up study in Finnish nondiabetic and diabetic subjects. Methods: The study design was a nested case-control study. Serum MG-H1-AGE levels in samples drawn at baseline were measured with a DELFIA type immunoassay in 220 diabetic subjects and 61 nondiabetic subjects who died from CVD during the follow-up, and age- and gender-matched 157 diabetic subjects and 159 nondiabetic subjects who did not die from CVD. Results: In type 2 diabetic subjects serum MG-H1-AGE levels were similar in subjects who died from CVD and in subjects who did not, 32.6 (24.6–42.1) (median (interquartile range)) vs. 31.3 (22.5–40.7)U/mL (p= 0.281). In nondiabetic subjects serum MG-H1 levels were significantly higher in subjects who died from CVD than in subjects who were alive, 35.4 (28.1–44.7) vs. 31.3 (24.2–38.6)U/mL (p = 0.025). Corre- sponding MG-H1 levels were 41.2 (35.6–58.7) vs. 31.1 (26.7–35.7)U/mL, p = 0.003, in women, and 34.4 (26.3–41.2) vs. 32.0 (22.8–40.3)U/mL, p = 0.270, in men. Multivariate logistic regression analysis showed a significant association of serum levels of MG-H1-AGE with CVD mortality in nondiabetic women (adjusted p = 0.021), but not in nondiabetic men. Conclusions: Our 18-year follow-up study shows that high baseline serum levels of MG-H1 type of AGE modified proteins were associated with CVD mortality in nondiabetic women, but not in nondiabetic men or in diabetic subjects. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Advanced glycation end products (AGEs) formation has been linked to atherosclerosis in patients with diabetes [1] as well as in nondiabetic subjects [2]. AGEs are short- and long-term modifi- cation products of glycation or glycoxidation of proteins and lipids [1]. These end products are a heterogeneous group of compounds with different biological effects, some of which are mediated by interacting with receptors, including receptor for AGE (RAGE) on ∗ Corresponding author at: Academy Professor, Department of Medicine, Univer- sity of Kuopio and Kuopio University Hospital, 70210 Kuopio, Finland. Tel.: +358 17 172151; fax: +358 17 173993. E-mail address: markku.laakso@kuh.fi (M. Laakso). endothelial cells, smooth muscle cells and macrophages [3]. Sev- eral AGE compounds have also been localized in atherosclerotic plaques [4]. AGEs may contribute to atherosclerosis by activating the transcription factor NF-B through the binding to RAGE, thus initiating induction of cellular adhesion molecule expression and cytokine activation [3], and through glycoxidation of lipoproteins and increased foam cell formation [5]. AGEs can be formed extracellularly as well as intracellularly. In endothelial cells biologically reactive dicarbonyl methylglyoxal (MG) has been identified as the major intracellular precursor in the formation of AGEs [6]. Methylglyoxal is formed by non- enzymatic elimination of phosphate from triosephosphates as well as enzymatically from dihydroxyacetone during glycolysis, and MG is detoxified to d-lactate by the glyoxalase system. Methylglyoxal reacts reversibly with arginine, lysine and cysteine 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.12.041