The Association Between Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Dysfunction Explained by Non-Alcoholic Fatty Liver Disease; A 7-year Follow-up of the CODAM Study


  • Johnny de Nóbrega Teixeira



Background. The risk for cardiovascular events and cardiovascular death in diabetic patients is twice as high compared to non-diabetic controls. Glucose-lowering therapy aimed at relieving these complications have led to minimally altered cardiovascular morbidity and mortality, implicating that other pathways may be involved in microand macrovascular diseases in diabetic patients. Experimental studies suggest that interaction of ligands and receptor for advanced glycation end products (RAGEs) play an important role in cardiovascular disease (CVD). Associations between non-alcoholic fatty liver disease (NAFLD) and CVD have been reported previously. Moreover, RAGE-dependent inflammation in steatotic livers may play a pivotal role in the pathogenesis of NAFLD. Thus, we hypothesize that signaling via RAGE contributes to the initiation and progression of cardiovascular dysfunction and disease, and this relation is partly the result of and effects of RAGE signaling on the development of NAFLD. Objective. We investigated the association between the soluble form of RAGE (sRAGE) and (incidence of) cardiovascular disease (CVD). Furthermore we investigated whether NAFLD may be an intermediate step to causing CVD. Methods. In the current analysis, we used data from 574 Caucasian participants from the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Plasma biomarkers for endothelial dysfunction and liver enzyme markers were measured. These biomarkers were subsequently converted into averaged standardized scores, ultimately creating one integrated measure for the liver function, i.e the LE score and for endothelial dysfunction, i.e the ED score. Liver fat percentage was estimated using a validated equation. CVD and cardiovascular events (CVE) were also identified. Atherosclerosis was identified using measures of carotid intima media thickness (cIMT) and ankle-arm-index (AAIx). For continuous outcomes multiple linear regression was performed, whereas for dichotomous outcomes binomial logistic regression analysis was performed. All analysis included adjustments for age, gender, glucose metabolism status, smoking, energy intake, alcohol consumption, physical activity, use of medication, and waist circumference. Results. Higher plasma sRAGE levels were associated with a higher score for endothelial dysfunction, However, no cross-sectional association was found with markers of atherosclerosis (cIMT, AAIx) or prevalence of CVD. NAFLD was positively associated with endothelial dysfunction, atherosclerosis, and CVD [β: 0.338; 95% CI: 0.251; 0.424], [β: 0.017; 95% CI: 0.001; 0.033], and [OR: 1.442; 95% CI: 1.023; 2.032]. Mediation analysis suggests that FLD accounts for 2.4% of the coefficient in the association between sRAGE and endothelial dysfunction. Next, prospective analysis indicated no association between sRAGE and CVD, CVE, or endothelial function. Furthermore, the prospective analysis indicated a strong association between LE markers and changes in endothelial dysfunction [β: -0.079; 95% CI: -0.116; -0.043], but not with CVD or CVE. Conclusion. These data suggest that cross-sectionally sRAGE can potentially contribute to progression of CVD, through its action on endothelial function. Additionally, the mediating role of NAFLD between sRAGE and endothelial dysfunction is negligible. However, prospective analysis indicated that only NAFLD, but not sRAGE, contributes to cardiovascular complications after 7 year follow-up


Organisation WH. 10 Facts About Diabetes 2015. Available from: diabetes/facts/en/index1.html.

Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375(9733):2215-22.

Scheen AJ, Charbonnel B. Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal. Diabetes Metab. 2014; 40(3):176-85

Schalkwijk CG, Stehouwer CDA. Comment on: Selvin et al. sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death. Diabetes 2013;62:2116–2121.

Schmidt AM, Hasu M, Popov D, Zhang JH, Chen J, Yan SD, et al. Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins. Proc Natl Acad Sci. 1994; 91(19):8807-11.

Skrha J, Jr., Kalousova M, Svarcova J, Muravska A, Kvasnicka J, Landova L, et al. Relationship of soluble RAGE and RAGE ligands HMGB1 and EN-RAGE to endothelial dysfunction in type 1 and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2012; 120(5):277-81.

Donners MM, Wolfs IM, Olieslagers S, Mohammadi-Motahhari Z, Tchaikovski V, Heeneman S, et al. A disintegrin and metalloprotease 10 is a novel mediator of vascular endothelial growth factor-induced endothelial cell function in angiogenesis and is associated with atherosclerosis. Arterioscler Thromb Vasc Biol. 2010; 30(11):2188-95.

Roberts AC, Porter KE. Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res. 2013; 10(6):472-82.

Wang LJ, Lu L, Zhang FR, Chen QJ, De Caterina R, Shen WF. Increased serum high-mobility group box-1 and cleaved receptor for advanced glycation endproducts levels and decreased endogenous secretory receptor for advanced glycation endproducts levels in diabetic and non-diabetic patients with heart failure. Eur J Heart Fail. 2011; 13(4):440-9. Yilmaz Y, Ulukaya E, Gul OO, Arabul M, Gul CB, Atug O, et al. Decreased plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) in patients with nonalcoholic fatty liver disease. Clin Biochem. 2009; 42(9):802-7.

Liu H, Lu HY. Nonalcoholic fatty liver disease and cardiovascular disease. World J Gastroenterol. 2014; 20(26):8407-15.

Fargion S, Porzio M, Fracanzani AL. Nonalcoholic fatty liver disease and vascular disease: State-of-the-art. World J Gastroenterol. 2014; 20(37):13306-24.

Tabit C, Chung W, Hamburg N, Vita J. Endothelial dysfunction in diabetes mellitus: Molecular mechanisms and clinical implications. Rev Endocr Metab Disord. 2010; 11(1):61-74.