High Serum Levels of Advanced Glycation End Products Predict Increased Coronary Heart Disease Mortality in Nondiabetic Women but not in Nondiabetic Men

Kilhovd, Bente; Juutilainen, Auni; Lehto, Seppo; Rönnemaa, Tapani; Torjesen, Peter A.; Birkeland, Kåre I.; Berg, Tore Julsrud; Hanssen, Kristian F.; Laakso, Markku

doi:10.1161/01.atv.0000158380.44231.fe

Cited by 113 publications

(98 citation statements)

References 34 publications

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“…Our study shows that high serum AGE levels predict total, CVD and CHD mortality in type 2 diabetic patients during long-term follow-up. The identification of AGE levels as a predictor of CVD in non-diabetic women in a previous study [19] and in type 2 diabetic women in this study implies that the effect of AGEs on mortality may be independent of diabetes.…”

Section: Discussionsupporting

confidence: 53%

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Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study

et al. 2007

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Aims/hypothesis AGEs, modification products formed by glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes. We investigated whether increased serum levels of AGEs predict total, cardiovascular (CVD) or CHD mortality in a population-based study. Subjects and methods Serum levels of AGEs were determined by immunoassay in a random sample of 874 Finnish diabetic study participants (488 men, 386 women), aged 45-64 years. These participants were followed for 18 years for total, CVD and CHD mortality. Results Multivariate Cox regression models revealed that serum levels of AGEs were significantly associated with total (p=0.002) and CVD mortality (p=0.021) in women, but not in men. Serum levels of AGEs in the highest sexspecific quartile predicted all-cause (hazards ratio [HR] 1.51; 95% confidence intervals [CI], 1.14-1.99; p=0.004), CVD (HR 1.56; 95% CI 1.12-2.19; p=0.009), and CHD (HR 1.68; 95% CI 1.11-2.52; p=0.013) mortality in women, even after adjustment for confounding factors, including high-sensitivity C-reactive protein. Conclusions/interpretation

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Section: Discussionsupporting

confidence: 53%

“…In a cross-sectional study, elevated levels of circulating AGEs correlated with the extent of coronary artery occlusion in type 2 diabetic patients [18]. We recently reported that high serum levels of AGEs predict mortality from CHD in nondiabetic women, but not in non-diabetic men [19].…”

Section: Introductionmentioning

confidence: 94%

Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study

et al. 2007

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“…High plasma concentrations of AGE have been associated with increased rates of CAD [34] as well as kidney damage [35]. AGE modifications have also been reported to cause changes in lipoprotein metabolism affecting properties of LDL particles [36], expression of lipoprotein lipase [37] and the functionality of scavenger receptors, including SR-B1 [38].…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

et al. 2007

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Aims/hypothesis AGE contribute to the pathogenesis of diabetic complications, including dyslipidaemia and atherosclerosis. However, the precise mechanisms remain to be established. In the present study, we examined whether AGE modification of apolipoprotein A-I (apoA-I) affects its functionality, thus altering its cardioprotective profile. Materials and methods The ability of AGE-modified apoA-I to facilitate cholesterol and phospholipid efflux, stabilise ATP-binding cassette transporter A1 (ABCA1) and inhibit expression of adhesion molecules in human macrophages and monocytes was studied. Results The ability of AGE-modified apoA-I to promote cholesterol efflux from THP-1 macrophages, isolated human monocytes and from ABCA1-transfected HeLa cells was significantly reduced (>70%) compared with unmodified apoA-I. This effect was reversed by preventing AGE formation with aminoguanidine or reversing AGE modification using the cross-link breaker alagebrium chloride. AGEmodification of HDL also reduced its capacity to promote cholesterol efflux. AGE-apoA-I was also less effective than apoA-I in stabilising ABCA1 in THP-1 cells as well as in inhibiting expression of CD11b in human monocytes. Conclusions/interpretation AGE modification of apoA-I considerably impairs its cardioprotective, antiatherogenic properties, including the ability to promote cholesterol efflux, stabilise ABCA1 and inhibit the expression of adhesion molecules. These findings provide a rationale for targeting AGE in the management of diabetic dyslipidaemia.

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“…These findings indicate that AGEs may indeed play an important role in the development of cardiovascular events in humans. However, epidemiological studies using plasma measurements of AGEs, which are more feasible than plaque measurements, have generated inconsistent associations with incident cardiovascular events (15)(16)(17)(18)(19)(20). These results may be conflicting because they were based on semiquantitative ELISA-based techniques to measure AGEs (measuring mostly one AGE only) instead of specific liquid chromatographybased techniques and did not take potential confounding factors (consistently) into account.…”

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confidence: 99%

Plasma Advanced Glycation End Products Are Associated With Incident Cardiovascular Events in Individuals With Type 2 Diabetes: A Case-Cohort Study With a Median Follow-up of 10 Years (EPIC-NL)

et al. 2014

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Experimental data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, epidemiological evidence of an association between high plasma AGEs and increased cardiovascular risk remains inconclusive. Therefore, in a case-cohort study comprising 134 cardiovascular case subjects and a random subcohort of 218 individuals (including 65 cardiovascular case subjects), all with T2DM and nested in the European Prospective Investigation into Cancer and Nutrition in the Netherlands (EPIC-NL) study, plasma levels of protein-bound Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and pentosidine were measured with liquid chromatography. AGEs were loge-transformed, combined in a z-score, and the association with incident cardiovascular events was analyzed with Cox proportional hazard regression, adapted for case-cohort design (Prentice method). After multivariable adjustment (sex, age, cohort status, diabetes duration, total cholesterol to HDL-cholesterol ratio, smoking, systolic blood pressure, BMI, blood pressure–, cholesterol- and glucose-lowering treatment, prior cardiovascular events, and triglycerides), higher plasma AGE z-scores were associated with higher risk of incident cardiovascular events in individuals without prior cardiovascular events (hazard ratio 1.31 [95% CI: 1.06–1.61]). A similar trend was observed in individuals with prior cardiovascular events (1.37 [0.63–2.98]). In conclusion, high plasma AGEs were associated with incident cardiovascular events in individuals with T2DM. These results underline the potential importance of AGEs in development of CVD.

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High Serum Levels of Advanced Glycation End Products Predict Increased Coronary Heart Disease Mortality in Nondiabetic Women but not in Nondiabetic Men

Abstract: Background-Advanced glycation end products (AGEs), modification products of glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes as well as in nondiabetic subjects.

Cited by 113 publications

References 34 publications

Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study

Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

Plasma Advanced Glycation End Products Are Associated With Incident Cardiovascular Events in Individuals With Type 2 Diabetes: A Case-Cohort Study With a Median Follow-up of 10 Years (EPIC-NL)

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