Bente Kilhovd

High Serum Levels of Advanced Glycation End Products Predict Increased Coronary Heart Disease Mortality in Nondiabetic Women but not in Nondiabetic Men A Population-Based 18-Year Follow-Up Study

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. Methods and Results—Serum levels of AGEs were measured with an immunoassay in samples obtained at baseline examination of a random sample of 1141 nondiabetic individuals (535 men and 606 women), aged 45 to 64 years, living in Kuopio, East Finland, or Turku, West Finland in 1982 to 1984. After 18 years of follow-up, all-cause mortality, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality were registered on the basis of copies of death certificates. Multivariate Cox regression model showed a significant association of serum AGEs with all-cause (P=0.012), CVD (P=0.018), and CHD (P=0.008) mortality in women but not in men. Fasting serum AGEs in the highest quartile were an independent risk factor for all-cause (hazards ratio [HR], 1.90; 95% CI, 1.16 to 3.11; P=0.011) and CHD (HR, 6.51; 95% CI, 1.78 to 23.79; P=0.005) mortality in women, even after the adjustment for confounding factors, including highly sensitive C-reactive protein. Conclusions—The present study is the first to show that serum levels of AGEs can predict total, CVD, and CHD mortality in nondiabetic women.

Increased serum levels of methylglyoxal-derived hydroimidazolone-AGE are associated with increased cardiovascular disease mortality in nondiabetic women

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). Corresponding 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.

Fibrin(ogen) may be an important target for methylglyoxal-derived AGE modification in elastic arteries of humans

Diabetes is associated with increased risk of cardiovascular disease. Advanced glycation end-products (AGEs) are considered to be a major pathogenic factor for diabetic vascular complications. The levels of AGEs are increased in diabetic patients. We have studied the presence of the major AGE methylglyoxal (MGO)-derived hydroimidazolone in human aorta and carotid arteries, using immunohistochemistry (IHC), western blotting and mass spectrometry. By IHC, MGO-derived modifications were detected mainly associated with cells in intimal thickenings and cells in microvessels in adventitia. In type V lesions MGO-derived AGE was also present, extracellular in the necrotic core and in cells at the border of the core. The highest degree of modification was probably associated with cell nuclei. By western blotting and mass spectrometry fibrin(ogen), the cytoskeleton-associated protein moesin and the nuclear proteins lamin A and C were identified as putative main targets for MGO-derived modification. LC-MS/MS studies of fibrin(ogen) modified in vitro with low concentrations of MGO identified the sites that were most prone to modification. These results indicate that AGE modifications occur preferentially on specific proteins. The modification of these proteins may play a role in vascular dysfunction and development of atherosclerosis in diabetes.

Infarct size as estimated from peak creatine kinase and lactate dehydrogenase is probably reduced in patients using calcium antagonists at the onset of symptoms.

In animal models, calcium antagonists (Ca-A) administered before ischemia and reperfusion reduced myocardial necrosis, attenuated postischemic contractile dysfunction, and reduced tissue calcium. In 753 patients with acute myocardial infarction (AMI), we examined if use of Ca-A at the onset of symptoms (n = 127 patients) reduced infarct size as estimated from peak creatine kinase (CKmax) and lactate dehydrogenase (LDmax) activities. The study had an observational exposed/nonexposed design, and both crude and adjusted effects were investigated. Crude effects: In the restricted cohort of patients not receiving thrombolytic treatment (thr− pts; n = 411 patients), CKmax and LDmax were lower in Ca-A+ patients than in Ca-A− patients, being 643 versus 887 U/l (2 p = 0.004) and 708 versus 867 U/l (2 p = 0.005), respectively. When using log (CKmax) and log (LKmax) as outcomes, the same results were found (2 p = 0.002). More of the restricted cohort of thr-pts used Ca-A in the lower quartiles of CKmax and LDmax (p for linear trend = 0.005 and 0.004 for CKmax and LDmax, respectively). Adjusted effects: Thrombolysis was an effect modifier of the association between Ca-A and peak enzyme levels. In thr-pts, the coefficients of Ca-A were negative and borderline significant for log (CKmax; 2 p = 0.088) and negative and highly significant for log (LDmax; 2 p = 0.010) when adjusting for confounders. The present observational study indicates that the use of a Ca-A at the onset of AMI reduces infarct size, as estimated from CKmax and LDmax activities.