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Biomedical subjects

C D Stehouwer

Publications and source records attributed to C D Stehouwer.

At least 91 records · Page 5Linked to original sources
PubMed1999

Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study.

Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.

Biomarkers↗
PubMed1999

von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study.

Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP) predict cardiovascular mortality in selected populations. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways. This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). vWf (>1.56 IU/mL) and CRP (>2.84 mg/L) levels in the upper tertile were associated with, respectively, a 3- and 2-fold increase in cardiovascular mortality after adjustment for age, sex, and glucose tolerance status. Analyses in nondiabetic and diabetic subjects separately gave similar results. After further adjustment for hypertension, levels of HDL cholesterol and triglyceride, smoking habits, ischemic heart disease, and peripheral arterial disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4 (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95% CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular mortality was independent of blood group (O versus non-O) and, moreover, similar among subjects with different blood groups. Repeating the analyses for all-cause mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to 3.5) after adjustment for all other risk factors. Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors. Mutual adjustment of vWf and CRP did not markedly change the results, favoring the hypothesis that vWf and CRP predict mortality through different pathways.

Acute-Phase Reaction↗
PubMed1999

Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study.

Microalbuminuria (MA) is associated with increased cardiovascular and all-cause mortality. It has been proposed that MA reflects generalized atherosclerosis and may thus predict mortality. To investigate this hypothesis, we studied the associations between, on the one hand, MA and peripheral arterial disease (PAD), a generally accepted marker of generalized atherosclerosis, and, on the other hand, cardiovascular and all-cause mortality in an age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years followed prospectively for 5 years. At baseline, the albumin-to-creatinine ratio (ACR) was measured in an overnight spot urine sample; MA was defined as ACR >2.0 mg/mmol. PAD was defined as an ankle-brachial pressure index below 0.90 and/or a history of a peripheral arterial bypass or amputation. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). Both MA and PAD were associated with a 4-fold increase in cardiovascular mortality. After adjusting for age, sex, diabetes mellitus, hypertension, levels of total and HDL-cholesterol and triglyceride, body mass index, smoking habits, and preexistent ischemic heart disease, the relative risks (RR) (95% confidence intervals) were 3.2 (1.3 to 8.1) for MA and 2.4 (0.9 to 6.1) for PAD. When both MA and PAD were included in the multivariate analysis, the RRs were 2.9 (1.1 to 7.3) for MA and 2.0 (0.7 to 5.7) for PAD. MA and PAD were both associated with an about 2-fold increase in all-cause mortality. The RRs of all-cause mortality associated with MA and PAD were about 4 times higher among hypertensive than among normotensive subjects. We conclude that both MA and PAD are associated with an increased risk of cardiovascular mortality. MA and PAD are mutually independent risk indicators. The associations of MA and PAD with all-cause mortality are somewhat weaker. They are more pronounced in the presence of hypertension than in its absence. These data suggest that MA affects mortality risk through a mechanism different from generalized atherosclerosis.

Age Factors↗
PubMed1999

C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?

C-reactive protein, a hepatic acute phase protein largely regulated by circulating levels of interleukin-6, predicts coronary heart disease incidence in healthy subjects. We have shown that subcutaneous adipose tissue secretes interleukin-6 in vivo. In this study we have sought associations of levels of C-reactive protein and interleukin-6 with measures of obesity and of chronic infection as their putative determinants. We have also related levels of C-reactive protein and interleukin-6 to markers of the insulin resistance syndrome and of endothelial dysfunction. We performed a cross-sectional study in 107 nondiabetic subjects: (1) Levels of C-reactive protein, and concentrations of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, were related to all measures of obesity, but titers of antibodies to Helicobacter pylori were only weakly and those of Chlamydia pneumoniae and cytomegalovirus were not significantly correlated with levels of these molecules. Levels of C-reactive protein were significantly related to those of interleukin-6 (r=0.37, P<0.0005) and tumor necrosis factor-alpha (r=0.46, P<0.0001). (2) Concentrations of C-reactive protein were related to insulin resistance as calculated from the homoeostasis model assessment model, blood pressure, HDL, and triglyceride, and to markers of endothelial dysfunction (plasma levels of von Willebrand factor, tissue plasminogen activator, and cellular fibronectin). A mean standard deviation score of levels of acute phase markers correlated closely with a similar score of insulin resistance syndrome variables (r=0.59, P<0.00005), this relationship being weakened only marginally by removing measures of obesity from the insulin resistance score (r=0.53, P<0.00005). These data suggest that adipose tissue is an important determinant of a low level, chronic inflammatory state as reflected by levels of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, and that infection with H pylori, C pneumoniae, and cytomegalovirus is not. Moreover, our data support the concept that such a low-level, chronic inflammatory state may induce insulin resistance and endothelial dysfunction and thus link the latter phenomena with obesity and cardiovascular disease.

Adipose Tissue↗
PubMed1999

Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease.

Elevated plasma total homocysteine (tHcy) levels, either measured in the fasting state or after oral methionine loading, are associated with an increased risk of atherothrombotic disease. Fasting and post-methionine hyperhomocysteinemia (HHC) overlap to a limited extent; both can occur as familial traits. We investigated determinants of fasting, postmethionine and delta (ie, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease and 349 without vascular disease. We focused on tHcy levels in relation to levels of vitamin B12, B6 and folate and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for the presence of vascular disease showed that fasting tHcy was significantly related to folate and vitamin B12, and the presence of the MTHFR TT genotype and the T allele, and to age, smoking habits, and serum levels of creatinine. Both post-methionine and delta tHcy levels were related to serum folate levels, and the presence of the MTHFR TT genotype and the T allele, and to postmenopausal status, and body mass index. An interaction was found between MTHFR TT genotype and serum folate levels for both fasting and post-methionine tHcy, ie, for a given decrease in serum folate, homocysteine levels increased more in subjects with the TT genotype than in those with the CC genotype. Fasting, post-methionine and delta tHcy were higher in patients with vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P<0.05), whereas the effect of MTHFR genotype was stronger (P=0.01). This study found evidence that post-methionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect remethylation. The explained variances of fasting, post-methionine and delta tHcy were 49%, 62%, and 78%, respectively. We also found evidence, in patients with premature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between folate and tHcy and amplifies the effect of the MTHFR genotype.

Adult↗
PubMed1999

Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women.

Obesity, the insulin resistance syndrome, and atherosclerosis are closely linked and may all be determinants of an increased acute-phase response. In this study, we examined the relationship of C-reactive protein (CRP) with measures of obesity, variables of the insulin resistance syndrome, and intima-media thickness of the common carotid arteries in 186 healthy, middle-aged women selected from the general population. Associations were assessed by regression analysis. CRP was strongly associated with body mass index (BMI) and waist circumference. CRP was also associated with other variables of the insulin resistance syndrome, including blood pressure, insulin, high density lipoprotein cholesterol, triglycerides, apolipoprotein A1 (inversely), plasminogen activator inhibitor-1 antigen, and tissue-type plasminogen activator antigen. Associations between CRP and the variables of the insulin resistance syndrome disappeared after controlling for BMI but remained significant for plasminogen activator inhibitor-1 antigen only. The association of CRP with common carotid artery intima-media thickness was weak and limited to ever-smokers. BMI explained 29.7% of the variance of CRP, whereas common carotid artery intima-media thickness explained only 3.7%. The results of this population-based study indicate that adiposity is strongly associated with CRP in healthy, middle-aged women. In this population, BMI accounted for the relationship between CRP and other variables of the insulin resistance syndrome. Further studies should determine whether losing weight ameliorates the inflammatory state.

Adult↗
PubMed1999

Sex steroids, insulin, and arterial stiffness in women and Men.

Arterial stiffness may be influenced by sex steroids and insulin; the association with fasting insulin level may be stronger in women than in men. Therefore, we analyzed the effects of sex steroid administration on (1) arterial stiffness and (2) the relationship between fasting insulin level and arterial stiffness. Twelve male-to-female transsexuals were treated with ethinyl estradiol and cyproterone acetate, and 18 female-to-male transsexuals were treated with testosterone esters, with assessments made at baseline and after 4 and 12 months. Changes in distensibility and compliance coefficients (DC and CC, respectively) of the common carotid artery, femoral artery (FA), and brachial artery (BA) were analyzed in relation to changes in fasting plasma levels of glucose, insulin, HDL-cholesterol, and triglycerides. After 4 months of estrogens and antiandrogens in men, significant reductions in the CC and DC of the FA (P=0.006 and P=0.04, respectively) and BA (P=0.04 and P=0.04, respectively) were observed. In women, testosterone, on average, did not affect DC or CC, but the changes in fasting insulin level were strongly negatively associated with changes in the CC and DC, especially in the FA and BA. These associations were significantly less strong in genetic men and were independent of age, mean arterial pressure, and glucose and lipid levels. This experimental study shows (1) that short-term administration of estrogens and antiandrogens increases FA and BA stiffness in men and (2) that the fasting insulin level is a stronger determinant of arterial stiffness in women than in men.

Adolescent↗
PubMed1999

Amadori albumin in type 1 diabetic patients: correlation with markers of endothelial function, association with diabetic nephropathy, and localization in retinal capillaries.

Nonenzymatic glycation is increased in diabetes. Most studies so far have focused on the role of advanced glycation end products (AGEs) in vascular complications, whereas the role of early glycation Amadori-modified proteins, which is the predominant form of glycated proteins, has not been systemically investigated in humans. We developed an antiserum against glycated human serum albumin (HSA) and used this to study the role of early glycation products in vascular complications in type 1 diabetic patients. Amadori albumin was determined to be the recognition epitope of the antiserum. The antibody recognized a specific glucose adduct and a conformational component specific for human albumin in Amadori albumin, with no recognition of AGEs. Plasma Amadori albumin levels were significantly higher in type 1 diabetic patients (n = 55) than in healthy control subjects (n = 60) (39.2+/-9.9 vs. 20.9+/-4.0 U/ml, P < 0.0005). Amadori albumin correlated with levels of plasma markers of endothelial function von Willebrand factor (r = 0.29, P < 0.05) and vascular cell adhesion molecule-1 (r = 0.41, P < 0.005), but not soluble E-selectin. In addition, Amadori albumin immunoreactivity was detected in the capillaries of retinas of diabetic patients. Plasma levels of Amadori albumin were determined in a second group of type 1 diabetic patients with long-standing diabetes with (n = 199) or without (n = 192) diabetic nephropathy. Patients with nephropathy had higher Amadori albumin levels than did those without it (50.9+/-9.5 vs. 45.1+/-6.3 U/ml, P < 0.0005). Age-, sex-, and diabetes duration-adjusted analyses showed that nephropathy was significantly associated with Amadori albumin with an odds ratio (OR [95% CI]) of 1.11 [1.08-1.15] per U/ml increase. After additional adjustment for levels of creatinine, glycated hemoglobin, cholesterol, triglycerides, blood pressure, preexistent retinopathy, and cardiovascular disease, Amadori albumin continued to be significantly associated with nephropathy (OR 1.06 [1.01-1.11]) per U/ml increase. Our results are consistent with a proposed pathophysiological role of Amadori albumin in microvascular complications of type 1 diabetic patients.

Adult↗
PubMed1999

Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene.

Friedreich's ataxia is associated with GAA trinucleotide repeat expansions in the frataxin gene. In the general population, these trinucleotide expansions are variable in length, and three types of expansions are seen: short, intermediate, and long repeats. Friedreich's ataxia patients are generally homozygous for the long repeats and exhibit diabetes as pronounced comorbidity. Ristow et al. recently reported an association between the intermediate-length normal allele in the frataxin gene and type 2 diabetes. We have investigated in 94 subjects with impaired glucose tolerance (IGT) as to whether the length of the GAA trinucleotide repeat polymorphism in the frataxin gene associates with parameters reflecting beta-cell function. A hyperglycemic clamp at 10 mmol/l glucose for 3 h was used to quantitate beta-cell characteristics. Carriers of one or two intermediate repeat alleles (n = 32) had a 50% higher median first- phase insulin response to glucose than the noncarriers. Furthermore, they needed less time to reach peak insulin. An analysis of the distribution of the various repeat lengths in elderly type 2 diabetic (n = 179) and control subjects (n = 183), with the same age and ethnic background, did not provide evidence for an association of the intermediate-length repeat allele with type 2 diabetes in Dutch Caucasians.

Aged↗
PubMed1999

Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease.

OBJECTIVE: The increased cardiovascular risk in subjects with NIDDM is partly explained by an association with established risk factors like hypertension, dyslipidemia, and obesity. Mild hyperhomocysteinemia has emerged as a new risk factor for cardiovascular disease. The purpose of this study was to assess its role in NIDDM. RESEARCH DESIGN AND METHODS: We studied predictors of homocysteine levels and correlations between homocysteine and (micro-)albuminuria, retinopathy, and history of cardiovascular disease in normotensive NIDDM subjects under stable metabolic control. This was done in 85 NIDDM subjects by measuring fasting and post-methionine-loading homocysteine levels together with blood pressure, BMI, serum cholesterol, triglyceride, HDL cholesterol, folate, vitamin B12, pyridoxal-5-phosphate, HbA1c, and (micro-)albuminuria and creatinine clearance in triplicate 24-h urine samples. The relationship between micro- and macrovascular complications and fasting homocysteine only was studied in an additional 65 subjects, giving a total of 150 subjects. RESULTS: In multiple regression analysis, significant (P < 0.05) predictors of fasting homocysteine were low-normal values of creatinine clearance (threshold effect at < 80 ml.min-1 .1.73 m-2), folate (< 20 nmol/l), and vitamin B12 (< 350 pmol/l), and postmenopausal status in women. Determinants of post-methionine homocysteine were pyridoxal-5-phosphate levels < 80 nmol/l, creatinine clearance, and sex (higher levels in women). Hyperhomocysteinemia did not cluster with other cardiovascular risk factors, like hypertension, obesity, or dyslipidemia. Regarding cardiovascular complications, fasting homocysteine, but not post-methionine homocysteine, was higher in subjects with a history of cardiovascular disease. There was a stepwise increase in the prevalence of subjects with cardiovascular disease with increasing fasting homocysteine. The prevalence of cardiovascular disease was 19.4% in the bottom quartile of fasting homocysteine, versus 55.0% in the top quartile (P for trend < 0.01). Neither fasting homocysteine nor post-methionine homocysteine correlated with (micro-)albuminuria or with retinopathy. CONCLUSIONS: The findings suggest that homocysteine levels in NIDDM rise even with modest deterioration of renal function and when vitamin status is in the low to low-normal range. Fasting homocysteine correlates with macrovascular disease, but we found no evidence of a correlation with retinopathy or (micro-)albuminuria. Post-methionine homocysteine levels do not show a correlation with micro- or macrovascular complications.

Administration, Oral↗
PubMed1999

Leptin and variables of body adiposity, energy balance, and insulin resistance in a population-based study. The Hoorn Study.

OBJECTIVE: Leptin is thought to play a key role in the control of body weight. There is a complex interrelationship between leptin and insulin or insulin resistance, but it is unknown how leptin is regulated. We therefore explored, in a large population-based study of 2,484 Caucasian subjects aged 50-74 years, the relationship between leptin and variables of body adiposity, energy balance, and insulin resistance. RESEARCH DESIGN AND METHODS: Leptin was measured by means of a radioimmunoassay. Multiple linear regression analyses were performed with leptin as dependent variable and age, sex, BMI, waist circumference, daily energy intake, physical activity, smoking, hypertension, fasting triglyceride concentrations, HDL cholesterol, fasting plasma glucose, and fasting plasma insulin concentrations as independent variables (determinants) RESULTS: Leptin concentrations were found to be four times higher in women than in men. Effect modification between sex and potential determinants was expected, and the analyses were performed separately for women and men. BMI was the strongest determinant of leptin in women and waist circumference the strongest determinant in men. BMI, waist circumference, insulin, and triglyceride concentrations were independently and significantly (P < 0.05) associated with leptin, while inverse associations were shown for smoking and daily energy intake (borderline significance). CONCLUSIONS: This study confirms the relationship between insulin and leptin and, in addition, suggests a relationship between triglyceride concentrations and leptin independent of sex, BMI, waist circumference, and insulin.

Adipose Tissue↗
PubMed1999

Postmenopausal hormone replacement, risk estimators for coronary artery disease and cardiovascular protection.

Menopause, regardless of age at onset, is associated with a marked increase in coronary artery disease (CAD) risk. A large body of observational clinical studies repeatedly demonstrated favorable associations between postmenopausal hormone replacement therapy (HRT) and cardiovascular morbidity, mortality, and risk factors. Estrogens may act in a gender-specific way on vascular endothelial cells and other components of the vessel wall, enhancing the synthesis and release of nitric oxide (NO) and other vasodilators, and by inhibiting the synthesis and release of vasoconstricting agents, thus favoring vasodilation. Menopause-related changes in metabolic cardiovascular risk factors are identifiable, as are HRT-related changes in these factors. The metabolic effects include changes in lipoprotein (a), coagulation and fibrinolysis as well as homocysteine metabolism. The various actions of estrogen alone and combined with progestogen on the vascular system are reviewed. Furthermore, the outcome of the recently published Heart and estrogen/progestin replacement study (HERS) data are put in perspective. In addition, we outline the present data on the effects of raloxifene, a new second generation selective estrogen receptor modulator (SERM), which has been shown to favorably alter several markers of cardiovascular risk in postmenopausal women.

Animals↗
PubMed1999

Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.

OBJECTIVE: To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women. DESIGN: Prospective, randomised, placebo-controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks. RESULTS: CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group. CONCLUSION: In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.

C-Reactive Protein↗
PubMed1999

Plasma homocysteine is weakly correlated with plasma endothelin and von Willebrand factor but not with endothelium-dependent vasodilatation in healthy postmenopausal women.

BACKGROUND: Hyperhomocysteinemia is an independent cardiovascular risk factor, possibly through the induction of endothelial dysfunction. The postmenopausal state is associated with increased plasma homocysteine. We examined whether increased homocysteine is associated with impaired endothelial function. METHODS: Sixty-three hysterectomized but otherwise healthy postmenopausal women (54.8 +/- 3.5 years) participated in this study. Fasting total plasma homocysteine (tHcy) was measured as free plus protein-bound homocysteine. Endothelial function was assessed by measuring plasma concentrations of the endothelium-derived proteins endothelin (ET), von Willebrand factor (vWF), and plasminogen activator inhibitor type 1 (PAI-1) as well as brachial artery flow-mediated, endothelium-dependent vasodilatation (FMD). RESULTS: Plasma tHcy was 9.6 +/- 2.5 micromol/L. After adjustment for possible confounders, a 1 micromol/L increase in tHcy was associated with an increase in ET of 0.08 ng/L (P = 0.045) and an increase in vWF of 4.2% (P = 0.05). No statistically significant association was present between tHcy and PAI-1 or FMD. CONCLUSIONS: Increased fasting homocysteine in postmenopausal women may impair some aspects of endothelial function. It is of clinical interest to study whether homocysteine lowering can improve endothelial function and thus cardiovascular morbidity and mortality in postmenopausal women.

Adult↗
PubMed1998

Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein.

In patients with diabetes, non-enzymatic glycation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis. alpha-Dicarbonyl compounds were identified as intermediates in the non-enzymatic glycation and increased levels were reported in patients with diabetes. We studied the effect of the alpha-dicarbonyl compound methylglyoxal (MG) on the physicochemical and biological properties of LDL. MG dose-dependently modifies LDL, as indicated by the formation of fluorescent products and the increase of a net negative charge. MG (10 mmol/l) induced major modifications of arginine residues (up to 85%) and minor lysine modifications (less than 6%). MG-LDL preparations generated small amounts of superoxide anion radicals as measured by the reduction of cytochrome c, but this was not accompanied by peroxidation of the polyunsaturated fatty acids of MG-LDL. MG-LDL showed diminished recognition and uptake by the human LDL receptor in cultured cells and a markedly increased plasma clearance rate in vivo in rats. The reduced association and degradation of 125I-oxidised LDL by murine macrophages indicates recognition of MG-LDL by a scavenger receptor. Surprisingly, MG-LDL caused significantly less cholesteryl ester synthesis in murine macrophages, as compared to native LDL and oxidised or acetylated LDL. Highly modified MG-LDL did not induce activation of human endothelial cells, as measured by the expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1.

Animals↗
PubMed1998

Hormone replacement therapy in postmenopausal women with specific risk factors for coronary artery disease.

Hormone replacement therapy (HRT) in postmenopausal women is associated with a reduction in the risk of developing coronary artery disease (CAD) of about 50%. Women with an elevated risk for CAD appear to benefit most by HRT. The HRT-associated cardiovascular protection may be related to favourable changes in several important cardiovascular risk estimators, such as circulating blood concentrations of cholesterol, lipoprotein(a) (Lp(a)) and homocysteine. This paper reviews the literature presently available on the effects of HRT on cholesterol, Lp(a) and homocysteine concentrations, and special attention will be given to the effects on their elevated concentrations. The effect of HRT in women with hypertension is reviewed as well. From this overview it can be concluded that risk factors such as cholesterol, Lp(a), and homocysteine can be favourably modulated by HRT, and especially, that the strongest reductions can be achieved in those women with the highest concentrations. Although clinical trials still need to demonstrate the impact of lowering concentrations of Lp(a) and homocysteine, HRT appears to be a promising risk reduction strategy in this respect.

Cholesterol↗