Biomedical subjects

C D Stehouwer

Publications and source records attributed to C D Stehouwer.

At least 37 records · Page 2Linked to original sources

PubMed2001

Homocysteine-lowering treatment: an overview.

Elevated fasting plasma concentrations of homocysteine have a high prevalence in subjects with cardiovascular disease and have also been associated with an increased risk of atherothrombosis in most, but not all, prospective studies. The most frequent causes of hyperhomocysteinaemia are genetic defects, such as cystathionine-beta-synthase (CBS) deficiency, deficiencies of folic acid and/or vitamin B12, renal failure and interference in homocysteine metabolism by drugs or metabolic alterations. In most cases, no underlying cause can be established. Subjects with CBS deficiency are treated with pyridoxine with additional folic acid and betaine if necessary. Folic acid and vitamin B12 deficiencies should be corrected by supplementation. Increases in folate intake by dietary changes or fortification can also lower plasma homocysteine in vitamin-replete subjects with normal plasma homocysteine levels. In renal failure, folic acid treatment (1-5 mg/day) ameliorates the plasma homocysteine level in most cases but hyperhomocysteinaemia persists in the majority of patients. Primary (fasting) hyperhomocysteinaemia can be treated with folic acid (0.5-5 mg/day). An abnormal methionine-loading test identifies additional patients at risk and postmethionine-loading hyperhomocysteinaemia should be treated with a combination of pyridoxine and folic acid. In the absence of dose-effect studies, a combination of pyridoxine (50 mg) and folic acid (5 mg) is advised. Large clinical trials are currently underway to establish the role of homocysteine-lowering therapy in the secondary prevention of atherothrombotic disease. In view of the effective, cheap and safe character of therapy with folic acid and pyridoxine, a policy can be accepted to screen and treat high-risk patients until these trials have been concluded.

Animals↗

PubMed2001

Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study.

OBJECTIVE: Measures of baroreflex sensitivity, heart rate variability (HRV), and the classical Ewing test parameters are currently used for the diagnosis of diabetic autonomic neuropathy and for mortality risk stratification after myocardial infarction. However, the strengths of the associations of these measures of autonomic function with risk of mortality have never been compared in one study population. Furthermore, no evidence is available on the possible effect of glucose tolerance on these associations. RESEARCH DESIGN AND METHODS: The study population (n = 605) consisted of a glucose tolerance-stratified sample from a general population (50-75 years of age). Cardiac cycle duration and continuous finger arterial pressure were measured under two conditions: at rest and on metronome breathing. From these readings, seven parameters of autonomic function were assessed (one Ewing, five HRV, and one baroreflex sensitivity). RESULTS: During 9 years of follow-up, 101 individuals died, 43 from cardiovascular causes. Subjects with diabetes and low levels of the autonomic function parameters, indicating impaired autonomic function, had an approximately doubled risk of mortality. This association was consistent, though not statistically significant, for all parameters. The elevated risk was not observed in subjects without diabetes, hypertension, or prevalent cardiovascular disease. CONCLUSIONS: Impaired autonomic function is associated with all-cause and cardiovascular mortality. Moreover, the results of the present study suggest that cardiac autonomic dysfunction in patients already at risk (diabetes, hypertension, or history of cardiovascular disease) may be especially hazardous.

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PubMed2001

Rapid progression of albumin excretion is an independent predictor of cardiovascular mortality in patients with type 2 diabetes and microalbuminuria.

OBJECTIVE: In patients with type 2 diabetes, microalbuminuria is associated with an increase in predominantly cardiovascular mortality. Considerable interindividual variability in the rate of progression of microalbuminuria exists. The prognostic significance of rate of progression of microalbuminuria with regard to cardiovascular and renal clinical end points is, however, unknown. The purpose of this study was to determine the prognostic significance of rate of progression of microalbuminuria for cardiovascular end points and renal function. RESEARCH DESIGN AND METHODS: In a previous prospective cohort study, progression of microalbuminuria (expressed as mean yearly change in albumin-to-creatinine ratio) was assessed in 58 patients with type 2 diabetes. During a median follow-up of 7 years after progression of microalbuminuria was determined, we registered all-cause mortality and coronary heart disease mortality as primary end points and coronary heart disease (fatal or nonfatal), peripheral vascular disease, ischemic stroke, retinopathy, macroalbuminuria, and change in serum creatinine as secondary end points. RESULTS: Seven subjects died during the study; five of these subjects died of coronary heart disease. Cox's regression analysis identified progression of microalbuminuria as a significant predictor of all-cause mortality (hazard ratio 1.46 per point increase in albumin-to-creatinine ratio per year, P < 0.001), coronary heart disease mortality (hazard ratio 2.32, P = 0.006), and macroalbuminuria (hazard ratio 1.79, P < 0.001). Adjustment for multiple cardiovascular risk factors did not affect these results. Identical analyses for baseline level of microalbuminuria instead of progression rate of microalbuminuria did not show significant hazard ratios. In addition, progression of microalbuminuria significantly predicted an increase in serum creatinine (r = 0.29, P = 0.04). CONCLUSIONS: In patients with type 2 diabetes and microalbuminuria, the rate of progression of albumin excretion seems to be a powerful independent predictor of mortality caused mainly by coronary heart disease.

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PubMed2000

Hyperhomocysteinemia is associated with the presence of retinopathy in type 2 diabetes mellitus: the Hoorn study.

BACKGROUND: Retinopathy is the leading cause of blindness among patients with type 2 diabetes mellitus (DM). Hyperhomocysteinemia is a recently recognized risk factor for cardiovascular disease, independent of established risk factors. OBJECTIVE: To study the association between the homocysteine level and retinopathy among subjects with and without DM. METHODS: We studied an age-, sex-, and glucose tolerance-stratified random sample of a 50- to 75-year-old general white population in the Hoorn Study (N = 625). Retinal vascular changes (retinopathy) were assessed using ophthalmoscopy and/or fundus photography. Hyperhomocysteinemia was defined as a serum total homocysteine level greater than 16 micromol/L. RESULTS: The prevalence of retinopathy was 9.8% (28/285) in subjects with normal glucose tolerance, 11.8% (20/169) in those with impaired glucose tolerance, 9.4% (10/106) in those with newly diagnosed type 2 DM, and 32.3% (21/65) in those with known type 2 DM. The prevalence of retinopathy was 10.3% (39/380) in subjects without hypertension and 16.3% (40/245) in subjects with hypertension; it was 12.0% (64/534) in subjects with a serum total homocysteine level of 16 micromol/L or less and 16.5% (15/91) in those with a serum total homocysteine level of more than 16 micromol/L. After stratification for DM and adjustment for age, sex, glycosylated hemoglobin, and hypertension, the odds ratio (95% confidence interval) for the relation between retinopathy and hyperhomocysteinemia was 0.97 (95% confidence interval, 0.42-2.82) in patients without DM and 3.44 (95% confidence interval, 1.13-10.42) in patients with DM (P =.08 for interaction). CONCLUSION: The findings suggest that hyperhomocysteinemia may be a risk factor for retinopathy in patients with type 2 DM, but probably not in patients without DM. Arch Intern Med. 2000;160:2984-2990

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PubMed2000

[Periodic fever due to hyper-IgD syndrome].

In a 45-year-old man who from early childhood had been suffering of periodic fever, which did not respond to any therapy attempted, the ultimate diagnosis was hyperimmunoglobulinaemia D syndrome (HIDS). HIDS attacks typically occur every 4-6 weeks and last 3-7 days. The most frequent symptoms are fever, diarrhoea, arthralgias, cold shivers, abdominal pain, vomiting and headache. Physical examination often reveals lymphadenopathy, skin lesions, arthritides, splenomegaly and serositis. Laboratory investigation includes an acute-phase response with granulocytosis and enhanced erythrocyte sedimentation rate. The serum concentration of IgD is increased as is the concentration of IgA. There is no causal therapy. A causative gene mutation was recently identified.

Acute-Phase Reaction↗

PubMed2000

Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study.

BACKGROUND: A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 (non-insulin-dependent) diabetes mellitus compared with nondiabetic subjects is not known. A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects. We therefore prospectively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality. METHODS AND RESULTS: Between October 1, 1989, and December 31, 1991, serum was saved from 2484 men and women, 50 to 75 years of age, who were randomly selected from the town of Hoorn, The Netherlands. Fasting serum tHcy concentration was measured in 171 subjects who died (cases; 76 of cardiovascular disease) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. The prevalence of hyperhomocysteinemia (tHcy >14 micromol/L) was 25. 8%. After adjustment for major cardiovascular risk factors, serum albumin, and HbA(1c), the odds ratio (95% CI) for 5-year mortality was 1.56 (1.07 to 2.30) for hyperhomocysteinemia and 1.26 (1.02 to 1. 55) per 5-micromol/L increment of tHcy. The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 (0.87 to 2.06) in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects (P=0.08 for interaction). CONCLUSIONS: Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects.

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PubMed2000

Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial.

BACKGROUND: A high plasma homocysteine concentration is associated with increased risk of atherothrombotic disease. We investigated the effects of homocysteine-lowering treatment (folic acid plus vitamin B6) on markers of subclinical atherosclerosis among healthy siblings of patients with premature atherothrombotic disease. METHODS: We did a randomised, placebo-controlled trial among 158 healthy siblings of 167 patients with premature atherothrombotic disease. 80 were assigned placebo and 78 were assigned 5 mg folic acid and 250 mg vitamin B6 daily for 2 years. The primary endpoint was the development or progression of subclinical atherosclerosis as estimated from exercise electrocardiography, the ankle-brachial pressure index, and carotid and femoral ultrasonography. FINDINGS: Ten participants in the treatment group, and 14 in the placebo group dropped out. Vitamin treatment, compared with placebo, was associated with a decrease in fasting homocysteine concentration (from 14.7 to 7.4 micromol/L vs from 14.7 to 12.0 micromol/L), and in postmethionine homocysteine concentration (from 64.9 to 34.9 micromol/L vs from 64.8 to 50.3 micromol/L). It was also associated with a decreased rate of abnormal exercise electrocardiography tests (odds ratio 0.40 [0.17-0.93]; p=0.035). There was no apparent effect of vitamin treatment on ankle-brachial pressure indices (0.87 [0.56-1.33]), or on carotid and peripheral-arterial outcome variables (1.02 [0.26-4.05] and 0.86 [0.47-1.59], respectively). INTERPRETATION: Homocysteine-lowering treatment with folic acid plus vitamin B6 in healthy siblings of patients with premature atherothrombotic disease is associated with a decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic coronary events.

Blood Pressure↗

PubMed2000

[Additional effects of statins independent of the cholesterol-lowering as yet not shown to be clinically relevant].

The reduction in cardiovascular morbidity and mortality during the use of statins is due to their cholesterol lowering effect. In addition, the statins are assumed to exert lipid lowering independent actions, which may contribute to the beneficial effect. However, the evidence for these effects is based on less solid sub- and post hoc analyses of clinical trials and in vitro and animal experiments in which unrealistic doses of statins are used. On closer examination, most of these so-called lipid independent effects are in fact based on either direct or indirect cholesterol lowering. The clinical relevance has to be shown in prospective clinical trials.

Anticholesteremic Agents↗

PubMed2000

Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus.

AIMS/HYPOTHESIS: The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel in the pancreatic beta cell. Mutations at nt -3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 of the gene for the sulphonylurea receptor (SUR1) associate with Type II (non-insulin-dependent) diabetes mellitus in several independent populations. We investigated whether these gene variants associate with changes in the pattern of glucose-stimulated insulin secretion. METHODS: Subjects who had normal glucose tolerance (n = 67) and subjects with an impaired glucose tolerance (n = 94), originating from two independent studies, were included in the study. Beta-cell function and insulin sensitivity were assessed by the hyperglycaemic clamp. RESULTS: Frequencies of the exon 16 -3t allele in the normal and impaired glucose tolerant groups were 46% and 44% respectively (p = NS). The more rare exon 18 T allele showed frequencies of 5 and 7% respectively (p = NS). We observed an approximately 25% reduced second-phase insulin secretion in carriers of the exon 16 -3t allele in both groups (p < 0.05). Estimates of insulin sensitivity did not show differences between carriers and non-carriers. The variant in exon 18 and the combined presence of variants in exon 16 and exon 18 were not associated with differences in insulin secretion or insulin sensitivity in our study groups. CONCLUSION/INTERPRETATION: The diabetes associated exon 16 -3t variant of the SUR1 gene associates with a functional change of the beta cell as reflected by reduced second-phase insulin secretion in response to a standardized hyperglycaemia in normal and impaired glucose tolerant subjects.

ATP-Binding Cassette Transporters↗

PubMed2000

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study.

AIMS/HYPOTHESIS: Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. METHODS: The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. RESULTS: Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. CONCLUSION/INTERPRETATION: The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs.

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PubMed2000

Increased plasma homocysteine after menopause.

Besides genetic defects in the enzymes involved in homocysteine metabolism and nutritional deficiencies in vitamin cofactors, sex steroid hormones may modulate plasma homocysteine levels. The post-menopausal state has been found to be associated with higher plasma homocysteine levels, but data are inconsistent and studies published so far did not adjust for age, which is an important confounding factor in studying the effect of menopause. In the present study total plasma homocysteine levels were measured in a meticulously selected population in which the contrast in estrogen status between pre- and postmenopausal women of the same age was maximized. The study comprised 93 premenopausal and 93 postmenopausal women of similar age (range 43-55 years). Women were selected from respondents to a mailed questionnaire on menopause, which was sent to all women aged 40-60 years in the Dutch town of Zoetermeer (n = 12675). Postmenopausal women who were at least three years after menopause or whose menses had stopped naturally before age 48 were age-matched with premenopausal women with regular menses and without menopausal complaints. Plasma homocysteine levels in the fasting state were related to menopausal status; the age-adjusted geometric mean was 10.7 micromol/l in premenopausal and 11.5 micromol/l in postmenopausal women (difference of 7%, 95% confidence interval 0.3-14%, P = 0.04). Additional adjustment for plasma creatinine, body mass index, smoking habit (yes, no) and alcohol intake did not influence this difference. The results of this population-based study indicate that plasma homocysteine is affected by menopause.

Adult↗

PubMed2000

Modulation of plasma endothelin levels by the menstrual cycle.

Blood pressure varies during the menstrual cycle, but the reason for this is unclear. Administration of (synthetic) sex hormones can influence the level of vasoactive substances such as endothelin (ET). However, it is not known whether short-term variations in sex hormone levels in physiological situations affect ET levels. We assessed the effects of the menstrual cycle on plasma ET-1 in 8 healthy premenopausal women not using oral contraceptives (OCs) and 8 premenopausal women using OCs. ET-1 levels were measured in all subjects on days 1 to 3 (menstrual phase), 9 to 12 (follicular phase), and 20 to 23 (luteal phase) of the menstrual cycle. ET-1 levels remained constant in OC users (2.4 +/- 0.4, 2.6 +/- 0.4, and 2.4 +/- 0.4 pg/mL on days 1 to 3, 9 to 12, and 20 to 23 of the pill cycle). In contrast, ET-1 levels in non-OC users decreased in all women during the follicular and luteal phase of the menstrual cycle compared with the menstrual (low-estrogenic) phase (3.6 +/- 0.5, 2.8 +/- 0.5, and 2.9 +/- 0.3 pg/mL for the menstrual, follicular, and luteal phase, respectively, P < .01 for menstrual vfollicular and P < .01 for menstrual v luteal). The differences between OC users and nonusers were significant in the menstrual phase of the cycle (P < .01). We conclude that ET levels fluctuate during the menstrual cycle. Previously reported effects of the menstrual cycle on blood pressure may be partly explained by the effects of sex hormones on the level of vasoactive mediators. This fluctuation is not present in OC users. Studies on hemodynamic parameters in premenopausal women should account for hormonal variations in the various phases of the menstrual cycle.

Adult↗

PubMed2000

Normohomocysteinaemia and vitamin-treated hyperhomocysteinaemia are associated with similar risks of cardiovascular events in patients with premature atherothrombotic cerebrovascular disease. A prospective cohort study.

BACKGROUND: Mild hyperhomocysteinaemia (HHC) is associated with an increased risk of premature atherothrombotic cerebrovascular disease. We investigated the clinical efficacy with regard to the incidence of cardiovascular events of treatment of mild HHC with vitamin B(6) plus folic acid. METHODS: We studied 224 consecutive patients with clinically manifest atherothrombotic cerebrovascular disease with onset before the age of 56. Follow-up was obtained in 203 (90.6%) patients. At baseline, 52 (25.6%) were hyperhomocysteinaemic after methionine loading and started treatment with vitamin B(6) (250 mg) plus folic acid (5 mg); 151 (74.4%) were normohomocysteinaemic (reference group). RESULTS: During follow-up (median 57 months), 31 (20.5%) of the normo- and 11 (21.2%) of the hyperhomocysteinaemic patients had a new cardiovascular event. The crude incidence rate per person-year for any cardiovascular event was similar in both groups (0.043 [CI, 0.029-0.057] in the normo- vs. 0.045 [CI, 0.021-0. 069] in the hyperhomocysteinaemic group). Multivariate Cox-regression analyses showed that hypertension and cholesterol levels were associated with an increased risk of new cardiovascular events in the total group [relative risk [RR] (yes vs. no), 7.4 (3. 4-16.0) and RR (per 1 mmol/l), 1.9 (CI, 1.4-2.7)]. The adjusted RR for new cardiovascular events in the hyper- as compared to the normohomocysteinaemic patients was 0.96 (CI, 0.48-1.92). CONCLUSION: These data are consistent with a protective effect of treatment with vitamin B(6) plus folic acid in patients with premature atherothrombotic cerebrovascular disease and post-methionine HHC.

Adult↗

PubMed2000

Serum homocysteine is weakly associated with von Willebrand factor and soluble vascular cell adhesion molecule 1, but not with C-reactive protein in type 2 diabetic and non-diabetic subjects - The Hoorn Study.

BACKGROUND: Hyperhomocysteinaemia may constitute an independent risk factor for cardiovascular disease, but it is still unclear by which pathophysiological mechanisms homocysteine (tHcy) may promote atherothrombosis. The aim of this study was firstly to examine whether tHcy is associated with endothelial dysfunction, increased adherence of leukocytes, and/or chronic low-grade inflammation, as estimated from plasma levels of von Willebrand factor (vWf), soluble vascular cell adhesion molecule 1 (sVCAM-1) and C-reactive protein (CRP), respectively. Secondly we investigated whether the presence of type 2 diabetes modifies these associations. MATERIALS AND METHODS: Six hundred and ten subjects of a general population of middle-aged and elderly subjects, 170 of whom had type 2 diabetes, participated in this cross-sectional study. Linear regression analyses were used to study whether tHcy was associated with vWf, sVCAM-1 and CRP, and whether the presence of diabetes modified these associations. RESULTS: After adjustment for confounders, tHcy was significantly but weakly associated with vWf (beta = 0.15, P = 0.05) and sVCAM-1 (beta = 0.082, P = 0.04). tHcy was not significantly associated with CRP (beta = 0.02, P = 0.91). The presence of diabetes did not significantly modify these associations. CONCLUSIONS: This study provides evidence that tHcy is, at most, weakly associated with endothelial dysfunction as estimated from plasma vWf, and with leukocyte adhesion as estimated from plasma sVCAM-1. tHcy was not significantly associated with chronic low-grade inflammation as estimated from plasma CRP. Our data thus suggest that the link between tHcy and atherothrombosis cannot be explained by associations of tHcy with vWf, sVCAM-1 or CRP.

Aged↗

PubMed2000

ACE-inhibition modulates some endothelial functions in healthy subjects and in normotensive type 1 diabetic patients.

BACKGROUND: The usefulness of treatment with an angiotensin-converting enzyme-inhibitor (ACE-inhibitor) in normotensive patients with type 1 diabetes is controversial. We investigated whether ACE-inhibition improves endothelial function in such patients and compared the responses to those in healthy subjects. DESIGN: We studied 23 healthy volunteers (controls, aged 29.8 [SD 7.0] years) and 24 type 1 diabetic patients (aged 28.7 [9. 6] years; HbA1c 8.1 [1.2]%; diabetes duration 13.8 [2-30] years; blood pressure < 140/90 mm Hg; 7 with microalbuminuria) after 5 weeks of ACE-inhibition (quinapril, 10 mg day-1) and placebo in a randomized, double-blind cross-over design. Estimates of endothelial function obtained were by flow-mediated vasodilation and plasma levels of endothelium-derived proteins. RESULTS: As estimated from the measurements on placebo, type 1 diabetic patients, as compared to the controls, had some impairment of endothelial function: plasma tissue-type plasminogen activator levels were lower (3.5 vs. 5.4 ng mL(-1), P<0.05), but there were no significant differences in brachial artery flow-mediated vasodilation or plasma levels of von Willebrand Factor, endothelin-1, plasminogen activator inhibitor-1, soluble E-selectin or vascular cell adhesion molecule-1. As compared to placebo, ACE-inhibition increased flow-mediated vasodilation in controls (by 3.84% points [95% CI, 0.66 - 7.02], P<0.05), but not in type 1 diabetic patients (0.82% points [95% CI, -2.72 - 4.36], P = 0.64; P = 0.08 vs. controls). On ACE-inhibition soluble E-selectin levels decreased both in controls (from 43.0 to 37.0 ng mL(-1), P<0.01) and in type 1 diabetic patients (from 41.0 to 39.0 ng mL(-1), P = 0.09). Other endothelial markers did not change during ACE-inhibition. CONCLUSION: Normotensive type 1 diabetic patients with normoalbuminara or microalbuminuria have mild endothelial dysfunction. Short-term ACE-inhibition improves endothelial function as reflected by a decreased sE-selectin in healthy subjects and in normotensive type 1 diabetic patients. In healthy subjects, ACE-inhibition increases flow-mediated vasodilation. In contrast, in type 1 diabetic patients, ACE-inhibition does not affect flow-mediated vasodilation.

Adult↗

PubMed2000

Hyperhomocysteinaemia is not associated with isolated crural arterial occlusive disease: The Hoorn Study.

OBJECTIVES: Hyperhomocysteinaemia is an independent risk factor for peripheral arterial disease (PAD). The localization of peripheral arterial disease is clinically relevant, because proximal (aortoiliac and femoropopliteal) disease is associated with a particularly poor overall prognosis, whereas isolated distal (i.e. crural) disease is associated with a better overall prognosis. The aim of the study was to investigate whether the strength of the association between hyperhomocysteinaemia and peripheral arterial disease differs according to the localization of the anatomical obstruction. DESIGN: Fasting serum total homocysteine (tHcy) was measured in an age-, sex- and glucose-tolerance stratified random sample (n = 631) of a 50- to 75-year-old general Caucasian population. History of a peripheral arterial reconstruction was recorded. Aortoiliac, femoropopliteal and crural arterial obstructions were registered by means of Doppler flow velocity curves. RESULTS: The median serum tHcy level was 12.2 micromol L-1 (interquartile range: 10.0-15.3) in men and 10.7 micromol L-1 (interquartile range: 9.0-13.3) in women. The prevalences of aortoiliac, femoropopliteal and crural obstructions were 2.1%, 2.7% and 11.9%, respectively. After adjustment for age, sex, systolic blood pressure, current smoking, serum cholesterol and diabetes mellitus, the odds ratios (95% confidence interval) per 5 micromol L-1 tHcy increment were 1.41 (1.05-1.89) for aortoiliac, 1.03 (0. 70-1.52) for femoropopliteal and 0.82 (0.59-1.15) for crural obstructions. Finally, diabetes mellitus, HbA1c and current smoking were significantly associated with crural and femoropopliteal disease, whereas systolic blood pressure was significantly associated with aortoiliac obstructions. CONCLUSIONS: The present study indicates that hyperhomocysteinaemia is associated with aortoiliac but not with isolated crural arterial occlusive disease.

Aged↗

PubMed2000

Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction.

Hyperhomocysteinemia has been associated with premature atherothrombotic vascular disease. It is not known whether hyperhomocysteinemia induces a distinct type of vascular disease. Its interaction, if any, with traditional risk factors also remains unclear. The pathophysiological mechanisms linking hyperhomocysteinemia to vascular disease have been extensively studied in vitro and in animals. From these studies, it has been suggested that homocysteine limits the bioavailability of nitric oxide (NO), increases oxidative stress, stimulates smooth cell proliferation, and alters elastic wall properties. The relevance of these proposed mechanisms in vivo is unclear, because clinical studies have yielded controversial results with regard to the relation between plasma homocysteine levels and indices of endothelial function, such as brachial artery flow-mediated vasodilatation and plasma levels of endothelium-derived marker proteins. Up till now, there have been no controlled data on the effects of homocysteine-lowering treatment on vascular function or clinical end points. The precise mechanisms (if any) by which homocysteine mediates its adverse vascular effects are in fact unknown but may relate to impaired endothelial and smooth muscle cell function.

Adult↗

PubMed2000

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy.

BACKGROUND: A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. METHODS: We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean+/-SD) 41+/-10 years, diabetes duration 28+/-8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43+/-10 years, diabetes duration 27+/-9 years). RESULTS: Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P<0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P=0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (epsilon2/epsilon3/epsilon4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0. 152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic epsilon4-allele compared with 12% in patients with the epsilon3,epsilon3 genotype, P<0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. CONCLUSIONS: The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.

Adult↗