Baseline Homocysteine Concentrations Research Articles

Homocysteine Is Associated With Future Venous Thromboembolism in 2 Prospective Cohorts of Women.

[Figure: see text].

Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial

In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk. Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400μg) and vitamin-B12 (500μg) versus placebo (n=2,919). Primary outcome was verified self-reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease. A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51-58], (n=662 and n=636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic- and any fracture (p=0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1μmol/l). No age-dependent effects were present. This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated.

Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients.

We aimed to examine whether baseline homocysteine (Hcy) concentrations affect antihypertensive responses to enalapril treatment among previously untreated hypertensive patients (n=10 783) in the CSPPT (China Stroke Primary Prevention Trial). After a 3-week run-in treatment with a daily dose of 10 mg enalapril, eligible hypertensive patients were randomly assigned to a double-blind daily treatment of a tablet of either enalapril (10 mg) and folic acid (0.8 mg) or enalapril (10 mg) alone for a median of 4.5 years. After the 3-week treatment period with enalapril alone, the systolic blood pressure-lowering effect was significantly reduced by 1.39 (95% confidence interval 0.40-2.37) and 3.25 (95% confidence interval 1.98-4.52) mm Hg, respectively, in those with baseline Hcy concentrations of 10 to 15 and ≥15 μmol/L (P for trend <0.001) as compared with those with Hcy concentration of <10 μmol/L. Similar results were observed after a 15-week treatment period with enalapril alone. After a median 4.5-year enalapril-based antihypertensive treatment period, compared with those with Hcy concentration of <10 μmol/L, the systolic blood pressure-lowering effect was still significantly reduced by 0.77 (95% confidence interval 0.01-1.53) and 1.70 (95% confidence interval 0.72-2.68) mm Hg, respectively, in those with Hcy concentrations of 10 to 15 and ≥15 μmol/L (P for trend <0.001). In addition, participants with higher baseline Hcy concentrations had persistently higher systolic blood pressure levels across the entire study treatment period. Similarly, baseline Hcy concentrations were inversely associated with diastolic blood pressure reduction during the short-term enalapril alone treatment. However, the inverse association between baseline Hcy and diastolic blood pressure reduction was attenuated and became insignificant after the long-term enalapril-based treatment period. Elevated Hcy concentrations significantly decreased the antihypertensive effect of the short-term and long-term enalapril-based antihypertensive treatment in previously untreated hypertensive patients.

Effect of Folic Acid, Betaine, Vitamin B₆, and Vitamin B12 on Homocysteine and Dimethylglycine Levels in Middle-Aged Men Drinking White Wine.

Moderate regular consumption of alcoholic beverages is believed to protect against atherosclerosis but can also increase homocysteine or dimethylglycine, which are putative risk factors for atherosclerosis. We aimed (1) to investigate the effect of alcohol consumption on vitamins and several metabolites involved in one-carbon metabolism; and (2) to find the most effective way of decreasing homocysteine during moderate alcohol consumption. Methods: Male volunteers (n = 117) were randomly divided into five groups: the wine-only group (control, 375 mL of white wine daily for one month) and four groups combining wine consumption with one of the supplemented substances (folic acid, betaine, and vitamins B12 or B6). Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B6 supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration.

Plasma S-adenosylhomocysteine is associated with the risk of cardiovascular events in patients undergoing coronary angiography: a cohort study

Although cross-sectional studies have shown that plasma S-adenosylhomocysteine (SAH), the metabolic precursor of homocysteine, is associated with cardiovascular disease, the prospective relation between plasma SAH and cardiovascular disease risk is unknown. The aim of this study was to prospectively evaluate the association between plasma SAH and cardiovascular disease risk in coronary angiography patients. Baseline plasma SAH and homocysteine concentrations were measured in 1003 patients aged between 21 and 87 y who underwent coronary angiography. Cox proportional hazards models were used to analyze the association between SAH and homocysteine and the risk of cardiovascular events, including fatal cardiovascular diseases, nonfatal myocardial infarction, and stroke. During the median follow-up period of 3.0 y, 93 participants developed cardiovascular events (32.7/1000 person-years). The age- and sex-adjusted hazard ratio of cardiovascular events was 3.38 (95% CI: 2.12, 5.39) for each 1-SD increase in the natural log-transformed SAH concentration. The age- and sex-adjusted hazard ratios of cardiovascular events across quartiles of SAH concentrations were 1.0, 2.25, 2.72, and 3.40 (P-trend = 0.007). Further adjustment for other cardiovascular disease risk factors and plasma homocysteine affected the results only slightly. This positive association between SAH and cardiovascular disease risk did not change when participants were stratified by age group, sex, and other baseline covariates. The results among a subset of participants with significant coronary stenosis were similar. Higher concentrations of plasma SAH are independently associated with an increased risk of cardiovascular events among patients undergoing coronary angiography. This trial was registered at www.chictr.org as ChiCTR-RNRC-08000270.

A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy

The lowest dose of folic acid required to achieve effective reductions in homocysteine is controversial but important for food fortification policy given recent concerns about the potential adverse effects of overexposure to this vitamin. We compared the effectiveness of 0.2 mg folic acid/d with that of 0.4 and 0.8 mg/d at lowering homocysteine concentrations over a 6-mo period. A randomized dose-finding trial with folic acid was conducted. Of 203 participants screened, 101 patients with ischemic heart disease and 71 healthy volunteers completed the study. Participants were randomly assigned to receive placebo or folic acid at doses of 0.2, 0.4, or 0.8 mg/d for 26 wk; subsamples of patients with ischemic heart disease were also examined at 6 or 12 wk. Participants with higher baseline homocysteine concentrations had the greatest reductions in homocysteine in response to folic acid doses of 0.2 mg (-20.6%), 0.4 mg (-20.7%), and 0.8 mg (-27.8%); in those with lower baseline homocysteine concentrations, the responses were -8.2%, -8.9%, and -8.3%, respectively. No significant differences in homocysteine responses to the different doses were observed. In the patient group sampled at intervals during the intervention, the maximal homocysteine response appeared to be achieved by 6 wk in the 0.8-mg/d group and by 12 wk in the 0.4-mg/d group. However, the homocysteine response was suboptimal in the 0.2-mg/d group at both 6 and 12 wk compared with that at 26 wk. A folic acid dose as low as 0.2 mg/d can, if administered for 6 mo, effectively lower homocysteine concentrations. Higher doses may not be necessary because they result in no further significant lowering, whereas doses even lower than 0.2 mg/d may be effective in the longer term. Previous trials probably overestimated the folic acid dose required because of a treatment duration that was too short. This trial was registered at clinicaltrials.gov as ISRCTN45296887.

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B12 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (P<0.01), 2 (P<0.001) and 3 (P<0.05) after treatment at all pemetrexed dose levels (400–700 mg m−2). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration–time curve (AUC) (r2=0.23, P<0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r2=0.58, P<0.001) and leucocytes (r2=0.26, P<0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r2=0.37, P<0.01 and r2=0.39, P<0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (P<0.005) and 15 (P<0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation.

Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus

To determine the rate of atherosclerosis progression as well as the relationship of traditional risk factors, systemic lupus erythematosus (SLE)-related factors, and treatment to atherosis progression in SLE patients. Outpatients in the Hospital for Special Surgery SLE Registry underwent serial carotid ultrasound and clinical assessment in a longitudinal study. Among 158 patients, 77 (49%) had persistent absence of atherosclerosis (carotid plaque), 36 (23%) had unchanged atherosclerosis, and 45 (28%) had progressive atherosclerosis, defined as a higher plaque score (new plaque in 25 patients and more extensive plaque in 20 patients) after a mean +/- SD interval of 34 +/- 9 months. Multivariate determinants of atherosclerosis progression were age at diagnosis (odds ratio [OR] 2.75, 95% confidence interval [95% CI] 1.67-4.54 per 10 years, P < 0.001), duration of SLE (OR 3.16, 95% CI 1.64-6.07 per 10 years, P < 0.001), and baseline homocysteine concentration (OR 1.24, 95% CI 1.06-1.44 per mumoles/liter, P = 0.006). SLE patients with stable plaque and progressive plaque differed only in baseline homocysteine concentration. Atherosclerosis progression was increased across tertiles of homocysteine concentration (16.2%, 36.4%, and 56.1%; P = 0.001), and homocysteine tertile was independently related to progression of atherosclerosis (OR 3.14, 95% CI 1.65-5.95 per tertile, P < 0.001). Less aggressive immunosuppressive therapy and lower average prednisone dose were associated with progression of atherosclerosis in univariate, but not multivariate, analyses. Inflammatory markers and lipids were not related to atherosclerosis progression. Atherosclerosis develops or progresses in a substantial minority of SLE patients during short-term followup (10% per year on average). Older age at diagnosis, longer duration of SLE, and higher homocysteine concentration are independently related to progression of atherosclerosis. These findings show that aggressive control of SLE and lowering of homocysteine concentrations are potential means to retard the development and progression of atherosclerosis in SLE.

Lowering Homocysteine with B Vitamins Has No Effect on Blood Pressure in Older Adults

An elevated circulating homocysteine concentration is associated with the risk of cardiovascular disease. The mechanism by which an elevated homocysteine increases cardiovascular risk is unclear but may be mediated in part by elevating blood pressure. It is well established that supplements containing folate, vitamins B-12, and B-6 lower homocysteine concentrations. However, the effect of homocysteine-lowering vitamins on blood pressure has not been well studied. We sought to determine whether lowering homocysteine with B vitamins lowers blood pressure in healthy older people with elevated homocysteine concentrations. Two hundred seventy-six healthy older participants (≥65 y) with a homocysteine ≥13 μmol/L were randomized to receive a daily supplement containing folate (1 mg), vitamin B-12 (500 μg), and vitamin B-6 (10 mg), or a placebo, for 2 y. Plasma homocysteine was lower in the Vitamins group than the Placebo group at both 1 [−4.3 μmol/L (95% CI; −4.9, −3.7)] and 2 y [−4.4 μmol/L (95% CI: −5.3, −3.6)]. Systolic and diastolic blood pressures as well as pulse pressure in the Vitamins group did not differ from the Placebo group over the duration of the trial. The mean differences in blood pressures, adjusted for baseline values, did not exceed 1 mm Hg. Supplemental B-vitamins lowered plasma homocysteine but had no effect on blood pressure in older people with elevated baseline homocysteine concentrations.

Prospective evaluation of folic acid supplementation on plasma homocysteine concentrations during weight reduction: a randomized, double-blinded, placebo-controlled study in obese women

Elevated total homocysteine concentrations and obesity are both associated with an increased risk of cardiovascular disease. However, previous studies of weight reduction on serum homocysteine concentrations have obtained inconsistent reports. We investigated the effect of folic acid supplementation on serum homocysteine concentrations via a randomized, double-blinded, placebo-controlled study. Seventy-four obese women [age (mean ± SEM) 41 ± 1 years; body mass index, 29.6 ± 0.5 kgs/m 2] completed a 12 weeks weight reduction program with dietary advice and light exercise. They were also randomized to take either folic acid supplementation (5 mg daily, n = 36) or placebo (n = 38) groups. This program led to a weight reduction of 7.7% and 8.9% of initial weight for folic acid supplementation and placebo groups, respectively. Serum folate concentrations increased for 3 folds (p < 0.001) in the folic acid group. In the folic acid group, there was a trend of lower fasting serum homocysteine concentratrions (7.6 ± 0.2 vs. 7.3 ± 0.3 μmol/L), but it did not reach statistical significance (p = 0.170). However, we found that serum homocysteine concentrations decreased significantly in those with higher baseline homocysteine concentrations (8.7 ± 1.3 vs. 7.8 ± 1.5 μmol/L, p = 0.004), while it did not change in those with lower baseline homocysteine concentrations (6.6 ± 0.6 vs. 6.8 ± 1.2 μmol/L, p = 0.334). Reduction of serum homocysteine concentrations did not correlate with elevation of serum folate concentrations (p = 0.646) in obese women with higher baseline homocysteine concentrations. In conclusion, serum homocysteine concentrations can be maintained in obese women during mild to moderate weight loss. Folic acid supplementation decreased serum homocysteine concentrations in those women who had higher serum homocysteine concentrations before participating in the weight reduction program.

Elevated plasma homocysteine: cause or consequence of myocardial infarction?

To determine whether a first myocardial infarction leads to increased plasma homocysteine concentrations and whether the association between homocysteine and myocardial infarction was greater at follow-up compared with baseline. A population-based, prospective, nested case-referent study. Screening took place at the nearest health survey centre in northern Sweden. Of more than 36,000 persons screened, 78 developed a first myocardial infarction (average 18 months after sampling). Fifty of these had participated in a follow-up health survey (average 8(1/2) years between surveys) and were sex- and age-matched with 56 referents. Comparison of plasma homocysteine levels in case and referent subjects before and after development of a first myocardial infarction. No statistically significant difference was found between cases and referents regarding homocysteine at baseline or follow-up. Plasma homocysteine and plasma creatinine increased significantly, and plasma albumin decreased significantly over time. Conditional univariate logistic regression indicated that high homocysteine at follow-up but not baseline was associated with first myocardial infarction (OR 2.49; 95% CI: 1.03-6.02), but the relation disappeared in multivariate analyses including plasma creatinine and plasma albumin. High plasma creatinine remained associated with first myocardial infarction at both baseline (OR 2.94; 95% CI: 1.05-8.21) and follow-up (OR 3.38; 95% CI: 1.21-9.48). In this study, first myocardial infarction did not cause increased plasma homocysteine concentration.

Homocysteine Lowering by B Vitamins and the Secondary Prevention of Deep-Vein Thrombosis and Pulmonary Embolism. A First Randomised, Placebo-Controlled, Double-Blind Trial.

Hyperhomocysteinemia is a risk factor for venous thrombosis and arterial vascular disease. Supplementation with B-Vitamins (folic acid, vitamin B12 and vitamin B6) reduces homocysteine concentrations by 25–30% in healthy subjects and in patients with venous thrombosis. Until now, there are no results of clinical trials of the effect of homocysteine lowering by B-vitamins on the risk of venous thrombosis.In the VITRO (Vitamins and Thrombosis) study, we investigated the effect of daily supplementation of 5 mg folic acid, 50 mg of pyridoxin and 0.4 mg hydroxycobalamin as secondary prevention of deep-vein thrombosis (DVT) and pulmonary embolism (PE). Patients with primary DVT or PE who were registered for out-patient treatment with an anticoagulation clinic, were asked to participate. Homocysteine was measured and information was retrieved about the diagnosis and circumstances in which patients developed their thrombosis. Patients between 20 to 80 years old with objectively confirmed proximal DVT or PE in the absence of other major risk factors for deep-vein thrombosis (surgery, pregnancy and child-bed, long-term immobility) and a homocysteine concentration in the top quartile entered the study. After informed consent they were randomised to high-dose multivitamin supplementation or placebo and were followed for 2.5 years. End-points were recurrent DVT or PE, as diagnosed by the physician of the patient. Parallel to this study a similar study was conducted in a random sample of patients in the lower three homocysteine quartiles.Subjects were divided according to their homocysteine level in a hyperhomocysteinemic (with a homocysteine concentration in the top quartile, n=360) and a normohomocysteinemic group (a random sample of patients with a homocysteine concentration in the lower three homocysteine quartiles, n=325). The number of recurrent events of thrombosis were 43 out of 348 in the vitamin group (54/1000yr) and 50 out of 353 in the placebo group( 64/1000yr).The relative risk associated with vitamin treatment in the hyperhomocysteinemic group was 1.14 (95%CI 0.65–1.98) and in the normohomocysteinemic group 0.58 (95%CI 0.31–1.07). The overall relative risk was 0.84 (95%CI 0.56–1.26). A baseline homocysteine above the 90th percentile was associated with an increased risk for recurrence of venous thrombosis (RR= 1.9 (95%CI 1.1 tot 3.3). This effect was independent of the treatment regimen. The results of our study does not provide evidence that homocysteine lowering by B-vitamin supplementation prevents recurrent venous thrombosis. The precision of our estimates does not allow to distinguish between ‘no effect' or a 10 to 20% relative risk reduction. However such risk reduction would mean low absolute risk reduction and a number needed to treat of about 50. The fact that baseline homocysteine concentration is a risk factor for recurrence of thrombosis, independent of the treatment, does suggest that other factors - related to homocysteine but not folate - might be involved in the pathogenesis of recurrent thrombosis.

Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene

Before dietary folate is absorbed, polyglutamate folates are deconjugated to monoglutamates by folylpoly-gamma-glutamyl carboxypeptidase in the small intestine. The 1561T allele of the glutamate carboxypeptidase II gene (GCPII), which codes for folylpoly-gamma-glutamyl carboxypeptidase, may impair intestinal absorption of dietary folates. Our aim was to study the bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid across GCPII 1561 genotypes. In a randomized study, 180 healthy adults aged 50-75 y received 323 nmol monoglutamyl folic acid/d (n = 59), 262 nmol heptaglutamyl folic acid/d (n = 61), or placebo (n = 60) for 12 wk. Genotypes were assessed after the intervention. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was calculated by using the changes in serum folate concentration in the treatment groups, after correction for changes in the placebo group and for the administered dose. No subjects with the TT genotype were encountered. At baseline, serum and erythrocyte folate concentrations were higher (P < 0.05) in subjects with the CT genotype [16.3 nmol/L (geometric x; 95% CI: 13.7, 19.3 nmol/L) and 863 nmol/L (735, 1012 nmol/L), respectively; n = 19] than in subjects with the CC genotype [13.7 (13.1, 14.3) and 685 (652, 721) nmol/L, respectively; n = 161]. Baseline homocysteine concentrations were not significantly different between genotypes. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was not significantly different between subjects with the CC (64%; 52%, 76%) and CT genotypes (70%; 49%, 91%). The 1561T allele of the GCPII gene does not impair the bioavailability of polyglutamyl folic acid. However, the allele is associated with higher folate status. This association may be explained by yet unidentified factors controlling the expression of the GCPII gene.

Homocysteine, B-vitamin supplementation, and stroke prevention: from observational to interventional trials

Homocysteine is an amino acid, the metabolism of which is linked to that of several vitamins-especially folic acid, B6, and B12. A high concentration of homocysteine in the plasma is linked to vascular disease, including stroke. Concentrations of homocysteine can be inexpensively and safely lowered by treatment with a combination of folate, vitamin B12, and vitamin B6. However, whether the association between high plasma concentrations of homocysteine and vascular disease is causal is unclear. Two studies have assessed the relation between dietary or supplementary B vitamin intake on the risk of stroke. In a prospective observational study of 43?732 healthy men, there was an inverse relation between dietary folate intake and the risk of ischaemic stroke. The Vitamin Intervention for Stroke Prevention study (VISP) was the first large-scale randomised interventional study that investigated the lowering of homocysteine concentrations with B vitamins in patients with ischaemic stroke. There was an association between baseline homocysteine concentrations and vascular risk in this trial. Plasma concentrations of homocysteine were only modestly reduced by high-dose versus low-dose formulation, and there was no treatment effect on recurrent stroke, coronary events, or deaths. Limitations of VISP included that only patients with mild increases in baseline homocysteine concentrations were studied, only modest reductions of homocysteine concentrations were achieved, and follow up was short. In addition, fortification of food with folate and treatment of low vitamin-B12 concentrations may have masked the effect of treatment on stroke risk. WHAT NEXT?: When exposure can be safely assigned at random, as in the case of B-vitamin therapy, randomised trials should be the standard proof to determine the effect of therapy. The results of the first randomised clinical trial of B vitamins for secondary prevention of stroke were neutral. Larger trials with longer follow-up, selection of patients with higher plasma concentrations of homocysteine, and systematic assessment of cognitive functions and dementia are needed. In the meantime, homocysteine-lowering treatment that is cheap and well-tolerated should be considered a rational approach in patients at high risk of stroke and high concentrations of homocysteine.

Does short-term smoking cessation reduce plasma total homocysteine concentrations?

Both elevated plasma total homocysteine and cigarette smoking are associated with an increased risk of occlusive cardiovascular disease. We examined whether smoking cessation for a mean time of 10-11 weeks lowered plasma total homocysteine concentrations in men and women with (n = 59) and without (n = 55) established cardiovascular disease. Blood tests were available for 58 quitters and 29 subjects who did not stop smoking. Compared with subjects who continued to smoke, quitters had statistically significant higher HDL cholesterol concentrations, but plasma total homocysteine concentrations did not differ between the two groups. Likewise, no differences were found between quitters and non-quitters whose baseline homocysteine concentrations were above the 75th percentile.

Hormone replacement therapy and plasma homocysteine levels

Objective: To compare the effects of 4 and 12 weeks of combined estradiol-progestogen replacement with unopposed estradiol therapy on fasting plasma total homocysteine concentrations in healthy postmenopausal women. Methods: In this prospective, 12-week study in healthy postmenopausal women, we randomly assigned 59 women to sequentially combined daily 2 mg estradiol (E2) plus either trimegestone 0.5 mg daily or dydrogesterone 10 mg daily ( n = 28), or to unopposed daily 2 mg estradiol ( n = 16), or to placebo ( n = 15). Results: Fasting plasma total homocysteine concentrations decreased by 9.4% in the combined estradiol-progestogen group and by 5.1% in the estradiol-only group, and they increased by 2.4% in the placebo group (analysis of covariance: combined hormone replacement therapy compared with placebo ( P = .02); combined therapy compared with estradiol ( P = .23); and estradiol compared with placebo ( P = .26). Reductions were detectable after 4 weeks of combined estradiol-progestogen treatment. The data suggest an additional progestogen-related reduction in homocysteine levels of 0.7 μmol/L and 0.4 μmol/L after 4 and 12 weeks, respectively. Women with a baseline homocysteine concentration in the highest quartile had significantly greater reductions in homocysteine compared with women with an initial homocysteine value in the lowest quartile. Conclusion: Fasting total homocysteine concentrations were significantly reduced by combined estradiol-progestogen replacement. Women with high homocysteine levels at baseline benefit the most. The progestogens used in this study did not have an unfavorable effect on homocysteine metabolism.