vitamin-b-12 and Carotid-Stenosis

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of 2 pathways: remethylation, which requires folic acid and B-12 coenzymes, and transsulfuration, which requires pyridoxal-5'-phosphate, the B-6 coenzyme. Data from several studies suggest that mild elevations of homocysteine in plasma are a risk factor for occlusive vascular disease. In the Framingham studies we have shown that plasma total homocysteine concentration is inversely related to the intake and plasma levels of folate and vitamin B-6 as well as vitamin B-12 plasma levels. Almost two-thirds of the prevalence of high homocysteine is attributable to low vitamin status or intake. Elevated homocysteine concentrations in plasma are a risk factor for prevalence of extracranial carotid artery stenosis of at least 25% in both men and women. Prospectively elevated plasma homocysteine is associated with increased total and CVD mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer's disease, increased incidence of bone fracture, and higher prevalence of chronic heart failure. This multitude of relationships between elevated plasma total homocysteine and diseases that afflict the elderly point to the existence of a common denominator that may be responsible for these diseases. Whether this denominator is homocysteine itself or whether homocysteine is merely a marker remains to be determined.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cardiovascular Diseases; Carotid Stenosis; Cohort Studies; Dementia; Diet; Female; Folic Acid; Fractures, Bone; Heart Failure; Homocysteine; Humans; Hyperhomocysteinemia; Male; Massachusetts; Middle Aged; Risk Factors; Stroke; Vascular Diseases; Vitamin B 12; Vitamin B 6

In our prospective study the effect of Sclerovit (0.8 mg folic acid, 20 mug vitamin B12,5 mg vitamin B6,100 mg vitamin E) on inflammatory markers, hemorheological parameters, platelet aggregation, von Willebrand factor activity as a marker of endothelium dysfunction, plasma lipids, plasma levels of folic acid, vitamin B12 and homocysteine (hcy), flow mediated vasodilatation (FMD) and thickness of carotis intima-media after 1 and 6 months of treatment in patients with vascular diseases (10 patients took 1 capsule, 10 patients 2 capsules of Sclerovit and 10 patients placebo) was determined.Plasma level of vitamin B12, folic acid and elongation index of red blood cells (RBC) increased significantly (p<0.05-0.001), hcy and triglyceride concentrations decreased significantly (p<0.05-0.001) in patients taking Sclerovit. HDL-cholesterol, RBC count, hematocrit, plasma and whole blood viscosity increased significantly (p<0.05-0.001) both in patients taking placebo or vitamins. Fibrinogen and CRP showed a significant (p<0.05-0.01) increase in patients on placebo, but did not change in patients on Sclerovit therapy. FMD showed a significant (p<0.05) amelioration in patients on 1 capsule of Sclerovit.Beside the favorable effects of Sclerovit on some of the measured parameters, the observed deterioration in hemorheological parameters can correlate with the contradictory results of large prospective studies with vitamins.

Topics: Aged; Atherosclerosis; Carotid Stenosis; Drug Combinations; Erythrocyte Deformability; Female; Folic Acid; Hemorheology; Homocysteine; Humans; Male; Middle Aged; Platelet Aggregation; Tunica Intima; Tunica Media; Vasodilation; Vitamin B 12; Vitamin B 6; Vitamin E; von Willebrand Factor

Many new therapies are being developed that are anti-atherosclerotic, but which do not change clinical parameters such as blood pressure or cholesterol. In order to measure the effects of these therapies it will be necessary to measure atherosclerosis. Elevated levels of plasma total homocysteine (tHcy) are associated with increased risk of stroke and myocardial infarction. Measurement of the effect of vitamin therapy on atherosclerosis has therefore been used as an example of this approach.. 2-Dimensional measurement of carotid plaque cross-sectional area has been used to measure effects of vitamin therapy in patients whose plaque is progressing despite intensive treatment of traditional risk factors. In clinic patients, addition of vitamin therapy halted progression of atherosclerosis, in samples of 50 patients over 2.5 years. However, in patients randomized to high-dose vs. low-dose vitamins in the Vitamin Intervention for Stroke Prevention trial, no difference in plaque progression was seen between high-dose and low-dose vitamin therapy. New methods have been developed for the measurement of 3-dimensional plaque volume, and for the measurement of plaque surface roughness.. The accuracy and reliability of the measurement of plaque volume is 95%. This will permit measurement of effects of new anti-atherosclerotic therapies with much smaller sample sizes, in a much shorter time, than previously available methods such as intima-media thickness.. Measurement of atherosclerotic plaque volume and roughness will greatly enhance the study of new anti-atherosclerotic therapies.

Topics: Aged; Carotid Stenosis; Dose-Response Relationship, Drug; Folic Acid; Homocysteine; Humans; Imaging, Three-Dimensional; Reproducibility of Results; Stroke; Ultrasonography; Vitamin B 12; Vitamin B 6; Vitamins

Both deficiency and, according to recent reports, excess of vitamin B12 (B12) are associated with increased mortality. Thus, it is difficult to estimate the effect of B12 on overall survival, which also depends on folate (FA) in homocysteine lowering. This study aimed to assess FA and B12 serum concentrations associated with long-term survival of vascular surgery patients by means of a prognostic index (PI).. This single-center, prospective cohort study comprised 485 consecutive carotid surgery patients. B-vitamin baseline concentrations of B12 and FA were used to compute a PI for postoperative overall survival from January 2003 to January 2012 (mean observation period 102.3 months).. Increasing B12 serum concentrations showed a nonlinear association with overall survival (P = .033). A B vitamin-based PI significantly predicted overall (hazard ratio [HR] per standard deviation = 1.97, confidence interval [CI] 1.37-2.82; P < .001), cardiovascular (HR = 3.03, CI 1.78-5.14; P < .001), and stroke-free survival (HR = 2.20, CI 1.22-3.98; P = .009), and revealed that the highest adverse event-free survival was predicted by high FA (16.3 ± 12.9 ng/mL) but only moderate B12 (360.3 ± 156.0 pmol/L) baseline concentrations.. Prediction of increased long-term overall, cardiovascular, and stroke-free survival is based on high FA but only moderate B12 serum concentrations. Excessive B12 concentrations might harbor a potential harm and are no requisite for low homocysteine concentrations. The association between B vitamins and survival might serve either as a tool for risk stratification or, if causative, as effective therapy, if optimal dosing of B vitamins is provided and on-treatment concentrations, including homocysteine and renal functions, are closely monitored.

Topics: Aged; Austria; Biomarkers; Carotid Stenosis; Disease-Free Survival; Endarterectomy, Carotid; Female; Folic Acid; Folic Acid Deficiency; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Nonlinear Dynamics; Proportional Hazards Models; Prospective Studies; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

The aim of the study was to investigate the association between methylenetetrahydrofolate (MTHFR) genotypes and levels of homocysteine (Hcy), folate, vitamin B12 and lipids as well as the association between apolipoprotein E (apo E) genotypes and levels of lipids in a Croatian healthy control group and a group of patients with > 70% carotid stenosis (CS). The study included 98 Croats, 38 patients with > 70% carotid stenosis and 60 age- and sex-matched controls. The MTHFR and apo E genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Hcy by enzyme immunoassay, vitamins by immunochemiluminiscence, and lipids by spectrophotometric method. There was no difference between control subjects and CS patients in the distribution of C677T MTHFR genotypes (p=0. 786) and alleles (p=0.904), however, differences in the frequencies of apo E genotypes (p=0.012) and alleles (p=0.029) were statistically significant. The odds ratio for apo E 3/4 genotype was 3.93 (95% CI 1.23-12.61). Hyperhomocysteinemia (> or =15 micromol/L) was found in 11% of CS patients and 5% of control subjects. Total cholesterol, triglycerides, vitamin B12 and folate were statistically different in "all MTHFR genotypes" (p<0.001, p<0.01, p=0.044 and p=0.036, respectively), and in TC/TT (p<0.001, p=0.003, p=0.030 and p=0.032, respectively) groups. The levels of total cholesterol, LDL cholesterol and triglycerides in the apo E 3/3, and total cholesterol in the apo E 3/4 group yielded statistical difference. An association was found of apo E 3/4 genotype but not of MTHFR genotypes with the risk of CS. MTHFR and apo E affect blood lipid levels, which was statistically confirmed. An association was also recorded between hyperhomocysteinemia and patients with CS. Vitamin status in CS showed a statistically verified association with TC/TT MTHFR genotype. In the group of patients with TC/TT MTHFR genotype, lower vitamin B12 and higher folate values were recorded. The results of multiple logistic analysis showed that there was no statistical significance of Hcy levels (OR 2.403, p=0.334) or conventional vascular risk factors such as smoking habit (OR 0.505, p=0.149), age (OR 1.048, p=0.087) or sex (OR 2.037, p=0.112) in predicting CS.

Topics: 5,10-Methylenetetrahydrofolate Reductase (FADH2); Apolipoproteins E; Carotid Stenosis; Female; Folic Acid; Gene Frequency; Genotype; Homocysteine; Humans; Male; Middle Aged; Mutation; Vitamin B 12

Carotid plaque area is a strong predictor of cardiovascular events. High homocysteine levels, which are associated with plaque formation, can result from inadequate intake of folate and vitamin B12. Now that folic acid fortification is widespread in North America, vitamin B12 has become an important determinant of homocysteine levels. We sought to determine the prevalence of low serum levels of vitamin B12, and their relation to homocysteine levels and carotid plaque area among patients referred for treatment of vascular disease since folic acid fortification of enriched grain products.. We evaluated 421 consecutive new patients with complete data whom we saw in our vascular disease prevention clinics between January 1998 and January 2002. We measured total carotid plaque area by ultrasound and determined homocysteine and serum vitamin B12 levels in all patients.. The patients, 215 men and 206 women, ranged in age from 37 to 90 years (mean 66 years). Most were taking medications for hypertension (67%) and dyslipidemia (62%). Seventy-three patients (17%) had vitamin B12 deficiency (vitamin B12 level < 258 pmol/L with homocysteine level > 14 mumol/L or methylmalonic acid level > 271 nmol/L). The mean area of carotid plaque was significantly larger among the group of patients whose vitamin B12 level was below the median of 253 pmol/L than among those whose vitamin B12 level was above the median: 1.36 (standard deviation [SD] 1.27) cm2 v. 1.09 (SD 1.0) cm2; p = 0.016.. Vitamin B12 deficiency is surprisingly common among patients with vascular disease, and, in the setting of folic acid fortification, low serum vitamin B12 levels are a major determinant of elevated homocysteine levels and increased carotid plaque area.

Topics: Adult; Aged; Aged, 80 and over; Carotid Stenosis; Cross-Sectional Studies; Edible Grain; Female; Folic Acid; Food, Fortified; Hematinics; Homocystine; Humans; Incidence; Male; Middle Aged; Risk Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Age Factors; Carotid Stenosis; Creatinine; Homocystine; Humans; Reference Values; Reproducibility of Results; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Biomarkers; Carotid Stenosis; Homocystine; Humans; Methylmalonic Acid; Reproducibility of Results; Vitamin B 12; Vitamin B 12 Deficiency

Hyperhomocysteinemia has been identified as a potential risk factor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) and focal plaque formation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenetetrahydrofolate reductase (MTHFR) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease.. In 1111 subjects (558 men, 553 women) 52+/-13 years old (mean+/-SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ultrasound. For the total population, mean tHcy was 12.1+/-4.0 micromol/L. Plasma tHcy levels were correlated with IMT (Spearman rank rs=0.31, P=0.0001). After adjustment for age, sex, and other conventional risk factors, subjects in the highest versus the lowest quartile of tHcy had an odds ratio of 2.60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82) for plaque. Serum and dietary folate levels and the C677T mutation in MTHFR were independent determinants of tHcy (all P=0.0001). The mutant homozygotes (10% of the population) had higher mean tHcy than heterozygotes or those without the mutation (14.2 versus 12.3 versus 11.6 micromol/L, respectively, P=0.0001). The inverse association of folate levels with tHcy was steeper in the mutant homozygotes. Despite this, the C677T MTHFR mutation was not independently predictive of increased carotid IMT or plaque formation.. Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness and plaque formation in a general population. Lower levels of dietary folate intake and the C677T mutation in MTHFR are important causes of mild hyperhomocysteinemia and may therefore contribute to vascular disease in the community.

Topics: Adult; Aged; Amino Acid Substitution; Arteriosclerosis; Carotid Arteries; Carotid Stenosis; Comorbidity; Diet; Female; Folic Acid; Gene Frequency; Genetic Predisposition to Disease; Genotype; Health Surveys; Homocysteine; Humans; Hyperhomocysteinemia; Hyperlipidemias; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation, Missense; Obesity; Odds Ratio; Oxidoreductases Acting on CH-NH Group Donors; Point Mutation; Pyridoxine; Risk Factors; Smoking; Tunica Intima; Ultrasonography; Vitamin B 12; Western Australia

Moderate elevation of plasma homocyst(e)ine is associated with increased risk for atherosclerotic vascular disease. In a previous study, we observed impaired vascular function in nonatherosclerotic monkeys with moderate hyperhomocyst(e)inemia. In this study, we tested the hypothesis that dietary intervention to lower plasma homocyst(e)ine corrects vascular dysfunction in atherosclerotic monkeys. Cynomolgus monkeys were fed an atherogenic diet that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. After 17 months, the atherogenic diet was supplemented with B vitamins (5 mg folic acid, 400 micrograms vitamin B-12, and 20 mg vitamin B-6 daily) for 6 months. Total plasma homocyst(e)ine decreased from 12.8 +/- 2.8 to 3.5 +/- 0.3 mumol/L (n = 9; mean +/- SE; P < .01) after vitamins were added to the diet, but plasma cholesterol remained elevated (522 +/- 63 versus 514 +/- 41 mg/dL; P > .05). In response to intra-arterial infusion of collagen, blood flow to the leg decreased by 30 +/- 3% and 38 +/- 5%, respectively, before and after vitamin supplementation (P > .05). In vivo responses of resistance vessels to endothelium-dependent vasodilators (acetylcholine or ADP) were impaired at baseline and did not improve after vitamin supplementation. In carotid artery studied ex vivo, relaxation to low doses of acetylcholine improved after vitamin supplementation, but maximal relaxation remained impaired. Ex vivo thrombomodulin anticoagulant activity was threefold higher in monkeys fed the atherogenic diet (with or without B vitamins) than in normal monkeys (P < .05). We conclude that normalization of plasma homocyst(e)ine is insufficient to restore normal vascular function in atherosclerotic monkeys with persistent hypercholesterolemia and that atherosclerosis, with or without hyperhomocyst(e)inemia, is associated with elevated thrombomodulin activity.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Arteriosclerosis; Carotid Arteries; Carotid Stenosis; Cholesterol; Collagen; Diet, Atherogenic; Enzyme Activation; Folic Acid; Homocysteine; Homocystine; Hypercholesterolemia; Leg; Macaca fascicularis; Nitroprusside; Protein C; Pyridoxine; Thrombomodulin; Vasodilation; Vasomotor System; Vitamin B 12

Recent studies demonstrated associations between occlusive vascular disease and hyperhomocysteinemia of both genetic and nutritional origin. In the present study we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to B vitamins and prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely associated with intakes of folate and vitamin B-6, but not vitamin B-12. Prevalence of high homocysteine (>14 micromol/l) was 29.3% in this cohort, and inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Prevalence of stenosis > or = 25% was 43% in men and 34% in women with an odds ratio of 2.0 for individuals in the highest homocysteine quartile (> or = 14.4 micromol/l) compared with those in the lowest quartile (< or = 9.1 micromol/l), after adjustment for sex, age, high density lipoprotein cholesterol, systolic blood pressure and cigarette smoking (Ptrend < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and folate intake were inversely associated with extracranial carotid stenosis after adjustment for age, sex and other risk factors.

Topics: Aged; Aged, 80 and over; Carotid Stenosis; Cohort Studies; Female; Folic Acid; Homocysteine; Humans; Male; Pyridoxine; Vitamin B 12

Topics: Aged; Cardiovascular Diseases; Carotid Stenosis; Folic Acid; Homocysteine; Humans; Male; Risk Factors; Vitamin B 12

Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia.. We performed a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study. We examined the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6. The subjects were classified into two categories according to the findings in the more diseased of the two carotid vessels: stenosis of 0 to 24 percent and stenosis of 25 to 100 percent.. The prevalence of carotid stenosis of > or = 25 percent was 43 percent in the men and 34 percent in the women. The odds ratio for stenosis of > or = 25 percent was 2.0 (95 percent confidence interval, 1.4 to 2.9) for subjects with the highest plasma homocysteine concentrations (> or = 14.4 mumol per liter) as compared with those with the lowest concentrations (< or = 9.1 mumol per liter), after adjustment for sex, age, plasma high-density lipoprotein cholesterol concentration, systolic blood pressure, and smoking status (P < 0.001 for trend). Plasma concentrations of folate and pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) and the level of folate intake were inversely associated with carotid-artery stenosis after adjustment for age, sex, and other risk factors.. High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.

Topics: Aged; Aged, 80 and over; Carotid Stenosis; Confidence Intervals; Cross-Sectional Studies; Female; Folic Acid; Homocysteine; Humans; Male; Odds Ratio; Pyridoxal Phosphate; Pyridoxine; Risk Factors; Ultrasonography; Vitamin B 12