MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial.

AIMS: To study how MTHFR 677C→T genotype modulates the effect of supplementation with B-vitamins on total homocysteine (tHcy) and B-vitamin concentrations. METHODS: 2381 patients with a personal history of cardiovascular disease were randomly assigned to one of four groups: 1) B-vitamins alone (560 µg of 5-methyl-THF, 3 mg of vitamin B6 and 20 µg of vitamin B12), 2) n-3 fatty acids alone (600 mg of EPA and DHA in a 2:1 ratio), 3) B-vitamins and n-3 fatty acids, and 4) placebo. Participants were followed up for 4.7 years. At baseline and annually thereafter, biological parameters were assessed. Multivariate and linear mixed models were fit to study the interaction between B-vitamins and MTHFR genotype. RESULTS: Among supplemented participants, concentrations of all three B-vitamins increased during the first year (all p<0.0001) across MTHFR genotype categories. tHcy decreased by 26.3% during the first year (p<0.0001), then steadily increased throughout the 5 years (ptrend<0.001). However, at the end of follow-up, that increase was smaller among TT than among CT or CC subjects (pinteraction<0.02). At baseline, the difference in tHcy concentrations between TT homozygous and CC homozygous subjects was 2.33 µmol/l (p<0.001). After 5 years, that difference was reduced to 1.06 µmol/l and remained statistically significant (p<0.001). CONCLUSION: Participants with the TT genotype exhibited a lower 5-year decrease in tHcy concentrations following a B-vitamin supplementation than did participants with the CC or CT genotype. CLINICAL TRIAL REGISTRATION: Current Controlled Trials # ISRCTN41926726.

Association between serum concentration of vitamin D and 1-year mortality in stroke patients.

BACKGROUND: The prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency is high in patients presenting with an acute stroke, and it may be associated with greater clinical severity and a poor early functional prognosis. However, no data about its impact on long-term prognosis is available. In this study, we aimed to assess the association between 25(OH)D levels and 1-year mortality in stroke patients. METHODS: From February to December 2010, 382 Caucasian stroke patients admitted to the Department of Neurology of the University Hospital of Dijon, France, were enrolled prospectively. Demographics and clinical information including stroke severity assessed using the National Institutes of Health Stroke Scale score were collected. The serum concentration of 25(OH)D was measured at baseline. Multivariable Cox regression models were used to evaluate the association between 1-year all-cause mortality and serum 25(OH)D levels treated as either a log-transformed continuous variable or dichotomized (<25.7 and ≥25.7 nmol/l) at the first tertile of their distribution. RESULTS: Of the 382 stroke patients included, 63 (16.5%) had died at 1 year. The mean 25(OH)D level was lower in these patients (32.3 ± 22.0 vs. 44.6 ± 28.7 nmol/l, p < 0.001), and survival at 1 year was worse in patients in the lowest tertile of 25(OH)D levels (defined as <25.7 nmol/l); log-transformed 25(OH)D levels were inversely associated with 1-year mortality (hazard ratio, HR = 0.62; 95% confidence interval, 95% CI: 0.44-0.87; p = 0.007), and patients with 25(OH)D levels <25.7 nmol/l were at a higher risk of death at 1 year (HR = 1.95; 95% CI: 1.14-3.32; p = 0.014). In multivariable analyses, the association was no longer significant but a significant interaction was found for age, and stratified analyses by age groups showed an inverse relationship between 25(OH)D levels and 1-year mortality in patients aged <75 years [HR = 0.38; 95% CI: 0.17-0.83; p = 0.015 for log-transformed 25(OH)D levels, and HR = 3.12; 95% CI: 0.98-9.93; p = 0.054 for 25(OH)D levels <25.7 vs. >25.7 nmol/l]. CONCLUSION: A low serum 25(OH)D level at stroke onset may be associated with higher mortality at 1 year in patients <75 years old. Further studies are needed to confirm these findings and to determine whether vitamin D supplementation could improve survival in stroke patients.

Arginine and nitric oxide synthase: regulatory mechanisms and cardiovascular aspects.

L-Arginine (L-Arg) is a conditionally essential amino acid in the human diet. The most common dietary sources of L-Arg are meat, poultry and fish. L-Arg is the precursor for the synthesis of nitric oxide (NO); a key signaling molecule via NO synthase (NOS). Endogenous NOS inhibitors such as asymmetric-dimethyl-L-Arg inhibit NO synthesis in vivo by competing with L-Arg at the active site of NOS. In addition, NOS possesses the ability to be "uncoupled" to produce superoxide anion instead of NO. Reduced NO bioavailability may play an essential role in cardiovascular pathologies and metabolic diseases. L-Arg deficiency syndromes in humans involve endothelial inflammation and immune dysfunctions. Exogenous administration of L-Arg restores NO bioavailability, but it has not been possible to demonstrate, that L-Arg supplementation improved endothelial function in cardiovascular disease such as heart failure or hypertension. L-Arg supplementation may be a novel therapy for obesity and metabolic syndrome. The utility of l-Arg supplementation in the treatment of L-Arg deficiency syndromes remains to be established. Clinical trials need to continue to determine the optimal concentrations and combinations of L-Arg, with other protective compounds such as tetrahydrobiopterin (BH4 ), and antioxidants to combat oxidative stress that drives down NO production in humans.

[What is a vitamin?]. / Qu'est-ce qu'une vitamine?

In industrialized countries, the major vitamin deficiency syndromes have virtually disappeared. Today they are superseded by marginal deficits, characterized by insufficient vitamins reserves to maintain normal physiologic state. These states strike populations such as infants, pregnant women, alcoholics and the elderly, and may have long-term adverse effects on health. This assumption stems from the analysis of studies that show an increase in the incidence of various diseases such as cancers and cardiovascular, ocular and osteoarticular pathologies in subjects with low vitamin status. Although causal relationships are difficult to establish, a huge scope for public health appears to be open for vitamins, substituting the notion of minimal intake, indispensable to prevent signs of deficiency, to that ensuring optimal health in the medium and long-terms. However, the paradoxical character of the results obtained in several randomized trials should prompt caution in the use of vitamin supplements to prevent chronic diseases.

Severe hypovitaminosis D correlates with increased inflammatory markers in HIV infected patients.

BACKGROUND: Even though it has been suggested that antiretroviral therapy has an impact on severe hypovitaminosis D (SHD) in HIV infected patients, it could be speculated that the different levels of residual inflammation on HAART (Highly Active Anti Retroviral Therapy) could contribute to SHD and aggravate bone catabolism in these patients. METHODS: A cross-sectional study was carried out in an unselected cohort of 263 HIV infected outpatients consulting during Spring 2010. Clinical examinations were performed and medical history, food habits, sun exposure and addictions were collected. Fasting blood samples were taken for immunological, virological, inflammation, endocrine and bone markers evaluations. RESULTS: Ninety-five (36%) patients had SHD. In univariate analysis, a significant and positive association was found between SHD and IL6 (p = 0.001), hsCRP (p = 0.04), increased serum C-Telopeptides X (CTX) (p = 0.005) and Parathyroid Hormon (PTH) (p < 0.0001) levels. In multivariate analysis, SHD deficiency correlated significantly with increased IL-6, high serum CTX levels, lower mean daily exposure to the sun, current or past smoking, hepatitis C, and functional status (falls), but not with the time spent on the current HAART (by specific drug or overall). CONCLUSIONS: SHD is frequent and correlates with inflammation in HIV infected patients. Since SHD is also associated with falls and increased bone catabolism, it may be of interest to take into account not only the type of antiretroviral therapy but also the residual inflammation on HAART in order to assess functional and bone risks. This finding also suggests that vitamin D supplementation may be beneficial in these HIV-infected patients.

Oxidative stress and myocardial gene alterations associated with Doxorubicin-induced cardiotoxicity in rats persist for 2 months after treatment cessation.

The molecular mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy include alterations in cardiomyocytes' oxidative stress status and in gene expression. Although such alterations have been reported during in vivo DOX treatment of animals, it remains to be clarified whether they persist after treatment cessation. To address this question, rats were injected with either saline (1 ml/kg/day i.p; control) or DOX (1 mg/kg/day i.p.) for 10 days, and 70 days later cardiac functional parameters were evaluated in vivo by left ventricular catheterization. Hearts were also harvested for histological analyses as well as measurements of oxidative stress parameters by various techniques and gene expression by quantitative polymerase chain reaction of markers of cardiac pathological remodeling, namely atrial natriuretic factor, myosin heavy chain ß, vascular endothelial growth factor A (VEGF-A), and sarcoplasmic reticulum Ca(+2) ATPase. Compared with controls, DOX-treated rats displayed marked alterations in most parameters even 2 months after cessation of treatment. These included 1) lower left ventricular contractility (+dP/dt), 2) increased levels of plasma and myocardial oxidative stress markers, namely thiobarbituric acid reactive substances or dihydroethidium fluorescence, and 3) markedly altered transcript levels for all measured markers of cardiac remodeling, except VEGF-A. These changes correlated significantly with +dP/dt values assessed in the two groups of animals. In conclusion, this study demonstrated that as many as 2 months after cessation of DOX treatment cardiac alterations persisted, reflecting increased oxidative stress and pathological remodeling, the latter being linked to the development of contractile dysfunction.

Effect of tomato product consumption on the plasma status of antioxidant microconstituents and on the plasma total antioxidant capacity in healthy subjects.

OBJECTIVES: to identify the plasma antioxidant microconstituents mainly affected by tomato product consumption, to check whether tomato product consumption can affect antioxidant status, and to identify tomato-product antioxidant-microconstituents mainly involved in the effect of these products on oxidative stress. DESIGN: Medium-term dietary supplementation study. SETTING: Human Nutrition Laboratory, Clermont-Ferrand, France. SUBJECTS: Twenty healthy young (20 < years < 40), non obese (18 < BMI (kg/m2) < 25), females were recruited by advertisement. All of them completed the study. INTERVENTION: The usual diet of the subjects was supplemented for three weeks with 96 g/day tomato puree. The volunteers then avoided tomato-product-rich foods for a subsequent three-week period. MEASURES OF OUTCOME: Fasting blood samples were collected the day before supplementation, the day after the supplementation period, and the day after the depletion period. The status of several antioxidant microconstituents (plasma microconstituent concentrations), and the antioxidant status (plasma total antioxidant capacity) were assessed. RESULTS: Supplementation with tomato puree significantly increased plasma lycopene, beta-carotene and lutein. Conversely it did not significantly affect plasma vitamin C and E, plasma antioxidant trace metals (Cu, Zn and Se), and plasma total antioxidant capacity. Avoidance of tomato-product-rich foods for three weeks significantly (p < 0.05) decreased plasma lycopene, beta-carotene, lutein and vitamin C, as well as plasma total antioxidant capacity. Plasma total antioxidant capacity, as measured by chemiluminescence, was positively related (p < 0.05) to the status of lycopene, vitamin C and beta-carotene. CONCLUSIONS: Tomato product consumption can affect not only the lycopene status, but also that of other antioxidant microconstituents (beta-carotene and lutein). Lycopene, but also beta-carotene, are apparently the main tomato microconstituents responsible for the effect of tomato products on antioxidant status.

Vitamin C deficiency exerts paradoxical cardiovascular effects in osteogenic disorder Shionogi (ODS) rats.

Vitamin C is considered to be a very efficient water-soluble antioxidant, for which several new cardiovascular properties were recently described. The aim of this study was to determine in vivo the effects of a severe depletion of vitamin C on cardiac and vascular variables and reperfusion arrhythmias. For this purpose, we used a mutant strain of Wistar rats, osteogenic disorder Shionogi (ODS). After 15 d of consuming a vitamin C-deficient diet, ODS rats had a 90% decrease in plasma and tissue levels of ascorbate compared with ODS vitamin C-supplemented rats and normal Wistar rats. However, plasma antioxidant capacity, proteins, alpha-tocopherol, urate, catecholamines, lipids, and nitrate were not influenced by the vitamin C deficiency in ODS rats. Moreover, there was no difference between ODS vitamin C-deficient and -supplemented rats in heart rate and arterial pressure. After 5 min of an in vivo regional myocardial ischemia, various severe arrhythmias were observed, but their intensities were not modified by vitamin C in vitamin C-deficient ODS rats. The vascular reactivity, measured in vitro on thoracic arteries, was not altered by ascorbate deficiency in ODS rats. These unexpected results suggest that unidentified compensatory mechanisms play a role in maintaining normal cardiac function and vascular reactivity in vitamin C-deficient rats.

Changes in serum retinol, alpha-tocopherol, vitamin C, carotenoids, xinc and selenium after micronutrient supplementation during alcohol rehabilitation.

OBJECTIVE: To test the effect of a 21-day supplementation with moderate doses of antioxidant nutrients on biochemical indicators of vitamin, carotenoid and trace element levels in alcohol-dependent patients during a program of alcohol rehabilitation. DESIGN: A randomized double-blind trial was performed comparing two groups receiving daily either a combination of micronutrients (beta-carotene: 6 mg, vitamin C: 120 mg, vitamin E: 30 mg, zinc: 20 mg, selenium: 100 micro g) or a placebo. SUBJECTS: 106 alcohol-dependent patients 20 to 60 years of age without severe liver disease, hospitalized for a 21-day rehabilitation program. Measure of Outcome: Vitamin C, retinol, alpha-tocopherol, zeaxanthin/lutein, beta-cryptoxanthin, lycopene, alpha- and beta-carotene, zinc and selenium were measured in serum, initially and after supplementation. RESULTS: (1) In the placebo group, after 21 days of rehabilitation, serum concentrations of vitamin C and all five carotenoids significantly increased, whereas retinol and alpha-tocopherol concentrations decreased; zinc and selenium levels were unaffected. (2) At the end of the hospital stay, serum indicators were significantly improved in the supplement group as compared to the placebo group for vitamin C, alpha-tocopherol, beta-carotene, zinc and selenium; conversely, lycopene changes were higher in the placebo group than in supplement group. (3) Of the serum antioxidants measured at entrance, only vitamin C was significantly depleted in heavy smokers, and, after the supplementation period, vitamin C was efficiently repleted in this later group. CONCLUSION: Our results indicate that a short-term supplementation with physiological doses of antioxidant vitamins, carotenoids and trace elements during alcohol rehabilitation clearly improves micronutrient status indicators. Heavy smokers in particular seem to respond to vitamin C supplementation.

Relation between homocysteine concentrations and the consumption of different types of alcoholic beverages: the French Supplementation with Antioxidant Vitamins and Minerals Study.

BACKGROUND: Previous studies on the effects of alcohol consumption on total plasma homocysteine (tHcy) concentrations showed contradictory results. The conflicting results may derive in part from confounding by the type of alcoholic beverage consumed. OBJECTIVE: The objective of the study was to evaluate in a predominantly wine-drinking French population whether the relation between alcohol consumption and homocysteine concentrations is dependent on the type of alcoholic beverage consumed. DESIGN: In 1996, a cross-sectional study measuring tHcy and red blood cell folate concentrations was conducted in 1196 middle-aged women and men from the French Supplementation with Antioxidant Vitamins and Minerals Study. Intakes of alcohol, energy, coffee, and B vitamins were assessed by 6 separate 24-h dietary records from the previous year. RESULTS: tHcy concentrations were positively associated with wine intake (P = 0.01) in the women and with beer intake in the men (P = 0.002). No association with the consumption of spirits was observed. The association between beer consumption and tHcy concentrations in the men was modified by the consumption of wine; the association was positive in wine drinkers, whereas an inverse trend was seen in those who drank no wine. CONCLUSION: Wine consumption may increase tHcy concentrations, whereas beer consumption seems to have no effect (or even an inverse effect) on tHcy.

Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study.

BACKGROUND: An elevated plasma total homocysteine (tHcy) concentration seems to increase the risk of cardiovascular disease. OBJECTIVE: We evaluated the determinants of tHcy in healthy French adults. DESIGN: tHcy was measured by HPLC and fluorometric detection in 1139 women and 931 men aged 35-60 y. Subjects were participants of the Supplementation with Antioxidant Vitamins and Minerals Study, which investigates the effects of antioxidant supplementation on chronic diseases. Red blood cell folate (RBCF), plasma vitamins B-6 and B-12, and cardiovascular disease risk factors were also measured. The habitual diet was assessed in 616 subjects. Cross-sectional analyses were adjusted for age, smoking, energy intake, and concentration or intake of folate and vitamin B-6, where appropriate. RESULTS: The mean (+/-SD) tHcy concentration was 8.74 +/- 2.71 micro mol/L in women and 10.82 +/- 3.49 micro mol/L in men. In women, tHcy was positively related to age (P = 0.001), apolipoprotein B (P < 0.01), serum triacylglycerol (P < 0.01), fasting glucose (P = 0.02), and coffee and alcohol consumption (both P < 0.01) and inversely related to RBCF (P = 0.11) and plasma vitamin B-12 (P = 0.08) and vitamin B-6 (P = 0.01) intakes. In men, tHcy was positively associated with body mass index (P = 0.03), blood pressure (P < 0.02), serum triacylglycerol (P < 0.01), fasting glucose (P = 0.01), and energy intake (P < 0.01) and inversely associated with physical activity (P = 0.04), RCBF (P = 0.02), plasma vitamin B-12 (P = 0.09), and dietary fiber (P < 0.01), folate (P = 0.03), and vitamin B-6 (P = 0.09) intakes. CONCLUSION: To control tHcy, decreasing coffee and alcohol consumption may be important in women, whereas increasing physical activity, dietary fiber, and folate intake may be important in men.