Biomedical subjects

M R Malinow

Publications and source records attributed to M R Malinow.

At least 37 records · Page 2Linked to original sources

PubMed1999

Increased dietary micronutrients decrease serum homocysteine concentrations in patients at high risk of cardiovascular disease.

BACKGROUND: Elevated blood homocysteine is a risk factor for cardiovascular disease. A 5-micromol/L increase is associated with an approximately 70% increase in relative risk of cardiovascular disease in adults. For patients with established risk factors, this risk is likely even greater. OBJECTIVE: Effects of increased dietary folate and recommended intakes of vitamins B-12 and B-6 on serum total homocysteine (tHcy) were assessed in individuals at high risk of cardiovascular disease. DESIGN: This trial was conducted at 10 medical research centers in the United States and Canada and included 491 adults with hypertension, dyslipidemia, type 2 diabetes, or a combination thereof. Participants were randomly assigned to follow a prepared meal plan (PMP; n = 244) or a self-selected diet (SSD; n = 247) for 10 wk, which were matched for macronutrient content. The PMP was fortified to provide >/=100% of the recommended dietary allowances for 23 micronutrients, including folate. RESULTS: Mean folate intakes at 10 wk were 601 +/- 143 microgram/d with the PMP and 270 +/- 107 microgram/d with the SSD. With the PMP, serum tHcy concentrations fell from 10.8 +/- 5.8 to 9.3 +/- 4.9 micromol/L (P < 0.0001) between weeks 0 and 10 and the change was associated with increased intakes of folate, vitamin B-12, and vitamin B-6 and with increased serum and red blood cell folate and serum vitamin B-12 concentrations. tHcy concentrations did not change significantly with the SSD. CONCLUSIONS: The PMP resulted in increased intakes and serum concentrations of folate and vitamin B-12. These changes were associated with reduced serum tHcy concentrations in persons at high risk of cardiovascular disease.

Adult↗

PubMed1999

Influence of exercise and menstrual cycle phase on plasma homocyst(e)ine levels in young women--a prospective study.

Plasma total homocysteine (tHcy) has been identified as an independent risk factor for cardiovascular diseases (CVD). The difference in tHcy between the sexes has most often been related to the sex hormones, but also to a higher muscle mass in men. The purpose of this study was to assess the effects of acute exercise, brief exhaustive training, and menstrual cycle phase on circulating plasma tHcy concentrations. Fifteen untrained eumenorrheic women (mean age [+/-SD]: 18.7+/-0.4 yr, body fat: 25.8+/-3.4%, VO2max: 43.8+/-2.3 ml x kg(-1) x min(-1)) volunteered for the present study, which covered two menstrual cycles. During the second cycle the subjects participated in two exhaustive 5-day training programs on a cycle ergometer: one in the follicular (FPh) and one in the luteal phase (LPh). Pre- and posttraining plasma tHcy and total estrogen (E) responses were determined in blood samples obtained immediately before, during and immediately after incremental exercise to exhaustion. tHcy levels showed a large between-subject variation, but differences between FPh and LPh levels were consistent (P=0.063). Mean tHcy levels at rest were 9.44+/-1.65 micromol/L and 8.93+/-1.71 micromol/L during the FPh and LPh, respectively. Brief exhaustive training did not elicit any changes in plasma tHcy concentrations, although posttraining LPh E levels were lower (P<0.01). Overall, the differences between FPh and LPh values for tHcy and E were attenuated by training. Acute exercise increased plasma tHcy concentrations (P<0.001). At exhaustion, tHcy levels increased by 17% and 16% during the FPh and LPh, respectively. This was also significantly above tHcy levels at submaximal exercise (P=0.044). After a short period of training tHcy levels did not increase as much during acute exercise as they did before training; however, the increments were still significant (P=0.048). In conclusion, acute exercise in women produces significant increases in plasma tHcy concentrations, whereas brief exhaustive training does not significantly alter plasma tHcy levels. Our findings also suggest that plasma tHcy concentrations are menstrual cycle phase-dependent and that there is a close association between estrogen status and tHcy levels.

Adolescent↗

PubMed1999

Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia.

OBJECTIVE: Elevated plasma homocyst(e)ine is a risk factor for endothelial dysfunction and vascular disease. In late gestation, levels of homocyst(e)ine are higher in preeclamptics, as compared with normotensive pregnant women. Our objective was to determine whether homocyst(e)ine elevations precede the development of preeclampsia. STUDY DESIGN: We used a prospective nested case-control study design to compare second trimester maternal serum homocyst(e)ine concentrations in 52 patients who developed preeclampsia (pregnancy-induced hypertension with proteinuria) compared with 56 women who remained normotensive throughout pregnancy. Study subjects were selected from a base population of 3, 042 women who provided blood samples at an average gestational age of 16 weeks and later delivered at our center. Serum homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Approximately 29% of preeclamptics, as compared to 13% of controls had homocyst(e)ine levels >/=5.5 micromol/l (upper decile of distribution of control values). Adjusted for maternal age, parity, and body mass-index, a second trimester elevation of homocyst(e)ine was associated with a 3. 2-fold increased risk of preeclampsia (adjusted OR = 3.2; 95% CI 1. 1-9.2; p = 0.030). There was evidence of a interaction between maternal adiposity (as indicated by her prepregnancy body mass index) and parity with second trimester elevations in serum homocyst(e)ine. Nulliparous women with elevated homocyst(e)ine levels experienced a 9.7-fold increased risk of preeclampsia as compared with multiparous women without homocyst(e)ine elevations (95% CI 2.1-14.1; p = 0.003). Women with a higher prepregnancy body mass index (>/=21.4 kg/m(2), or upper 50th percentile) and who also had elevated homocyst(e)ine levels, as compared with leaner women without homocyst(e)ine elevations were 6.9 times more likely to later develop preeclampsia (95% CI 1.4-32.1; p = 0.016). CONCLUSION: Our findings are consistent with other indications of vascular endothelial dysfunction predating clinical preeclampsia. Studies designed to examine the effect of dietary and/or pharmacological mediators of homocyst(e)ine metabolism in preeclampsia are warranted.

Adult↗

PubMed1999

Impaired anticoagulant response to infusion of thrombin in atherosclerotic monkeys associated with acquired defects in the protein C system.

To examine the effects of atherosclerosis on the protein C anticoagulant pathway in vivo, we measured anticoagulant responses to intravenous administration of human alpha-thrombin or activated protein C (APC) in cynomolgus monkeys. Two groups of monkeys were fed either a control diet (n=18) or an atherogenic diet (n=12) that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. A third group (n=8) was fed an atherogenic diet for 15 months, and then fed the atherogenic diet supplemented with B vitamins for 6 months to correct the hyperhomocyst(e)inemia. The plasma homocyst(e)ine level was higher in monkeys fed the atherogenic diet (9.6+/-1.0 micromol/L) than in monkeys fed the control diet (3.7+/-0.2 micromol/L) or the atherogenic diet with B vitamins (3.6+/-0.2 micromol/L) (P<0.001). Infusion of thrombin produced a much greater prolongation of the activated partial thromboplastin time in monkeys fed the control diet (52+/-10 seconds) than in monkeys fed the atherogenic diet either with (24+/-4 seconds) or without (27+/-5 seconds) supplemental B vitamins (P<0.02). Thrombin-dependent generation of circulating APC was higher in control (294+/-17 U/mL) than in atherosclerotic (240+/-14 U/mL) monkeys (P<0.05), although levels of fibrinogen, plasminogen, D-dimer, and thrombin-antithrombin complexes were similar in each group. Injection of human APC produced a similar prolongation of the activated partial thromboplastin time in control (31+/-3 seconds) and atherosclerotic (29+/-2 seconds) monkeys. These findings provide evidence for impaired anticoagulation, due partly to decreased formation of APC, in atherosclerosis. The blunted anticoagulant response to thrombin in hypercholesterolemic monkeys was not corrected by supplementation with B vitamins.

Animals↗

PubMed1999

Plasma homocyst(e)ine concentration, but not MTHFR genotype, is associated with variation in carotid plaque area.

BACKGROUND AND PURPOSE: Elevated plasma homocyst(e)ine [H(e)] concentration is associated with premature atherosclerosis. A common cause of elevated plasma H(e) concentration is a thermolabile mutation (677T) in the gene encoding methylenetetrahydrofolate reductase (MTHFR). We sought to determine whether plasma H(e) concentration or MTHFR genotype would be more strongly associated with carotid plaque area (CPA), a potential intermediate phenotype of atherosclerosis. METHODS: In 307 subjects who were ascertained through a premature atherosclerosis clinic, we measured CPA with 2-dimensional ultrasound and also determined traditional atherosclerosis risk factors, in addition to plasma H(e) concentration and MTHFR genotypes. RESULTS: We found that the frequency of the MTHFR 677T allele was 0.363 in this sample. Mean plasma H(e) concentration was significantly higher in 677T/T homozygotes than in 677T/C heterozygotes and 677C/C homozygotes (17. 1+/-13.7 versus 13.5+/-6.1 versus 12.6+/-5.9 micromol/L, respectively, P<0.001). Analysis of variance showed that CPA was significantly associated with age, sex, smoking, diabetes, hypertension, and hyperlipidemia (each P<0.05). When plasma H(e) concentration was included in the model, it was significantly associated with CPA (P<0.05). However, when the MTHFR genotype was included in the model, it was not associated with CPA (P=0.50). Furthermore, there was a significant correlation of CPA with plasma H(e) (r=0.23, P<0.0001). However, the mean CPA did not differ between subjects according to genotype. CONCLUISONS: Thus, plasma H(e), but not MTHFR genotype, is significantly associated with carotid atherosclerosis, suggesting that the biochemical test may be sufficient to identify patients who may be at increased risk of atherosclerosis through this mechanism.

Adult↗

PubMed1999

Homocyst(e)ine and risk of cerebral infarction in a biracial population : the stroke prevention in young women study.

BACKGROUND AND PURPOSE: Genetic enzyme variation and vitamin intake are important determinants of blood homocyst(e)ine levels. The prevalence of common genetic polymorphisms influencing homocyst(e)ine levels varies by race, and vitamin intake varies by socioeconomic status. Therefore, we examined the effect of vitamin intake, race, and socioeconomic status on the association of homocyst(e)ine with stroke risk. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. One hundred sixty-seven cases of first ischemic stroke among women aged 15 to 44 years were compared with 328 controls identified by random-digit dialing from the same region. Risk factor data were collected by standardized interview and nonfasting phlebotomy. Plasma homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Blacks and whites did not differ in median homocyst(e)ine levels, nor did race modify the association between homocyst(e)ine and stroke. After adjustment for cigarettes per day, poverty status, and regular vitamin use, a plasma homocyst(e)ine level of >/=7.3 micromol/L was associated with an odds ratio for stroke of 1.6 (95% CI, 1.1 to 2.5). CONCLUSIONS: The association between elevated homocyst(e)ine and stroke was independent not only of traditional vascular risk factors but also of vitamin use and poverty status. The degree of homocyst(e)ine elevation associated with an increased stroke risk in young women is lower than that previously reported for middle-aged men and the elderly and was highly prevalent, being present in one third of the control group.

Adolescent↗

PubMed1999

Homocyst(e)ine, vitamins and genetic interactions in vascular disease.

Blood homocyst(e)ine levels are an important, independent and frequent risk factor for clinical atherosclerosis and venous thrombosis. Folic acid, vitamins B6 and B12, renal and thyroid functions, certain medications and certain genotypes are known to modulate plasma homocyst(e)ine levels. Intake of B vitamins through diet, supplementation and fortified foods effectively reduces homocyst(e)ine concentration and thus may reduce the risk of cardiovascular disease. This is true even in individuals who are genetically predisposed to hyperhomocyst(e)inemia. Randomized clinical trials are needed to investigate these effects further.

Arteriosclerosis↗

PubMed1998

Premenopausal black women have more risk factors for coronary heart disease than white women.

Premenopausal black women have a 2- to 3-fold greater rate of coronary heart disease (CHD) than premenopausal white women. The purpose of this study was to provide greater insight into the reasons for this difference, which are currently unclear. We compared CHD risk factors in 99 black and 100 white, healthy premenopausal women, aged 18 to 45 years, and of relatively advantaged socioeconomic status. Compared with white women, black women had a higher body mass index (32.0 +/- 9.2 vs 29.0 +/- 9.4 kg/m2, p = 0.021), and higher systolic (124 +/- 17 vs 115 +/- 14 mm Hg, p <0.0001) and diastolic (79 +/- 14 vs 75 +/- 11 mm Hg, p = 0.048) blood pressures. The mean plasma lipoprotein(a) concentration was markedly higher in the black women (40.2 +/- 31.3 mg/dl) than in the white women (19.2 +/- 23.7 mg/dl, p <0.0001). The plasma total homocysteine level was also higher in the black women (8.80 +/- 3.38 vs 7.81 +/- 2.58 micromol/L, p = 0.013). The black women, however, had lower plasma triglyceride levels (0.91 +/- 0.46 vs 1.22 +/- 0.60 mmol/L, p <0.0001), and a trend toward higher high-density lipoprotein (HDL) cholesterol levels (1.37 +/- 0.34 vs 1.29 +/- 0.31 mmol/L, p = 0.064) than the white women. Plasma total and low-density lipoprotein (LDL) cholesterol levels were similar, despite a greater consumption of saturated fat and cholesterol by the black women. Rates of cigarette smoking and alcohol intake were low and similar between the races. In summary, premenopausal black women had a higher mean body mass index, blood pressure, lipoprotein(a), and plasma total homocysteine level, and a greater consumption of saturated fat and cholesterol than white women. These differences in coronary risk factors may place the black women in our study at increased risk for CHD compared with the white women.

Adolescent↗

PubMed1998

Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are needed. METHODS AND RESULTS: We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center-adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5'-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5'-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C677T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene. CONCLUSIONS: Our prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD. Our findings point more strongly to the possibility that vitamin B6 offers independent protection. Randomized trials, some of which are under way, are needed to better clarify the interrelationships of tHcy, B vitamins, and cardiovascular disease.

Arteriosclerosis↗

PubMed1998

Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease.

BACKGROUND: The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. METHODS: To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. RESULTS: Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 microg of folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increased plasma folic acid by 31 percent (P=0.045) but decreased plasma homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals providing 499 and 665 microg of folic acid daily increased plasma folic acid by 64.8 percent (P<0.001) and 105.7 percent (P=0.001), respectively, and decreased plasma homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent (P=0.001), respectively. CONCLUSIONS: Cereal fortified with folic acid has the potential to increase plasma folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether folic acid fortification may prevent vascular disease. Until then, our results suggest that folic acid fortification at levels higher than that recommended by the FDA may be warranted.

Aged↗

PubMed1998

The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism.

OBJECTIVE: Data on fetal blood homocyst(e)ine concentrations are not available. We tested the hypothesis that homocyst(e)ine crosses the maternal/placental/fetal interphases and is sequestered by the fetus. STUDY DESIGN: The concentration of homocyst(e)ine was determined at parturition in peripheral venous plasma from 35 nulliparous healthy pregnant women and umbilical arterial and venous plasma from their conceptus. RESULTS: Findings demonstrated a descending concentration gradient of plasma homocyst(e)ine from maternal vein to umbilical vein and to umbilical artery; the decrease at each interphase approximated 1 micromol/L. The neonate weight and gestational age were inversely related to maternal homocyst(e)ine concentrations. CONCLUSION: The umbilical vein to umbilical artery homocyst(e)ine decrement suggests that uptake of homocyst(e)ine occurs in the fetus. The likely incorporation of homocyst(e)ine into the fetal metabolic cycle may implicate maternal homocyst(e)ine as having a potential nutritional role in the fetus. Further studies are required to explain the role of homocyst(e)ine in fetal metabolism and development.

Adult↗

PubMed1997

Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene.

BACKGROUND: In a population-based study, we examined the relationship between the risk of myocardial infarction (MI) among young women and plasma total homocysteine (tHCY), folate, vitamin B12, and a common cytosine (C) to thymine (T) polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR). METHODS AND RESULTS: In-person interviews and nonfasting blood samples were obtained from 79 women < 45 years old diagnosed with MI and 386 demographically similar control subjects living in western Washington state between 1991 and 1995. Compared with control subjects, case patients had higher mean tHCY concentrations (13.4+/-5.2 versus 11.1+/-4.4 micromol/L, P=.0004) and lower mean folate concentrations (12.4+/-13.4 versus 16.1+/-12.2 nmol/L, P=.018). There was no difference in vitamin B12 concentrations between case patients and control subjects (346.8+/-188.4 versus 349.7+/-132.4 pmol/L, P=.90). After adjusting for cardiovascular risk factors, we found that women with tHCY > or = 15.6 micromol/L were at approximately twice the risk of MI as women with tHCY < 10.0 micromol/L (OR, 2.3; 95% CI, 0.94 to 5.64). Women with folate > or = 8.39 nmol/L had an approximately 50% lower risk of MI than women with folate < 5.27 nmol/L (OR, 0.54; 95% CI, 0.23 to 1.28). There was no association with vitamin B12 concentration. Among control subjects, 12.7% were homozygous for the MTHFR T677 allele, and these women had higher plasma tHCY and lower plasma folate than women with other genotypes. Ten percent of case patients were homozygous for the T677 allele, and there was no association of homozygosity for T677 with MI risk (OR, 0.90; 95% CI, 0.31 to 2.29). CONCLUSIONS: These data support the hypothesis that elevated plasma tHCY and low plasma folate are risk factors for MI among young women. Although homozygosity for MTHFR T677 is related to increased plasma tHCY and low plasma folate, this genetic characteristic is not a risk factor for MI in this population.

Adult↗

PubMed1997

Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism.

BACKGROUND: Because patients with rare familial homocystinuria who also carry factor V Leiden have an increased incidence of venous thromboembolism (VTE), we hypothesized an interrelation of moderate hyperhomocyst(e)inemia, factor V Leiden, and risk of VTE in the general population. METHODS AND RESULTS: In a large prospective cohort, we determined total homocysteine level and factor V Leiden mutation in baseline blood samples from 145 initially healthy men who subsequently developed VTE and among 646 men who remained free of vascular disease during a 10-year follow-up period. Hyperhomocyst(e)inemia was defined as a total homocysteine level above the 95th percentile (17.25 mumol/L). Compared with men with normal total homocysteine levels, those with hyperhomocyst(e)inemia had no increase in risk of any VTE but were at increased risk of idiopathic VTE (relative risk [RR] = 3.4, P = .002). Compared with men without Leiden mutation, those with mutation were at increased risk of developing any VTE (RR = 2.3, P = .005) as well as idiopathic VTE (RR = 3.6, P = .0002). Compared with men with neither abnormality, those affected by both disorders had a 10-fold increase in risk of any VTE (RR = 9.65, P = .009) and a 20-fold increase in risk of idiopathic VTE (RR = 21.8, P = .0004). CONCLUSIONS: Apparently healthy men with coexistent hyperhomocyst(e)inemia and Leiden mutation are at substantially increased risk of developing future VTEs, particularly those events considered idiopathic. In these data, the risk of VTE among doubly affected individuals was far greater than the sum of the individual risks associated with either abnormality alone.

Aged↗

PubMed1997

Correlation between plasma homocyst(e)ine and aortic atherosclerosis.

Plasma homocyst(e)ine [H(e)] levels correlate with the prevalence of arterial occlusive diseases. Recently, transesophageal echocardiography (TEE) has been used to evaluate patients with atherosclerotic plaques in the thoracic aorta. The purpose of this study was to determine whether H(e) levels correlate with the degree of atherosclerotic plaque in the thoracic aorta (ATH) as seen on TEE. Maximum plaque areas for three locations in the thoracic aorta (arch, proximal descending, and distal descending) were measured with TEE in 156 patients. Maximum plaque areas for these locations were added to yield an estimate of ATH. ATH and H(e) levels, and levels of folic acid, vitamin B12, and pyridoxal 5'-phosphate were measured in a double-blind manner. Univariate analysis demonstrated a significant correlation of H(e) with ATH (r = 0.3, p< 0.001). On multivariate analysis, H(e) was independently predictive of ATH (r for the model including H(e) was 0.63, p < 0.0001). Plasma H(e) levels are therefore significantly and independently correlated with the degree of atherosclerosis in the thoracic aorta.

Aged↗

PubMed1997

Elevated homocyst(e)ine levels with preeclampsia.

OBJECTIVE: To determine whether homocyst(e)ine, a relatively new risk factor for possible endothelial cell dysfunction and premature vascular disease, is elevated in nulliparous pregnant women with preeclampsia. METHODS: We measured plasma homocyst(e)ine, folic acid, and vitamin B12 levels in 40 nulliparas, 20 with and 20 without preeclampsia at the time of their delivery. RESULTS: Mean (+/- standard deviation) plasma homocyst(e)ine levels in the 20 nulliparous women with preeclampsia were significantly higher than in the 20 nulliparous women without preeclampsia (8.66 +/- 3.05 versus 4.99 +/- 1.11 mumol/L, P < .001). Folic acid and vitamin B12 concentrations were not significantly different between the two groups. CONCLUSION: Homocyst(e)ine levels are elevated in pregnant nulliparas with preeclampsia at the time of their delivery. Further studies are necessary to determine what role homocyst(e)ine may play in the etiology of preeclampsia.

Adult↗

PubMed1997

Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults.

PURPOSE: Many epidemiologic studies have identified elevated plasma homocyst(e)ine as a risk factor for atherosclerosis and thromboembolic disease. To examined the relationship between vitamin intakes and plasma homocyst(e)ine, we analyzed dietary intake data from a case-control study of 322 middle-aged individuals with atherosclerosis in the carotid artery and 318 control subjects without evidence of this disease. METHODS: All of these individuals were selected from a probability sample of 15,800 men and women who participated in the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS: Plasma homocyst(e)ine was inversely associated with intakes of folate, vitamin B6, and vitamin B12 (controls only for this vitamin)--the three key vitamins in homocyst(e)ine metabolism. Among nonusers of vitamin supplement products, on average each tertile increase in intake of these vitamins was associated with 0.4 to 0.7 mumol/L decrease in plasma homocyst(e)ine. An inverse association of plasma homocyst(e)ine was also found with thiamin, riboflavin, calcium, phosphorus, and iron. Methionine and protein intake did not show any significant association with plasma homocyst(e)ine. CONCLUSIONS: In almost all analyses, cases and controls showed similar associations between dietary variables and plasma homocyst(e)ine. Plasma homocyst(e)ine among users of vitamin supplement products was 1.5 mumol/L lower than that among nonusers. Further studies to examine possible causal relationships among vitamin intake, plasma homocyst(e)ine, and cardiovascular disease are needed.

Analysis of Variance↗

PubMed1997

Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.

Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.

Arteriosclerosis↗

PubMed1997

Consequences of hyperhomocyst(e)inemia on vascular function in atherosclerotic monkeys.

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.

Acetylcholine↗