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Background We examined the relationship of maternal plasma concentrations of soluble vascular cell adhesion molecule–1 (sVCAM-1), a specific marker of endothelial dysfunction, and risk of preeclampsia. We also evaluated the relationship in the presence and absence of maternal hypertriglyceridemia and hyperhomocystein(e)mia. Methods A total of 170 women with preeclampsia and 184 control subjects were included in this case-control study analysis. Maternal postdiagnosis plasma sVCAM-1 concentrations were determined using immunoassays. Total plasma homocysteine (tHcy) was measured using high-performance liquid chromatography with electrochemical detection procedures; and triglyceride concentrations were determined using standard enzymatic procedures. Logistic regression procedures were used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounders. Results The relative risk of preeclampsia (as estimated by the OR) was increased 3.6-fold for women with sVCAM-1 concentrations ≥842 ng/mL compared with women who had lower concentrations (OR = 3.6; 95% CI 1.8 to 7.4). Of the three biological markers investigated, elevated sVCAM-1 concentrations was most strongly related to preeclampsia risk (OR = 4.6, 95% CI 1.6 to 13.5), followed by hyperhomocysten(e)mia (OR = 2.4, 95% CI 0.8 to 7.4) and hypertriglyceridemia (OR = 2.1, 95% CI 0.9 to 5.0). Compared with women who did not have any of the three risk factors, those with all three risk factors had an extremely high risk of preeclampsia (OR = 26.4; 95% CI 8.5 to 81.9). Conclusions These findings suggest that elevated sVCAM-1 concentrations are associated with an increased risk of preeclampsia. Our findings extend the literature by documenting progressively increased risk with increasing numbers of biological markers of dyslipidemia and endothelial dysfunction.

Hyperhomocyst(e)inemia (HH) is an established independent risk factor for coronary, cerebral and peripheral vascular diseases. Recent studies have indicated that certain cardiovascular risk factors, including diabetes and hypercholesterolemia, impair expression of vascular endothelial growth factor (VEGF) and endogenous angiogenesis. In this study, we investigate the impact of moderate HH on angiogen- esis and VEGF pathway in a mouse model of hindlimb ischemia. Upon induction of unilateral hindlimb ischemia, endogenous angiogenesis, expression of VEGF, and phosphorylation of the VEGF receptor Flk-1 were evaluated in mice heterozygous for a deletion of the cystathionine �-synthase gene (CBS) and compared with those observed in CBS�/� mice. CBS�/� mice exhibit moderate HH, as demonstrated by measuring plasma total homocyst(e)ine (tHcy) levels, which were significantly higher in these animals compared with CBS�/� mice (4.77 � 0.82 vs 2.10 � 0.28, p � 0.01). Twenty-eight days after induction of ischemia, hindlimb blood flow was significantly reduced in CBS�/� mice compared with CBS�/� animals (0.49 � 0.03, n � 12 vs 0.71 � 0.09, n � 10; p � 0.05). In addition, there was a significant negative correlation between plasma homocyst(e)ine levels and the laser Doppler perfusion ratio in CBS�/� mice (p � 0.0087, r �� 0.7171). While VEGF expression and Flk-1 phosphorylation were not impaired in the ischemic muscles of CBS�/� mice, phos- phorylation of the endothelial cell survival factor Akt was significantly inhibited by homocyst(e)ine in a dose-dependent manner in human umbilical vein endothelial cell (HUVECs) in vitro. In conclusion, our findings demonstrate that endogenous angiogenesis is inversely related to plasma levels of homocyst(e)ine in genetically engineered, heterozygous mice with moderate HH. This impairment, however, is not dependent on reduced expression of VEGF or impaired phosphorylation of its recep- tor Flk-1. In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH.

Hyperhomocyst(e)inemia (HHcy) is a risk factor of endothelial dysfunction and preeclampsia. Soluble vascular cell adhesion molecule-1 (sVCAM-1), a specific marker of endothelial dysfunction, is elevated in preeclampsia. Few have assessed the joint contribution of these biomarkers in predicting preeclampsia. We assessed the extent to which HHcy and elevated sVCAM-1 are independently and jointly associated with preeclampsia. We conducted a case-control analysis of 100 preeclampsia cases and 100 controls to test our study hypothesis. Maternal plasma was collected before labor onset. Total plasma homocysteine (tHcy) was measured using high-performance liquid chromatography with electrochemical detection procedures. Plasma sVCAM-1 was determined using ELISA. Using the distribution of each analyte among controls, elevated tHcy was defined as plasma tHcy >6.6 µmol/l and elevated sVCAM-1 was defined as plasma concentrations >845 ng/ml (i.e., values above the median). Odds ratios (OR) and 95% confidence intervals (CIs) were calculated. Compared with women without elevated tHcy and without elevated sVCAM-1 (the referent group), those with elevated sVCAM-1 alone had a 4.1-fold increased risk of preeclampsia (95% CI 1.2–13.8). The OR for women with elevated tHcy alone was 2.2 (95% CI 0.6–7.9). The OR for women with elevated tHcy and sVCAM-1 was 13.2 (95% CI 4.1–42.2). Elevated tHcy and sVCAM-1 together were strongly associated with an increased risk of preeclampsia. Larger, prospective studies are needed to confirm these findings and to determine the extent to which elevated tHcy and sVCAM-1 together in early pregnancy are predictive of preeclampsia risk.

Background— Endothelial function is impaired by hyperhomocyst(e)inemia. We have previously shown that homocyst(e)ine (Hcy) inhibits NO production by cultured endothelial cells by causing the accumulation of asymmetric dimethylarginine (ADMA). The present study was designed to determine if the same mechanism is operative in humans. Methods and Results— We studied 9 patients with documented peripheral arterial disease (6 men; 3 women; age, 64±3 years), 9 age-matched individuals at risk for atherosclerosis (older adults; 9 men; age, 65±1 years), and 5 young control subjects (younger adults; 5 men; age, 31±1 years) without evidence of or risk factors for atherosclerosis. Endothelial function was measured by flow-mediated vasodilatation of the brachial artery before and 4 hours after a methionine-loading test (100 mg/kg body weight, administered orally). In addition, blood was drawn at both time points for measurements of Hcy and ADMA concentrations. Plasma Hcy increased after the methionine-loading test in each group (all, P P P P =0.03, r =0.450), as well as ADMA and flow-mediated vasodilatation ( P =0.002, r =0.623). Conclusions— Our results suggest that experimental hyperhomocyst(e)inemia leads to accumulation of the endogenous NO synthase inhibitor ADMA, accompanied by varying degrees of endothelial dysfunction according to the preexisting state of cardiovascular health.

PURPOSE: To determine whether homocyst(e)ine (H(e)) is related to hemostatic factors in a population-based sample without evidence of cardiovascular disease. METHODS: A subsample of 660 participants—67 African-American women, 53 African-American men, 201 white women, and 339 white men—was selected from the Atherosclerosis Risk in Communities Study baseline cohort. This was based on carotid intimal-medial wall thickness above the 90th percentile or below the 75th percentile of the population distribution, assessed by B-mode ultrasonography. Unadjusted and multivariable-adjusted associations between fasting plasma H(e) and the hemostatic factors fibrinogen, factor VII:c, factor VIII:c, protein C antigen, hematocrit, platelet count, β-thromboglobulin (β-TG), tissue plasminogen activator (tPA), PAI-1, D-dimer, and lipoprotein[a] were examined. RESULTS: Mean age-adjusted H(e) was positively, albeit weakly, correlated with β-TG, tPA, hematocrit, D-dimer and PAI-1; inversely correlated with protein C; and was higher in smokers, men and African-Americans. In multivariable regression, β-TG, tPA, and factor VII:c were positively associated with H(e), as well as age, black race, male sex, and current cigarette smoking. CONCLUSIONS: These cross-sectional data for a biracial group of middle-aged individuals suggest that H(e) levels falling below values consistent with homocyst(e)inemia are associated with several prothrombotic factors after adjustment for sociodemographic factors. If H(e) change is antecedent to altered hemostasis, FDA-mandated fortification of grain products with folic acid for prevention of fetal neural tube defects may lead to both reduced plasma H(e) levels and improved hemostatic profiles.

Chronic rejection (CR) and transplant vascular sclerosis (TVS) cause the majority of graft failures in cardiac transplantation. Hyperhomocyst(e)inemia [hH(e)] is associated with human TVS without a proven causal relationship. This study investigated the effect of hH(e) on graft survival and TVS in allogeneic and syngeneic rat cardiac transplants. Lewis recipients of heterotopic F344 heart allografts, received normal or hH(e)-inducing (folate, methionine) diets [controls: syngeneic transplanted [+/- hH(e), + CsA] and nontransplanted rats [+/- hH(e), +/- CsA]]. Serial plasma homocyst(e)ine [H(e)] levels were measured. TVS was assessed in clinically rejected grafts and a subset of pre-rejection normal diet allografts (day 64) (neointimal index, NI). The hH(e) diet elevated plasma H(e) levels. When compared with normal diet controls (n = 9), hH(e) diet allografts (n = 9) had decreased time to onset of CR (40 +/- 9 vs. 72 +/- 10d, p = 0.02), and graft failure (64 +/- 10 vs. 107 +/- 12d, p = 0.009). hH(e) diet allografts at rejection (n = 9, 64d) had more severe TVS (NI = 68 +/- 2) than both time-matched normal diet allografts (NI = 49 +/- 6, n = 8, 64d, p0.001) and normal diet allografts at rejection (NI = 58 +/- 5, n = 9, 107d, p = 0.007). hH(e) induced TVS in syngeneic grafts (NI=50 +/- 3, n = 10 vs. NI = 5 +/- 3, n = 10, 130d, p0.001). hH(e) accelerated rejection and increased the severity of TVS in allogeneic cardiac transplants, and induced TVS in syngeneic cardiac transplants.

Background and Purpose —; Elevated plasma homocyst(e)ine [H(e)] concentration has been associated with an increased risk of stroke. Although the literature suggests that H(e) increases from the acute to the convalescent phase after a stroke, it is not known whether H(e) changes within the acute period. Methods —; A prospective, multicenter study was conducted to examine changes in H(e) during the 2 weeks after an incident stroke. Blood samples were collected at days 1, 3, 5, 7, and between 10 and 14 days after the stroke. Results —; Seventy-six participants (51 men) were enrolled from 9 sites from February 1997 through June 1998. Mean age was 65.6 years, and subjects had at least two H(e) measurements. The estimated mean H(e) level at baseline was 11.3±0.5 μmol/L, which increased consistently to a mean of 12.0±0.05, 12.4±0.5, 13.3±0.5, and 13.7±0.7 μmol/L at days 3, 5, 7, and 10 to 14, respectively. The magnitude of the change in H(e) was not affected by age, sex, smoking status, alcohol use, history of hypertension or diabetes, or Rankin Scale Score. Conclusions —; These data suggest that the clinical interpretation of H(e) after stroke and the eligibility for clinical trials assessing treatment for elevated H(e) levels require an adjustment in time since stroke to properly interpret the observed H(e) levels.

Purpose: Hyperhomocyst(e)inemia (hH[e]) is a risk factor for atherosclerosis. Neointimal hyperplasia (NH) after vessel injury can contribute to atherosclerosis. In this study, we investigated the effects of hH(e) on NH formation after arterial balloon injury in rats. Methods: Lewis rats that were given a hH(e)-inducing (high methionine, low folate) or normal diet for 150 days underwent common carotid artery (CCA) balloon injury. Two and 4 weeks after injury, CCAs were formalin perfusion-fixed, sectioned, and stained for elastin. Neointimal index (NI, percent lumen occlusion) and neointima (N) and media (M) area were measured by using computer-interfaced microscopy. Results: Plasma homocyst(e)ine (H[e]) levels were elevated in rats given the study diet compared with rats given the normal diet at days 40 and 90 (69 ± 8 and 73 ± 9 μmol/L vs 4 ± 0.4 and 4 ± 0.6 μmol/L, P

Background —Hyperhomocysteinemia is associated with increased risk of atherosclerotic and thrombotic vascular disease. In many patients, hyperhomocysteinemia can be treated or prevented by dietary supplementation with B vitamins, but the clinical benefit of B vitamins for the prevention of vascular disease has not been proven. Methods and Results —Using an atherogenic diet that produces both hyperhomocysteinemia and hypercholesterolemia, we tested the hypothesis that dietary supplementation with B vitamins (folic acid, vitamin B 12 , and vitamin B 6 ) would prevent hyperhomocysteinemia, vascular dysfunction, and atherosclerotic lesions in monkeys. After 17 months, plasma total homocysteine increased from 3.6±0.3 to 11.8±1.7 μmol/L in monkeys fed an unsupplemented atherogenic diet ( P P P Conclusions —These findings demonstrate that supplementation with B vitamins prevents hyperhomocysteinemia but is not sufficient to prevent the development of vascular dysfunction or atherosclerotic lesions in monkeys with marked hypercholesterolemia, even in the absence of preexisting atherosclerosis.

We tested the hypothesis that cessation of habitual ingestion of breakfast cereals would be associated with elevated plasma homocyst(e)ine concentrations. We anticipated that those subjects who reported consuming breakfast cereals containing 100 to 400 ,microg of folic acid per serving before entering the study would achieve higher plasma homocyst(e)ine concentrations if, in addition to their regular diet, they began ingesting a daily serving of breakfast cereal that contained less than 10 microg of folic acid per serving.Seventy-nine subjects consumed a daily serving of breakfast cereal containing either10 microg or folic acid per serving (placebo) or breakfast cereal containing 200 microg of folic acid per serving (folic acid fortified).Cessation of intake of commercially available breakfast cereal was associated with homocyst(e)ine elevation. Breakfast cereal containing 200 microg folic acid per day was sufficient to maintain the homocyst(e)ine lowering effects of commercial cereals.Habitual consumption of commercially available fortified breakfast cereals, usually containing 100 to 400 microg folic acid per serving, had significant homocyst(e)ine lowering effects as shown by the homocyst(e)ine increase after cessation of habitual intake of commercial breakfast cereal. Substitution of breakfast cereal containing only 200 microg folic acid per day was sufficient to maintain the homocyst(e)inelowering effects of commercial cereals.

Premenopausal black women have a two to threefold greater rate of coronary heart disease than premenopausal white women. This study was designed to provide greater insight into the reasons for this difference which is currently unclear. Coronary heart disease risk factors were compared in 100 black and 100 white, healthy premenopausal women, ages 18-45 years, and of relatively advantaged socioeconomic status. Compared to 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, p0.0001) 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, p0.0001). The plasma total homocysteine level was also higher in the black women (8.80±3.38 vs. 7.81±2.58 mmol/L, p=0.013). The black women, however, had lower plasma triglyceride levels (0.91±0.46 vs. 1.22±0.60 mmol/L, p0.0001) and a trend toward higher high-density lipoprotein 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 cholesterol levels were similar. Black women consumed more saturated fat and cholesterol. Rates of cigarette smoking and alcohol intake were low and similar between the races. In summary, compared to white women, black women had a higher mean body mass index, higher blood pressures, higher lipoprotein(a) and plasma total homocysteine levels, and greater consumption of saturated fat and cholesterol. The differences in coronary risk factors between these two premenopausal groups may explain the higher incidence of coronary heart disease in black women. (c) 2000 by CHF, Inc.

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 μmol/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.

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.*Homocyst(e)ine and total homocysteine indicate the sum of the amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins. 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 μmol/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.

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 B 12 , 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. (Am Heart J 1997;133:534-40.)

PURPOSE: Many epidemiologic studies have identified elevated plasma homocyst(e)ine as a risk factor for atherosclerosis and thromboembolic diseases. To examine the relationship between vitamin intakes and plasma homocyst(e)ine, we analyzed dietary intake data from a case-control study of 322 middleaged 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 μmol/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 μmol/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.

High serum levels of lipoprotein(a) and homocyst(e)ine are considered independent risk factors for atherothrombotic disease. In a prospective study in patients undergoing coronary artery bypass grafting, the preoperatively determined lipoprotein(a) and homocyst(e)ine levels were related to the frequency of 1-year graft occlusion. A cohort of 610 patients who underwent coronary artery bypass surgery was followed through the first postoperative year. Shunt angiography was performed in 581 patients (95%) at a mean of 12.1 +/- 1.5 months after the operation. The serum levels of lipoprotein(a) (n = 570) and homocyst(e)ine (n = 565) in patients with occluded internal mammary artery (IMA) grafts were not significantly different from the levels in those with open IMA grafts. Also, the serum lipoprotein(a) and homocyst(e)ine levels in patients with > or = 1 occluded vein graft were not significantly different from those in patients with all vein grafts patent. This study also determined the incidence of graft occlusion in quartiles of the lipoprotein(a) and homocyst(e)ine levels, respectively, and tested for linear trends. No significant trends in the incidence of graft occlusion were found, but the number of patients with vein graft occlusions was higher in the lowest quartile of lipoprotein(a) than that in the upper 3 quartiles (odds ratio, 1.82, 95% confidence interval, 1.21 to 2.74, p = 0.0025). Controlling for background variables in multivariate models only slightly modified the results. Thus, apart from an unexplained excess of vein graft occlusions in the lowest quartile of lipoprotein(a) levels, no association between the preoperative serum lipoprotein(a) or homocyst(e)ine levels and the frequency of 1-year graft occlusion could be demonstrated.

To test the hypothesis that plasma homocyst(e)ine (H|e|) level is a risk factor for early familial coronary heart disease (EFCHD), H(e) was measured in frozen samples from 33 men and 4 women with EFCHD and in 30 male and 18 female control participants matched for age and sex from the University of Utah Cardiovascular Genetics Research Clinic, Salt Lake City, Utah. To test for familial correlation, these participants were selected to include 13 males sibling pairs with EFCHD, 13 male sibling pairs as control subjects, and 13 spouse pairs as control subjects (all matched for age). Compared with control subjects, mean H(e) levels were significantly higher in persons with EFCHD for both men (14.31 vs. 11.09 nmol/mL; P=0.022) and women (9.51 vs 7.40; P=0.020). Most of the difference came from a few cases in 3 EFCHD sibling pairs. This observation was confirmed by a commingling analysis, which detected significant bimodality of plasma H(e) levels among the men with EFCHD (P=0.02). One sibling pair with early coronary heart disease despite normal plasma lipids, lipoproteins, and apolipoproteins, showed concordant elevations of H(e) levels greater than any levels seen among control subjects. Strong familial correlation of plasma H(e) was observed among all 26 male sibling pairs (r=0.52; P

Background An elevated plasma total homocysteine (tHcy) level is associated with an increased risk of vascular disease. Some studies have shown associations between tHcy level and small-vessel disease of the brain on magnetic resonance imaging (MRI). Design In the Cardiovascular Health Study, 622 elderly participants without a history of transient ischemic attack or stroke had results for tHcy level and cranial MRI. We sought associations between tHcy level and MRI findings of ventricular grade, sulcal grade, white matter grade, and infarcts. We controlled for other factors, including levels of creatinine, folate, and vitamins B 6 and B 12 and methylenetetrahydrofolate reductase genotype. Results After controlling for age and sex, tHcy level was not associated with the individual MRI findings. Further adjustments for other factors and other blood tests had little effect on these findings. The only significant finding was a linear trend across quintiles of tHcy level and a pattern of MRI findings combining infarcts and high white matter grade. The linear trend remained significant after controlling for other risk factors and atherosclerotic markers (top quintile vs bottom quintile odds ratio, 3.3; 95% confidence interval, 0.96-11.20; P = .04 for linear trend) but was slightly diminished after further controlling for creatinine, folate, and vitamins B 6 and B 12 (odds ratio, 3.2; 95% confidence interval, 0.81-13.10; P = .07 for linear trend). Conclusion We were unable to confirm the results of previous studies with respect to tHcy level and individual MRI findings, although an association was seen for an MRI pattern combining infarcts and high white matter grade.

Hyperhomocysteinemia has been proposed to inhibit the protein C anticoagulant system through 2 mechanisms: decreased generation of activated protein C (APC) by thrombin, and resistance to APC caused by decreased inactivation of factor Va (FVa). We tested the hypotheses that generation of APC by thrombin is impaired in hyperhomocysteinemia in monkeys and that hyperhomocysteinemia produces resistance to APC in monkeys, mice, and humans. In a randomized crossover study, cynomolgus monkeys were fed either a control diet or a hyperhomocysteinemic diet for 4 weeks. Plasma total homocysteine (tHcy) was approximately 2-fold higher when monkeys were on the hyperhomocysteinemic diet than when they were on the control diet (9.8 ± 2.0 μM versus 5.6 ± 1.0 μM; P .05). The activated partial thromboplastin time was prolonged to a similar extent by infusion of thrombin in monkeys fed the control diet and in those fed the hyperhomocysteinemic diet. The sensitivity of plasma FV to human APC was identical in monkeys on control diet and those on hyperhomocysteinemic diet. We also did not detect resistance of plasma FV to APC in hyperhomocysteinemic mice deficient in cystathionine β-synthase (plasma tHcy, 93 ± 16 μM) or in human volunteers with acute hyperhomocysteinemia (plasma tHcy, 45 ± 6 μM). Our findings indicate that activation of protein C by thrombin and inactivation of plasma FVa by APC are not impaired during moderate hyperhomocysteinemia in vivo.

Folic acid is presently the mainstay of treatment for most subjects with elevated plasma homocyst(e)ine concentrations [Plasma or serum homocyst(e)ine, or total homocysteine, refers to the sum of the sulfhydryl amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocystein-cysteine, whether free or bound to plasma proteins.] Changes in homocyst(e)ine in response to folic acid supplementation are characterized by considerable interindividual variation. The purpose of this study was to identify factors that contribute to heterogeneity in short-term responses to folic acid supplementation. The effects of folic acid supplementation (1 or 2 mg per day) for 3 wk on plasma homocyst(e)ine concentrations were assessed in 304 men and women. Overall, folic acid supplementation increased mean plasma folate 31.5 +/- 98.0 nmol/L and decreased mean plasma homocyst(e)ine concentrations 1.2 +/- 2.4 micromol/L. There was evidence of substantial interindividual variation in the homocyst(e)ine response from -18.5 to +7.1 micromol/L, including an increase in homocyst(e)ine in 20% of subjects (mean increase 1.5 +/- 1.4 micromol/L). Basal homocyst(e)ine, age, male gender, cigarette smoking, use of multivitamins, methylene tetrahydrofolate reductase, and cystathionine beta-synthase polymorphisms accounted for 47.6% of the interindividual variability in the change in homocyst(e)ine after folic acid supplementation, but about 50% of variability in response to folic acid was not explained by the variables we studied.

Hyperhomocyst(e)inemia (hH[e]) is a risk factor for atherosclerosis. Neointimal hyperplasia (NH) after vessel injury can contribute to atherosclerosis. In this study, we investigated the effects of hH(e) on NH formation after arterial balloon injury in rats.Lewis rats that were given a hH(e)-inducing (high methionine, low folate) or normal diet for 150 days underwent common carotid artery (CCA) balloon injury. Two and 4 weeks after injury, CCAs were formalin perfusion-fixed, sectioned, and stained for elastin. Neointimal index (NI, percent lumen occlusion) and neointima (N) and media (M) area were measured by using computer-interfaced microscopy.Plasma homocyst(e)ine (H[e]) levels were elevated in rats given the study diet compared with rats given the normal diet at days 40 and 90 (69 +/- 8 and 73 +/- 9 micromol/L vs 4 +/- 0.4 and 4 +/- 0.6 micromol/L, P.001). After balloon injury, the CCA NI and N/M ratio, but not the M area, were increased by hH(e) compared with normal plasma H(e) (2 weeks [n = 6,7]: NI = 7.3 +/- 1.7 vs 2.9 +/- 0.7, P =.002, and N/M = 0.31 +/- 0.08 vs 0.08 +/- 0.02, P.001; 4 weeks [n = 4,7]: NI = 13.1 +/- 2.2 vs 6.3 +/- 1.3, P =.002, and N/M = 0.36 +/- 0.08 vs 0.17 +/- 0.03, P.001).hH(e) accelerates NH in a rat CCA balloon-injury model. The effect of hH(e) on NH may contribute to increased atherosclerosis in humans with hH(e).

Abstract —Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S -adenosylmethionine (SAM) and its metabolite S -adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS +/– ) and wild-type (CBS +/+ ) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS +/– mice compared with CBS +/+ mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L; P P P P +/– mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated ≈2-fold in liver and brain of CBS +/– mice, and correlations were observed between plasma total homocysteine and SAH in liver ( r =0.54; P r =0.67; P +/– mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.

Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine beta-synthase. However, the mechanism by which homocysteine promotes the development and progression of hepatic steatosis is unknown. We report here that homocysteine-induced endoplasmic reticulum (ER) stress activates both the unfolded protein response and the sterol regulatory element-binding proteins (SREBPs) in cultured human hepatocytes as well as vascular endothelial and aortic smooth muscle cells. Activation of the SREBPs is associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake and with intracellular accumulation of cholesterol. Homocysteine-induced gene expression was inhibited by overexpression of the ER chaperone, GRP78/BiP, thus demonstrating a direct role of ER stress in the activation of cholesterol/triglyceride biosynthesis. Consistent with these in vitro findings, cholesterol and triglycerides were significantly elevated in the livers, but not plasmas, of mice having diet-induced hyperhomocysteinemia. This effect was not due to impaired hepatic export of lipids because secretion of VLDL-triglyceride was increased in hyperhomocysteinemic mice. These findings suggest a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides. Furthermore, this mechanism likely explains the development and progression of hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.

Methionine synthase (MS) encodes an enzyme that catalyzes the remethylation of homocysteine to methionine using a methyl group donated by 5-methyltetrahydrofolate, which is the major circulating form of folate in the body. Functional genetic variants of the MS may alter total homocysteine (tHcy) as well as folate levels which are independent risk factors for vascular disease. The influence of a common genetic polymorphism (2756A→G, D919G) of the MS gene on plasma tHcy and folate levels and its relation to the risk of myocardial infarction (MI) in a prospective study of male physicians in the US was investigated. A nested case-control study was conducted within the Physicians’ Health Study which was originally designed as a double-blind trial of aspirin and beta-carotene among 22 071 US male physicians, aged 40–84 years in 1982. Sixty-eight percent of participants also donated a blood sample. The study included 387 incident MI case and 767 controls matched on age, smoking status, and time from randomization in 6-month intervals. Individuals with GG genotype had a non-significant reduction of MI risk (RR 0.51, 95% CI 0.17–1.16) compared to individuals with DD genotype after adjusting for MI risk factors. The MS polymorphism was associated with decreased tHcy (10.55, 9.87 and 9.57 nmol/ml for DD, DG and GG genotypes, respectively) and increased folate levels (3.95, 3.78, 7.31 ng/ml for DD, DG and GG genotypes, respectively) only among controls but not cases. It was concluded that influence of the MS (D919G) polymorphism on the plasma tHcy and folate levels is at most moderate, but should be further investigated in other large prospective studies.

The authors measured maternal third trimester plasma folate, vitamin B(12), and homocyst(e)ine concentrations among 125 women with preeclampsia and 179 normotensive women in Lima, Peru (1997-1998), to determine whether these analytes were associated with the occurrence of preeclampsia. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios and 95% confidence intervals. Relative to women in the upper quartile of the control distribution of maternal plasma folate concentrations, women with values in the lowest quartile experienced a 1.6-fold increased risk of preeclampsia (odds ratio = 1.6; 95% confidence interval: 0.8, 3.2). There was no evidence of an increased risk of preeclampsia associated with low plasma vitamin B(12) concentrations. The unadjusted relative risk of preeclampsia increased across successively higher quartiles of plasma homocyst(e)ine level (odds ratios were 1.0, 1.0, 1.5, and 2.9, respectively, with the lowest quartile used as the referent; p for linear trend = 0.0004). After adjustment for maternal age, parity, gestational age, use of prenatal vitamins, whether the pregnancy had been planned, and educational attainment, the relative risk between extreme quartiles was 4.0 (95% confidence interval: 1.8, 8.9). These findings are consistent with earlier reports suggesting that hyperhomocyst(e)inemia in pregnancy may be a risk factor for preeclampsia.

Hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Moderate hyperhomocysteinemia is associated with impaired endothelial function, but the mechanisms responsible for endothelial dysfunction in hyperhomocysteinemia are poorly understood. We have used genetic and dietary approaches to produce hyperhomocysteinemia in mice. Heterozygous cystathionine beta-synthase-deficient mice (CBS +/-), which have a selective defect in homocysteine transsulfuration, and wild-type (CBS +/+) littermates were fed either a control diet or a diet that is relatively deficient in folic acid for 6 wk. Plasma total homocysteine was 5.3 +/- 0.7 microM in CBS +/+ mice and 6.4 +/- 0.6 microM in CBS +/- mice (P = 0.3) given the control diet. Plasma total homocysteine was 11.6 +/- 4.5 microM in CBS +/+ mice and 25.1 +/- 3.2 microM in CBS +/- mice (P = 0.004) given a low-folate diet. In mice fed the control diet, relaxation of aortic rings in response to the endothelium-dependent vasodilator acetylcholine did not differ significantly between CBS +/+ mice and CBS +/- mice. In contrast, in mice fed a low-folate diet, maximal relaxation to acetylcholine was markedly impaired in CBS +/- mice (58 +/- 9%) compared with CBS +/+ mice (84 +/- 4%) (P = 0.01). No differences in relaxation to the endothelium-independent vasodilator sodium nitroprusside were observed among the four groups of mice. These data indicate that CBS-deficient mice are predisposed to hyperhomocysteinemia during dietary folate deficiency, and moderate hyperhomocysteinemia is associated with marked impairment of endothelial function in mice.

Elevated total plasma homocysteine (tHcy) is an established risk factor for the development of vascular disease and neural tube defects. Total homocysteine levels can be lowered by folic acid supplements but individual response is highly variable. In this case–control study, involving 142 coronary artery disease (CAD) patients and 102 controls, we have typed six genetic polymorphisms in three homocysteine metabolizing genes and examined their relationship to the incidence of CAD, tHcy levels, and lowering of tHcy levels in response to folic acid supplementation. We found that two single nucleotide polymorphisms in the cystathionine beta synthase ( CBS ) gene, 699C → T and 1080T → C, are associated with decreased risk of CAD and increased responsiveness to the tHcy lowering effects of folic acid. Individuals homozygous for 699T were significantly underrepresented in CAD patients as compared to controls (4.9% vs 17.3%, P = 0.0015), as were individuals homozygous for the 1080C (29.6% vs 44.2%, P = 0.018). Additionally, 699T and 1080C homozygous individuals were the most responsive to folate supplementation. 699T homozygotes lowered tHcy levels 13.6% on average, compared to 4.8% lowering in 699C homozygotes ( P = 0.009), while 1080C homozygotes lowered 12.9% compared to just 2.7% for 1080T homozygotes ( P = 0.005). The two polymorphisms in CBS are third codon changes and would not be predicted to affect the underlying protein. However, there is strong linkage disequilibrium between these two positions, suggesting that they may also be linked to other as yet unidentified polymorphisms within the CBS gene. These observations suggest that specific CBS alleles are a risk factor for the development of vascular disease and that genetic information could be predictive of individual response to folic acid supplementation.

We conducted a case control study at Harare Maternity Hospital, Zimbabwe. We genotyped a total of 171 cases with preeclampsia or eclampsia and 185 normotensive control subjects for the methylenetetrahydrofolate reductase (MTHFR) 677 C → T genotype. The wild-type allele frequency among cases and controls was 91.2 and 91.3%, respectively. Only one subject (0.3%) was homozygous for the 677 C → T MTHFR genotype and this subject had preeclampsia. After adjustment for confounding factors, there was statistically no significant association between maternal MTHFR genotype and risk of preeclampsia (adjusted odds ratio = 1.0; 95% CI, 0.5–1.9). In addition, plasma homocyst(e)ine, vitamin B 12 , and folate concentrations were not statistically different between normotensive control subjects with wild-type genotype as compared with normotensive subjects who were heterozygous for the mutant allele. Conversely, there was a strong graded association between maternal plasma folate concentration and risk of preeclampsia. Women with plasma folate concentrations less than 5.7 nmol/L experienced a 10.4-fold increase in risk of preeclampsia. There was no clear pattern of preeclampsia risk and vitamin B 12 concentrations.

Hyperhomocysteinemia is an important addition to the growing list of potentially reversible risk factors for coronary heart disease (CHD). A compelling case can be made for performing screening measurements of plasma homocysteine concentrations in most if not all patients with myocardial infarction or a high risk of coronary artery disease. The genetic basis for regulation of plasma homocysteine levels suggests that approximately 50% of first-degree relatives of patients with hyperhomocysteinemia also may be hyperhomocysteinemic. Appropriate intervention includes correction of secondary causes of elevated homocysteine levels and treatment with folic acid, possibly in combination with vitamins B6 and B12. This intervention can effectively reduce plasma homocysteine concentrations in most patients and is predicted to prevent cardiovascular complications. Aggressive treatment of traditional CHD risk factors also is indicated, particularly among patients known to have atherosclerotic vascular disease. Verification of the clinical benefit and safety of homocysteine-lowering will require the completion during the next 5 to 10 years of 10 ongoing large scale prospective randomized clinical intervention trials involving more than 61,000 subjects.

In recent years, there has been an upsurge of interest in elevation of the plasma concentration of homocysteine and closely related metabolites as an independent risk factor for cardiovascular disease (reviewed, for example, in References 1 through 3). Homocysteine itself is a thiol(sulfhydryl-) containing amino acid, but in normal human plasma and other tissues, a variety of related disulfide derivatives may be present. Different authors have written about these compounds and their effects by using differing terminologies. To promote clarity of meaning and to minimize uncertainty, perhaps even confusion, it is important that each article discussing these compounds either defines explicitly the terms and/or abbreviations used or cites a prior publication in which such definitions are provided. Optimally, a more uniform consensus terminology will be developed and adopted by the field. This article describes very briefly the structures of the relevant compounds and sets forth terms and abbreviations that, it is hoped, may provide a basis

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.

Objective: To examine the relationship between plasma homocyst(e)ine and risk of eclampsia and preeclampsia among sub-Saharan African women who delivered at Harare Maternity Hospital in Zimbabwe. Methods: We ran a hospital-based, case-control study at Harare Maternity Hospital, University of Zimbabwe, Harare, Zimbabwe comprising 33 pregnant women with eclampsia and 138 with preeclampsia. Controls were 185 normotensive pregnant women. Plasma was collected postpartum and homocyst(e)ine levels were measured by high-performance liquid chromatography and electrochemical detection. Results: Women with eclampsia or preeclampsia had significantly higher mean homocyst(e)ine levels than normotensive controls (12.54 or 12.77 μmol/L versus 9.93 μmol/L, respectively, P < .001). The odds ratio (OR) for eclampsia was 6.03 among women in the highest quartile of the control homocyst(e)ine distribution (median 13.9 μmol/L) compared with women in the lowest quartile (median 6.2 μmol/L). The corresponding OR for preeclampsia was 4.57. Nulliparas with elevated homocyst(e)ine had a 12.90 times higher risk of preeclampsia compared with multiparas without elevated homocyst(e)ine. Conclusion: Postpartum plasma homocyst(e)ine concentrations are higher among Zimbabwean women with eclampsia and preeclampsia compared with normotensive women.

Background: Premenopausal black women have a greater rate of coronary artery disease (CAD) than do premenopausal white women. Plasma total homocysteine concentrations, a risk factor for CAD, have not been reported in premenopausal black women. Objective: The purpose of this study was to compare plasma total homocysteine, folate, and vitamin B-12 concentrations in premenopausal black and white women. Design: Eighty-nine black and 90 white, healthy, premenopausal women living in Portland, OR, were recruited. Dietary histories were obtained by using the Diet Habit Survey, a 40-item eating-behavior questionnaire. Plasma concentrations of total homocysteine, folate, and vitamin B-12 were measured. Results: Black women had higher plasma total homocysteine (8.32 compared with 7.60 μmol/L; P = 0.013), lower plasma folate (6.62 compared with 9.88 nmol/L; P < 0.0001), and higher vitamin B-12 (355 compared with 283 pmol/L; P < 0.001) concentrations than white women. White women had a greater rate of daily multivitamin supplement use (42.4% compared with 24.7%; P = 0.019) and ate more ready-to-eat cereal than did black women. After adjustment for multivitamin use and intake of ready-to-eat cereal, plasma total homocysteine concentrations did not differ significantly, but plasma folate remained significantly lower in the black women. None of the black women but 12.3% of the white women (P = 0.013) were homozygous for the cytosine to thymidine mutation at nucleotide 677 in the methylenetetrahydrofolate reductase gene. Conclusions: Black women had higher plasma total homocysteine and lower plasma folate concentrations than white women, largely because of lifestyle factors, which may contribute to the greater rate of CAD in premenopausal black than in white women.

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 B 12 , 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 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 B 12 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 ≥15.6 μmol/L were at approximately twice the risk of MI as women with tHCY 12 concentration. Among control subjects, 12.7% were homozygous for the MTHFR T 677 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 te T 677 allele, and there was no association of homozygosity for T 677 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 T 677 is related to increased plasma tHCY and low plasma folate, this genetic characteristic is not a risk factor for MI in this population.

Numerous authors have documented elevated plasma/serum homocysteine (tHcy) levels in patients with coronary artery disease. Terms used interchangeably are: coronary artery disease (CAD), coronary heart disease (CHD), and ischemic heart disease (IHD), although these terms are not necessarily synonymous. We have adopted CAD as a generic definition of coronary arterial lesions, resulting in a clinical syndrome associated with stenotic coronary arteries. It is usually implied that coronary atherosclerosis is the underlying pathology. However, there are no anatomical studies that support such causation in adult subjects with moderate hyperhomocyst(e)inemia.

Several studies suggest that the concentration of plasma homocysteine (tHcy) is regulated by hereditary factors, as implied by concordance of tHcy levels in family members. The present chapter will illustrate significant correlations in tHcy concentration among sibships and parent-offsprings. Moreover, the possible influence of environmental factors, as illustrated by significant correlations of tHcy levels between genetically unrelated spouses, cannot be ruled out in the presence of familial concordances.

Elevated plasma homocyst(e)ine (HCS) is an independent risk factor for coronary artery disease (CAD) among middle aged adults. Moveover, HCS also increases with age. This study assessed plasma HCS among 384 elderly (ages 73 ± 7 y) patients undergoing coronary angiography. The degree of CAD was scored using proximal and diffuse (Freisenger) indices. Plasma HCS, serum Vitamin B12 and folate and left ventricular ejection fraction (LVEF) were measured and risk factors for CAD were recorded. There was no apparent correlation between plasma HCS and extent of CAD after adjusting for age. Nine percent of patients (pts) had Vitamin B12 deficiency (B12 def), ie. Vitamin B12. l 300 pg/ml as well as HCS g 16 nmol/ml. LVEF for the 32 B12 def pts = 40.5% was significantly less than for 326 non B12 def pts with LVEF = 50.6% (p l 0.001). Significance remained after adjusting for proximal and Freisenger indices, history of smoking, diabetes, previous myocardial infarction, age and sex. (Adjusted Difference of LVEF = 8.2, 95% CI 2.6–13.8). In conclusion we did not find a significant correlation between plasma HCS and extent of CAD as assessed angiographically using proximal and diffuse indices. The data demonstrate that B12 def pts (with elevated HCS levels) had significantly lower LVEF than non B12 def pts. Whether low LVEF results in malabsorption of Vitamin B12 and B12 def or, conversely, whether B12 def and its marker, ie, elevated HCS, depress LVEF, warrants further investigation.

Plasma homocyst(e)ine (that is, the sum of free and bound homocysteine and its oxidized forms, homocystine and homocysteine-cysteine mixed disulfide) levels were determined in 170 men (mean age +/- SD 50 +/- 7 years) with premature coronary artery disease diagnosed at coronary angiography and in 255 control subjects clinically free of coronary artery disease (mean age 49 +/- 6 years). Patients with coronary artery disease had a higher homocyst(e)ine level than control subjects (13.66 +/- 6.44 versus 10.93 +/- 4.92 nmol/ml, p less than 0.001). High density lipoprotein (HDL) cholesterol levels were lower (32 +/- 10 versus 46 +/- 13 mg/dl, p less than 0.001) and triglycerides levels were higher (193 +/- 103 versus 136 +/- 106 mg/dl, p less than 0.001) in the coronary disease group. Plasma total cholesterol and low density lipoprotein (LDL) cholesterol levels were not significantly different between patients with coronary disease and control subjects. The presence of hypertension, smoking or diabetes mellitus did not significantly alter homocyst(e)ine levels in the patient or the control group. Patients who were not taking a beta-adrenergic blocking drug (n = 70) had a nonsignificantly higher homocyst(e)ine level than did patients taking this class of drugs (n = 100) (14.67 +/- 8.92 versus 12.95 +/- 3.77 nmol/ml, p = 0.087). By design, none of the control subjects were taking a beta-blocker. No significant correlations were observed between homocyst(e)ine and age, serum cholesterol, LDL cholesterol, HDL cholesterol or triglyceride levels. It is concluded that an elevated plasma homocyst(e)ine level is an independent risk factor for the development of premature coronary atherosclerosis in men.

Population screening for plasma cholesterol is an effective method of detecting hypercholesterolemia; however, follow-up and treatment are essential components of such a progrma. After a city-wide screening in 1987 of more than 19,872 persons, using a mailed survey with a response rate of 48%, we evaluated subsequent actions of 3,078 individuals with high plasma cholesterol levels. Slightly more than half the population was aware of high blood cholesterol levels prior to the time of screening and apparently used the program for follow-up. Overall, after the screening, 65% consulted a physician within 5 months of screening and blood cholesterol levels were remeasured in 80% of the sample. Procastination and expense were cited as the primary reasons for failing to consult a physician. If screening is to be effectively utilized as a means of reducing the prevalence of high plasma cholesterol levels, diligent follow-up must be made of all individuals identified to be at increased risk on the basis of their initial values.

HYPERHOMOCYST(E)INEMIA & ELEVATED SOLUBLE VASCULAR CELL ADHESION MOLECULE-1 IN PREDICTING PREECLAMPSIA SURAB VADACHKORIA, SANCHEZ SIXTO, CHUNFANG QIU, MARTIN MUY-RIVERA, M. RENE MALINOW, MICHELLE WILLIAMS, Swedish Medical Center, Center for Perinatal Studies, Seattle, WA Dos de Mayo Hospital, Lima-1, Peru Oregon Regional Primate Research Center, Beaverton, OR OBJECTIVE: Hyperhomocystinemia (HHcy) is a risk factor of endothelial dysfunction and preeclampsia (PE). Soluble vascular cell adhesion molecule-1 (sVCAM-1), a specific marker of endothelial dysfunction, is elevated in PE. Few have assessed the joint contribution of these biomarkers in predicting PE. We assessed the extent to whichHHcy and elevated sVCAM-1 are independently and jointly associated with PE risk. STUDY DESIGN: We used information from a case-control study of 100 PE cases and 100 controls to test our study hypothesis. Maternal plasma was collected before labor onset. Total plasma homocysteine (tHcy) was measured using high-performance liquid chromatography with electrochemical detection procedures. Plasma sVCAM-1 was determined using ELISA. Using the distribution of each analyte among controls, elevated tHcy was defined as plasma tHcy > 6.6 lmol/L and elevated sVCAM-1 was defined as plasma concentrations >845 ng/mL (i.e., values above the median). Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: Plasma tHcy was weakly correlated with sVCAM-1 in cases (r = 0.18, P = 0.08), but not in controls (r = 0.04, P = 0.70). Compared with women without elevated tHcy and without elevated sVCAM-1 (the referent group), those with elevated sVCAM-1 alone experienced a 4.1-fold increased risk of PE (CI 1.2-13.8). Women with elevated tHcy alone experienced a 2.2-fold increased risk of PE (OR = 2.2; CI 0.6-7.9). Women who had elevated tHcy and sVCAM-1 were 13.2 times more likely to experience PE (CI 4.1-42.2). CONCLUSION: Elevated tHcy and sVCAM-1 concentrations together are strongly associated with an increased risk of PE. Our results suggest that combining these two biomarkers may be particularly powerful in predicting the risk of PE. Future larger, prospective studies are needed to confirm these findings.

P121 INTRODUCTION. Elevated plasma homocyst(e)ine concentration [H(e)] has been associated with an increased risk of stroke. Clinical trials such as the Vitamin Intervention for Stroke Prevention trial (VISP) are underway to determine whether lowering H(e) will reduce recurrent stroke. VISP limits enrollment to stroke patients who meet the H(e) criterion of > 9.5 μmol/L for men and > 8.5 μmol/L for women. VISP allows blood for H(e) analysis to be drawn up to 100 days following the qualifying stroke, however the appropriate earliest time is not known. The literature suggests that H(e)levels increase from the acute to the convalescent phase after stroke but changes during the acute phase have not been studied. METHODS. A prospective, multicenter study was conducted to examine changes in H(e)over two-weeks following an incident stroke. Blood samples for H(e) analysis were collected at days 1 (24–48 hrs), 3, 5, 7, and between 10–14 days after the stroke. Total plasma H(e) was determined by high-performance liquid chromatography and electrochemical detection at a Central Lab. Analyses were performed using the mixed models of Laird and Ware. RESULTS. Eighty-one patients (54 men, 27 women, mean age 66.8) were enrolled at 9 sites from 02/97 to 06/98. The estimated mean H(e) level at the five time periods increased with time from stroke (see table). Differences between any two time periods were significant (pCONCLUSONS. Plasma H(e) levels are frequently measured following stroke. These data suggest that: 1) interpretation of observed values of H(e) require an adjustment for time since stroke; 2) case-control studies assessing H(e) after stroke may be biased in overestimating its impact as a risk factor.