血浆同型半胱氨酸与老年单纯收缩期高血压

同型半胱氨酸（homoeysteine，Hcy）由DeVigneaud于1932年发现，其后不断有研究发现Hcy在冠心病、心肌梗死、高血压、老年痴呆等心脑血管疾病的发生发展中起着重要的作用。特别是近年研究发现，以动脉粥样硬化（AS）为主要病理改变的单纯收缩期高血压（ISH）患者血浆Hcy水平明显增高。国内有学者通过对比研究老年ISH、老年单纯舒张期高血压（IDH）、收缩期与舒张期均高即全期高血压（SDH）患者的血浆Hcy水平发现：各类型老年高血压患者Hcy水平升高，且以老年ISH患者的升高水平尤其显著。可见，老年ISH与血浆Hcy水平之间似乎有某种更为密切的联系。本文通过总结目前有关Hcy研究的现状、探讨其与老年ISH的关系，以期有助于老年ISH的机理和临床的进一步研究。     

H型高血压合并冠心病患者血浆非对称性二甲基精氨酸与同型半胱氨酸的相关性

目的:探讨H型高血压合并冠心病患者血浆非对称性二甲基精氨酸(ADMA)水平与血浆同型半胱氨酸(Hcy)水平的相关性。方法:选择2016-01-2016-11于我院住院的原发性高血压病患者222例(其中单纯高血压病组66例,高血压合并冠心病组156例),采用酶联免疫吸附法检测血浆ADMA、Hcy水平。根据血浆Hcy水平,将单纯高血压组分为H型高血压亚组46例和非H型高血压亚组20例;将高血压合并冠心病组进一步分为H型高血压合并冠心病亚组104例、非H型高血压合并冠心病亚组52例。比较各组血浆ADMA水平,分析血浆ADMA与Hcy的相关性。结果:高血压合并冠心病组血浆ADMA、Hcy水平均高于单纯高血压组。H型高血压亚组血浆ADMA、Hcy水平高于非H型高血压亚组,H型高血压合并冠心病亚组血浆ADMA、Hcy水平高于非H型高血压合并冠心病亚组,差异有统计学意义(P0.05);线性相关分析显示,高血压合并冠心病患者血浆ADMA与Hcy水平有相关性(r=0.76,P0.01);进一步多元逐步回归分析显示,血浆Hcy是ADMA的影响因素。结论:H型高血压患者及H型高血压合并冠心病患者血浆Hcy、ADMA水平均高于非H型高血压患者及非H型高血压合并冠心病患者,高血压合并冠心病患者血浆ADMA水平与Hcy水平呈正相关。     

H型高血压病人Hcy水平、血压及冠状动脉病变程度的相关性研究

目的分析H型高血压病人Hcy水平、血压与冠状动脉病变程度的相关性。方法选取山西医科大学第二医院心血管内科行冠状动脉造影的235例病人,根据同型半胱氨酸(Hcy)及血压水平分为H型高血压组、非H型高血压组、Hcy正常组、高Hcy组,记录各组一般资料以及血糖、血脂、肾功能等生化指标检验结果,同时测定各组Hcy水平,记录冠状动脉病变支数。分析Hcy水平、高血压程度及冠状动脉病变支数之间的相关性。结果高血压分级、Hcy水平与冠状动脉病变程度均呈正相关。结论 Hcy和高血压均会加重冠状动脉粥样硬化的发生,随着Hcy水平及血压的增高,冠状动脉病变程度加重。     

同型半胱氨酸与高血压患病风险的关联研究

目的本研究拟揭示中国汉族人群Hcy血浆水平与高血压的关系。方法采用循环酶法检测4989例山东日照社区人群血浆Hcy水平,分析Hcy血浆水平与血压及高血压患病的关系。结果 (1)随着Hcy血浆水平升高,高血压患者比例逐渐增加,Hcy血浆水平第二、三、四四分位组的高血压患者比例分别为第一四分位组的1.58倍、2.09倍和2.25倍,P0.001;(2)高血压患病与Hcy血浆水平升高显著相关,logistic回归校正了年龄、性别、体重指数、吸烟、饮酒等传统危险因素后,与Hcy水平最低四分位相比,第四四分位危险比(95%CI)为1.30(1.03-1.66),P0.05;进一步校正TC、HDL-C、LDL-C、血糖、尿酸、TG后,其相关性则不再有显著意义。结论 Hcy血浆水平升高与高血压患病显著相关,是高血压患病的标志物,但不是高血压患病的独立危险因素。     

高血压早期肾损伤患者血清同型半胱氨酸和尿微量清蛋白水平变化及其临床意义

目的观察高血压早期肾损伤患者血清同型半胱氨酸(Hcy)和尿微量清蛋白(U-m ALB)水平变化,探讨其临床意义。方法选取2012—2014年在扬州市医学检验中心门诊部就诊的U-m ALB20 mg/L的高血压患者56例作为高血压早期肾损伤组,同时选取在扬州市疾控中心进行体检的单纯高血压患者52例作为单纯高血压组,无高血压者58例作为健康对照组。检测3组受试者血清Hcy和U-m ALB水平。结果高血压早期肾损伤组、单纯高血压组患者血清Hcy和U-m ALB水平均高于健康对照组,高血压早期肾损伤组患者血清Hcy和U-m ALB水平高于单纯高血压组(P0.01)。不同血清Hcy水平高血压患者U-m ALB水平比较,差异有统计学意义(P0.01)。结论高血压早期肾损伤患者血清Hcy和U-m ALB水平明显升高,40岁以上高血压患者应定期监测血清Hcy及U-m ALB水平,以及时发现早期肾损伤。     

老年高血压并缺血性脑卒中患者血浆同型半胱氨酸变化的临床意义

对66例老年原发性高血压患者、68例高血压并缺血性脑卒中患者及65例老年健康人进行血浆同型半胱氨酸（Hcy）、叶酸及维生素B12检测。结果显示，高血压和高血压并缺血性脑卒中组患者血浆Hcy水平均高于健康者（P〈0．01），而叶酸、维生素B12低于健康者（均P〈0．05）。认为老年高血压病及伴缺血性脑卒中患者的发病与血浆Hcy水平升高及叶酸、维生素B12水平降低有关，补充叶酸、维生素B12可能有助于减少老年脑血管病的发生。     

民航飞行人员同型半胱氨酸与高血压病的关系及其与血脂的相关性

目的 分析同型半胱氨酸（homocysteine，Hcy）与原发性高血压（高血压病）的关系及其Hcy与血脂的相关性。 方法 28例健康体检者为对照组，38例高血压病患者为高血压病组，高血压病组又分为调脂组20例和未调脂组18例。分别测定各组受试对象血浆Hcy及血脂指标。 结果 与对照组比较，高血压组Hcy水平显著升高（P<0.01）；与未调脂组比较，调脂组总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白B(ApoB)显著降低（P <0.01），但Hcy水平下降不显著；Pearson相关性分析显示:调脂组Hcy与三项血脂指标TC、LDL-C、ApoB均无相关性。 结论 高Hcy血症（HHcy）是民航飞行员高血压患者的危险因素；Hcy与TC、LDL-C水平无相关性，调脂治疗并不能够改善血浆Hcy水平。     

高血压患者血浆同型半胱氨酸水平及亚甲基四氢叶酸还原酶基因多态性的研究

目的探讨高血压患者血浆同型半胱氨酸(Hcy)水平及亚甲基四氢叶酸还原酶(MTHFR)A1298C基因多态性对血浆Hcy水平的影响。方法选择原发性高血压患者145例,采用荧光偏振免疫法测定血浆Hcy水平,依据Hcy水平将研究对象分为H型高血压组及非H型高血压组。并应用聚合酶链反应-限制性内切酶片段长度多态性技术检测MTHFR基因多态性。结果 H型高血压组及非H型高血压组血浆平均Hcy水平分别为(16.74±6.14)μmol/L,(8.50±1.02)μmol/L,两者差异有统计学意义(P<0.05)。H型高血压组及非H型高血压组MTHFRA1298C多态位点AA、AC及CC基因型频率分布及C等位基因频率差异均无统计学意义(P>0.05)。AA、AC和CC 3种基因型间的平均血浆Hcy水平比较差异无统计学意义(P<0.05)。结论 H型高血压患者血浆Hcy水平较非H型高血压显著升高,MTHFR A1298C多态位点对血浆Hcy水平无明显影响。     

脑梗死患者hs-CRP在不同血压、Hcy水平中的临床意义

高血压和高同型半胱氨酸（Hcy）是引起动脉粥样硬化性脑梗死的重要危险因素之一。中国人原发性高血压合并高同型半胱氨酸血症在高血压人群中的比例相当高,一项国内6城市的研究数据显示,我国成年高血压患者平均Hcy水平为15μmol/L,约75%的患者（男性91%、女性63%）伴有血浆Hcy水平升高。故有学者提出伴有Hcy水平升高的高血压被定义为＂H型＂高血压。大量研究证实,高血压和血清Hcy水平升高在导致动脉粥样硬化性心脑血管事件上具有协同作用。炎症反应过程是动脉粥样硬化形成的学说之一,超敏-CRP（hs-CRP）是反映机体内环境炎症反应的客观指标之一。本研究旨在探讨急性脑梗死患者高血压、Hcy与hs-CRP的相关性及临床意义。     

原发性高血压病人同型半胱氨酸水平与动脉病变及左心室肥厚的关系探讨

目的研究原发性高血压病人同型半胱氨酸水平(Hcy)与动脉病变及左心室肥厚关系。方法选取2012年10月-2015年8月我院收治的120例原发性高血压病人作为研究对象,根据Hcy水平分为A组(Hcy≥15 mmol/L)和B组(Hcy1 5 mmol/L),每组70例;根据高血压分级分为3组:高血压1级组25例,高血压2级组56例,高血压3级组39例。选取同期来我院进行体检的80名健康者作为对照组,采用多普勒超声对所有病人左心室形态结构进行测定,计算左心室质量指数(LVMI)及左心室质量(LVM),比较各组左心室肥厚指标以及Hcy水平。结果 B组LVMI、LVM、左心室舒张末期内径(LVEDD)、室间隔厚度(IVST)、左心室厚壁厚度(LVPWT)、左室舒张末期内径(LVESD)指标,与A组相比差异有统计学意义(P0.05);高血压病人Hcy水平以及颈动脉内中膜厚度与对照组相比,差异有统计学意义(P0.05),Hcy水平以及颈动脉内中膜厚度与高血压严重程度成正比,对照组和高血压1级组病人颈动脉斑块发生率明显低于高血压2级组、高血压3级组,差异有统计学意义(P0.05);左心室肥厚高血压病人的Hcy水平明显高于无左心室肥厚高血压病人,差异有统计学意义(P0.05)。结论原发性高血压发生、发展与Hcy水平密切相关,Hcy水平是反映动脉病变及左心室肥厚严重程度的重要指标。     

Consequences of homocysteine export and oxidation in the vascular system

The risk for arteriosclerosis and thrombosis of patients with severe hyperhomocysteinemia is reduced by homocysteine-lowering therapy. Whether this is the case in patients with mild hyperhomocysteinemia remains to be proved. Another challenge for researchers is to establish a satisfying pathological mechanism of the vasotoxicity of a disturbed homocysteine metabolism. Unfortunately, most in vitro studies use physiologically irrelevant concentrations or forms, or both, of homocysteine. The role of the different oxidized and reduced forms of homocysteine in its metabolism has gained little attention. In the cell, homocysteine is mainly present in its reduced form. In this article export of homocysteine out of the cell is reported to be regulated by a "reduced-homocysteine carrier." In vitro endothelial cells export homocysteine at a constant rate in a folate dose-dependent matter. Even at high-normal folate levels, endothelial cells export homocysteine. As soon as homocysteine is exported out of the cell, it will be oxidized to a disulfide with any compound containing a thiol function or undergo a disulfide exchange reaction, both resulting in formation of disulfides of homocysteine. Consequently, in plasma, about 99% of homocysteine is bound to disulfides. Before homocysteine can be metabolized, it needs to be taken up by the cell via carriers, channels, or receptors recognizing the different homocysteine disulfides. In the cell, the homocysteine disulfides are reduced, liberating homocysteine in its reduced form. Next, homocysteine can be metabolized after binding to the homocysteine-converting enzymes. In particular, the liver and kidney supposedly take up and metabolize significant amounts of homocysteine.     

The dose-response relation between serum homocysteine and cardiovascular disease: implications for treatment and screening.

BACKGROUND: With the recognition that serum homocysteine may cause cardiovascular disease there is clinical interest in homocysteine measurement to guide treatment with folic acid. It is uncertain whether treatment is best directed at those with high homocysteine or those at high risk irrespective of initial homocysteine. DESIGN AND METHODS: Dose-response plots of the associations between serum homocysteine and ischaemic heart disease and deep vein thrombosis were determined from retrospective (case-control) studies (a meta-analysis of 12 age-matched studies) prospective studies and studies of the C677T MTHFR polymorphism (a comparison of risk in three genotypes in a meta-analysis of 72 studies). The value of serum homocysteine as a screening test was assessed from distributions of serum homocysteine in men who did and did not die from ischaemic heart disease in a large prospective study. RESULTS: There were straight-line relationships between serum homocysteine and disease events in the three types of study; a given decrease in homocysteine would produce a similar proportional risk reduction from any pre-treatment level. There was substantial overlap between the distributions of serum homocysteine in men who did and did not die of ischaemic heart disease, indicating poor screening performance; there was no serum homocysteine cut-off that concentrated the majority of disease events into a small minority of the population. CONCLUSION: Interventions to lower serum homocysteine, if judged to be worthwhile, should not be limited to people with a high homocysteine but should be offered to everyone at high risk, regardless of pre-treatment homocysteine.     

Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis

Editing of the nonprotein amino acid homocysteine by certain aminoacyl-tRNA synthetases results in the formation of the thioester homocysteine thiolactone. Here we show that in the presence of physiological concentrations of homocysteine, methionine, and folic acid, human umbilical vein endothelial cells efficiently convert homocysteine to thiolactone. The extent of this conversion is directly proportional to homocysteine concentration and inversely proportional to methionine concentration, suggesting involvement of methionyl-tRNA synthetase. Folic acid inhibits the synthesis of thiolactone by lowering homocysteine and increasing methionine concentrations in endothelial cells. We also show that the extent of post-translational protein homocysteinylation increases with increasing homocysteine levels but decreases with increasing folic acid and HDL levels in endothelial cell cultures. These data support a hypothesis that metabolic conversion of homocysteine to thiolactone and protein homocysteinylation by thiolactone may play a role in homocysteine-induced vascular damage.     

Homocysteine and methionine metabolism in renal failure

Renal insufficiency is invariably accompanied by elevated plasma concentrations of the sulfur-containing and potentially vasculotoxic amino acid homocysteine. There is a strong relationship between glomerular filtration rate and plasma homocysteine concentration. Unlike creatinine, however, homocysteine is avidly reabsorbed in the renal tubules, and its urinary excretion is minimal. There is no evidence that homocysteine is actively removed by the human kidney. In renal insufficiency, plasma concentrations of S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, and sulfate are elevated, pointing to a remethylation or distal transsulfuration/oxidation block as the cause of hyperhomocysteinemia in renal failure. Stable isotope techniques have shown that both whole-body homocysteine remethylation and methionine transmethylation are decreased in renal failure, whereas homocysteine transsulfuration seems intact. Metabolic homocysteine clearance (i.e., transsulfuration relative to plasma homocysteine) is decreased to a major extent. These metabolic disturbances in renal failure can only be partially restored with current treatments. Folic acid treatment lowers plasma homocysteine concentration and increases remethylation and transmethylation rates. Plasma homocysteine, however, is not normalized, and metabolic homocysteine clearance by transsulfuration remains impaired. According to the currently available data, effective normalization of plasma homocysteine can only be obtained when its metabolic clearance through transsulfuration is restored.     

Redox status of plasma homocysteine and other plasma thiols in stroke patients

Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Studies are difficult as a result of the fact that little is known about the formation of different homocysteine species in vivo. Since extracellular glutathione and cysteine may influence the formation of different homocysteine species, we have in the present study investigated the different fractions of homocysteine and their relation to the different fractions of glutathione and cysteine in stroke patients and control subjects. We found a ratio of about 32-33% between reduced and total plasma glutathione concentrations and 2.6 3.0% between reduced and total plasma cysteine concentrations both in patients and in healthy control subjects. We noted an elevated concentration of total plasma homocysteine in stroke patients, but no difference in the ratio between reduced and total plasma homocysteine concentrations in patients and control subjects (mean value 1.20 and 1.10%, respectively). However, in a subgroup of patients with higher concentrations of total plasma homocysteine, we observed a significantly lower ratio of reduced to total plasma homocysteine compared to a subgroup of patients with lower concentration of total plasma homocysteine. A low reduced/total ratio of plasma homocysteine in combination with elevated plasma homocysteine concentrations might reflect an increased pro-oxidant activity in plasma from these patients. Thus, increased pro-oxidant activity in plasma might be one factor, besides genetic and nutritional factors, that could explain hyperhomocysteinemia. Since substantial evidence indicates that progression of atherosclerosis is related to enhanced pro-oxidant activity, the premature vascular disease associated with increased plasma homocysteine concentration might be as a result of increased pro-oxidant activity and the elevated plasma homocysteine concentration may only reflect the increased oxidative stress.     

Homocysteine and coronary heart disease

Children with homocystinuria have markedly elevated plasma homocysteine concentrations and increased risks of stroke and coronary heart disease (CHD). Supplementation with folic acid, vitamin B6, and vitamin B12 lower homocysteine levels and such therapy is remarkably effective in delaying the occurrence of vascular events in affected individuals. The relevance, if any, of moderately elevated homocysteine levels to cardiovascular disease in the general population is uncertain. The results of retrospective studies of homocysteine and risk of cardiovascular disease (where blood is collected after the onset of disease) indicate that CHD or stroke patients invariably have higher homocysteine levels than age-matched controls. In contrast, the results of prospective studies (where blood is collected before onset of disease) show much weaker associations of homocysteine with cardiovascular disease. This article examines the background, epidemiological evidence relating homocysteine with vascular disease, and effects of vitamin supplements on homocysteine concentrations. Large-scale clinical trials of folic acid-based vitamin supplements are currently in progress to test whether lowering blood homocysteine levels can reduce the risks of CHD and stroke.     

Homocysteine and lipid metabolism in atherogenesis: effect of the homocysteine thiolactonyl derivatives, thioretinaco and thioretinamide

In order to study the relation of homocysteine and lipid metabolism to atherogenesis, rabbits were fed a synthetic atherogenic diet and treated with parenteral thioretinaco (N-homocysteine thiolactonyl retinamido cobalamin), thioretinamide (N-homocysteine thiolactonyl retinamide) or homocysteine thiolactone hydrochloride. All three substances were found to increase dietary atherogenesis. Thioretinaco and thioretinamide increase total homocysteine of serum, but there is no effect of parenteral homocysteine thiolactone hydrochloride on serum homocysteine. The synthetic diet with corn oil significantly lowers serum homocysteine, compared either to baseline chow diet or to the synthetic diet with butter. Atherogenesis is correlated with total homocysteine, total cholesterol and LDL + VLDL cholesterol, and serum homocysteine is correlated with total cholesterol, LDL + VLDL, and HDL cholesterol in the total sample. Both synthetic diets elevate serum cholesterol, triglycerides and LDL + VLDL, but not HDL, compared to baseline values. Thioretinamide causes significant elevation of cholesterol and LDL + VLDL, compared to controls. The results show that increased dietary saturated fat and cholesterol cause deposition of lipids within the arteriosclerotic plaques produced by homocysteine, converting fibrous to fibrolipid plaques. Facilitation of atherogenesis is attributed to the effect of homocysteine on artery wall, either from parenteral homocysteine or from the increased synthesis of homocysteine from methionine, produced by thioretinaco and thioretinamide.     

Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis.

Plasma homocysteine levels are elevated in 20-30% of all patients with premature atherosclerosis. Although elevated homocysteine levels have been recognized as an independent risk factor for myocardial infarction and stroke, the mechanism by which these elevated levels cause atherosclerosis is unknown. To understand the role of homocysteine in the pathogenesis of atherosclerosis, we examined the effect of homocysteine on the growth of both vascular smooth muscle cells and endothelial cells at concentrations similar to those observed in clinical studies. As little as 0.1 mM homocysteine caused a 25% increase in DNA synthesis, and homocysteine at 1 mM increased DNA synthesis by 4.5-fold in rat aortic smooth muscle cells (RASMC). In contrast, homocysteine caused a dose-dependent decrease in DNA synthesis in human umbilical vein endothelial cells. Homocysteine increased mRNA levels of cyclin D1 and cyclin A in RASMC by 3- and 15-fold, respectively, indicating that homocysteine induced the mRNA of cyclins important for the reentry of quiescent RASMC into the cell cycle. Furthermore, homocysteine promoted proliferation of quiescent RASMC, an effect markedly amplified by 2% serum. The growth-promoting effect of homocysteine on vascular smooth muscle cells, together with its inhibitory effect on endothelial cell growth, represents an important mechanism to explain homocysteine-induced atherosclerosis.     

Relationship of systolic blood pressure with plasma homocysteine: importance of smoking status

BACKGROUND: Elevated plasma homocysteine is a risk factor for cardiovascular disease. Elevations in plasma homocysteine occur in both smokers and hypertensives, but the combined effect of smoking and hypertension on homocysteine is unknown. METHODS: Resting plasma homocysteine levels and blood pressure were determined in 56 normotensives (12 smokers) and 20 essential hypertensives (10 smokers). RESULTS: Plasma homocysteine was significantly higher in all smokers versus all non-smokers (9.46 +/- 0.5 versus 7.9 +/- 0.5 micromol/l, P = 0.041) by two-way ANOVA, and was also significantly higher in all hypertensives versus all normotensives (9.8 +/- 0.6 versus 7.6 +/- 0.4 micromol/l, P = 0.004). There was no interaction between the effects of hypertension and smoking on plasma homocysteine. Hypertensive smokers had significantly higher plasma homocysteine than either normotensive non-smokers (10.65 +/- 0.84 versus 7.05 +/- 0.26 micromol/l), hypertensive non-smokers (7.88 +/- 0.64 micromol/l) or normotensive smokers (8.36 +/- 0.5 micromol/l). In subjects overall, homocysteine levels were correlated (r = 0.306, P = 0.015) with systolic blood pressure but not with diastolic (r = 0.186). This relationship was also significant in smokers, but not non-smokers. Furthermore, subjects in the highest quintile for plasma homocysteine had significantly higher systolic BP than those in the lowest quintile. This effect was not observed when smokers were removed from the analysis. CONCLUSION: Smoking compounds the modest effect of hypertension on plasma homocysteine. The strong relationship between systolic blood pressure and homocysteine that exists only in smokers suggests that smoking-induced homocysteine elevations may raise systolic blood pressure. We speculate that smoking compounds the risk of cardiovascular disease in hypertensives, in part, by elevating homocysteine.     

Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual?

BACKGROUND: Accumulating data from epidemiological studies suggest that individuals with elevated blood levels of homocysteine have increased risks of cardiovascular disease. We reviewed the currently available evidence of an association between homocysteine and cardiovascular disease and examined whether the strength of the evidence varies according to study design. METHODS: We used a computerized MEDLINE literature search, 1966 through September 1998, to identify all epidemiological studies that examined the relationship of homocysteine level with risks of coronary heart or cerebrovascular disease. Two measures of plasma homocysteine level and its association with risk of cardiovascular disease were extracted: mean homocysteine level in cases and controls, and relative risk of cardiovascular disease for elevated homocysteine level. RESULTS: A total of 43 studies were reviewed. Most crosssectional and case-control studies indicated higher mean homocysteine levels (either fasting or after methionine load) and/or a greater frequency of elevated homocysteine level in persons with cardiovascular disease as compared with persons without cardiovascular disease. Results of most prospective studies, however, indicated smaller or no association. The few prospective studies that reported a positive association between homocysteine level and risks of cardiovascular disease included patients with preexisting vascular disease. CONCLUSIONS: In contrast to cross-sectional and case-control studies, results of prospective studies indicated less or no predictive ability for plasma homocysteine in cardiovascular disease. Instead, elevated homocysteine level may be an acute-phase reactant that is predominantly a marker of atherogenesis, or a consequence of other factors more closely linked to risks of cardiovascular disease. Randomized trials are necessary to test reliably whether lowering homocysteine levels will decrease risks of cardiovascular disease.