叶酸、维生素B6、维生素B12与冠心病的防治

高同型半胱氨酸血症已被证实为冠心病的独立危险因子,但以叶酸为基础的联合维生素B6、B12降低同型半胱氨酸疗法在冠心病防治中作用尚有争论。研究提示该方案可明显降低同型半胱氨酸水平,并可改善血管内皮功能,调节血小板聚集,抗氧化应激所介导的细胞凋亡。但在临床试验中有着不同结论,本综述拟介绍叶酸、维生素B6、B12与同型半胱氨酸的代谢关系及该方案在冠心病防治中作用的研究进展。     

高同型半胱氨酸血症与冠心病

同型半胱氨酸是蛋氨酸和半胱氨酸代谢过程中一个重要的中间产物。研究发现血液中同型半胱氨酸增高，即高同型半胱氨酸血症，能够导致血管内皮损害，促进低密度脂蛋白的氧化、血小板集聚及血管平滑肌细胞增殖，从而促发动脉粥样硬化的发生。人们已经逐渐认识到它是引起心脑血管意外的独立危险因素。近年来，高同型半胱氨酸血症与冠心病，尤其是急性冠状动脉综合征的研究越来越多，然而，结果并非完全一致。遗传和环境两方面的因素共同决定了血浆同型半胱氨酸的水平，补充B族维生素可以降低血浆同型半胱氨酸的水平。     

叶酸、VitB_(12)和VitB_6在冠心病防治中的作用

本文对近年来国内外有关叶酸、Vit B6 、Vit B1 2 在冠心病防治中的作用进行综述 ,其机制主要是通过降低血清同型半胱氨酸的浓度 ,改善了冠心病患者血管内皮功能 ,调节血小板聚集 ,血管张力和血栓形成 ,从而支持了补充 B族维生素能降低心血管疾病危险性的观点     

同型半胱氨酸与动脉粥样硬化的关系

近年来有关研究证实除高血压、高血脂和吸烟等传统因素外,同型半胱氨酸被认为是心血管疾病的独立危险因子,其中遗传和环境因素又影响同型半胱氨酸的代谢。本文浅述同型半胱氨酸与动脉粥样硬化之间的关系,以及叶酸、维生素B6和维生素B12对同型半胱氨酸的干预作用。     

调脂药与叶酸、维生素B12对高脂血症和高同型半胱氨酸血症的疗效比较

为了探讨叶酸、维生素B12 治疗高同型半胱氨酸血症前后以及调脂药治疗高脂血症前后血脂和同型半胱氨酸的变化 ,应用舒降之及 /或力平脂治疗高脂血症 ,应用叶酸、维生素B12 治疗高同型半胱氨酸血症 ,并测定治疗前后同型半胱氨酸和血脂水平。结果发现 ,经调脂药治疗后 ,血脂下降显著 (P <0 .0 5 ) ,同型半胱氨酸下降不显著 (P >0 .0 5 ) ;应用叶酸、维生素B12 治疗后 ,同型半胱氨酸下降显著 (P <0 .0 0 1) ,血脂改变不显著。结果提示 ,调脂药降低血脂浓度 ,但对同型半胱氨酸作用不明显 ;叶酸、维生素B12 降低同型半胱氨酸水平 ,对血脂作用不明显     

血浆同型半胱氨酸水平与帕金森病相关研究

目的探讨血浆同型半胱氨酸（homocysteine,Hcy）水平与帕金森病（Parkinson＇s disease,PD）之间的相关性,观察B族维生素、恩他卡朋治疗左旋多巴诱导的高同型半胱氨酸血症的疗效。方法选择年龄及性别基本匹配的PD病例90例（未治疗的病例15例、非左旋多巴治疗的病例21例、左旋多巴治疗的病例54例）。体检健康老年人90例。检测PD患者、健康老年人的血浆同型半胱氨酸、维生素B12和叶酸水平。将左旋多巴治疗的PD病例采用随机数字表法随机分为3组,分别给予口服安慰剂、B族维生素（维生素B12 1 mg/d、叶酸500 ug/d）和恩他卡朋200 mg/d,检测三组用药前后的血浆Hcy水平。结果各组血浆Hcy水平差异有统计学意义（F=25.580,P=0.001）。PD患者血浆Hcy水平高于健康老年人组（P〈0.05）。左旋多巴治疗PD组血浆Hcy水平高于未治疗PD组和非左旋多巴胺治疗PD组（P〈0.05）。PD组叶酸水平低于健康老年人组（P〈0.05）。维生素B12、叶酸和恩他卡朋均能使左旋多巴治疗的PD患者血浆Hcy水平下降（P〈0.05）。相关分析显示,PD患者血浆Hcy水平与叶酸水平呈负相关（r=-0.425,P=0.000）。结论高同型半胱氨酸血症可能是帕金森病的危险因素之一,并与缺乏B族维生素和使用左旋多巴治疗有一定的联系。B族维生素、恩他卡朋可能降低左旋多巴引起的高同型半胱氨酸血症。     

血浆同型半胱氨酸水平与叶酸、维生素B12水平关系的研究

目的 探讨血浆同型半胱氨酸(Hcy)水平与叶酸、维生素B12水平的关系及口服叶酸对高同型半胱氨酸血症的疗效。方法 对220例中老年人血浆Hcy、叶酸以及维生素B12进行检测分析以探讨它们之间的关系，进而对35例高Hcy血症病人给予口服叶酸治疗观察。结果 高Hcy血症组的血浆叶酸及维生素B12水平显著低于正常组；在血浆叶酸水平低于6μg／L或维生素B12水平低于300ng/L时，高Hcy血症发生率明显高于其它组，口服叶酸可以显著降低血浆Hcy水平。结论 高同型半胱氨酸血症这一心血管危险因素与血浆叶酸和维生素B12水平减低密切相关，提高血浆叶酸和维生素B12水平能减少高同型半胱氨酸血症的发生。     

MTHFR基因多态性及同型半胱氨酸与心血管疾病相关性研究进展

高同型半胱氨酸血症被认为是多种心血管疾病的独立危险因素,其机制可能是通过抑制内皮细胞生长和损伤后内皮修复,诱导内皮功能障碍,促进血管重塑,炎性单核细胞分化等形式损伤血管导致心血管疾病的产生。而亚甲基四氢叶酸还原酶（MTHFR）作为同型半胱氨酸（Hcy）代谢的关键调节酶,可能参与心血管疾病的发生发展。本文通过对MTHFR基因多态性、高同型半胱氨酸血症引起心血管疾病的机制进行综述,并对补充叶酸降低同型半胱氨酸水平防治心血管疾病的进展分析总结。     

B族维生素干预对脑梗死患者血浆同型半胱氨酸、D-二聚体、高敏C-反应蛋白的影响

<正>同型半胱氨酸(Hcy)又名高半胱氨酸,属于硫氨酸的代谢产物,许多临床资料研究证明,Hcy是引发脑血管疾病的重要危险因素,高Hcy血症与脑梗死的发生、发展和预后有密切关系〔1,2〕。2010年,我国在卒中防治指南中均建议对具有高Hcy血症的脑卒中高危人群采用B族维生素进行有效干预〔3〕,但目前关于脑梗死后患者血浆Hcy、D-二聚体、超敏C-反应蛋白(hsCRP)变化及B族维生素干预效果的相关报道仍较少。本文对急性脑梗死患者通过B族维生素干预后的血浆Hcy、D-二聚     

不同剂量叶酸、B族维生素对冠心病患者血浆同型半胱氨酸的影响

目的探讨不同剂量叶酸、B族维生素对冠心病患者血浆同型半胱氨酸(Hcy)水平的影响。方法对90例血浆同型半胱氨酸增高的冠心病患者随机分为A、B、C三组,每组30例,A、B组为治疗组,口服不同剂量的叶酸、B族维生素;C组为对照组,不服用上述药物。治疗前和治疗4周后分别测定血浆同型半胱氨酸的变化。结果A组、B组干预治疗4周后血浆Hcy明显下降,与C组比较P<0.001,A组、B组治疗前后自身比较P<0.001,A、B两组间比较差异无统计学意义(P>0.05)。结论冠心病患者用叶酸、B族维生素干预治疗后,血浆Hcy明显下降。其下降程度与药物剂量无明显关系,小剂量应用可达防治目的,可作为冠心病患者的早期预防药物。     

Hyperhomocysteinemia and endothelial function in young subjects: effects of vitamin supplementation

BACKGROUND: The relationship between hyperhomocysteinemia and cardiovascular disease has not been totally elucidated. HYPOTHESIS: The study aimed to verify the association between hyperhomocysteinemia and endothelial dysfunction before and after modification of total homocysteine (tHcy) serum levels with vitamin supplementation in young male subjects devoid of any other cardiovascular risk factor. METHODS: Twenty hyperhomocysteinemic (tHcy > 15 [micromol/l) male volunteers (< or = 40 years) and 20 age-matched subjects with normal tHcy levels (tHcy < 13 micromol/l) were included. Exclusion criteria were smoking, hypertension, diabetes, vitamin ingestion, obesity, hypercholesterolemia, renal failure, and positive antiphospholipid antibodies. Serum tHcy, folate, vitamin B12 levels, activated protein C and S, protein C resistance, fibrinogen, prothrombin, thrombin, antithrombin III, and in vitro oxidation of low-density lipoprotein (LDL) particles were measured. Noninvasive ultrasound measurements of endothelium-dependent (EDD) and -independent dilatation (EID) of the brachial artery were performed. Each pair was then randomly assigned to receive a vitamin capsule (0.6 mg folic acid, 0.8 mg B12. and 2.0 mg B6) oran identical placebo during 8 weeks, in a double-blind study design. After the treatment phase, blood samples and vascular reactivity were repeated. RESULTS: Nine pairs of volunteers received vitamins and 11 received placebo. Hyperhomocysteinemic subjects had lower baseline serum levels of vitamin B12. Serum folate levels, antithrombotic function, in vitro LDL oxidation, and EDD were similar in all groups. After the vitamin supplementation, serum folic acid levels increased significantly both in normo- and hyperhomocysteinemic subjects, unlike vitamin B12, which increased only in the hyperhomocysteinemic individuals. Plasma tHcy decreased significantly in the supplemented groups. Treatment with vitamins was not associated with improvement in EDD or antithrombotic function. CONCLUSIONS: Mild hyperhomocysteinemia is not associated with endothelial dysfunction in young male subjects with no additional cardiovascular risk factors, and reduction of tHcy by vitamin supplementation does not modify EDD in this age group. In this sample, tHcy was more related to vitamin B12 than to folic acid status.     

Additive effect of homocysteine- and cholesterol-lowering therapy on endothelium-dependent vasodilation in patients with cardiovascular disease

Aim : Endothelial dysfunction is a marker for development and progression of atherosclerosis. Statin therapy improves endothelial function in cardiovascular patients by reducing LDL‐cholesterol and by pleiotropic effects. B‐group vitamin supplementation restores endothelial function mainly by reducing homocysteine‐induced oxidative stress. Thus, we evaluated the effect of rosuvastatin, B‐group vitamins and their combination on endothelial function in high‐risk cardiovascular patients. Methods : Thirty‐six patients with cardiovascular disease were randomly, double‐blinded assigned to either rosuvastatin 10 mg (group R, n = 18) or vitamin supplementation consisting of folic acid 1 mg, vitamin B12 0.4 mg, and B6 10 mg (group V, n = 18) for 6 weeks. After 6 weeks all patients received rosuvastatin and vitamin supplementation in combination for additional 6 weeks. Endothelial function was assessed by flow‐mediated vasodilation (FMD) at baseline and after 6‐ and 12‐week treatment. Results : At baseline, FMD, plasma lipids, vitamins, and homocysteine were comparable between both groups. After 6 weeks, FMD improved in both groups (from 4.4 ± 1.6 to 6.9 ± 1.4% group R, P= 0.0004 and from 4.9 ± 1.8 to 6.4 ± 1.8% group V, P= 0.0002). This improvement in FMD was mainly associated with a decrease of plasma lipids in group R and a decrease of homocysteine in group V. After 12 weeks, the combined therapy with rosuvastatin and vitamins further improved FMD to the normal range in 26/33 patients compared to 5/36 at baseline (P < 0.0001). Conclusions : In conclusion, both treatments, rosuvastatin and B‐group vitamin supplementation, improved endothelial function in high‐risk cardiovascular patients. The combination of both therapies had an additive effect on endothelial function suggesting different mechanisms of action.     

ADMA and hyperhomocysteinemia

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Like many other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). The molecular mechanisms responsible for decreased NO bioavailability in hyperhomocysteinemia are incompletely understood, but emerging evidence suggests that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may be a key mediator. Homocysteine is produced during the synthesis of ADMA and can alter ADMA metabolism by inhibiting dimethylarginine dimethylaminohydrolase (DDAH). Several animal and clinical studies have demonstrated a strong association between plasma total homocysteine, plasma ADMA, and endothelial dysfunction. These observations suggest a model in which elevation of ADMA may be a unifying mechanism for endothelial dysfunction during hyperhomocysteinemia. The recent development of transgenic mice with altered ADMA metabolism should provide further mechanistic insights into the role of ADMA in hyperhomocysteinemia.     

The homocysteine controversy

Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions.     

Chronic mild hyperhomocysteinemia induces aortic endothelial dysfunction but does not elevate arterial pressure in rats

Mild hyperhomocysteinemia is prevalent in the general population and has been linked to endothelial dysfunction and high arterial pressure (AP) in clinical studies. The present study was designed to determine whether a rise in AP was induced by mild hyperhomocysteinemia and whether the potential rise in AP is secondary or prior to endothelial dysfunction. Experiments were performed in a rat model of mild hyperhomocysteinemia induced by oral administration of homocysteine for 1-4 months. Aortic endothelial dysfunction was observed 2 months after homocysteine treatment while endothelium-independent vasodilation was normal. In parallel, homocysteine treatment increased phenylephrine-induced contraction in aortas with endothelium, but did not modify the contraction in aortas without endothelium, suggesting a decrease of basal NO production. In conscious unrestrained rats, AP was not significantly different 1, 2, 3 and 4 months after homocysteine treatment. In correlation, endothelial function of a resistance vessel (mesenteric artery), mainly non-NO nonprostanoid factor mediated, was preserved, indicating that homocysteine treatment only affected the NO pathway. In conclusion, mild hyperhomocysteinemia alone is not sufficient to elevate arterial blood pressure, at least in the rat model. Aortic endothelial dysfunction produced by mild hyperhomocysteinemia is independent of hemodynamic factors.     

Homocysteine lowering and cardiovascular disease risk: lost in translation

Studies of the general population have suggested that high homocysteine levels are associated with cardiovascular morbidity and mortality. In chronic kidney disease, homocysteine levels rise, and cardiovascular risk increases with declining kidney function. While some studies in this population have found an association between elevated homocysteine and cardiovascular risk, others have noted that this association is largely attenuated by adjustment for kidney function, and several studies of patients with kidney failure have found that lower homocysteine levels predict mortality. Homocysteine levels can be lowered with folate, vitamin B6 and vitamin B12. Three large, randomized, controlled trials of patients with pre-existing cardiovascular disease and two smaller, randomized, controlled trials of patients with kidney failure failed to detect any cardiovascular benefit from homocysteine-lowering vitamins. Several more interventional trials are ongoing, but the available data thus far do not support screening for or treatment of hyperhomocysteinemia.     

同型半胱氨酸水平与冠心病的关系

目的观察同型半胱氨酸(Hey)水平与冠心病(CHD)的关系,并探讨蛋氨酸合成酶还原酶(MTRR)A66G基因多态性、叶酸、维生素B12(VitB12)与Hcy水平及CHD的关系。方法 选择190例经冠状动脉造影证实的CHD患者(CHD组)和100例冠状动脉造影正常者为对照组。应用荧光偏振免疫分析法测定Hey水平,离子捕获分析法测定叶酸水平,微粒酶免疫分析法测定VitB12水平。聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法分析MTRRA66G基因多态性。结果 CHD组血Hcy水平显著高于对照组(15.8±8.8)μmol/L与(12.9±6.3)μmol/L,P=0.002。叶酸、VitB12水平与血Hcy水平呈负相关。叶酸、VitB12与CFD无关。MTRR A66G基因多态性GG纯合子、AG杂合子和AA野生型3种基因型组间血Hcy水平差异无显著性意义。(P=0.908)。MTRR A66G各基因型在CHD组和对照组的分布差异无显著性意义(P=0.198)。结论CHD患者血Hcy水平升高,叶酸、VitB12水平与血Hcy水平呈负相关。MTRR A66G基因多态性与血Hcy水平及与CHD均无关。     

Homocysteine. The cardiovascular risk factor of the next millennium?

Several epidemiologic studies have demonstrated that hyperhomocysteinemia is a risk factor for arteriosclerosis in coronary, cerebral, peripheral and aortic arteries. This risk is independent of other cardiovascular risk factors, and it is dose related. However, prospective studies show contradictory findings. Hyperhomocysteinemia is also associated with a higher risk of venous thrombosis to which other coagulation disorders, such as factor V Leiden, could contribute. Hyperhomocysteinemia can be due to genetic defects in the enzymes that control homocysteine metabolism, and also to other factors, mainly nutritional (deficiencies in vitamin B6, vitamin B12, or folic acid). Dietary supplements of these vitamins reduce plasma homocysteine levels. Randomized clinical trials are still needed to demonstrate that reducing plasma homocysteine levels will reduce the risk for cardiovascular disease.