大剂量叶酸对介入治疗后的冠心病患者血管内皮功能的影响

目的探讨大剂量叶酸能否改善冠心病患者介入治疗后的血管内皮功能。方法共46例冠心病患者,在行冠状动脉介入治疗术后分为叶酸治疗(20mg/d)组23例和对照组23例,随访6个月,观察两组间同型半胱氨酸水平,以超声测定肱动脉血流介导的舒张功能(FMD)变化来评价血管内皮功能,并观察两组间的差别。结果大剂量叶酸治疗组血浆同型半胱氨酸水平低于对照组(8·82±3·32μmol/L比12·67±3·07μmol/L,P<0·01)。叶酸治疗后FMD由4·70%±1·71%增加至8·53%±1·44%(P<0·01)。结论大剂量叶酸治疗可能通过降低同型半胱氨酸以外的途径改善血管内皮功能,对介入治疗后的冠心病患者发挥潜在益处。     

叶酸对冠心病患者支架术后血管内皮功能的影响

目的 探讨叶酸能否改善冠心病患者支架术后的血管内皮功能.方法 共184例冠心病患者,在行冠状动脉支架术后,随机分为叶酸治疗（20 mg/d）92例和对照组92例.随访6个月,观察两组同型半胱氨酸水平.以超声测定肱动脉血流介导的舒张功能（FMD）变化来评价血管内皮功能,并观察两组间的差别.结果 叶酸治疗组血浆同型半胱氨酸水平低于对照组[（8.83±3.33）μmol/L比（13.18±5.08）μmol/L,P＜0.01].叶酸治疗后,FMD由（4.72±1.73）%增加至（8.54±1.45）%,P＜0.01.结论 叶酸治疗可能通过降低同型半胱氨酸以外的途径改善血管内皮功能,对介入治疗后的冠心病患者发挥潜在益处.     

Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease

OBJECTIVES: We evaluated the effect of therapy with folic acid and cobalamin on coronary endothelial function, expressed as a change in volumetric coronary blood flow (CBF), in hyperhomocysteinemic patients with coronary artery disease (CAD). BACKGROUND: Hyperhomocysteinemia is an independent risk factor for CAD. The mechanism responsible for this increased risk is unclear, but it is generally assumed that hyperhomocysteinemia causes endothelial dysfunction. It is unknown whether lowering plasma homocysteine levels with folic acid and cobalamin improves coronary endothelial function in patients with hyperhomocysteinemia and symptomatic CAD. METHODS: Fifteen patients scheduled for elective percutaneous transluminal coronary angioplasty (PTCA) with plasma homocysteine levels of >or=16 micromol/l were randomized for six months of treatment with folic acid 5 mg and cobalamin 400 microg daily or placebo. Coronary endothelial function was evaluated in a non-PTCA vessel using acetylcholine infusion in dosages of 10(-8) M, 10(-7) M, and 10(-6) M. Endothelium- dependent CBF is determined using intracoronary Doppler velocity and quantitative coronary angiography at baseline and after six months. RESULTS: In the folic acid/cobalamin treated group, CBF increased after acetylcholine infusion with 96% (standard deviation 54; 95% confidence interval [CI]: 44% to 154%) compared with a decrease of 16% (standard deviation 35; 95% CI: -20% to +30%) of the CBF in the placebo-treated group (p < 0.005). CONCLUSIONS: This is the first prospective randomized placebo-controlled intervention study evaluating coronary endothelial function in hyperhomocysteinemic patients with CAD. Our results suggest that coronary endothelial function improves after treatment with folic acid and cobalamin.     

High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease

OBJECTIVES: We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans. BACKGROUND: Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known. METHODS: Fourteen patients with ischemic heart disease, age 62 +/- 12 years (mean +/- SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as "normal" versus "abnormal" on the basis of MBF response to adenosine 140 microg/kg/min (normal = MBF >1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis. RESULTS: Folate was associated with a reduction in mean arterial pressure (100 +/- 12 mm Hg vs. 96 +/- 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 +/- 0.59 ml/min/g vs. 2.16 +/- 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 +/- 0.59 vs. ml/min/g 1.41 +/- 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 +/- 0.61 ml/min/g vs. 2.12 +/- 0.69 ml/min/g, placebo vs. folate, p = NS). CONCLUSIONS: The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.     

Testosterone and coronary vascular tone: implications in coronary artery disease

The greater incidence of coronary artery disease in men compared to women has often suggested possible harmful effects of male sex steroids that could promote coronary atherogenesis and vasoconstriction. However, antiatherogenic and coronary vasodilator effects of testosterone have also been suggested. The interaction of testosterone (T) with its specific receptors may trigger not only long-term genomic effects, but also acute non-genomic vasodilator responses. Testosterone may activate the endothelium and stimulate the nitric oxide-cGMP and/or the hyperpolarization-mediated vascular relaxation pathway. T may also inhibit the signaling mechanisms of smooth muscle contraction such as [Ca2+]i and protein kinases. The T-induced stimulation of endothelium-dependent mechanisms of vascular relaxation and inhibition of the mechanisms of coronary smooth muscle contraction represent potential beneficial effects of T against coronary artery disease.     

Effects of folic acid and N-acetylcysteine on plasma homocysteine levels and endothelial function in patients with coronary artery disease

OBJECTIVE: Hyperhomocysteinaemia is related with premature coronary artery disease and adverse cardiac events in patients with coronary artery disease (CAD). It is assumed that hyper-homocysteinaemia causes endothelial dysfunction. In this study, the effect of folic acid and oral N-acetylcysteine (NAC) therapies on plasma homocysteine levels and endothelial function were evaluated in hyperhomocysteinaemic patients with CAD. METHODS AND RESULTS: 60 patients were randomized to either folic acid 5 mg or NAC 600 mg or placebo daily for eight weeks. Brachial artery endothelial functions were studied by using high-resolution ultrasound and assessed by measuring endothelium-dependent dilation (EDD) and endothelium-independent dilation (NEDD). Folic acid and NAC therapies decreased plasma homocysteine (from 21.7 +/- 8.7 micromol/l to 12.5 +/- 2.5 micromol/l, P < 0.001; from 20.9 +/- 7.6 micromol/l to 15.6 +/- 4.3 micromol/l, P = 0.03, respectively), and increased EDD (6.7 +/- 6.1% P = 0.002, 4.4 +/- 2.6% P < 0.001, respectively) compared with placebo. There was no significant difference in improving EDD between the folic acid and the NAC group (6.7 +/- 6.1%, 4.4 +/- 2.6%, P = 0. 168). In the univariate analyses there was an inverse correlation between the post-treatment homocysteine level and the percent change in EDD with folic acid therapy (r= -0.490, P = 0.028), but there was no correlation with the NAC therapy (r = 0.259, P = 0.333) CONCLUSION: In patients with hyperhomocysteinaemic CAD, folic acid and NAC lowered plasma homocysteine levels and improved endothelial function.The effects of both treatments in improvement of EDD were similar.     

A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease

OBJECTIVES: This study was designed to determine the effects of folic acid therapy on endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Hyperhomocysteinemia, a risk factor for CAD, may cause atherosderosis by oxidative endothelial injury. Folic acid reduces plasma homocysteine, but the effect on adverse vascular events is unknown. METHODS: In a double-blind placebo-controlled trial, 90 patients (mean age [range] 63 [46 to 79] years, 79 men) with CAD were randomized to either folic acid 5 mg or placebo daily for 12 weeks. Endothelial function was assessed by measuring: 1) flow-mediated endothelium-dependent dilation (EDD) of the brachial artery; 2) combined serum nitrite/nitrate (NOx) concentrations and; 3) plasma von Willebrand factor (vWF) concentration. RESULTS: At the end of the study, plasma homocysteine was lower in the folic acid group compared with the placebo group (mean [95% confidence interval] 9.3 (8.5 to 10.1) vs. 12.3 [11.3 to 13.4] micromol/l, p < 0.001). Although there were no significant differences in EDD, serum NOx or plasma vWF between the two groups, there was a greater increase in EDD from baseline in the folic acid group compared to placebo (1.2 [0.7 to 1.8] vs. 0.4 [-0.3 to 1.1]%, p = 0.07). CONCLUSIONS: Folic acid reduced plasma homocysteine and was associated with a trend toward improved endothelial function in patients with CAD. The absence of an unequivocally positive result may have been due to inadequate sample size or chance. This reinforces the need for the results of large randomized controlled trials before the implementation of routine folic acid supplementation.     

依那普利叶酸片对冠心病患者血管内皮功能保护的作用机制

目的探讨依那普利叶酸片对冠状动脉粥样硬化性心脏病(冠心病)血管内皮功能保护的作用机制。方法Wistar大鼠给予高脂、高蛋氨酸饲料建立冠心病模型。造模成功后随机分为4组,分为模型对照组,依那普利叶酸片小剂量(5.4 mg/kg·d)、中剂量(10.8 mg/kg·d)组和高剂量(16.2 mg/kg·d)组,每组各10只,另取10只大鼠为正常对照组。治疗8周后,麻醉大鼠,取腹腔静脉血检测血清同型半胱氨酸(Hcy)。分离大鼠胸主动脉,分别测定血管内膜增生情况、血管内皮功能指标一氧化氮(NO)、一氧化氮合酶(NOS)、内皮素-1(ET-1)和非对称二甲基精氨酸(ADMA)及NOX4 mRNA和蛋白表达。结果①依那普利叶酸中剂量组大鼠血管NO和NOS较依那普利叶酸小剂量组显著增加(P<0.05),ET-1和ADMA较正常对照组显著增加(P<0.05);依那普利叶酸大剂量组大鼠血管NO和NOS较依那普利叶酸中剂量组显著增加(P<0.05),ET-1和ADMA较依那普利叶酸中剂量组显著增加(P<0.05)。②依那普利叶酸小剂量组血清Hcy较模型对照组显著减少(P<0.05),依那普利叶酸中剂量组大鼠血清Hcy和血管内膜厚度较依那普利叶酸小剂量组显著减少(P<0.05),依那普利叶酸大剂量组大鼠血清Hcy和血管内膜厚度较依那普利叶酸中剂量组显著增加(P<0.05)。③依那普利叶酸中剂量组大鼠血管NOX4 mRNA和蛋白的表达较依那普利叶酸小剂量组显著减少(P<0.05),依那普利叶酸大剂量组大鼠血管NOX4 mRNA和蛋白的表达较依那普利叶酸中剂量组显著减少(P<0.05)。结论依那普利叶酸片可显著抑制冠心病大鼠血管内膜增厚,改善血管内皮功能,该作用可能与其降低血清Hcy水平及抑制血管内皮NOX4基因介导NOX4信号通路有关。     

Homocysteine, folic acid and coronary artery disease: possible impact on prognosis and therapy

Within the past four decades, the efforts of investigators worldwide have established the amino acid homocysteine (Hcy) as an important factor in arteriosclerosis and ageing. The amino acid homocysteine is a unique candidate for the study of different age-related pathological conditions, namely vascular diseases, dementia disorders and late-life depression, due to its multiple roles in different pathways leading to atherosclerosis and neurotoxicity. Especially, the role of homocysteine in predicting risk for atherothrombotic vascular disease has been evaluated in several observational studies in a large number of patients. These studies show that the overall risk for vascular disease is small, with prospective, longitudinal studies reporting a weaker association between homocysteine and atherothrombotic vascular disease compared to retrospective case-control and cross-sectional studies. Furthermore, randomised controlled trials of homocysteine-lowering therapy have failed to prove a causal relationship. On the basis of these results, there is currently insufficient evidence to recommend routine screening and treatment of elevated homocysteine concentrations with folic acid and other vitamins to prevent atherothrombotic vascular disease.     

Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

OBJECTIVES: The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD). BACKGROUND: Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress. METHODS: In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level > or =9 micromol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment. RESULTS: Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 +/- 3.6% to 5.2 +/- 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 +/- 2.4% to 4.0 +/- 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group. CONCLUSIONS: Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.     

Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12

An increased plasma homocysteine concentration is a risk factor for atherosclerosis. Folic acid lowers homocysteine but the optimal dose in patients with coronary artery disease (CAD) is unclear. This placebo-controlled, single-blind, dose-ranging study evaluates the effect of low-dose folic acid on homocysteine levels in 95 patients aged 61 +/- 11 years (mean +/- SD) with documented CAD. Patients in each group were given either placebo or 1 of 3 daily supplements of folic acid (400 microg, 1 mg, or 5 mg) for 3 months. Each active treatment arm also received 500 microg vitamin B12 and 12.5 mg vitamin B6. Total plasma homocysteine levels were measured after 30 and 90 days. Folic acid 400 microg reduced homocysteine levels from 13.8 +/- 8.8 to 9.6 +/- 2.0 micromol/L at 90 days (p = 0.001). On 1- and 5-mg folic acid, levels decreased from 13.0 +/- 6.4 to 9.8 +/- 4.0 micromol/L (p = 0.001) and from 14.8 +/- 6.9 to 9.7 +/- 3.3 micromol/L (p < 0.001), respectively. The decrease was similar in all treatment groups. There was no significant change with placebo. Although the sample size is small, these findings suggest that daily administration of 400 microg/day folic acid combined with vitamin B12 and vitamin B6 may be equivalent to higher doses in reducing homocysteine levels in patients with CAD.     

老年冠心病患者血管内皮功能与动脉粥样硬化的关系

目的 观察老年冠心病(CAD)患者血管内皮舒张功能、动脉硬化的状况及与冠状动脉病变的相关性.方法 选择经冠状动脉造影确诊为CAD的患者90例(CAD组),冠状动脉造影证实无冠状动脉狭窄并无其他疾病史的患者30例为对照组,采用二维超声检测肱动脉内皮依赖性和非依赖性舒张功能及动脉内膜的变化,应用二维彩色多普勒超声检查颈动脉、股动脉,观察管腔、管径、内膜及有无斑块、血流变化、血流频谱形态及性质.动脉粥样硬化斑块积分采用Crouse法.对血管内皮细胞功能、动脉硬化与冠状动脉病变程度进行分析.结果 反应性充血引起的肱动脉内径变化在单支组及多支组明显减弱[(9.08±2.28)%、(6.14±2.21)%],与对照组[(15.58±2.20)%]比较,差异有统计学意义(P<0.01).CAD组颈动脉内膜中层厚度(IMT)高于对照组(P<0.05).结论 内皮细胞功能障碍和动脉粥样硬化与冠状动脉粥样硬化的病变密切相关.     

Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease

Mitochondria produce reactive oxygen species that may contribute to vascular dysfunction. alpha-Lipoic acid and acetyl-L-carnitine reduce oxidative stress and improve mitochondrial function. In a double-blind crossover study, the authors examined the effects of combined alpha-lipoic acid/acetyl-L-carnitine treatment and placebo (8 weeks per treatment) on vasodilator function and blood pressure in 36 subjects with coronary artery disease. Active treatment increased brachial artery diameter by 2.3% (P=.008), consistent with reduced arterial tone. Active treatment tended to decrease systolic blood pressure for the whole group (P=.07) and had a significant effect in the subgroup with blood pressure above the median (151+/-20 to 142+/-18 mm Hg; P=.03) and in the subgroup with the metabolic syndrome (139+/-21 to 130+/-18 mm Hg; P=.03). Thus, mitochondrial dysfunction may contribute to the regulation of blood pressure and vascular tone. Further studies are needed to confirm these findings and determine the clinical utility of alpha-lipoic acid/acetyl-L-carnitine as antihypertensive therapy.     

The influence of low-dose atorvastatin on lipid levels and endothelial vascular function in patients with significant coronary artery stenosis

BACKGROUND: Hyperlipidaemia is a well-established risk factor of the progression of coronary artery disease (CAD). Statins such as atorvastatin, as lipid-lowering agents, can not only normalise serum lipid levels, but also may improve endothelial function, reduce vascular inflammation and enhance plaque stability. AIM: To evaluate the efficacy of a low-dose atorvastatin regimen (10 mg daily) in patients with CAD. METHODS: Seventy-nine patients with stable angina of II or III functional class and angiographically significant stenosis of coronary arteries (>70%) entered a 12-week treatment period with atorvastatin 10 mg/day. Lipid profile, which included total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were assessed at baseline and after treatment at week 12. In addition, flow-mediated vasodilatation (FMD) and nitrate-induced dilation (NID) of the brachial artery were measured before and after treatment. RESULTS: Among 79 patients included in the study, in 54 (68%) the target TC value <5.0 mmol/l, and in 51 (65%) the LDL-C level <3.0 mmol/l were achieved. Atorvastatin decreased TC level by 31% (p<0.01), LDL-C level by 35% (p<0.01), TG level by 23% (p<0.01) and increased HDL-C level by 8% (p<0.01). FMD was increased by 61 % (p<0.01) and normalised in 88% of patients after 3-month therapy of atorvastatin. NID was increased by 16% (p<0.05). CONCLUSION: Low-dose treatment with atorvastatin (10 mg daily) is effective in reducing blood lipids and is associated with the improvement of endothelial function in patients with CAD.