Early statin therapy restores endothelial function in children with familial hypercholesterolemia

OBJECTIVES: This study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH). BACKGROUND: Endothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD. METHODS: The study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment. RESULTS: At baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% +/- 4.3% vs. 1.2% +/- 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (-2.16 +/- 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (-2.13 +/- 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = -0.31, p < 0.05) and LDL-C (r = -0.31, p < 0.05). CONCLUSIONS: Our data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible.     

Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study

High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean+/-S.D.) N: +3.25+/-3.88%, C: +1.03+/-2.71% in low tertile HDL-C 相似文献   

停用辛伐他汀对冠心病及冠心病危险因素患者血管内皮功能的影响

目的 观察在冠心病及冠心病危险因素患者中,停用辛伐他汀治疗对血管内皮功能的影响,并探讨相应作用机制。方法 入选33例血清胆固醇（Tc）水平未达标的冠心病及冠心病危险因素患者,分别于基线水平、停药前（即辛伐他汀20mg治疗4周后）及停用辛伐他汀1周时,采用高分辨超声技术检测肱动脉血流介导性扩张（FMD）评估血管内皮依赖性舒张功能,并测定一氧化氮（NO）、血浆内皮素（ET）、6-酮-前列腺素F1α（6-keto-PGF1α）和血栓素B2（TXB2）的水平及主要血脂参数的变化。结果 辛伐他汀治疗4周后可有效降低冠心病及冠心病危险因素患者TC、低密度脂蛋白胆固醇（LDL-C）水平,并明显改善患者肱动脉内皮依赖性舒张功能（FMD）。然而,停用辛伐他汀治疗1周后,所有患者肱动脉内皮依赖性舒张功能均较停药前明显下降（4．82士0．71）％与11．51±0．87％,P〈0．01）,甚至低于未服用辛伐他汀时的基线水平（4．82±0．71％与5．89±0．65％,P〈0．01）,其中冠心病患者停药后FMD下降幅度较仅有冠心病危险因素患者更显著（65．6％与56．3％,P〈0．01）。停药1周后,患者血清NO水平较停药前及基础值均明显降低,而血浆ET水平升高。血浆TXB,水平在停药前后无明显变化。此外,停药后患者血清LDL-C水平虽较治疗4周时有所升高,但仍未恢复至基线水平。停药后肱动脉FMD的变化仅与血清NO降低幅度呈正相关关系（r=0．674。P=0．004）,而与血清LDL-C水平变化无明显相关性（r=-0．414,P=0．083）。结论 在TC水平未达标的冠心病及冠心病危险因素患者中突然终止辛伐他汀治疗可在1周内完全逆转该药对血管内皮功能的改善作用,甚至还可能导致血管内皮功能进一步恶化。并且这种撤药反应随基础疾病的严重性增加。停药所致血管内皮功能损害可能与血管内皮源性的NO减少有关,是非胆固醇依赖性作用。     

The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes

We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk, prospective, randomized, placebo-controlled, double-blind clinical trial. The flow- mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (endothelium independent) in the brachial artery and the vascular reactivity at the forearm skin were measured. FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05]. A similar improvement of FMD was found in atorvastatin-treated diabetic patients [median (25-75 percentile), 5.6 (3.9-7.9) at exit visit vs. 4.2 (3.2-7.2) at baseline; P = 0.07]. No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group. In the at-risk group, there was a decrease in the C-reactive protein [median (25-75 percentile), 0.12 mg/dl (0.07-0.27 mg/dl) at exit visit vs. 0.24 mg/dl (0.07-0.35 mg/dl) at baseline; P < 0.05] and TNF alpha [median (25-75 percentile), 2.6 pg/ml (1.8-4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6-6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean +/- SD, 0.97 +/- 0.29 pg/ml at exit visit vs. 1.19 +/- 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25-75 percentile), 18 ng/ml (9-24 ng/ml) at exit visit vs. 27 ng/ml (7-41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation.     

Time course differences for statin-induced pleiotropic effects in hypercholesterolemic patients

BACKGROUND: It is unclear whether there are temporal differences for the pleiotropic effects for different members of the statin class. The present study investigated differences in the short- and intermediate-term pleiotropic effects of statins in hypercholesterolemic patients. METHODS: Thirty-five hypercholesterolemic patients were randomly treated with either atorvastatin or cerivastatin for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) at baseline and after 2 weeks and 3 months of therapy. RESULTS: After 2 weeks of therapy, atorvastatin decreased the low density lipoprotein (LDL) cholesterol, small, dense LDL cholesterol (34+/-22 vs. 18+/-20%, P<0.01), remnant-like particles (RLP) cholesterol (8.8+/-6.0 vs. 5.1+/-2.6 mg/ml, P<0.01), and TBARS (3.3+/-1.0 vs. 3.1+/-0.9 nmol/ml, P<0.05), and cerivastatin decreased LDL cholesterol. After 3 months of therapy, atorvastatin decreased small dense LDL cholesterol (8+/-13%, P<0.0001) additionally, and cerivastatin decreased small, dense LDL cholesterol (51+/-11 vs. 12+/-22%, P<0.0001) and plasminogen activator inhibitor type 1 (68+/-32 vs. 51+/-21 ng/ml, P<0.05). FMD increased significantly in both groups after 2 weeks, although the relative change in FMD was greater with cerivastatin therapy after 2 weeks than atorvastatin therapy (60+/-78 vs. 23+/-26%, P<0.05). However, FMD was the same for both groups after 3 months (58+/-65 vs. 66+/-61%, NS), because atorvastatin additionally increased FMD. There was no correlation between these pleiotropic effects and the improvement in the lipid profile for either group. CONCLUSIONS: These findings suggest that the degree of pleiotropic effect as well as the time course for the effect are different among members of the statin class of drugs.     

停用辛伐他汀对健康男性肱动脉内皮功能的影响

目的 观察停用辛伐他汀对Tc水平正常健康男性肱动脉内皮功能的影响.方法 16例健康青年男性服用20mg辛伐他汀4周后停药,分别检测停药前后不同时间点肱动脉内皮依赖性舒张功能(FMD),并测定血管活性物质--NO、血浆内皮素和6-酮-前列腺素F1α(6-keto-PGF1α)以及血脂参数的变化.结果 健康男性服用辛伐他汀4周后,在停药第1天观察到FMD较停药前明显降低,甚至低于未服药时的基线水平(P＜0.05).停药后血清NO水平较停药前和基础值亦明显降低,其变化与FMD的变化一致.停药后血浆内皮素水平升高,6-keto-PGF1α水平降低.血清LDL-C在停药后最初2d内无明显改变,其变化与FMD无明显相关.结论 健康男性服用辛伐他汀后突然停药,不仅使该药对肱动脉内皮功能的改善作用迅速消失,而且还对血管内皮功能造成进一步损害,该不良影响可能与循环中NO水平降低有关,是非TC依赖性的.     

Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor,of patients with heterozygous familial hypercholesterolemia

The clinical efficacy and safety of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor, during long-term treatment, were examined in 25 patients (male/female=11/14, mean age=53+/-13 (mean+/-SD) years) with heterozygous familial hypercholesterolemia (FH). After a period on placebo of >4 weeks, 2 mg/day of pitavastatin was administered for 8 weeks, and the dose was increased to 4 mg/day for up to 104 weeks. Total cholesterol (TC) decreased by 31% from the initial value of 340+/-57 to 237+/-40 mg/dl (P<0.0001) at week 8. During treatment with the higher dose, TC decreased even further to 212+/-35 mg/dl at week 12; it decreased by 37% from the initial value (P<0.0001). Similarly, the baseline low-density lipoprotein (LDL)-cholesterol (LDL-C) decreased by 41% at week 8, and by 49% at week 12, from 267+/-61 mg/dl at baseline. These findings indicate a dose-dependent effect of the drug on TC and LDL-C concentrations. To examine whether the levels of circulating matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases: TIMPs) are altered during lipid-lowering therapy, we also measured their plasma levels. The mean levels of MMP-2 and -3 were significantly increased. No significant alteration was found in MMP-9, TIMP-1 and -2 levels. As for the safety of pitavastatin, adverse reactions were observed in one case (4%) of subjective and objective symptoms. The effects of pitavastatin on TC and LDL-C were stable during long treatment of patients with heterozygous FH.     

阿德福韦酯治疗e抗原阳性慢性乙型肝炎的疗效预测指标探讨

目的 评价HBeAg阳性慢性乙型肝炎患者治疗前ALT、HBeAg、HBV DNA水平以及治疗12周时HBV抑制程度对阿德福韦酯(ADV)治疗52周患者疗效的预测价值.方法 98例HBeAg阳性成年慢性乙型肝炎患者进入研究.筛选时血浆HBV DNA定量≥1×106拷贝/ml,血清ALT水平1.5～10倍正常值上限(ULN).患者接受ADV 10mg/d,共52周治疗.定期随访,检测血清HBV标志物及HBV DNA.比较不同基线ALT、HBeAg、HBV DNA水平以及治疗12周时不同血清HBV DNA水平患者治疗52周时的疗效差异. 结果 ADV治疗52周时,血清HBV DNA＜103拷贝/ml的患者,基线ALT＞5 × ULN者(72.7%)高于ALT＜2×ULN者(38.0%),P＜0.05;基线HBeAg≤350 s/co者(66.7%)高于HBeAg＞350 s/co者(30.2%),P＜0.01;基线HBV DNA≤108拷贝/ml者(53.0%)高于血清HBV DNA＞108拷贝/ml者(34.4%),P＜0.05.52周HBeAg血清学转换率在基线HBeAg水平≤350 s/co者和HBeAg＞350 s/co者分别为42.2%和7.5%(P＜0.01).治疗12周时血清HBV DNA＜103拷贝/ml、103～105拷贝/ml和＞105拷贝/ml组患者,52周时血清HBV DNA＜103拷贝/ml的比例分别为82.6%、57.1%和17.5%,组间差异均有统计学意义(P值均＜0.05);3组患者HBeAg血清学转换率分别为52.2%、25.7%和5.0%,组间差异均有统计学意义(P值均＜0.05);3组患者52周ALT复常率分别为100%、83%和75%,血清HBV DNA＜103拷贝/ml组高于＞105拷贝/ml组(P＜0.05).相关分析显示,治疗52周时的血清HBV DNA水平及HBeAg血清转换与治疗12周时血清HBV DNA水平中度相关(P＜0.01).结论 HBeAg阳性慢性乙型肝炎患者ADV治疗12周时血清HBV DNA水平对治疗52周的疗效的预测价值优于基线指标,治疗12周时血清HBV DNA＜103拷贝/ml者,52周时能达到更佳的疗效.     

Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy

OBJECTIVE: The endothelium is a newly recognised target tissue of parathyroid hormone (PTH). It is not clear whether hyperparathyroidism affects endothelial function and whether parathyroidectomy (Ptx) has an influence on arterial vessel wall properties. We studied brachial flow-mediated vasodilation (FMD) and brachial and carotid intima-media thickness (IMT) in patients with primary hyperparathyroidism (pHPT) before and after Ptx and in healthy controls. METHODS: 19 patients with pHPT (mean+SEM, age 45+/-4.7 years, PTH 238+/-52 ng/l) were studied. Diabetes, hypertension and vascular disease were excluded. Twenty healthy volunteers matched for age, sex and blood pressure served as controls. Enddiastolic diameter, FMD and nitroglycerine-induced (NMD) dilation of the brachial artery were measured by a multigate pulsed doppler system (echo-tracking), IMT was determined using automatic analysis of the M-line signal. Healthy volunteers where studied on one occasion, patients were studied at baseline and 6 months after Ptx. RESULTS: Six months after Ptx PTH had decreased to normal, blood pressure levels remained unchanged. Endothelium dependent FMD at baseline was impaired in patients compared to controls (4.7+/-1.2 vs. 18.2+/-3.7%, P<0.01), however, FMD improved significantly after Ptx (16.7+/-3.0%, P<0.01). Nitroglycerine-induced dilation, IMT and artery diameter were not different between groups and did not change after Ptx. CONCLUSIONS: Impaired endothelium dependent vasodilation in patients with primary hyperparathyroidism improves after successful parathyroidectomy. Endothelial dysfunction associated with primary hyperparathyroidism occurs without detectable structural wall alterations of the brachial artery and appears therefore to be an early and reversible arterial alteration.     

Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus.

AIMS: Arterial endothelial dysfunction is a key early event in atherogenesis, and occurs in asymptomatic adults with Type 1 diabetes mellitus (DM). As angiotensin converting enzyme (ACE) inhibitors have been reported to reverse microvascular endothelial dysfunction acutely, we assessed the longer term effect of ACE inhibition on large vessel endothelial physiology in a randomized, crossover double-blind controlled clinical trial. METHODS: Flow-mediated arterial dilatation (FMD), which is largely due to endothelial release of nitric oxide, was assessed by vascular ultrasound in 20 Type 1 DM subjects with known endothelial dysfunction. These subjects, aged 28+/-5 years, were studied before and after 12 weeks oral therapy with either the ACE inhibitor perindopril 4 mg daily or the diuretic hydrene (triamterene 50 mg with hydrochlorothiazide 25 mg) daily. RESULTS: Although perindopril lowered both systolic and diastolic blood pressure by 2.7/3.2 mmHg, respectively (F3,78 = 4.7, P= 0.006; F3,78 = 3.2, P = 0.03), there was no significant effect of either perindopril or hydrene on FMD (baseline FMD before perindopril 4.6+/-2.5%, after 4.1+/-3.4%, baseline FMD before hydrene 5.4+/-3.6%, after 6.0+/-3.3%; F3,78= 1.9, P=0.1). Glycaemic control deteriorated slightly on hydrene whilst lipid levels, heart rate, resting blood flow and the arterial responses to nitroglycerine, a smooth muscle dilator, were unaffected by the treatment given. CONCLUSION: ACE inhibitor therapy for 3 months did not improve arterial endothelial function in Type 1 DM subjects.     

Effects of atorvastatin therapy on the low-density lipoprotein subfraction, remnant-like particles cholesterol, and oxidized low-density lipoprotein within 2 weeks in hypercholesterolemic patients.

The short- and intermediate-term pleiotropic effects of atorvastatin were investigated in 18 hypercholesterolemic patients, as well as the temporal differences in these pleiotropic effects. Atorvastatin was given for 3 months and fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) were measured at baseline and after 2 weeks and 3 months of therapy. Atorvastatin reduced the total cholesterol (273+/-34 vs 188+/-31 mg/dl, p<0.0001), low-density lipoprotein-cholesterol (LDL-C: 174+/-28 vs 111+/-23 mg/dl, p<0.0001), small, dense LDL-C (34+/-22 vs 18+/-20%, p<0.01), remnant-like particles cholesterol (RLP-C: 8.8+/-6.0 vs 5.1+/-2.6 mg/ml, p<0.01), and TBARS (3.3+/-1.0 vs 3.1+/-0.9 nmol/ml, p<0.05) after 2 weeks. Atorvastatin decreased the concentration of small, dense LDL-C again after 3 months (8+/-13%, p<0.0001). The plasma concentrations of the fibrinolytic parameters did not change significantly after 3 months of atorvastatin therapy. FMD increased significantly after 2 weeks (5.6+/-2.1 vs 6.3+/-2.0%, p<0.01) and additionally increased after 3 months of therapy (8.3+/-1.9%, p<0.0001). There were no correlations between the pleiotropic effects and the improvement in the lipid profile. The results indicate some short-term pleiotropic effects of atorvastatin therapy within 2 weeks, which may be important with respect to the early benefits of statin therapy.     

Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: a dose-response effect dependent on endothelial nitric oxide synthase

BACKGROUND: Patients with coronary artery disease (CAD) have impaired endothelial function. Simvastatin therapy has been demonstrated to significantly improve endothelial function in these patients. Although withdrawal of statins is a frequent problem in clinical practice, the effects after discontinuation of statins treatment on endothelial function in patients with CAD are largely unknown. OBJECTIVE: This study investigated the effects after withdrawal of simvastatin on brachial artery endothelial function in patients with CAD and the underlying mechanisms. METHODS: We recruited 30 patients with established CAD. They were treated with 20 mg simvastatin for 4 weeks. Endothelial dependent flow-mediated vasodilation (FMD) was assessed in the brachial artery using high-resolution ultrasound at baseline, 4 weeks during simvastatin treatment, and 1 week after termination of therapy. 20 healthy subjects were also studied as a control group. Furthermore, we investigated underlying mechanisms on human umbilical vein endothelial cells (HUVECs) confluent monolayers at passages 2-3. HUVECs were exposed to simvastatin. After 24 h cells were repeatedly washed to remove the drugs, and the conditioned mediums were collected at the indicated time points. The nitric oxide (NO) production and levels of eNOS mRNA after 24 h of withdrawal of statins were examined. RESULTS: (1) Abrupt discontinuation of simvastatin treatment leads to a rebound of serum total cholesterol (21.3%) and LDL cholesterol (18.2%) in patients within 1 week, but they were still lower than the baseline values (P<0.05 for each parameter). (2) A significant decreased of FMD (-59.3%) was observed in patients after discontinuation of simvastatin in 1 week, and furthermore, the FMD was even lower than the baseline levels (4.6% vs. 5.6%, P<0.05). The reduction of FMD was not correlated with the change of LDL cholesterol (r=-0.343, P=0.081). In contrast to the unchanged LDL cholesterol level, abrupt discontinuation of therapy caused a rapid and significant decrease in FMD from 10.6% to 5.2% in healthy subjects at day 1, but it returned to baseline levels within 1 week. (3) In HUVECs, a maximum decrease of nitrite levels (-80%) was observed at 6 h after stopping simvastatin treatment, which was below the control levels. 24 h after stopping 10(-5) mmol/L and 10(-6) mmol/L simvastatin treatment, eNOS mRNA expression decreased to -71% and -42% (P<0.05), respectively. CONCLUSIONS: Abrupt withdrawal of simvastatin treatment not only acutely and completely abrogates its beneficial effects on endothelial function in patients with CAD, but also induced further vascular injury compared with pretreatment status, independent of cholesterol levels. The underlying mechanism of these negative effects may be related to the suppression of endothelial NO production, which are dose-dependent.     

Effects of simvastatin treatment on sICAM-1 and sE-selectin levels in hypercholesterolemic subjects

This study was performed to determine whether the levels of soluble intercellular adhesion molecule-1 (sICAM-l) and soluble endothelial molecule-1 (sE-selectin) were elevated in subjects with hypercholesterolemia who presented with no other risk factors or evidence of atherosclerosis. The effects of administration of an HMG-CoA reductase inhibitor on the serum levels of these molecules were also examined. Forty hypercholesterolemic subjects (HCh) (19 males and 21 females), without hypertension or cardiovascular disease, received placebo for 4 weeks. The patients were then randomized in two groups; 20 of them (simvastatin group) were treated with simvastatin (20 mg/day) and the other 20 (placebo group) continued placebo administration. After 12 and 24 weeks of either simvastatin or placebo treatment, sICAM-1 and sE-selectin levels were measured. The same parameters were measured in 20 control subjects (C) with normal cholesterol levels, matched for sex and age. HCh had sICAM-1 basal values higher than C (352.4+/-57.9 ng/ml versus 114.9+/-89.6 ng/ml; P<0.001); however, sE-selectin basal values were not different in the two groups. No correlation was observed between HCh sICAM-1 levels and cholesterol levels (total and low-density lipoprotein). Furthermore, cholesterol-lowering treatment with simvastatin did not significantly diminish sICAM-1 levels. Our findings would support the hypothesis that patients with isolated hypercholesterolemia and without clinical atherosclerosis may be silent carriers of arterial subendothelial inflammation, expressed as an increase of sICAM-1.     

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.     

Correlation of flow mediated dilation with inflammatory markers in patients with impaired cardiac function. Beneficial effects of inhibition of ACE

Impaired cardiac function is frequently accompanied by peripheral vascular dysfunction and a pro-inflammatory condition, which may be associated with elevated levels of angiotensin II. We hypothesized that the magnitude of flow mediated dilatation (FMD) of the brachial artery of post myocardial infarction patients will correlate with serum levels of tumor necrosis factor alpha (TNFalpha) and C-reactive protein (CRP), and that treatment with angiotensin converting enzyme inhibitors (ACEI) will increase FMD by reducing TNFalpha and CRP. Patients were treated with low dose (10 mg/day) quinapril (Q) or enalapril (E) and their effects on FMD and inflammatory markers were evaluated after 8 and 12 weeks. Before treatment, in both groups FMD showed a low value (Q: 2.95+0.42% and E: 3.3+/-0.33%), whereas TNF-alpha (Q: 31.65+/-8.23 pg/ml and E: 29.5+/-5.9 pg/ml) and CRP (Q: 7.28+/-2.96 mg/ml and E: 7.08+/-3.02 mg/ml) were elevated. In the Q group, but not in the E group FMD increased significantly, (to 5.96+1.10%), whereas TNF-alpha (19.0+/-12.21 pg/ml) and CRP (to 3.91+/-1.82 mg/L) significantly decreased after 8 and 12 weeks of Q treatment. Moreover, the magnitude of FMD showed a strong inverse correlation with serum levels of TNF-alpha and CRP after Q treatment. Thus, in post myocardial infarction patients endothelial dysfunction assessed by FMD correlates with elevated levels of plasma inflammatory markers, and low dose quinapril improves endothelial function, likely by reducing vascular inflammation.     

The effect of amlodipine on endothelial function in young adults with a strong family history of premature coronary artery disease: a randomised double blind study

Endothelial dysfunction, an early event in atherogenesis, has been demonstrated in young asymptomatic subjects with a strong family history of premature coronary artery disease (CAD). In these subjects, preventive measures involving risk factor modification are not appropriate, and strategies employing novel antiatherogenic agents, such as the dihydropyridine calcium channel blocker, amlodipine, may be useful. Ninety-one subjects (mean age, 28.6 years; range, 18-40) with a strong family history of premature CAD and no other identified vascular risk factors were randomised to either 5 mg amlodipine (49 subjects) or placebo (42 subjects). Brachial artery flow mediated dilatation (FMD) (endothelium-dependent response) and response to glyceryltrinitrate (GTN) (direct smooth muscle dilator) were assessed non-invasively at baseline, and after 12 and 24 weeks using high-resolution vascular ultrasound. In those treated with amlodipine, mean FMD increased from 2.32+/-2.23% at baseline to 3.52+/-3.1% at 24 weeks (P<0.005). However, FMD also increased in the placebo group from 1.64+/-2.12 to 3.37+/-2.68% (P<0.002), and the difference between the FMD response in the amlodipine and placebo groups was not significant. Dilatation to GTN did not change in either group. Therefore, impaired endothelial function improved in family history subjects taking both amlodipine and placebo, but there is no difference between the groups.     

Effect of losartan in aging-related endothelial impairment

Aging is associated with progressive deterioration in endothelial function. We hypothesized that losartan may represent a useful therapeutic strategy to ameliorate endothelial function in aged subjects. Eighteen healthy older subjects (mean age 75 +/- 3 years) were prospectively randomized in a double-blind, crossover fashion to receive either losartan 50 mg/day or placebo for 6 weeks. Subjects were switched to the opposite arm after a 2- week washout period. Flow-mediated dilation (FMD) in the brachial artery and plasma levels of vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM), moncocyte chemoattractant 1 protein, and E-selectin were measured in both arms at the beginning and end of the 6-week period. Losartan resulted in a 6-mm Hg decrease in systolic blood pressure (from 130 +/- 12 to 124 +/- 13 mm Hg), which was no different from placebo (132 +/- 12 to 127 +/- 13 mm Hg). FMD increased from 3.1 +/- 0.6% to 3.9 +/- 0.6% after losartan, and decreased from 3.3 +/- 0.3% to 2.4 +/- 0.6% after placebo (p = NS for both). In contrast, losartan reduced circulating concentrations of vascular cell adhesion molecule 1 (750 +/- 73 to 572 +/- 39), ICAM (405 +/- 26 to 196 +/- 10), and moncocyte chemoattractant 1 protein (560 +/- 56 to 423 +/- 35) (p <0.01 for all by analysis of variance), but not E-selectin. On univariate analyses, the strongest predictor of baseline endothelial function and change in FMD with losartan was low-density lipoprotein. There was a negative correlation between baseline endothelial function and change in FMD in response to losartan (r(2) = -0.75, p = 0.0003). Baseline ICAM levels alone significantly correlated with low-density lipoprotein cholesterol (r(2) = 0.54, p = 0.02) and weakly correlated with total cholesterol (r(2) = 0.47, p = 0.05). Thus, administration of losartan for a duration of 6 weeks has favorable effects on inflammatory markers in healthy older subjects, but does not alter peripheral conduit endothelial function.     

Serum levels of sICAM-1 and sE-selectin in patients with dengue virus infection

The purpose of this study was to measure the serum level of sICAM-1 and sE-selectin as markers for endothelial damage in patients with dengue fever (DF) and dengue hemorrhagic fever (DHF). Twenty-nine patients with serologically-proven dengue virus infection (age 10.6 +/- 2.4 years, 55% male, DF = 13 and DHF = 16) were enrolled. Serum samples were collected from 25 healthy children (age 10.6 +/- 2.3 years, 40% male) as the control group. A follow-up was done at a mean interval of 15.9 +/- 1.6 days. The level of sICAM-1 at the toxic stage was significantly elevated compared to its level at the follow-up (494.1 +/- 107.4 versus 358.2 +/- 67.6 ng/ml, P = 0.001), but no difference was found between patients with DF and patients with DHF (444.1 +/- 158.0 versus 465.1 +/- 154.6 ng/ml, P = 0.74). The sICAM-1 level at the follow-up was similar to that of the control group (396.9 +/- 113.0 ng/ml, P = 0.56). The level of sE-selectin at the toxic stage was not different from its level at the follow-up (75.9 +/- 33.0 versus 75.5 +/- 31.7 ng/ml, P = 0.96), and no difference was found between the DF group and the DHF group (64.1 +/- 25.7 versus 78.8 +/- 39.9 ng/ml, P = 0.30). These levels were not elevated compared to the sE-selectin level that was determined in 8 patients in the control group (94.7 +/- 20.5 ng/ml, P = 0.12). In conclusion, there is evidence of endothelial activation by an increased sICAM-1 level in patients with dengue virus infection. However, the degree of endothelial activation alone may be similar for patients with DF and patients with DHF, and this fact by itself cannot explain the difference between the two clinical syndromes of dengue virus infection. The sE-selectin level was not elevated for patients included in this study.     

The levels of soluble adhesion molecules in diabetic and nondiabetic patients with combined hyperlipoproteinemia and the effect of ciprofibrate therapy

Cell adhesion molecules are thought to play a role in atherosclerosis. Several clinical trials have shown that fibrate treatment leads to a reduction in coronary events, although the mechanisms are not fully understood. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin plasma concentrations were measured in 10 obese dyslipidemic men (group A), in 10 obese dyslipidemic type 2 diabetic men without coronary artery disease (CAD) (group B), and in 10 dyslipidemic type 2 diabetic men with angiographically documented CAD (group C) before and after 12 weeks of treatment with ciprofibrate. Compared with nondiabetic dyslipidemic men, diabetic patients with CAD or without documented CAD had significantly increased levels of sVCAM-1 (512 +/-39 versus 750 +/-139 ng/mL; p<0.0001 and 566 +/-78 ng/mL; p<0.01, respectively) and sE-selectin (54.8 +/-6.9 versus 65.9 +/-8.8 ng/mL; p<0.001 and 62.6 +/-9.4 ng/mL; p=0.056, respectively). The levels of sICAM-1 were similar in all 3 groups. Multivariate analyses showed that the higher sCAM levels in patients occurred independently of lipoprotein levels. Waist circumference as a marker of abdominal adiposity was the only independent predictor of elevated concentrations of all 3 cell adhesion molecules in multivariate analyses. sE-selectin was associated with HbA1C levels (p<0.01) in diabetic men at baseline. After 12 weeks of ciprofibrate therapy, sVCAM-1 levels were reduced by 13.5 +/-2.1%, sICAM-1 levels by 11.8 +/-2.2%, and sE-selectin levels by 17.1 +/-3.5% (p<0.01 for all) with the greatest sE-selectin reduction in the diabetic subgroups (p<0.001). There was no correlation between the lowering of soluble adhesion molecules and the magnitude of lipid-lowering effect. An increased level of circulating adhesion molecules may be a mechanism by which dyslipidemia and/or diabetes mellitus promotes atherogenesis, and treatment with ciprofibrate may alter vascular cell activation.     

感染卡氏肺孢子虫大鼠血清中可溶性细胞黏附分子-1（sICAM-1）变化的研究

目的 检测卡氏肺孢子虫肺炎(PCP)大鼠血清中可溶性细胞黏附分子-1（sICAM-1）水平, 以及经复方磺胺甲噁唑（TMP-SMZ）治疗后对sICAM-1含量的影响。 方法 纯系Wistar大鼠50只, 随机分为 PCP模型组（P组18只）、TMP?鄄SMZ治疗组（S组18只）及正常对照组（N组14只）。P组及S组于大鼠后腿肌肉注射地塞米松（1 mg/只，每周2次、间隔3 d），诱导建立PCP大鼠模型。N组同法注射生理盐水。镜检确认PCP诱导成功后，S组从第3周起灌胃TMP-SMZ[每天1次, 250 mg/（kg·d）］，5 d为1 疗程，间隔2周，共3个疗程。分别于第0、3、6、9及12周取血, 检测血清中sICAM-1水平，观察肺脏、肝脏病理及病原学变化。 结果 血清sICAM-1水平，P组第3周的(1.847±0.50)ng/ml显著低于第0周的（2.407±0.81) ng/ml(P<0.05)； S组第3周的(1.787±0.59) ng/ml显著低于第0周的（2.478±0.59) ng/ml(P<0.01), 以后逐渐上升。P组第9周的（3.233±0.83) ng/ml、 12周（3.984±0.87) ng/ml显著高于第0周的（2.407±0.81) ng/ml(分别为P<0.05, P<0.01)； S组第12周的（3.621±1.62) ng/ml显著高于第0周的（2.478±0.59) ng/ml(P<0.05)。P组与S组第9、12周[分别为(2.697±0.78) ng/ml及(3.621±1.62) ng/ml] 均显著高于N组(分别为P<0.05、P<0.01)。S组与P组间差异无统计学意义(P>0.05)。 结论 大鼠血清中sICAM-1含量较低，但在诱导PCP后其含量显著增高。