Circulating endothelial progenitor cell deficiency contributes to impaired arterial elasticity in persons of advancing age

Reduced arterial elasticity is a hallmark of ageing in healthy humans and appears to occur independently of coexisting disease processes. Endothelial-cell injury and dysfunction may be responsible for this fall in arterial elasticity. We hypothesized that circulating endothelial progenitor cells (EPCs) are involved in endothelial repair and that lack of EPCs contributes to impaired arterial elasticity. A total of 56 healthy male volunteers were divided into young (n=26) and elderly (n=30) groups. Large and small artery elasticity indices were noninvasively assessed using pulse wave analysis. The number of circulating EPCs was measured by using flow cytometry. Cells demonstrating DiI-acLDL and FITC-ulex lectin double-positive fluorescence were identified as EPCs. C1 large artery elasticity and C2 small artery elasticity indices were significantly reduced in the elderly group compared with the young group (11.73+/-1.45 vs 16.88+/-1.69 ml/mm Hg x 10, P<0.001; 8.40+/-1.45 vs 10.58+/-1.18 ml/mm Hg x 100, P<0.001, respectively). In parallel, the number of circulating EPCs was significantly reduced in the elderly group compared with the young group (0.13+/-0.02 vs 0.17+/-0.04%, P<0.05). The number of circulating EPCs correlated with C1 large and C2 small artery elasticity indices (r=0.47, P<0.01; r=0.4, P<0.01). The present findings suggest that the fall in circulating EPCs with subsequently impaired endothelial-cell repair and function contributes to reduced arterial elasticity in humans with ageing. The decrease in circulating EPCs may serve as a surrogate biologic measure of vascular function and human age.     

年龄相关的循环内皮祖细胞变化与动脉弹性关系的研究

目的　研究年龄对循环内皮祖细胞及动脉弹性的影响,探讨循环内皮祖细胞水平与动脉弹性损伤的关系。方法　56例健康男性志愿者分成青年组(n=26)和老年组(n=30)。采用桡动脉脉搏分析法无创性评价健康志愿者大动脉弹性指数(C1 )和小动脉弹性指数(C2 ), 流式细胞仪测定外周血中CD34+单个核细胞的水平,单个核细胞体外培养2周,荧光显微镜鉴定FITC UEA I和DiI acLDL双染色阳性细胞为内皮祖细胞。结果　老年组与青年组相比较,C1 和C2 明显降低[C1(11. 73±1 .45)比(16 .89±1 .69)ml/mmHg×10, P<0. 001; C2 (8 .40±1 45)比(10. 58±1 .18)ml/mmHg×100, P<0 .001 ];循环内皮祖细胞数目明显减少[ ( 0 .13±0. 02 )比( 0 .17±0. 04 )%,P<0 .05];循环内皮祖细胞水平与动脉弹性指数变化呈正相关(r=0. 47, P<0. 01;r=0 .4, P<0. 01),荧光显微镜鉴定贴壁细胞FITC UEA I和DiI acLDL双染色阳性。结论　增龄导致循环内皮祖细胞数量减少,提示血管内皮修复能力下降和功能障碍,损伤动脉弹性,循环内皮祖细胞水平有可能作为评价血管功能的替代指标。     

Relationship between arterial elasticity indices and carotid artery intima-media thickness

Functional and structural changes of the arterial wall appear to serve as early hallmarks of the hypertensive disease process. Structural vascular changes can be studied by the determination of the intima-media wall thickness (IMT) at the carotid artery. The elastic behavior of the proximal and distal parts of the arterial tree can be assessed from noninvasively recorded radial artery waveforms. The aim of the study was to compare large (proximal, C1) and small (distal, C2) artery elasticity indices in two age-matched study groups with high- and low-normal blood pressure (BP) and to assess the relation between elasticity indices and IMT. A total number of 22 subjects with high-normal BP (40 +/- 2 years; BP, 147 +/- 2.5/84 +/- 1.5 mm Hg) and 22 matched controls with low-normal BP (40 +/- 2 years; BP, 123 +/- 1.9/69 +/- 1.5 mm Hg) were enrolled. The IMT was echographically determined at the common carotid artery by the leading-edge technique. Large artery (C1) and small artery (C2) elasticity indices were calculated from a third-order, four-element model of the arterial circulation. In the group with high-normal BP large and small artery elasticity indices were significantly decreased versus controls with low-normal BP (C1: 1.63 +/- 0.08 v 1.99 +/- 0.09 mL/mm Hg, P < .01; C2: 0.059 +/- 0.005 v 0.076 +/- 0.007 mL/ mm Hg, P < .05) and IMT increased significantly (0.607 +/- 0.039 v 0.516 +/- 0.027 mm, P < .05). Moreover, there was an inverse relationship between IMT and small artery elasticity index (r = -0.60, P = .004). In subjects with a high-normal BP there is already a change in the IMT of the carotid artery versus normotension. The IMT is related to the small artery elasticity index (C2).     

Arterial elasticity identified by pulse wave analysis and its relation to endothelial function in patients with coronary artery disease

Patients with coronary artery disease (CAD) have impaired endothelial function. Arterial elasticity is modulated by endothelial function. The association between arterial elasticity and endothelial function has not been reported in patients with CAD. The present study was designed to investigate whether endothelial dysfunction contributes to impaired arterial elasticity. Thirty patients with CAD and 30 control subjects were recruited. Large and small artery elasticity indices were non-invasively assessed using pulse wave analysis. Brachial artery endothelium-dependent and -independent function were assessed by vascular response to flow-mediated vasodilation (FMD) and sublingual nitroglyceride (NTG), respectively. C1 large artery elasticity index was not different in the CAD group compared with the control group. However, C2 small artery elasticity index was significantly reduced in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) was also impaired in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) in the brachial artery correlated with C2 small arterial elasticity index. But NTG-mediated brachial artery vasodilation was similar between the two groups. The present findings suggest that the patients with CAD have reduced C2 small arterial elasticity index and impaired FMD. Endothelial dysfunction is involved in diminished arterial elasticity, suggesting that C2 small arterial elasticity index is a novel surrogate measure for the clinical evaluation of endothelial function.     

Increased circulating CD31+/CD42- microparticles are associated with impaired systemic artery elasticity in healthy subjects

BACKGROUND: Impaired artery elasticity has been found in various pathological conditions related to endothelial dysfunction. Recently, CD31+/CD42- microparticles (MPs) emerged as a marker of endothelial injury. Whether CD31+/CD42- MPs, generated under physiological conditions, are correlated with artery properties has not been reported. METHODS: We evaluated brachia-ankle pulse-wave velocity (baPWV) (n = 76) and C1 large-artery and C2 small-artery elasticity indices (n = 56), using noninvasive devices for pulse-wave analysis in a group of healthy persons. The number of circulating CD31+/CD427- MPs (n = 76) was measured by flow cytometric analysis. RESULTS: Circulating CD31+/CD42- MPs were positively correlated with values of baPWV (r = 0.371, P = .008) and with C1 large-artery and C2 small-artery elasticity indices (r = -0.294, P = .037; and r = -0.310, P = .027, respectively). Multivariate analysis identified CD31+/CD42- MPs as potent contributors to the development of impaired systemic artery elasticity. CONCLUSIONS: The level of circulating CD31+/CD42- MPs, an important biomarker of dysfunctional endothelium and vascular injury, is closely associated with impaired systemic artery elasticity in healthy subjects. The present study suggests that CD31+/CD42- MPs may be a novel surrogate marker for the clinical evaluation of vascular damage.     

Impaired endothelial progenitor cell activity is associated with reduced arterial elasticity in patients with essential hypertension

Endothelial dysfunction is related to reduced arterial elasticity in patients with essential hypertension. Circulating endothelial progenitor cells (EPCs), an important endogenous repair approach for endothelial injury, is altered in hypertensive patients. However, the association between alteration in circulating EPCs and hypertension-related reduced arterial elasticity has not been reported. The purpose of this study is to investigate the association between alteration in circulating EPCs and hypertension-related reduced arterial elasticity. We measured the artery elasticity profiles including brachial-ankle PWV (baPWV) and C1 large and C2 small artery elasticity indices in patients with essential hypertension (n = 20) and age-matched normotensive subjects (n = 21). The number and activity of circulating EPCs isolated from peripheral blood were determined. Compared to normotensive subjects, the patients with hypertension exhibited decreased C1 large and C2 small artery elasticity indices, as well as increased baPWV. The number of circulating EPCs did not differ between the two groups. The migratory and proliferative activities of circulating EPCs in hypertensive patients were lower than those in normotensive subjects. Both proliferatory and migratory activities of circulating EPCs closely correlated with arterial elasticity profiles, including baPWV and C1 large and C2 small artery elasticity indices. Multivariate analysis identified both proliferative and migratory activities of circulating EPCs as independent predictors of the artery elasticity profiles. The present study demonstrates for the first time that impaired activity of circulating EPCs is associated with reduced arterial elasticity in patients with hypertension. The fall in endogenous repair capacity of vascular endothelium may be involved in the pathogenesis of hypertension-related vascular injury.     

冠心病患者血管内皮功能障碍与动脉弹性关系的研究

目的　探讨冠心病患者血管内皮功能障碍与动脉弹性的关系。方法　采用高分辨率血管超声法检测 30例冠心病患者与 30例正常对照组肱动脉血流介导的内皮依赖性血管舒张功能(FMD);应用动脉弹性功能检测仪测定受试者的大动脉弹性指数 (C1 )和小动脉弹性指数 (C2 )。结果　冠心病组血流介导的肱动脉舒张反应明显低于对照组[ (5 17±2 13)% 与 (11 10±4 36)%,P<0 05];冠心病组与正常对照组的C1 差异无统计学意义 [ ( 11 59±4 56 )ml/mmHg( 1mmHg=0 133kPa) ×10与 (12 11±3 82)ml/mmHg×10, P>0 05],但冠心病组的C2 明显低于正常对照组[ (4 20±1 80)ml/mmHg×100与 (6 26±2 36)ml/mmHg×100, P<0 05],冠心病组血流介导的肱动脉舒张反应与C2 呈正相关(r=0 53, P<0 05)。结论　冠心病患者肱动脉内皮依赖血管舒张功能受损和C2 降低,且两者之间呈正相关,提示C2 可作为一种评价血管内皮功能的新指标。     

Non-invasive evaluation of endothelial function in hypertensive elderly patients

Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium. The aim of the present study was to investigate the effects of aging and hypertension on endothelial function. Sixty-six geriatric subjects with ages over 60 (48 hypertensive and 18 healthy) and 40 middle-aged subjects (16 hypertensive and 24 healthy) were included in the study. Systemic vascular endothelial function was evaluated through measuring brachial arterial vasodilation, a physiologic answer to reactive hyperemia occured with increased blood flow in the vessel after transient ischemia (flow-mediated dilation, FMD%), and with carotid artery intima-media thickness (IMT) measurement, using high-resolution ultrasonography. Endothelial independent vasodilation was also measured after administration of sublingual isosorbide dinitrate (isosorbide dinitrate mediated dilation, IDNMD%). FMD% was significantly decreased in elderly and/or hypertensive (HT) patients (geriatric HT: 9.5 +/- 4.7%, geriatric non-HT: 12.7 +/- 5.5%, middle-aged HT: 12.9 +/- 4.3% and middle-aged non-HT: 18.9 +/- 8.1%) (geriatric HT versus geriatric non-HT (P = 0.02), geriatric HT versus middle-aged HT (P = 0.01), geriatric non-HT versus middle-aged non-HT (P = 0.008)). Both FMD% and IDNMD% were inversely correlated with age, baseline vessel diameter and carotid artery intima-media thickness. FMD% was also inversely correlated with diastolic blood pressure. No correlation was found between FMD% and systolic blood pressure, serum cholesterol and triglyceride levels. Endothelium dependent (EDD) and independent dilatation of large arteries decreased with aging even in the healthy elderly, and FMD further declined in HT elderly patients, indicating that age and hypertension independently impair endothelial function. Positive correlations with age and hypertension, and significant inverse correlation with FMD, makes carotid artery IMT a possible indicator of endothelial function.     

Isradipine improves endothelium-dependent vasodilation in normotensive coronary artery disease patients with hypercholesterolemia

OBJECTIVE: The dihydropyridine calcium antagonist isradipine has anti-atherosclerotic effects in animals and improves endothelium-mediated nitric oxide (NO)-dependent vasodilation in vitro. As improved endothelial function may be beneficial we investigated its effects in patients with a high likelihood of endothelial dysfunction. DESIGN: Thirty patients (two female, age 55.4 +/- 10.5 years) with known coronary artery disease and elevated (> 6 mmol/l) total cholesterol (cholesterol: mean 6.7 +/- 0.78 mmol/l) or a cholesterol/high density lipoproteins (HDL) ratio of > 5 not on lipid lowering therapy, participated in the study. Endothelial vasodilator function was assessed before and after double-blind, randomized administration of isradipine 5 mg/day or placebo for 3 months. METHODS: Endothelial function was assessed as forearm blood flow (FBF, venous occlusion plethysmography) responses to graded brachial artery infusions of acetylcholine (Ach), to the NO-synthase blocker NG-monomethyl-L-arginine (L-NMMA) and to the endothelium-independent vasodilator sodium nitroprusside (SNP). Blood pressure was measured either directly from the brachial arterial or by sphygmomanometer during clinic visits. RESULTS: Blood pressure was unchanged in both groups after 3 months (isradipine: 88.8 versus 92.1 mmHg; placebo: 81.0 versus 82.5 mmHg; NS) but cholesterol levels decreased similarly in both groups (isradipine: 6.7 versus 6.1 mmol/l, NS; placebo: 6.6 versus 5.9 mmol/l, P< 0.05). The vasodilator response to SNP and the decrease in FBF in response to blockade of NO synthesis by L-NMMA were unchanged in both groups. However, isradipine, but not placebo, enhanced the NO-dependent vasodilator response to Ach (P < 0.05). CONCLUSION: Isradipine improves acetylcholine-mediated vasodilation in hypercholesterolemic patients independent of changes in lipids or blood pressure.     

Studies on flow-mediated vasodilation and intima-media thickness of the brachial artery in patients with primary hyperparathyroidism

The endothelium is a newly recognized target organ of parathyroid hormone (PTH) and may contribute to its effects on vascular tone and blood pressure regulation. Flow-mediated vasodilation (FMD), brachial and carotid intima-media thickness (IMT) were studied in patients with primary hyperparathyroidism (pHPT) and controls to evaluate endothelial function and structural arterial vessel wall alterations. Sixteen patients with pHPT (mean +/- SEM, age 44 +/- 5 years; PTH 229 +/- 72 ng/L; serum calcium 3.0 +/- 0.06 mmol/L; serum phosphate 2.0 +/- 0.2 mg/L) and 16 normocalcemic control subjects matched for age, sex, and blood pressure were included. Diabetes, hypertension, and vascular disease were excluded in both groups. End-diastolic diameter, flow-mediated (FMD) and nitroglycerin-mediated (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. Endothelium-dependent FMD was impaired in patients compared to controls (4.6 +/- 1.6% v 19.2 +/- 3.9%, P < .001). NMD (23.8 +/- 3.1% v. 22.4 +/- 2.8%, P = NS), carotid and brachial IMT (0.60 +/- 0.04 mm v 0.64 +/- 0.06 mm, P = NS, and 0.46 +/- 0.04 mm v 0.47 +/- 0.08 mm, P = NS, respectively) and artery diameters were not different. Endothelium-dependent vasodilation is impaired in patients with primary hyperparathyroidism despite normal IMT. Endothelial dysfunction may contribute to increased cardiovascular morbidity and mortality in pHPT.     

Arterial function and intima-media thickness in hypertensive patients with erectile dysfunction

OBJECTIVE: Erectile dysfunction is a predictor of cardiovascular risk with high prevalence in hypertensive men. We investigated whether erectile dysfunction is related to arterial structure and function in hypertensive patients. METHODS: We evaluated arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic erectile dysfunction and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment. RESULTS: Hypertensive patients with erectile dysfunction had higher common carotid intima-media thickness (0.95 +/- 0.19 vs. 0.83 +/- 0.18 mm, P = 0.003) and carotid-femoral pulse-wave velocity (8.89 +/- 1.38 vs. 8.11 +/- 1.10 m/s, P = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 +/- 1.64 vs. 4.07 +/- 1.68%, P = 0.003) and a higher level of the systemic endothelial dysfunction marker asymmetric dimethylarginine (0.67 +/- 0.13 vs. 0.57 +/- 0.16 mumol/l, P = 0.003), and the inflammatory markers high-sensitivity C-reactive protein [2.03 (1.16-2.89) vs. 1.23 (0.67-1.90) mg/l, P = 0.029] and interleukin-6 (4.13 +/- 2.38 vs. 2.77 +/- 1.92 pg/ml, P = 0.011). Multivariable analysis adjusting for age, mean pressure, other risk factors and treatment showed independent associations between erectile dysfunction and parameters of arterial structure and function. In the erectile dysfunction group, there were no significant relationships between the severity of erectile dysfunction (as expressed by the Sexual Health Inventory for Men score) and the above arterial indices and level of circulating markers (all P = NS). CONCLUSION: In hypertensive men, the presence but not the severity of vasculogenic erectile dysfunction is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation.     

N(G)-monomethyl-L-arginine alters insulin-mediated calf blood flow but not glucose disposal in the elderly

It has been proposed that an important component of glucose disposal is insulin-mediated vasodilation via a nitric oxide (NO)-dependent mechanism. Normal aging is characterized by a resistance to insulin-mediated glucose disposal and deficient endothelial NO production. Impairment of insulin-mediated vasodilation could contribute to this insulin resistance. We tested the hypothesis that the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) would decrease insulin-mediated calf vasodilation and whole-body glucose disposal in young subjects but would have little or no effect in the elderly. Experiments were performed on healthy young (n = 10) and old (n = 10) subjects on 2 study days. Insulin was infused for 4 hours at 40 mU/m(2)/min (young) and 34 mU/m(2)/min (old) during both studies, and L-NMMA (0.1 mg/kg/min) was coinfused during the last 2 hours of insulin on one of these sessions. Calf blood flow was measured by venous occlusion plethysmography, and calf vascular conductance was derived from calf blood flow and mean arterial blood pressure (MABP). L-NMMA increased whole-body insulin-mediated glucose uptake (IMGU) in young subjects (from 11.22 +/- 0.08 to 12.22 +/- 0.87 mg/kg/min, P <.05) but decreased calf blood flow (from 6.53 +/- 0.62 to 5.49 +/- 0.43 mL/100 mL/min, P <.05). In contrast, L-NMMA had no effect on IMGU in elderly subjects (control v L-NMMA, 7.58 +/- 0.46 v 7.86 +/- 0.37 mg/kg/min, P = nonsignificant) but increased calf blood flow (from 3.65 +/- 0.36 to 4.50 +/- 0.32 mL/100 mL/min, P <.01). L-NMMA decreased calf vascular conductance in young subjects (from 0.083 +/- 0.008 to 0.064 +/- 0.005 mL/100 mL/min/mm Hg, P <.05) but not in the elderly (control v L-NMMA, 0.038 +/- 0.004 v 0.040 +/- 0.002 mL/100 mL/min/mm Hg), consistent with the concept that skeletal muscle endothelial NO production is reduced with age. We therefore conclude that (1) L-NMMA has different or opposite actions on calf blood flow and IMGU in both age groups, indicating that the effect of insulin on skeletal muscle blood flow is independent of its influence on glucose disposal in young and old, and (2) skeletal muscle NO production decreases with age.     

Non-invasive assessment of arterial stiffness by pulse-wave velocity correlates with endothelial dysfunction

BACKGROUND: Pulse-wave velocity is the speed of the blood pressure wave to travel a given distance between two sites of the arterial system and is determined by the elasticity, wall thickness and blood density. Pulse-wave velocity correlates well with arterial distensibility and stiffness and is a useful non-invasive index to assess arteriosclerosis. Arterial endothelial dysfunction is one of the key early events in atherogenesis, preceding structural atherosclerotic changes. This study sought to establish the correlation of non-invasive estimation of arterial wall stiffness by pulse-wave velocity and its association with endothelial dysfunction in subjects at higher risk for atherosclerosis. METHODS AND RESULTS: A total of 102 subjects (60 males and 42 females, mean age 51 years), including those with hypertension (n = 39), type 2 diabetes mellitus (n = 26), concomitant type 2 diabetes mellitus and hypertension (n = 29) and primary dyslipidemia without diabetes mellitus and hypertension (n = 8). Pulse-wave velocity was measured by the Vascular Profiler 1000 (VP-1000) waveform analysis and vascular evaluation system, an automated, non-invasive, screening device. Endothelial function was assessed by flow-mediated dilation of the brachial artery. The brachial-artery diameter was measured on B-mode ultrasound images, with the use of a 7.0 MHz linear-array transducer. Mean brachial artery pulse-wave velocity on the right extremity was 1699 cm/s and on the left 1694 cm/s. Mean flow-mediated dilation in the study subjects was 3.6 +/- 8.4%. Mean brachial artery pulse-wave velocity in the right and left extremities and the higher value of brachial artery pulse-wave velocity of the two extremities showed a negative and significant correlation with flow-mediated dilation of the brachial artery (correlation coefficient r = -0.32, p = 0.001; r = -0.40 p < 0.0001; r = -0.37, p = 0.001, respectively). Mean heart-brachial pulse-wave velocity also showed a negative and significant correlation with flow-mediated dilation of the brachial artery (r = -0.23, p = 0.022). Mean arterial stiffness was 36.2 +/- 22%. Arterial stiffness in the right extremity and the higher value of the two extremities showed a negative and significant correlation with flow-mediated dilation of the brachial artery (correlation coefficient r = -0.31, p = 0.002; r = -0.32, p = 0.001, respectively). CONCLUSIONS: Increased values of pulse-wave velocity reflecting upon arterial stiffness show an excellent correlation with reduced values of brachial artery flow-mediated dilation. We propose that the non-invasive modalities of estimation of the pulse-wave velocity and endothelial function estimation by flow-mediated dilation of brachial artery be used in clinical practice in assessment of pre-clinical atherosclerosis.     

Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening

OBJECTIVE: We sought to study arterial endothelial function and carotid intima-media thickness (IMT), both early markers of atherosclerosis, in overweight compared to normal children. DESIGN: Case-control comparison. SUBJECTS: A total of 36 asymptomatic overweight children (body mass index (BMI)>23; mean 25+/-3) aged 9-12 y and 36 age- and gender-matched nonobese healthy children (BMI<21) from a school community. MEASUREMENTS: The key parameters were: BMI, arterial endothelial function (ultrasound-derived endothelium-dependent dilation) and carotid artery IMT. The secondary parameters measured included body fat content, waist-hip ratio (WHR), blood pressures, blood lipids, insulin and glucose. RESULTS: The two groups were well matched for blood pressures, cholesterol and glucose levels, but BMI (P<0.0001), body fat (P=0.001), WHR (P<0.05), fasting blood insulin (P=0.001) and triglyceride levels (P<0.05) were higher in obese children. Overweight was associated with impaired arterial endothelial function (6.6+/-2.3 vs 9.7+/-3.0%, P<0.0001) and increased carotid IMT (0.49+/-0.04 mm vs 0.45+/-0.04 mm, P=0.006). The degree of endothelial dysfunction correlated with BMI (P<0.003) on multivariate analysis. CONCLUSION: Obesity, even of mild-to-moderate degree, is independently associated with abnormal arterial function and structure in otherwise healthy young children.     

The effects of atorvastatin on coronary endothelial function in patients with recent myocardial infarction

BACKGROUND: Endothelial dysfunction is a key early event in atherosclerosis that occurs in acute coronary syndrome. It was reported that atorvastatin improves the endothelial function of skeletal muscle vessels, but the effect on the coronary artery is unknown. HYPOTHESIS: The purpose of this study is to determine the effects of atorvastatin on coronary endothelial function in humans. METHODS: Non-infarct-related coronary arteries of 48 patients with acute myocardial infarction who had undergone successful percutaneous transluminal coronary angioplasty were examined. Three groups were studied: hyperlipidemia with use of atorvastatin (Group 1, n=17), hyperlipidemia without statin use (Group 2, n=18), and normal cholesterol level controls (Group 3, n=13). Statin treatment was started at discharge. Acetylcholine (Ach) was infused into the coronary artery and the diameter was assessed by quantitative angiography at baseline and after 6 months. RESULTS: Acetylcholine given in doses of 1, 3, 10, and 30 mg/min increased the coronary artery diameter change in a dose-dependent manner. In the initial study, patients in the three groups had similar responses to Ach. The mean diameter change after 6 months was significantly improved in Group 1 compared with Groups 2 and 3 (-11 +/- 3% vs. -20 +/- 7% and -21 +/- 6%, respectively; p < 0.01 in each case). Multivariate regression analysis showed that atorvastatin (p < 0.01) was the significant determinant for improvement of endothelial function. CONCLUSIONS: These findings suggest that atorvastatin improves endothelial function of the coronary artery in patients with myocardial infarction.     

Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction

Isolated systolic hypertension is associated with increased cardiovascular risk. It is thought to result from large artery stiffening, which is determined by structural components within the vasculature but also by functional factors including NO and endothelin-1. We hypothesized that endothelial dysfunction would account for increased arterial stiffness in patients with isolated systolic hypertension. The aim of this study was to investigate the relationship between endothelial function and arterial stiffness in these patients along with control subjects. We studied 113 subjects: 35 patients with isolated systolic hypertension (mean age+/-SD: 68+/-6 years), 30 age-matched control subjects (65+/-5 years), and 48 young control subjects (37+/-9 years). Aortic pulse wave velocity (PWV) was derived by sequential carotid/femoral waveform recordings. Conduit artery endothelial function was determined by flow-mediated dilatation. Aortic PWV was higher (9.65+/-2.56 m/s versus 8.26+/-0.85 m/s; P=0.009), and flow-mediated dilatation was lower (2.67+/-1.64% versus 4.79+/-3.1%; P=0.03) in patients with isolated systolic hypertension compared with age-matched control subjects. Similarly, aortic PWV was also higher, and flow-mediated dilatation lower, in older versus young control subjects (8.26+/-0.85 m/s versus 7.09+/-1.01 m/s and 4.79+/-3.1% versus 6.94+/-2.7%; P=0.004 for both). Overall, aortic PWV correlated inversely with flow-mediated dilatation (r=-0.3; P=0.001), which remained significant after adjustment for confounding factors (P=0.01). Patients with isolated systolic hypertension have higher aortic PWV and decreased endothelial function compared with age-matched control subjects. Our results suggest that endothelial function contributes significantly to increased arterial stiffness in patients with isolated systolic hypertension and with age.     

Effects of tetrahydrobiopterin on coronary vascular reactivity in atherosclerotic human coronary arteries

OBJECTIVES: Reduced nitric oxide (NO) bioavailability is a key mechanism in the development of endothelial dysfunction. The NO synthase cofactor, tetrahydrobiopterin (BH4), increases NO availability, yet its effect in the human coronary circulation, particularly following PCI, remains uncertain. This study was designed to evaluate the effects of intracoronary BH4 in human coronary arteries with non-critical coronary artery disease or following percutaneous coronary intervention (PCI). METHODS: The study group consisted of 57 stable patients, 10 of which were controls. Active drug was administered in 47 patients, with either de novo non-critical coronary disease (non-stent group; n=25) or following PCI (stent group; n=22). Coronary blood flow (CBF) was measured (0.014-inch Doppler flow wire) in each of these groups in response to sequential intracoronary infusions of acetylcholine (Ach, 10(-7) & 10(-6) M), BH4 (250 mug/min & 500 mug/min) and a co-infusion of BH4 (500 mug/min) and Ach (10(-7) & 10(-6) M). The primary endpoint evaluated the % change in CBF to Ach compared to co-infusion of Ach and BH4. RESULTS: Mean age was 60+/-10 years (M 45:F 12). Regarding the primary hypothesis, no difference was observed between Ach response compared to co-infusion of BH4 and Ach in the % change in CBF in either the non-stent group (Ach 97+/-122%, Ach/BH4 87+/-95%) or the stent group (Ach 77+/-105%, Ach/BH4 55+/-97%). CONCLUSIONS: In native non-critical coronary artery disease or following PCI, coronary microvascular endothelial function is not improved by co-administration of Ach and BH4.     

Effects of GH replacement on endothelial function and large-artery stiffness in GH-deficient adults: a randomized, double-blind, placebo-controlled study

OBJECTIVES: Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening. DESIGN AND PATIENTS: In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied. MEASUREMENTS: Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured. RESULTS: At baseline, FMD (mean +/- SD) was impaired in GH-deficient subjects vs. controls (3.4 +/- 2.3 vs. 5.7 +/- 2.0%, P < 0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23 +/- 12 vs. 14 +/- 14%, P < 0.01). GH-deficient subjects had higher LDL cholesterol (4.1 +/- 0.8 vs. 3.5 +/- 0.8 mmol/l, P < 0.01) and lower HDL cholesterol (1.1 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P < 0.05) and between FMD and the augmentation index (r = - 0.58, P < 0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0 +/- 2.6 vs. 2.8 +/- 1.9%, P < 0.01). There were decreases in central aortic systolic pressure (117 +/- 15 vs. 123 +/- 17 mmHg, P < 0.01), diastolic pressure (82 +/- 10 vs. 86 +/- 8 mmHg, P < 0.01) and the augmentation index (22 +/- 8% vs. 26 +/- 10%, P < 0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5 +/- 0.8 vs. 4.2 +/- 0.8 mmol/l, P < 0.01). There were no significant changes in the placebo group. CONCLUSIONS: Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.     

Endothelial function in offspring of Type 1 diabetic patients with and without diabetic nephropathy.

AIMS: Familial aggregation of diabetes and nephropathy has been observed in several populations. Various interpretations have included underlying genetic mechanisms possibly mediated by a predisposition to hypertension. Endothelial dysfunction is now recognized as central to these conditions and offers a unifying mechanism to explain the disease aggregation. To test this hypothesis, we have examined endothelial function in healthy subjects at differing risks for diabetic nephropathy. METHODS: Endothelial function was assessed in 12 healthy offspring (nine male (M)/three female (F); age 25.8+/-1.2 years, mean +/- SEM) of parents with Type 1 diabetes mellitus (DM) and end-stage renal disease compared with 12 control offspring (9 M/3 F; age 26.3+/-1.3 years) of parents with long duration (>20 years) Type 1 DM but without evidence of nephropathy. Forearm blood flow responses to brachial artery infusion of acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), noradrenaline and the competitive inhibitor of basal nitric oxide release N(G)-monomethyl-L-arginine were assessed using venous occlusion plethysmography. RESULTS: There were no significant differences between the groups in von Willebrand factor, fasting plasma glucose (4.2+/-0.1 vs. 4.0+/-0.2 mmol/l) or in 24-h ambulatory blood pressure. Similarly, the groups did not differ in vasodilation to acetylcholine (P = 0.75) and sodium nitroprusside (P = 0.79) or in vasoconstriction to noradrenaline (P = 0.45) and N(G)-monomethyl-L-arginine (P = 0.30). CONCLUSION: These data do not support a role for endothelial dysfunction in the familial aggregation of diabetic nephropathy.     

Prolonged deterioration of endothelial dysfunction in response to postprandial lipaemia is attenuated by vitamin C in Type 2 diabetes.

BACKGROUND: Endothelial dysfunction (ED) has been described in Type 2 diabetes (T2DM). We have described previously a diminution of flow-mediated arterial dilatation and, by implication, further ED in T2DM in response to postprandial lipaemia (PPL) at 4 h. This is possibly mediated by oxidative stress/alteration of the nitric oxide (NO) pathway. T2DM subjects tend to exhibit both exaggerated and prolonged PPL. We therefore studied the relationship of PPL to the duration of ED in T2DM subjects and oxidative stress with or without the antioxidant, vitamin C. METHODS: Twenty subjects with T2DM with moderate glycaemic control (mean HbA1c 8.4%) were studied. After an overnight fast, all subjects consumed a standard fat meal. Endothelial function (EF), lipid profiles, and venous free radicals were measured in the fasting, peak lipaemic phase (4 h) and postprandially to 8 h. The study was repeated in a double-blinded manner with placebo, vitamin C (1 g) therapy for 2 days prior to re-testing and with the fat meal. Oxidative stress was assessed by lipid-derived free radicals in plasma, ex vivo by electron paramagnetic resonance spectroscopy (EPR) and by markers of lipid peroxidation (TBARS). Endothelial function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery. RESULTS: There was a significant decrease in endothelial function in response to PPL from baseline (B) 1.3 +/- 1.3% to 4 h 0.22 +/- 1.1% (P < 0.05) and 8 h 0.7 +/- 0.9% (P < 0.05) (mean +/- sem). The endothelial dysfunction seen was attenuated at each time point with vitamin C. Baseline EF with vitamin C changed from (fasting) 3.8 +/- 0.9-2.8 +/- 0.8 (at 4 h) and 2.9 +/- 1.3 (at 8 h) in response to PPL. Vitamin C attenuated postprandial (PP) oxidative stress significantly only at the 4-h time point [301.1 +/- 118 (B) to 224.7 +/- 72 P < 0.05] and not at 8 h 301.1 +/- 118 (B) to 260 +/- 183 (P = NS). There were no changes with placebo treatment in any variable. PPL was associated with a PP rise in TG levels (in mmol/l) from (B) 1.8 +/- 1 to 2.7 +/- 1 at 4 h and 1.95 +/- 1.2 at 8 h (P = 0.0002 and 0.33, respectively). CONCLUSION: PPL is associated with prolonged endothelial dysfunction for at least 8 h after a fatty meal. Vitamin C treatment improves endothelial dysfunction at all time points and attenuates PPL-induced oxidative stress. This highlights the importance of low-fat meals in T2DM and suggests a role for vitamin C therapy to improve endothelial function during meal ingestion.