Enhancement of endothelium-dependent flow-mediated vasodilation in hyperthyroidism

OBJECTIVE: Vascular responsiveness changes in hyperthyroid patients remains controversial. This study attempts to determine whether the vasomotor activity can be influenced by hyperthyroid conditions, and, if so, whether changes induced by hyperthyroidism may be restored to normal during the euthyroid state after treatment. DESIGN: A case-control clinical study. PATIENTS AND MEASUREMENTS: Forty-five pretreated hyperthyroid patients (mean age 36.62 +/- 10.12 years, 36 female) were compared with 45 gender- and age-matched control subjects (mean age 38.98 +/- 11.17 years, 40 female). Brachial artery endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation (NMD) responses were assessed noninvasively by high-resolution ultrasound imaging. Among the 45 hyperthyroid patients, 27 patients underwent the same procedures prospectively in the post-treatment euthyroid state. RESULTS: The FMD values were significantly increased in hyperthyroid patients vs. those of controls (8.94 +/- 5.65%vs. 3.77 +/- 3.42%, P < 0.001), whereas NMD levels were not significantly different (18.17 +/- 7.76%vs. 17.28 +/- 6.63%, P = 0.560). Multiple regression analysis revealed that the presence of hyperthyroidism was the only significant factor associated with FMD. In the follow-up study of 27 hyperthyroid patients, the FMD values were significantly decreased in the post-treatment euthyroid state compared with those in the pretreated hyperthyroid state (6.40 +/- 4.27%vs. 8.83 +/- 4.61%, P = 0.021), although these values were still higher than those of controls. CONCLUSIONS: This study demonstrated that endothelium-dependent FMD was increased in the hyperthyroid patients, and could be partially restored by treatment with antithyroid agents.     

Protective effect of high density lipoprotein on endothelium-dependent vasodilatation

Low concentrations of high-density lipoprotein cholesterol (HDL-C) have been associated with increased risk of coronary heart disease (CHD) even when the total cholesterol (TC) and triglyceride (TG) levels are not elevated. The mechanism by which HDL confers protection against atherosclerosis remains speculative. Using high-resolution ultrasound, we measured the dilatation changes of brachial arteries during reactive hyperemia and after sublingual glyceryl trinitrate (GTN) in 63 patients with established (CHD) and 45 controls, in which the serum TC level was normal. The results showed that both flow-mediated dilatation (FMD) and GTN-induced dilatation of brachial arteries in patients with CHD were much reduced compared with control group (2.31+/-2.46% vs. 7.43+/-4.10% and 16.41+/-6.15% vs. 22.44+/-8.63%, respectively, P<0.001 for all). Univariate analysis indicated that FMD of brachial arteries was inversely related to age (r=-0.226, P<0.05), hypertension (r=-0.229, P<0.05), baseline diameter (r=-0.299, P<0.01) and LDL-C (r=-0.237, P<0.05) and positively related to HDL-C (r=0.491, P<0.01). GTN induced vasodilatation was inversely related to age (r=-0.216, P<0. 05) and baseline diameter (-0.476, P<0.01). Multiple stepwise regression analyses in two groups taken together showed that HDL-C and age were the independent predictors of the FMD of brachial arteries (beta=0.466, P=0.000 and beta=-0.184, P=0.020, respectively). Baseline diameter was significant predictor of GTN-induced vasodilatation (beta=-0.390, P=0.000). The analysis in the group of CHD patients showed that only HDL-C was significantly relate to the FMD of brachial arteries (beta=0.295, P=0.018 ) and in controls that hypertension and HDL-C were significantly relate to the FMD of brachial arteries (beta=-0.395, P=0.004 and beta=0.344, P=0.011, respectively). These finding suggest that endothelium-dependent and endothelium-independent vasodilatation are impaired in the patients with CHD. HDL exerts a protective effect on endothelium-dependent vasodilatation in TC being relatively normal population.     

Endothelial dysfunction in patients with polycythaemia vera

Patients with polycythaemia vera (PV) are at increased risk of developing arterial and venous thromboembolic complications. We investigated whether endothelium-dependent, flow-mediated vasodilatation (FMD) is impaired in PV patients without clinical evidence of artery disease as observed in patients with conventional cardiovascular risk factors. FMD and endothelium-independent, nitroglycerine-induced vasodilatation (NMD) were assessed using high-resolution ultrasound in the brachial artery of 20 patients with PV and 20 sex- and age-matched control subjects (CTL). FMD was markedly impaired in PV patients compared with CTL (7.6 +/- 2.9% versus 11.6 +/- 5.7%, P = 0.009) whereas NMD was similar in both study groups. The impairment of FMD was independently related to the presence of PV (r = -0.434, P = 0.009) and vessel size (r = -0.107, P = 0.038) but was not related to haematocrit values and platelet counts. The results demonstrate that PV is associated with endothelial dysfunction in the pre-clinical phase of arterial disease. However, the precise mechanisms by which PV leads to this altered vascular reactivity remain unclear.     

Endothelial function in patients with vasculogenic erectile dysfunction

OBJECTIVES: Erectile dysfunction (ED) commonly coexists with coronary artery disease (CAD) and/or risk factors for atherosclerosis. Because the silent or documented atherosclerosis or vascular risk factors are very frequent, the possibility of endothelial dysfunction in ED patients is expected to be increased. Our aim was to evaluate the endothelial functions in patients with vasculogenic ED with vascular risk factors and compare them with age-matched non-ED patients or healthy controls. DESIGN: We studied 36 patients with presumed vasculogenic ED, 39 age-matched patients with similar risk factors without ED and 25 age-matched healthy controls without ED, known cardiovascular disease or risk factors. Erectile function was evaluated by the International Index of Erectile Dysfunction (IIEF) scores. Brachial artery flow-mediated dilatation (FMD) and nitroglycerine-mediated dilatation (NMD) were measured. RESULTS: Baseline demographics were similar except the IIEF score and duration of diabetes in patients with ED. Brachial artery FMD and NMD were significantly reduced in patients with ED (3.2+/-3. vs. 6+/-4, p<0.0001 for FMD, 12.2+/-6 vs. 15.4+/-6 p=0.032 for NMD). In patients with similar risk factors but without ED, FMD was significantly lower but NMD were not different compared with healthy controls (6+/-4 vs. 10.2+/-3, p<0.0001 for FMD and 15.4+/-8 vs. 16.4+/-6, p=0.81). IIEF scores were weakly correlated with FMD (r=0.25, p=0.028) in patients with ED. There were significant correlations between FMD and NMD in patients with ED (r=0.46, p=0.05) and with risk factors (r=0.72, p<0.0001) but not in healthy controls (r=0.54, p=0.792). Vasculogenic ED patients have more markedly impaired endothelial and smooth muscle functions compared with patients with similar risk factors but no ED.     

老年周围动脉闭塞性疾病内皮和非内皮依赖性舒张功能的无创研究

目的　探讨老年周围动脉闭塞性疾病 (peripheralarterialocclusivedisease,PAOD)内皮依赖性舒张功能 ,即血流介导的血管扩张功能 (flow mediateddilation ,FMD)和硝酸甘油介导的非内皮依赖性舒张功能 (nitroglycerin mediateddi lation,NMD)状况及其相关因素。方法　采用超声多普勒检测 33例已确诊为PAOD的老年患者肱动脉FMD及NMD ,并分别与 40例健康老年人及 30例具有心血管危险因素的老年非PAOD患者进行对照研究。结果　老年PAOD患者FMD及NMD均显著低于对照组 ;肱动脉基础内径、收缩压、低密度脂蛋白胆固醇与FMD呈负相关 ;FMD与NMD呈正相关 ,肱动脉基础内径与NMD呈负相关。结论　老年PAOD患者FMD及NMD均受损 ;肱动脉基础内径、收缩压、低密度脂蛋白胆固醇可能是FMD独立的预测因子 ;而FMD及肱动脉基础内径与NMD密切相关。     

Evaluation of endothelial function in hypertensive elderly patients by high-resolution ultrasonography.

BACKGROUND: Multiple investigations, both in experimental models and in middle-aged patients with essential hypertension, demonstrate impaired endothelium-dependent vasodilatation. HYPOTHESIS: We attempted to determine whether hypertension still exerts additional negative effect on endothelial function of large arteries in hypertensive elderly patients who may already be affected by endothelial dysfunction due to aging. METHODS: We compared 13 elderly patients with hypertension [69 +/- 9 years, (mean +/- standard deviation)] with 13 matched healthy elderly subjects (72 +/- 6 years) as controls. Using high-resolution vascular ultrasound, we measured brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilatation) and sublingual nitroglycerin (causing endothelium-independent dilatation). RESULTS: Flow-mediated dilatation correlated inversely with age (r = -0.60, p = 0.03) in the controls. Flow-mediated dilatation was significantly impaired in hypertensive elderly patients (6.7 +/- 3.3 vs. 13.3 +/- 1.8% in controls, p < 0.0001). No significant difference could found in nitroglycerin-induced dilatation between controls (12.1 +/- 4.9%) and hypertensive elderly patients (10.2 +/- 6.8%, p = 0.5). On multivariate analysis, flow-mediated dilatation in hypertensive elderly patients was inversely related to aging (r = -0.37, p = 0.04) and mean blood pressure (r = -0.57, p = 0.03). CONCLUSIONS: Our study showed decreased flow-mediated dilatation with aging even in the healthy controls, and further decline in flow-mediated dilatation in hypertensive elderly patients compared with controls. This impairment of flow-mediated dilatation in hypertensive elderly patients was related to age and mean blood pressure, indicating that aging and hypertension may independently impair endothelial function in the brachial artery of these patients.     

Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity

OBJECTIVE: Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. We assessed endothelial dysfunction and atherosclerosis in RA in context with laboratory markers. METHODS: Fifty-two patients with RA and 40 matched healthy controls were studied. We assessed common carotid intima-media thickness (ccIMT) and flow- (FMD) and nitroglycerine-mediated vasodilation (NMD). We also assayed numerous immunological and metabolic laboratory markers. RESULTS: FMD was significantly lower in RA (5.32% +/- 4.66%) compared to controls (8.30% +/- 3.96%) (p = 0.001). NMD was preserved in RA. ccIMT was significantly greater in patients with RA (0.63 +/- 0.14 mm) versus controls (0.54 +/- 0.15 mm) (p = 0.012). In patients with RA, ccIMT correlated with FMD% (R = -0.318, p = 0.022), age (R = 0.831, p < 0.001), and anti-dsDNA levels (R = 0.463, p = 0.006). FMD% correlated with serum interferon-gamma (IFN-gamma) levels (R = 0.516, p = 0.014). NMD% correlated inversely with the percentage of Th0 lymphocytes (R = -0.636, p = 0.006), serum immune complex (R = -0.692, p < 0.001), and IgM levels (R = -0.606, p = 0.003). Patients with RA were divided as "low" (< 0.65 mm) versus "high" (> 0.65 mm) ccIMT groups, and into "normal" (> 5%) versus "impaired" (< 5%) FMD% subsets. Low and high ccIMT groups differed significantly in age and serum interleukin 1 (IL-1) and anti-dsDNA levels. RA patients with normal versus impaired FMD% differed significantly in age, disease duration, and serum IFN-gamma levels. Lipoprotein(a) [Lp(a)] also correlated with rheumatoid factor (RF) and C-reactive protein (CRP); homocysteine (HCy) correlated with CRP and correlated inversely with folate and vitamin B12 production. Paraoxonase-1 (PON-1) activity correlated with serum tumor necrosis factor-alpha(TNF-alpha) and IL-6 levels. CONCLUSION: This was a well characterized RA population, where FMD and ccIMT were impaired, indicating early endothelial dysfunction and accelerated atherosclerosis, respectively. RA-related autoimmune-inflammatory mechanisms and metabolic factors including anti-CCP, RF, CRP, circulating immune complexes, IgM, TNF-alpha, IL-6, Th0/Th1 ratio, HCy, folate, vitamin B12, and PON-1 may all be involved in the development of vascular disease in RA. Although ccIMT and FMD, as well as some laboratory factors, have been assessed by other investigators in RA-associated atherosclerosis, our results regarding the possible involvement of anti-CCP, anti-dsDNA, Lp(a), some cytokines, and PON-1 activity are novel. Early determination of FMD% and ccIMT may be useful to assess RA patients with high cardiovascular risk.     

Peripheral vascular endothelial function in essential hyperhidrosis.

BACKGROUND: Essential hyperhidrosis, a disorder of the eccrine sweat glands, is associated with sympathetic overactivity and the aim of the present study was to determine endothelium-dependent vasodilator function in patients with this condition. METHODS AND RESULTS: Using high-resolution ultrasound, the diameter of the brachial artery at rest and during reactive hyperemia (flow-mediated dilatation, %FMD endothelial-dependent stimulus to vasodilatation), as well as after sublingual administration of nitroglycerin (%NTG endothelium-independent vasodilatation) was measured in 18 subjects (mean age 27+/-5 years) with essential hyperhidrosis and 24 healthy control subjects (mean age 29+/-5 years). Baseline brachial artery diameter and FMD were comparable in both groups (BAD: 4.1+/-0.7 mm vs 4.3+/-0.5 mm (control), p = 0.8; FMD: 5.6+/-1.9% vs 6.7+/-2.2%, p=0.1). The time-averaged flow velocity during peak reactive hyperemia was similar in the 2 groups (75+/-11 cm/s vs 72+/-10 cm/s, p = 0.5), nor did NTG-induced dilatation in the patients with essential hyperhidrosis differ significantly from that in healthy control subjects (12.8+/-2.7% vs 14.0+/-3.6%, p = 0.3). CONCLUSION: These findings suggest that endothelium-dependent dilatation of large conduit arteries is preserved in essential hyperhidrosis and it seems to be a localized disorder of the eccrine sweat glands rather than a generalized disorder involving vascular endothelium.     

Enhanced coronary calcification determined by electron beam CT is strongly related to endothelial dysfunction in patients with suspected coronary artery disease

BACKGROUND: Coronary artery calcification determined by electron beam CT (EBCT) is strongly associated with total plaque burden but is not related to systemic vascular inflammation.Aims: We sought to test the hypothesis that enhanced coronary artery calcification, a marker of atherosclerosis and plaque burden, was related to endothelial dysfunction in patients with suspected coronary artery disease (CAD). METHODS AND RESULTS: One hundred twenty-four subjects with suspected CAD were enrolled. Coronary artery calcification was detected by EBCT. A noninvasive method of brachial ultrasound was used to measure endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation (NMD). Serum high-sensitivity C-reactive protein (hsCRP) and monocyte chemoattractant protein-1 (MCP-1) levels were also determined. Of the 124 patients, the calcium scores ranged from 0 to 4,394. All subjects were classified into three groups according to coronary calcium scores: group 1, score 0 (n = 26); group 2, scores 1 to 199 (n = 50); group 3, scores > or = 200 (n = 48). There was an inverse association between the degree of coronary artery calcification and the endothelium-dependent FMD in the three groups (6.9 +/- 0.6% vs 5.3 +/- 0.3% vs 3.7 +/- 0.3%, respectively; p < 0.001) but not the endothelium-independent NMD. Besides, no significant difference in serum levels of hsCRP and MCP-1 were found among the three groups. However, both the serum levels of hsCRP and MCP-1 were correlated significantly with endothelium-dependent FMD (r = - 0.211, p = 0.019; and r = - 0.188, p = 0.037, respectively). By multivariate analysis, enhanced coronary calcification was a strong independent predictor of endothelial dysfunction (p < 0.001). CONCLUSION: Enhanced coronary artery calcification strongly predicted endothelial dysfunction in patients with suspected CAD. Also, serum levels of hsCRP and MCP-1 were significantly correlated with endothelial function. These findings suggested that both calcium deposition and inflammation were involved in endothelial dysfunction.     

Exercise training enhances endothelial function in young men

OBJECTIVES: The present study was designed to assess whether exercise training can enhance endothelium-dependent dilatation in healthy young men. BACKGROUND: Exercise has been shown to reduce cardiovascular morbidity and mortality, but the mechanisms for this benefit are unclear. Endothelial dysfunction is an early event in atherogenesis, and animal studies have shown that exercise training can enhance endothelial function. METHODS: We have examined the effect of a standardized, 10-week, aerobic and anaerobic exercise training program on arterial physiology in 25 healthy male military recruits, aged 17 to 24 (mean 20) years, of average fitness levels. Each subject was studied before starting, and after completing the exercise program. Baseline vascular reactivity was compared with that of 20 matched civilian controls. At each visit, the diameter of the right brachial artery was measured at rest, during reactive hyperemia (increased flow causing endothelium-dependent dilation) and after sublingual glyceryltrinitrate (GTN; an endothelium-independent dilator), using high-resolution external vascular ultrasound. RESULTS: At baseline, flow-mediated dilatation (FMD) and GTN-mediated dilatation were similar in the exercise and control groups (FMD 2.2+/-2.4% and 2.4+/-2.8%, respectively, p = 0.33; GTN 13.4+/-6.2 vs. 16.7+/-5.9, respectively, p = 0.53). In the military recruits, FMD improved from 2.2+/-2.4% to 3.9+/-2.5% (p = 0.01), with no change in the GTN-mediated dilation (13.4+/-6.2% vs. 13.9+/-5.8%, p = 0.31) following the exercise program. CONCLUSION: Exercise training enhances endothelium-dependent dilation in young men of average fitness. This may contribute to the benefit of regular exercise in preventing cardiovascular disease.     

Impaired endothelial function in hypertensive elderly patients evaluated by high resolution ultrasonography.

BACKGROUND: Multiple investigations both in experimental models and in middle-aged patients with essential hypertension have demonstrated impaired endothelium-dependent vasodilation. OBJECTIVE: To determine whether hypertension exerts an additional negative effect on endothelial function of large arteries in hypertensive elderly patients who may already be affected by endothelial dysfunction due to aging. PATIENTS AND METHODS: Thirteen elderly patients with hypertension (69 9 years of age [mean SD]) were compared with 13 matched healthy elderly subjects (72 6 years of age). High resolution vascular ultrasound was used to measure brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilation) and to sublingual nitroglycerine (causing endothelium-independent dilation). RESULTS: Flow-mediated diameter (FMD) was significantly impaired in the hypertensive elderly group (6.7 3.3% versus 13.3 3.8% in the control group, P<0.05). No significant difference could be found in nitroglycerine-induced dilation between the elderly control group (12.1 4.9%) and the hypertensive elderly (10.2 6.8%). On simple linear analysis, FMD was inversely correlated with age (r=-0.60, P=0. 03) in the healthy elderly group. FMD in the hypertensive elderly was inversely related to age (r=-0.41, P=0.04) and mean blood pressure (r=-0.67, P=0.01). CONCLUSIONS: This study showed decreased FMD with aging even in the healthy elderly, with a further decline in hypertensive elderly compared with healthy elderly subjects. This impairment of FMD in the hypertensive elderly group was related to age and mean blood pressure, indicating that aging and hypertension may impair endothelial function in the brachial artery of elderly patients with hypertension.     

Reduction of peripheral flow reserve impairs endothelial function in conduit arteries of patients with essential hypertension

BACKGROUND: A diminished flow reserve in resistance vessels is a hallmark of hypertensive microvascular disease. Hypertension is associated with structural alterations in the microcirculation and a reduced endothelium-dependent dilation in conduit arteries. Both have been demonstrated to predict future cardiovascular events. OBJECTIVE: We hypothesized that a reduced peripheral flow reserve impairs endothelial function in upstream conduit arteries in patients with arterial hypertension. DESIGN: In 43 hypertensive patients (HT) and 38 normotensive controls (NT) endothelial function of the brachial artery was assessed by measurement of flow-mediated dilatation (FMD), using high-resolution ultrasound. Peripheral flow reserve (FR) was determined via measurements of forearm blood flow at rest and during increments of reactive hyperaemia, using venous occlusion plethysmography. RESULTS: FMD was markedly impaired in HT (3.6 +/- 0.3%) as compared with NT (10.2 +/- 0.3%), whereas maximum brachial artery diameter following endothelium-independent dilatation was similar in both groups. In hypertensive patients FR was significantly reduced (HT, 3.2 versus NT, 6.0) during reactive hyperaemia after 5 min of ischaemia. FR was associated with FMD (r = 0.68, P < 0.01). Multiple stepwise regression analysis identified FR as a strong independent variable determining the extent of FMD (r2 = 0.46, P < 0.01). In HT the dose-response curve of FMD upon stepwise increases of FR was shifted significantly to the right. Normalization of FR improved FMD in HT by more than 60%. CONCLUSIONS: In essential hypertension a reduced FR contributes to the endothelial dysfunction of upstream conduit arteries. These findings may have therapeutic and prognostic implications in patients with arterial hypertension.     

Evaluation of coronary calcium score by multidetector computed tomography in relation to endothelial function and inflammatory markers in asymptomatic individuals.

BACKGROUND: Coronary calcification has been correlated with the presence and extent of coronary artery disease (CAD), so in the present study the associations between coronary artery calcification score (CACS) and endothelial dysfunction, as well as the important inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and oxidized low-density lipoprotein (OxLDL), were studied in asymptomatic individuals at intermediate risk for CAD. METHODS AND RESULTS: The study group comprised 177 subjects (103 males) aged 50.6+/-5.9 years. CACS was measured by multidetector computed tomography using the Agatston method. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent nitroglycerin-mediated dilatation (NMD) were measured by high-resolution external brachial ultrasound. Coronary artery calcification (CAC) was detected in 82 subjects (52 males), and the median CACS was 143 [31-311.25] units. After adjusting for gender and body mass index, log (CACS +1) correlated positively with age (r=0.401, p<0.001) and IL-6 levels (r=0.442, p<0.001), and negatively with FMD (r=-0.511, p<0.001). The correlations of log (CACS +1) with CRP and OxLDL levels, and with NMD, were non-significant. In a multivariate-adjusted logistic regression model, age (odds ratio (OR) =1.083 [1.014-1.156]), serum IL-6 level (OR=3.837 [2.166-6.798]) and FMD (OR=0.851 [0.793-0.913]) were significantly and independently associated with CAC. CONCLUSIONS: Peripheral endothelial function inversely correlated with CACS, whereas IL-6 level was associated with CACS. Testing for endothelial function and IL-6 level may improve cardiovascular risk assessment and help target the therapeutic strategies in asymptomatic patients at intermediate CAD risk.     

Discrepancy between simultaneous digital skin microvascular and brachial artery macrovascular post-occlusive hyperemia in systemic sclerosis

OBJECTIVE: Vascular impairment, a main feature of the pathogenesis of systemic sclerosis (SSc), involves both the macro- and the microvasculature. We compared and correlated simultaneously measured skin microvascular and brachial artery macrovascular post-occlusive hyperemia in 3 groups: patients with SSc, patients with primary Raynaud's phenomenon (RP), and healthy volunteers. METHODS: Thirty-three healthy volunteers, 36 patients with primary RP, and 42 patients with SSc were enrolled. For each subject, brachial artery flow-mediated dilation (FMD) and cutaneous post-occlusive reactive hyperemia (PORH) were simultaneously recorded after 5-minute occlusion of the brachial artery. Local thermal hyperemia, nitroglycerin-mediated dilation (NMD), intima-media thickness (IMT), and pulse wave velocity (PWV) were also assessed. RESULTS: Digital cutaneous peak PORH was altered in patients with primary RP and SSc compared to healthy controls, whereas FMD was not significantly different among all groups. We observed a correlation between digital peak cutaneous vascular conductance and brachial FMD in healthy controls (r = 0.49; p = 0.004), but not in patients with primary RP or SSc. Thermal hyperemia was altered only in patients with SSc. Brachial NMD, IMT, and PWV were not different among all groups. CONCLUSION: We observed a loss of the correlation between brachial FMD and digital cutaneous PORH in patients with SSc and primary RP. Microvascular function is impaired in SSc, whereas brachial artery endothelial function is normal.     

Urinary albumin excretion is associated with impaired flow- and nitroglycerin-mediated brachial artery dilatation in hypertensive adults

We investigated whether the urinary albumin/creatinine ratio (UACR), a measure of albuminuria, is associated with non-invasive measures of arterial function in hypertensive adults without known coronary heart disease (CHD) or stroke. UACR was measured in the first voided morning urine sample in 469 non-Hispanic white hypertensive individuals (mean age 62.2+/-9.8 years, 41% men) belonging to hypertensive sibships. High-resolution ultrasonography of the brachial artery was used to assess flow-mediated dilatation (FMD)--an endothelium-dependent response--and nitroglycerin-mediated dilatation (NMD)--an endothelium-independent response. Because of skewed distribution, UACR was log transformed after addition of 0.1. The association of log (UACR+0.1) with FMD and NMD, before and after adjustment for CHD risk factors, serum creatinine, and hypertension medication and statin use was assessed using linear regression analyses. In univariable analyses, variables associated with lower FMD were greater age, male sex, history of smoking, lower high-density lipoprotein (HDL) cholesterol, higher serum creatinine and higher log (UACR+0.1); variables associated with lower NMD were greater age, male sex, higher systolic blood pressure, lower HDL cholesterol, higher serum creatinine and higher log (UACR+0.1). In separate stepwise multivariable regression analyses that adjusted for conventional CHD risk factors, serum creatinine and hypertension medication and statin use, higher log (UACR+0.1) was associated with lower brachial artery FMD (P=0.035) and NMD (P=0.0002). These findings highlight the association of increased urinary albumin excretion with impaired vascular reactivity in hypertensive individuals.     

The influence of homocysteine levels on endothelial function and their relation with microvascular complications in T2DM patients without macrovascular disease

The aim of this study was to investigate the influence of homocysteine (hcy) levels on endothelial function by the method of brachial artery ultrasonography and their relation with microvascular complications in type 2 diabetes mellitus (T2DM) patients without macrovascular disease. Fifty-nine T2DM patients with a mean age of 53.4+/-8.6 years and diabetes duration of 8.1+/-6.2 years and 16 healthy controls with a mean age of 47+/-14.5 years were included in the study. Endothelialdependent and endothelium-independent flow-mediated dilatation (FMD) were evaluated via brachial artery ultrasonography. Fasting plasma glucose (FPG), glycosylated haemoglobin (A1c), lipid profile, hcy, B12 and folic acid levels were measured. Diabetic patients and control group individuals were compared with regard to the laboratory values and brachial artery vascular reactivity. Factors influencing endothelium-dependent FMD were investigated with linear regression analysis. Age, gender, body mass index, lipid profiles and hcy levels were similar in both groups (p>0.05). Endothelium-dependent FMD percentages were significantly lower in diabetics than in the control group (7.7+/-5.9 vs. 11.7+/-7.1%, p<0.05). Endothelial-independent FMD percentage was similar for both groups (p>0.05). The upper limit of the reference hcy value was found to be 12.6 micromol/l in the control group. In the diabetic group, hcy levels were high in 33 patients and normal in 26 patients. No difference was detected between the patients with high hcy levels and those with a normal level with regard to endothelium-dependent and endothelium-independent FMD values (p>0.05). Mean hcy levels were 16+/-1.7 and 13.3+/-4.3 micromol/l in T2DM patients with microvascular complication and those with no microvascular complication, respectively (p<0.05). Regression analysis revealed that the main factors influencing the endothelial-dependent FMD were FPG, total cholesterol (TC), triglycerides (TG) and high-density lipoprotein (HDL-C) levels (p<0.05, p=0.05, p=0.05, p=0.02, respectively). Hcy, folic acid and B12 values did not influence endothelium-dependent FMD (p>0.05). Diabetes duration and A1c levels were close to being significant although they did not reach statistical significance (p=0.07 and p=0.08 respectively). Hcy levels have no effect on endothelium-dependent and endothelium-independent FMD in T2DM patients without macrovascular complications. The influence of classical atherogenic factors (such as FPG, TC, TG and HDL-C levels) on endothelium functions, detected with endothelium-dependent FMD, is greater.     

Carvedilol improves endothelium-dependent dilatation in patients with coronary artery disease

OBJECTIVE: Flow-mediated, endothelium-dependent dilatation (FMD) of the coronary and peripheral circulation is impaired by increased oxidative stress in patients with coronary artery disease (CAD). Carvedilol is a novel beta-blocker that also shows an antioxidant effect in vitro. However, the effect of carvedilol on endothelial dysfunction associated with established coronary atherosclerosis has not been examined in the clinical setting. METHODS: We studied 29 patients with CAD, including 17 with recent myocardial infarction and 12 with stable effort angina pectoris. Nineteen patients received carvedilol (10 with infarction and 9 with angina), and 10 were treated with placebo (7 with infarction and 3 with angina). We also studied 13 age- and sex-matched control subjects. Brachial FMD during reactive hyperemia and nitroglycerin-induced, endothelium-independent dilatation were assessed by high-resolution ultrasound. RESULTS: FMD was smaller in patients with CAD compared with controls, although nitroglycerin-induced dilatation was similar. Carvedilol significantly improved FMD after long-term treatment (5. 1% +/- 0.4% at baseline to 7.8% +/- 0.3% after 4 months; P <.01) but not after short-term treatment (5.1% +/- 0.4% at baseline to 5.0% +/- 0.7% after 2 hours). Placebo therapy had no effect on endothelial dysfunction. Neither carvedilol nor placebo had an effect on nitroglycerin-induced dilatation after short- and long-term treatment. Long-term carvedilol therapy also significantly decreased the plasma level of thiobarbituric acid-reactive substances compared with placebo (carvedilol, 5.8 +/- 0.4 nmol/mL to 4.6 +/- 0.3 nmol/mL, P <.01; placebo, 5.9 +/- 0.4 nmol/mL to 5.8 +/- 0.4 nmol/mL, P = not significant). CONCLUSION: These findings suggest that the improvement of endothelial function by carvedilol may be caused by its antioxidant activity.     

Correlation of endothelial function in large and small arteries in human essential hypertension

OBJECTIVES: The structure and function of blood vessels varies along the vascular tree, and alterations found in hypertension are also different. The aim of this study was to determine whether non-invasive measurement of endothelial function in conduit arteries reflects that of subcutaneous resistance arteries measured in vitro. METHODS AND RESULTS: Sixteen essential hypertensive patients (aged 50 +/- 2 years) were studied. Flow-mediated dilation (FMD) during reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin (NTG)-induced dilatation (endothelium-independent) were assessed in brachial arteries by ultrasound. Structure, and acetylcholine (10(-9) to 10(-4) mol/l) and sodium nitroprusside (SNP, 10(-8) to 10(-3) mol/l)-induced vasorelaxation of resistance arteries dissected from gluteal subcutaneous biopsies were measured in vitro using a pressurized myograph. Brachial artery FMD and NTG-induced dilatation were 8.4 +/- 1.0 and 18.1 +/- 1.4%, respectively. Resistance arteries of hypertensive patients showed greater media:lumen ratio (8.6 +/- 0.4 versus 5.9 +/- 0.3% in normotensive subjects, P< 0.01), and maximal acetylcholine responses was diminished to 75 +/- 6% compared to normotensive subjects (97 +/- 2%, P< 0.01). FMD correlated with maximal acetylcholine responses (r2 = 0.57, P< 0.001). FMD did not correlate significantly with the media: lumen ratio of resistance arteries (r2 = -0.22, P= 0.07). By multivariate analysis, FMD predicted resistance artery endothelial function independently of age, sex, body mass index, blood lipid status and lumen diameter of brachial artery (beta = 0.81, P< 0.001). CONCLUSIONS: Endothelial dilatory responses are similar in large and small arteries in hypertensive patients. Abnormal FMD in the brachial artery predicts the presence of endothelial dysfunction in human resistance arteries, suggesting that impairment of endothelial function is a generalized alteration in hypertension. Ultrasound measurement of endothelial dysfunction in the brachial artery appears to be less sensitive than in-vitro measurement in resistance arteries.     

Plasma nitric oxide level and its role in slow coronary flow phenomenon

Previous studies have suggested that microvascular abnormalities and endothelial dysfunction cause slow coronary flow (SCF). The objective of this study was to assess the plasma nitric oxide (NO) level and determine its role in the pathogenesis of SCF phenomenon. Thirty-six patients with SCF (group 1) and otherwise patent coronary arteries and 34 subjects with normal coronary flow (group 2) were included in the study. Coronary flow was quantified according to the TIMI Frame Count (TFC) method. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and nitroglycerin (NTG)-induced endothelium-independent dilatation were studied in both groups. In addition, plasma NO levels were measured and their contribution to FMD was determined. The sex, age, body mass index, arterial blood pressure, and heart rate distributions were similar in both groups. TFC was significantly higher in group 1 compared to group 2 for each artery. The plasma NO level was lower in patients with SCF than in control subjects (18.4 +/- 4.4 versus 25.2 +/- 6.3 micromol/L P = 0.001). FMD was significantly smaller in group 1 than in group 2 (4.0 +/- 3.2% versus 10.6 +/- 5.8%, P = 0.0001). The percent NTG-induced dilatation was similar in the two groups (16.8 +/- 1.1% versus 17.1 +/- 1.1%, P = 0.42). In group 1, the plasma NO level was correlated with percent of FMD. Also, the plasma NO level was inversely correlated with TFC for each artery. Reduced NO bioactivity as well as impaired FMD support the presence of endothelial damage in the pathogenesis of SCF phenomenon.     

Non invasive evaluation of endothelial function in patients with Anderson-Fabry disease.

AIM: Fabry's disease is an X-linked recessive abnormality of glycosphingolipid metabolism. Increased levels of endothelial prothrombotic factors have recently been demonstrated in Fabry's disease, whereas endothelial function has not been studied using high resolution ultrasound. METHODS: We enrolled 6 patients (4 male, 2 female; mean age, 37 years) and 12 sex matched control subjects (mean age, 37 years). Patients' exclusion criteria included a prior history of cardiac disease, diabetes and treated or untreated hypertension. Patients underwent: anamnesis, physical examination, EKG, 2-dimensional echocardiography with tissue Doppler, measurement of body weight and height, blood pressure. Biochemistry variables were also considered: fasting blood sugar, total cholesterol, HDL-C, LDL-C, triglycerides, fibrinogen, C reactive protein and homocysteine. Using high resolution ultrasound, we assessed the brachial vasodilator response to reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin (NTG) (endothelium-independent). Flow-mediated dilatation (FMD) was expressed as percentage change in post-stimulus diameter in comparison with the baseline. RESULTS: In baseline condition, there was no significant difference between patients and controls in the brachial artery diameter (3.5+/-0.55 vs 3.1+/-0.4). After reactive hyperemia, the FMD change was significantly higher in controls than in patients (16.5+/-6.3% vs 9.3+/-6.2%, P<0.05). After NTG, endothelium-independent vasodilation did not show a significant difference between cases and controls (15+/-7.7% vs 13.8+/-7.1%). CONCLUSIONS: Our study demonstrated the presence of endothelial dysfunction in patients with Fabry's disease in comparison to controls. We hypothesized that endothelial dysfunction may contribute to the pathogenesis of ischemic events in patients with Fabry's disease.