Brachial reactivity and extent of coronary artery disease in patients with first ST-elevation acute myocardial infarction

We examined peripheral endothelial function, as measured by brachial artery reactivity, in 49 stable patients with a first episode of acute ST-segment elevation myocardial infarction to examine the relation between extent of coronary disease and peripheral vascular reactivity. Brachial artery reactivity was assessed by ultrasound and flow-mediated dilation (FMD) was calculated as the change in brachial artery diameter after release of suprasystolic blood pressure cuff inflation. FMD was classified as abnormal in (< or =6%) 19 patients (group 1) and as normal in 30 patients (group 2). Average FMDs were 2 +/- 2% in group 1 and 11 +/- 4% in group 2. Patients in group 1 were older (62 +/- 5 vs 54 +/- 11 years, p = 0.02) and more often had a history of hypertension (n = 10, 52%, vs 6, 20%, p = 0.017). Patients with abnormal endothelial function (group 1) had a larger number of coronary obstructive (>or =50%) lesions (3.6 +/- 2.4 vs 2.0 +/- 1.7, p = 0.01) and more extensive coronary disease (1.9 +/- 0.8 vs 1.4 +/- 0.8 vessel disease, p = 0.05). In patients with 3-vessel disease, FMD was lower (4.0 +/- 1.8% vs 8.2 +/- 0.8%, p = 0.04) than in those with lesser coronary involvement. In conclusion, in patients with a first episode of ST-segment elevation myocardial infarction, there was a strong correlation between extent of coronary artery disease and brachial artery reactivity. Patients with localized coronary disease had relatively normal brachial reactivity, whereas those with diffuse coronary disease had more severe abnormal brachial artery reactivity.     

Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: a substudy of the Women's Angiographic Vitamin and Estrogen (WAVE) trial

We measured flow-mediated dilation (FMD) by high-resolution brachial ultrasound in 61 women who participated in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a randomized controlled trial. There were no significant differences in the baseline demographics of women receiving hormone therapy (0.625 mg/day of conjugated equine estrogen plus 2.5mg of medroxyprogesterone acetate for women who had not had a hysterectomy) or placebo; or vitamins (400 IU of Vitamin E and 500 mg of Vitamin C twice daily) or placebo. Baseline FMD was impaired in all subjects (3.3+/-7.6%). Neither hormone therapy (4.1+/-5.2% at baseline, 4.2+/-5.0% at 3 months, and 4.1+/-6.5% at 34 months) nor antioxidant vitamins (3.0+/-8.3% at baseline; 3.5+/-4.6% at 3 months; 3.1+/-7.6% at 34 months) improved FMD (all p-values=NS). Endothelium-independent vasodilation, induced by nitroglycerin (NTG) was similar at baseline and was not affected by either therapy. In univariate and multivariate analysis, neither hormone therapy nor antioxidant vitamins were associated with FMD. Women with established coronary artery disease have impaired flow-mediated vasodilation of the brachial artery that does not improve after 3 months or up to 34 months of treatment with postmenopausal hormone therapy or antioxidant vitamins.     

Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen

The gender difference in cardiovascular disease has been partly attributed to higher androgenic hormone levels. Although testosterone in women may not affect lipids, it remains unknown whether it negates favorable estrogenic effects on endothelial function. We have investigated the effects of testosterone implant therapy on arterial reactivity encompassing endothelial-dependent and -independent vasodilation in women using hormone replacement therapy (HRT). B-mode ultrasound measurements of resting brachial artery diameter, following reactive hyperemia [endothelium-dependent flow- mediated dilation (FMD)] and following glyceryl trinitrate (GTN) (endothelium-independent dilation), were recorded in 33 postmenopausal women stabilized on HRT (>6 months), at baseline, and 6 weeks after a testosterone implant (50 mg), with 15 postmenopausal nonusers of HRT serving as controls. In the brachial artery, baseline resting diameter was similar (0.40 +/- 0.01 vs. 0.41 +/- 0.01 cm, P = 0.5). In the treated group, testosterone levels increased (0.99 +/- 0.08 to 4.99 +/- 0.3 nmol/L, P < 0.001), associated with a mean 42% increase in FMD (6.4% +/- 0.7 to 9.1% +/- 1.1, P = 0.03). The control group did not change (8.1% +/- 1.4 to 5.6% +/- 1.0, P = 0.4). ANOVA of repeated measures (P = 0.04) and mean change (P = 0.02) in FMD both demonstrated significantly greater improvement with testosterone compared with controls. GTN induced vasodilation increased with testosterone treatment (14.9% +/- 0.9 to 17.8% +/- 1.2, P = 0.03). Our preliminary data indicate that parenteral testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation.     

A comparison of brachial artery flow-mediated vasodilation using upper and lower arm arterial occlusion in subjects with and without coronary risk factors

BACKGROUND: The ultrasound assessment of brachial artery flow-mediated vasodilation provides a noninvasive means for measuring endothelial function. The test is performed using either upper or lower arm blood pressure cuff arterial occlusion to induce hyperemia. Upper arm occlusion produces a greater hyperemic stimulus. Brachial artery flow-mediated vasodilation is abnormal in the presence of coronary risk factors. HYPOTHESIS: The study sought to compare the ability of the upper and lower arm occlusion techniques to differentiate endothelial function in subjects with and without risk factors. METHODS: We measured brachial artery flow-mediated vasodilation in 20 subjects, 10 without and 10 with a single risk factor (hypertension, hypercholesterolemia, or cigarette smoking) using both the upper and lower arm occlusion techniques (5 min blood pressure cuff occlusion). Using 11 MHz ultrasound, Doppler blood flow velocities were measured before and immediately after cuff deflation. Brachial artery vasodilation was measured 1 min after cuff deflation, compared with baseline, and expressed as a percent increase. RESULTS: The immediately postocclusion hyperemia (% increase in flow) was significantly greater (p < 0.01) using the upper versus the lower arm technique in both the normal (530 +/- 152 vs. 383 +/- 51%) and the risk factor (583 +/- 153 vs. 409 +/- 114%) groups. Flow-mediated vasodilation was significantly greater (p < 0.01) using the upper arm versus the lower arm occlusion technique in both the normal (13.4 +/- 5.3 vs. 5.6 +/- 3.4%) and risk factor (7.9 +/- 3.6 vs. 3.9 +/- 2.2%) groups. Vasodilation was significantly greater (p < 0.01) in the normal subjects than in the risk factor subjects (13.4 +/- 5.3 vs. 7.9 +/- 3.6%) using the upper arm technique, but was not statistically different in the two groups using the lower arm technique. CONCLUSIONS: Our study demonstrates that upper arm compared with lower arm cuff occlusion undertaken to induce hyperemia for the assessment of brachial artery flow-mediated vasodilation results in significantly greater hyperemia and vasodilation. Flow-mediated vasodilation obtained using the upper arm technique better separates subjects with and without coronary risk factors.     

Flow-mediated dilation in brachial artery in the second half of pregnancy and prediction of pre-eclampsia

Endothelial injury and increased vascular reactivity are involved in the pathogenesis of pre-eclampsia (pregnancy-induced hypertension). To investigate whether flow-mediated dilation (endothelium-dependent dilation) and the reactive hyperemic response can predict pre-eclampsia, we prospectively measured flow-mediated dilation and the Doppler flow velocity pattern (V, cm/s) in the brachial artery using high-resolution ultrasound in 43 pregnant women (32+/-5 years old) in the second half of their pregnancy, and compared the findings with traditional risk factors. Regarding the Doppler flow velocity pattern, the pulsatility index (PI)=(systolic V-diastolic V)/mean V and resistance index (RI)=(systolic V-diastolic V)/systolic V were calculated. For the flow-mediated dilation, the per cent diameter changes were determined based on those from baseline to hyperemic conditions. Nine women suffered from pre-eclampsia and 34 women remained normotensive. Only flow-mediated dilation was found to be significantly lower in the subsequently developed pre-eclampsia patients (1.6+/-1.0% in subsequently developed pre-eclampsia patients vs 11.0+/-4.5% in normotensive patients, P<0.05). Neither the other traditional factors nor the Doppler flow velocity pattern were significantly different between the subsequently developed pre-eclampsia and normotensive patients. If a normal cutoff value of 3.0% obtained from age-matched 14 nonpregnant women (32+/-7 years old) in our laboratory was used, the positive predictive value of flow-mediated dilation (<3.0%) for subsequent pre-eclampsia is 90% and the negative predictive value is 100%. In conclusion, flow-mediated dilation in brachial artery can be a simple and noninvasive modality to predict pre-eclampsia.     

Vascular endothelial function and oxidative stress mechanisms in patients with Behçet's syndrome

OBJECTIVES: We sought to test the hypothesis that vascular endothelial function is impaired in Beh?et's syndrome and reflects increased levels of oxidative stress. BACKGROUND: Beh?et's syndrome is a multisystem inflammatory disorder commonly complicated by vascular thrombosis and arterial aneurysm formation. The precise mechanisms underlying vascular disease in Beh?et's syndrome are not known. METHODS: We studied 19 patients with Beh?et's syndrome (18 to 50 years old, 9 men) and 21 healthy volunteers (18 to 50 years old, 10 men). Brachial artery flow-mediated dilation (endothelium-dependent), and nitroglycerin (NTG)-induced dilation (endothelium-independent) were measured. To investigate oxidative stress mechanisms, vascular studies were repeated 1 h after administration of vitamin C (1 g, intravenous) in 12 patients and 12 control subjects. RESULTS: Flow-mediated dilation was reduced in patients with Behcet's syndrome as compared with control subjects (0.7 +/- 0.9% vs. 5.7 +/- 0.9%, p = 0.001). In contrast, there were no significant differences in the brachial artery diameter (4.2 +/- 0.2 vs. 4.0 +/- 0.2 mm, p = 0.47) or NTG-induced dilation (19.7 +/- 1.9% vs. 19.7 +/- 1.2%, p = 0.98). In regression analysis, Beh?et's syndrome was associated with impaired flow-mediated dilation independent of age, gender, brachial artery diameter, blood pressure, cholesterol and glucose. Vitamin C increased flow-mediated dilation in Beh?et's syndrome (0.2 +/- 0.7% to 3.5 +/- 1.0%, p = 0.002), but not in control subjects (4.3 +/- 0.6% to 4.7 +/- 0.4%, p = 0.51). In both groups, NTG-induced dilation and brachial artery diameter were unchanged after vitamin C treatment. CONCLUSIONS: Vascular endothelial function is impaired in Behcet's syndrome and can be rapidly improved by vitamin C treatment. Our results support a role for oxidative stress in the pathophysiology of Beh?et's syndrome and provide a rationale for therapeutic studies aimed at reducing vascular complications in this disorder.     

Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina.

OBJECTIVES: We sought to examine whether estradiol (E2) supplementation suppresses anginal attacks in women with variant angina. BACKGROUND: Estrogen is known to improve endothelial function. Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, and endothelial dysfunction seems to be involved in the pathogenesis of coronary spasm. METHODS: Fifteen postmenopausal women with variant angina (mean age 54.2 years) were given a hyperventilation (HV) test, a provocation test for coronary spasm, in the early morning of day 1 (baseline), day 3 (after 2-day transdermal E2 supplementation, 4 mg) and day 5 (after 2-day placebo administration). We measured the flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery with the ultrasound technique before each HV test. RESULTS: The anginal attacks with ST segment elevation were induced by HV in all patients on days 1 and 5. However, no attacks were induced on day 3. Supplementation with E2 augmented FMD (3.5 +/- 0.6*, 8.9 +/- 0.7 and 4.0 +/- 0.5* on days 1, 3 and 5, respectively; *p < 0.01 vs. day 3). The serum E2 levels on days 1, 3 and 5 were 22.7 +/- 2.8*, 96.2 +/- 9.2 and 30.7 +/- 7.1* pg/ml, respectively (*p < 0.01 vs. day 3). CONCLUSIONS: The present results demonstrated for the first time, to our knowledge, that E2 supplementation suppresses the HV-induced attacks in women with variant angina, in part because of the improvement of endothelial function.     

Effect of exercise on upper and lower extremity endothelial function in patients with coronary artery disease

Aerobic exercise training improves endothelial vasomotor function in the coronary circulation of patients with coronary artery disease (CAD), an effect that has been attributed to local repetitive increases in shear stress on the endothelium. To study the effects of exercise on endothelial function in the peripheral circulation, we used vascular ultrasound to examine flow-mediated dilation and nitroglycerin-mediated dilation in the brachial and posterior tibial arteries of 58 subjects with CAD. Studies were performed at baseline and after 10 weeks in 40 subjects (aged 59 +/- 10 years) who participated in a supervised cardiac rehabilitation program that predominantly involved moderate intensity leg exercise (three 30-minute sessions/week), and 18 matched patients who did not exercise and maintained a sedentary lifestyle. Exercise was associated with a 29% increase in functional capacity (7.3 +/- 2.2 vs 9.4 +/- 2.7 METs, p <0.001), and significant improvement in endothelium-dependent, flow-mediated dilation in a conduit artery of the leg, but not the arm. Nitroglycerin-mediated dilation in the upper arm and lower extremity was unaffected. These findings suggest that exercise improves endothelial function in peripheral conduit arteries of patients with CAD and that the beneficial effect may be more marked in the vascular beds of the exercised limbs.     

Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women

The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5+/-10.7 micromol/L and increased to 36.3+/-11.4 micromol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreased to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.     

Endothelial function and peripheral vasomotion in the brachial artery in neurally mediated syncope

BACKGROUND: Paradoxical peripheral vasodilation is one of the suspected mechanisms of neurally mediated syncope. Parasympathetic stimulation following sympathetic activation during orthostatic stress mainly contributes to this vasodilation. HYPOTHESIS: Since endothelial function modulates peripheral vascular tone, this study aimed to determine whether endothelial function and inappropriate peripheral vasomotion has a significant role in the pathogenesis of neurally mediated syncope. METHODS: To investigate whether endothelial function is augmented or whether abnormal peripheral vasomotion exits, flow-mediated dilation (FMD, endothelium-dependent vasodilation) and sublingual glyceryl trinitrate-induced dilation (0.3 mg, GTN-D, endothelium-independent vasodilation) were measured in the brachial artery in 16 patients with neurally mediated syncope, aged 33 +/- 10 years, by using high-resolution ultrasound. All patients underwent positive head-up tilt testing. These measures were compared with those in 16 control subjects matched with the patients by age, gender, and coronary risk factors. For FMD, percent diameter changes were obtained from baseline to hyperemic conditions (1 min after 5 min occlusion of the forearm artery). There were five smokers in both the patient and the control groups, but there was no structural heart disease in either group. RESULTS: Baseline brachial artery diameters were comparable (3.8 +/- 0.6 vs. 3.8 +/- 0.7 mm, NS). Flow-mediated dilation in patients with neurally mediated syncope had a normal value of 9.8 +/- 5.0% despite the inclusion of five smokers. Flow-mediated dilation and GTN-D in patients with neurally mediated syncope were significantly greater than those in controls (9.0 +/- 5.0 vs. 3.0 +/- 3.5%, p<0.05; 18.4 +/- 5.5 vs. 14.1 +/- 4.4%, p<0.05). CONCLUSIONS: Augmented endothelial function and/or abnormal peripheral vasomotion in peripheral arteries are important in patients with neurally mediated syncope in selected populations.     

Long-term prognostic role of flow-mediated dilatation of the brachial artery after acute coronary syndromes without ST elevation

Coronary endothelial vasodilator dysfunction is associated with increased cardiac events; the close relation between coronary vasomotor dysfunction and brachial artery vasoreactivity has been previously described. This study assessed the prognostic value of noninvasively assessed brachial artery vasoreactivity in survivors of acute coronary syndromes without ST-segment elevation. We examined 98 men (63.1 +/- 10.8 years) who were referred to our hospital for acute coronary syndromes without ST-segment elevation. Brachial artery endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitrate-mediated dilation were examined in all patients using high-resolution echocardiographic Doppler ultrasound within 24 hours of admission. Plasma malondialdehyde, a marker of oxidative stress, and left ventricular ejection fraction were also assessed. Twenty-seven patients underwent coronary revascularization. Patients were followed for 24.8 +/- 5.9 months. Cardiovascular death, myocardial infarction, stroke, and unstable angina were designated as cardiovascular events (CEs). Twenty CEs were recorded. Kaplan-Meyer analysis showed that patients with FMD <1.9% (tertile 1 of FMD values) were more likely to have CEs than those with FMD >1.9% (log rank 5.29, p = 0.021). Multivariate Cox regression analysis showed that FMD <1.9% predicted CEs with an adjusted hazard ratio of 3.035 (95% confidence interval 1.148 to 8.023, p = 0.025) after adjustment for age, risk factors, troponin T, ejection fraction, revascularization procedures, number of diseased vessels, and medication. In conclusion, endothelium-dependent dilation of the brachial artery is a strong independent predictor of adverse outcome in survivors of acute coronary syndromes without ST-segment elevation.     

Brachial endothelial function is impaired in patients with systemic lupus erythematosus

OBJECTIVE: To verify if endothelial function is impaired in pre-menopausal women with systemic lupus erythematosus (SLE) and whether endothelial dysfunction is related to disease duration, cumulative prednisone dose, antimalarial use, anticardiolipin antibody (aCL), hypertension, Raynaud's phenomenon, disease activity score, and vasculitis. METHODS: Using high-resolution ultrasound, we measured the diameter of brachial artery at rest, during reactive hyperemia, and after glyceryl trinitrate (GTN). We compared 69 pre-menopausal female patients with SLE (mean age 29 +/- 8 years) with 35 age and sex-matched controls (mean age 29 +/- 6 years), The mean disease duration was 72 months. RESULTS: There was no significant difference in baseline brachial artery diameter. The flow-mediated dilation (endothelial dependent dilation) was significantly impaired in SLE patients when compared to controls (5.0 +/- 5.0% vs 12.0 +/- 6.0%, p < 0.001), even in the subgroup of patients without coronary artery disease risk factor (4.5 +/- 4.0% vs 12.0 +/- 6.0%, p < 0.001). The GTN induced dilation (endothelial independent dilation) was significantly lower in the aCL positive SLE patients when compared to the controls (11.9 +/- 4.0% vs 16.3 +/- 6.0%, p < 0.05). The endothelium-dependent dilation was not related to disease duration, cumulative prednisone dose, antimalarial use, anticardiolipin antibody, hypertension history, Raynaud's phenomenon, SLE disease activity score or vasculitis. CONCLUSION: This is the first study using brachial artery ultrasound imaging to evaluate endothelium function in SLE. Patients with SLE presented lower flow mediated dilation (endothelium dependent dilation) than sex and age-matched controls, even in patients without traditional cardiovascular risk factors and this may represent an early atherosclerotic process.     

Different effect of antihypertensive drugs on conduit artery endothelial function

To compare the effect of antihypertensive drugs on endothelium-dependent vasodilation in the peripheral conduit arteries of patients with essential hypertension, in a prospective, randomized, parallel group study, endothelial function was assessed in 168 hypertensive patients before and after 6-month treatment with randomly assigned nifedipine GITS (30 to 60 mg, n=28), amlodipine (5 to 10 mg, n=28), atenolol (50 to 100 mg, n=29), nebivolol (5 to 10 mg, n=28), telmisartan (80 to 160 mg, n=29), and perindopril (2 to 4 mg, n=28). If necessary, hydrochlorothiazide (25 mg) was added to each compound. We evaluated brachial artery flow-mediated, endothelium-dependent dilation (high-resolution ultrasound) compared with endothelium-independent response to glyceryl trinitrate (25 microg/s). Brachial artery diameter was measured by automatic computerized analysis. Forty healthy subjects were evaluated as a control group. Oxidative stress production was evaluated by measuring plasma malondialdehyde and plasma lipoperoxides; plasma antioxidant capacity was assessed as ferric-reducing antioxidant power. Hypertensive patients showed a significantly (P<0.01) lower flow-mediated dilation (5.2+/-1.9%) as compared with healthy control subjects (7.1+/-2.6%). Response to glyceryl trinitrate was similar in control subjects and patients. At baseline, blood pressure, diameter, flow-mediated dilation, and response to glyceryl trinitrate were similar in the different treatment groups. All treatments similarly reduced blood pressure, but only perindopril increased flow mediated dilation (from 5.1+/-2 to 6.4+/-2.4%; P<0.01) without modifying the response to glyceryl trinitrate. Perindopril but also telmisartan nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity. In patients with essential hypertension, ACE inhibitors appear to be the only compounds able to improve conduit artery endothelium-dependent vasodilation.     

Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension

Hypertension is associated with endothelial dysfunction that is attributable to oxidative stress and a proinflammatory state. Under these conditions, enhanced expression of cyclooxygenase-2 might lead to increased production of vasoconstrictor prostanoids and reactive oxygen species that reduce the bioavailability of endothelium-derived nitric oxide. To investigate the contribution of cyclooxygenase-2 activity to endothelial dysfunction in human hypertension, we evaluated brachial artery vasodilator function by ultrasound in 29 hypertensive patients before and after treatment with the selective cyclooxygenase-2 inhibitor celecoxib or placebo in a randomized, double-blind study. Brachial artery flow-mediated dilation improved from a baseline of 7.9+/-4.5% to 9.9+/-5.1% (P=0.005) 3 hours after the first dose and to 10.1+/-6.1% (P=0.006) after 1 week of treatment with celecoxib. In contrast, placebo treatment had no significant effect on flow-mediated dilation (8.1+/-4.4%, 8.3+/-3.5%, and 8.0+/-3.2%, respectively). Neither treatment altered nitroglycerin-mediated dilation, extent of reactive hyperemia, or baseline arterial diameter. Celecoxib treatment had no significant effect on the urinary concentrations of F2 isoprostane or thromboxane metabolites. However, urinary concentrations of the prostacyclin metabolite 2,3-dinor-6-ketoprostglandin F1alpha were significantly lower after 1 week of celecoxib treatment. Thus, cyclooxygenase-2 products contribute to endothelial dysfunction in hypertension, and treatment with a cyclooxygenase-2 inhibitor could have a beneficial effect in this setting. However, cyclooxygenase-2 inhibition also has an adverse effect on prostacyclin production that could promote thrombosis, and the net clinical consequences of improved endothelial function versus loss of prostacyclin merits further investigation.     

Large brachial artery diameter is associated with angiographic coronary artery disease in women

Background Noninvasive methods are needed for the identification of women at highest risk for coronary artery disease (CAD) who might benefit most from aggressive preventive therapy. Identification of brachial artery atherosclerosis, which correlates with coronary artery atherosclerosis, may be useful to estimate or stratify CAD risk. Because atherosclerosis disrupts the arterial architecture that regulates vessel size, we hypothesized that noninvasively measured large brachial artery diameter is a manifestation of atherosclerosis that is associated with angiographic CAD in women with chest pain. Methods We examined 376 women (mean age, 57.1 years) with chest pain in the National Heart, Lung, and Blood Institute's Women's Ischemia Syndrome Evaluation study who underwent B-mode ultrasound scan measurement of brachial artery diameter at rest and during hyperemic stress (to quantify flow-mediated dilation), quantitative coronary angiography, and risk factor assessment. Results Large resting brachial artery diameter was associated with significant angiographic CAD (3.90 ± 0.79 mm vs 3.52 ± 0.59 mm in women with CAD vs no CAD; P < .001). Impaired flow-mediated dilation, which correlated with resting diameter (r = −0.17; P = .001), was weakly associated with significant CAD (2.74% ± 7.11% vs 4.48% ± 9.52% in CAD vs no CAD; P = .046). After adjustment for age, body size, and CAD risk factors, women with large resting brachial artery diameters (>4.1 mm) had 3.6-fold increased odds (95% confidence interval, 1.8 to 7.1; P < .001) of significant angiographic CAD compared with those with small brachial arteries (≤3.6 mm). Conclusion Large resting brachial artery diameter is an independent predictor of significant CAD in women with chest pain. Therefore, a simple ultrasonographic technique may be useful in the identification of women with chest pain who are at increased risk for CAD. (Am Heart J 2002;143:802-7.)     

Decreased nitrate-mediated dilatation in patients with coronary artery ectasia: an ultrasonographic evaluation of brachial artery

BACKGROUND: Coronary artery ectasia has been defined as localized or diffuse nonobstructive lesions of the epicardial coronary arteries with a luminal dilation exceeding the 1.5-fold of normal adjacent segment or vessel diameter. Although coronary artery disease is supposed to be responsible for more than 50% of coronary ectasia, the precise pathology of coronary artery ectasia is not clearly understood. The brachial artery ultrasound test for flow-mediated endothelial-dependent vasodilatory function includes administration of sublingual nitrates to examine the vasodilating effect of an exogenous source of nitric oxide. In the present study, we aimed to compare flow-mediated and nitrate-mediated responses of brachial artery in patients with coronary artery ectasia and patients with coronary artery disease. MATERIALS AND METHODS: Thirty-six consecutive patients with coronary artery ectasia in combination with coronary artery disease and 42 age-matched and sex-matched patients with coronary artery disease alone were included in the study. Flow-mediated and nitrate-mediated dilatations were measured in all patients using a high-resolution B-mode ultrasonographic system. RESULTS: Baseline brachial artery diameters in patients with coronary artery ectasia were not statistically different from those in patients with coronary artery disease (4.2+/-0.6 vs. 4.0+/-0.6 mm, respectively, P=0.16). Although the forearm flow-mediated dilatation of the patients with coronary artery ectasia did not differ from that of patients with coronary artery disease alone (5.5+/-3.8 vs. 4.8+/-3.6%, respectively, P=0.41), nitrate-mediated dilatation was significantly lower than that of patients with coronary artery disease alone (7.9+/-5.2 vs. 10.9+/-5.4%, respectively, P=0.02). CONCLUSION: We have shown that patients with coronary artery ectasia have decreased nitrate-mediated response of brachial artery compared with patients with coronary artery disease alone, suggesting more severe dysfunction or, possibly, destruction of the media layer in coronary artery ectasia than in coronary artery disease.     

Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C

Endothelial dysfunction in the coronary artery contributes to the pathogenesis of variant angina, and endothelial dysfunction in variant angina may be associated with increased oxidant stress in the systemic arteries. We investigated whether endothelial dysfunction exists in the peripheral artery in patients with variant angina, and also examined the effect of vitamin C, an antioxidant, on endothelium-dependent vasodilation. Using high-resolution ultrasound, both the flow-mediated vasodilation (FMD, endothelium-dependent vasodilation) and sublingual nitroglycerin-induced vasodilation (NTG-D, endothelium-independent vasodilation) in the brachial artery were measured in 28 patients with variant angina and 24 control subjects who had normal coronary arteries. FMD was significantly impaired in patients with variant angina compared with control subjects (1.8 +/- 2.2% vs 6.4 +/- 4.9%, p <0.001). FMD and NTG-D before and after intravenous administration of either vitamin C or placebo were measured in 17 patients with variant angina. FMD significantly improved after the administration of vitamin C (from 2.2 +/- 2.4% to 4.5 +/- 1.6%, p <0.01), but not after administration of the placebo (from 2.0 +/- 2.6% to 1.7 +/- 1.9%). The improved FMD due to vitamin C in patients with variant angina, however, was not significantly different from that in the control subjects. NTG-D was not significantly different between patients with variant angina and control subjects (14.0 +/- 7.8% vs 13.6 +/- 5.0%) and it was also not affected by vitamin C. In conclusion: (1) FMD in the brachial artery is impaired in patients with variant angina, and (2) the acute administration of the antioxidant, vitamin C, was observed to reverse this endothelial dysfunction. These findings support the theory that the systemic inactivation of nitric oxide due to oxidative stress might exist in patients with variant angina.     

Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.     

Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter.

BACKGROUND: Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform. METHODS: We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4,040 ultrasound examinations from subjects aged 14 to 98 years. RESULTS: Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 +/- 0.10% (mean +/- standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 +/- 0.87 mm and 0.15 +/- 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P< 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2,315) had significantly larger per cent change in diameter than men (n=1,725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001). CONCLUSIONS: Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.     

Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy

Normal menopause is associated with vascular endothelial dysfunction, an early stage of atherosclerosis. The effect of premature ovarian failure (or premature menopause) on endothelial function in young women is unknown. Endothelial function was assessed in 18 women with premature ovarian failure before and after 6 months of hormone therapy and was compared with the endothelial function of 20 age- and body mass index-matched premenopausal women. Brachial artery diameter was measured both during hyperemia (an index of endothelium-dependent vasodilation) and in response to glyceryl trinitrate (an index of endothelium-independent vaso-dilation). Flow-mediated dilation was significantly lower in women with premature ovarian failure at baseline (increase in brachial artery diameter during hyperemia by 3.06 +/- 4.33%) than in control women (increase by 8.84 +/- 2.15%; P < 0.0005). Glyceryl trinitrate-induced vasodilation did not differ between the groups. After hormone therapy for 6 months, flow-mediated dilation was improved in women with premature ovarian failure, increasing by more than 2-fold (7.41 +/- 3.86%; P < 0.005 compared with pretreatment) and reaching normal values (P not significant compared with control women). Glyceryl trinitrate-induced vasodilation did not change after treatment in women with premature ovarian failure. Young women with premature ovarian failure have significant vascular endothelial dysfunction. Early onset of endothelial dysfunction associated with sex steroid deficiency may contribute to the increased risk of cardiovascular disease and mortality in young women with premature ovarian failure. Hormone therapy restores endothelial function within 6 months of treatment.