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.     

Endothelial dysfunction in normotensive Chinese with a family history of essential hypertension

Endothelial dysfunction is seen in patients with essential hypertension. However, it is still debated whether impaired endothelial function occurs before the development of hypertension. The aim of our study was to investigate whether endothelial dysfunction occurs in genetically vulnerable normotensive Chinese, and whether the endothelial dysfunction is worse as essential hypertension progresses. Endothelial function was assessed by high-resolution vascular ultrasound (7.5 MHz). The diameters of brachial arteries were measured at rest, during reactive hyperemia, and after sublingual administration of nitroglycerine (GTN) in 58 subjects with a mean age of 46.7 +/- 10.1 years. Among them, 18 patients had essential hypertension (Group 2), 20 normotensive subjects had a family history of hypertension (Group 3), and 20 normotensive subjects without a family history of cardiovascular diseases served as controls (Group 1). There was no difference in age among the three groups (Group 1: 46.5 +/- 10.5 versus Group 2: 46.7 +/- 9.5 versus Group 3: 44.50 +/- 11.21 years, P = NS). Flow-mediated dilatation of brachial arteries was significantly reduced in Group 2 and 3 as compared with Group 1 (Group 1: 13.2 +/- 5.9% versus Group 2: 8.0 +/- 3.6 versus Group 3: 4.86 +/- 3.5, both p < .01). On the other hand, nonflow mediated vasodilatation in response to GTN did not differ among the three groups. Endothelium-dependent vasodilatation is impaired not only in normotensive subjects with a family history of hypertension, but also becomes worse in the hypertensive patients.     

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.     

Maladaptive arterial remodeling with systemic hypertension associated with increased concentrations in blood of plasminogen activator inhibitor type-1 (PAI-1)

Increased carotid artery intima-media thickness (IMT), but not necessarily peripheral vessel IMT, accompanies atherosclerosis. We hypothesized that IMT in a peripheral, muscular artery known to be resistant to atherosclerotic changes would increase with hypertension, thereby limiting increases in wall stress and potentially preserving endothelial cell function reflected by flow-mediated dilation (FMD). Plasminogen activator inhibitor type-1 (PAI-1) can inhibit vascular smooth muscle cell migration contributing to increased IMT. Thus, increased PAI-1 may attenuate the mural adaptive response. A high-resolution scanner designed to delineate brachial artery FMD and IMT was used in studies of previously untreated patients with essential hypertension (n = 18) and age- and gender-matched normotensive subjects (n = 15). Brachial IMT was increased with hypertension (0.36 +/- 0.07 vs 0.27 +/- 0.03 mm in controls, p <0.01), and FMD was lower (3.6 +/- 1.5% vs 7.8 +/- 3.6, p <0.01). PAI-1 antigen in blood was increased (40.5 +/- 31.8 vs 26.3 +/- 11.6 ng/ml, p <0.05). IMT and FMD correlated positively (r = 0.63, p <0.05) in hypertensive patients. FMD correlated inversely with wall stress (r = -0.57, p <0.05). IMT correlated inversely with PAI-1 (r = -0.61, p <0.05). These observations support the hypothesis that increased PAI-1 attenuated increases in neointimal vascular smooth muscle cell cellularity. Thus, increased PAI-1 may attenuate a mural, adaptive response to hypertension associated with preservation of endothelial cell function.     

The relationship of left ventricular mass to endothelium-dependent vasodilation of the brachial artery in patients with hypertension.

Although echocardiographically determined left ventricular mass and geometry predict cardiovascular morbid events in patients with hypertension, the mechanisms underlying this relation are unclear. There is considerable evidence that endothelium-dependent vasodilation is impaired in patients with hypertension. Thus, endothelial dysfunction may contribute to the mechanism that causes cardiovascular morbid events. This study was designed to examine the relationship between left ventricular geometry and endothelial function in patients with hypertension. The percentage increase in brachial arterial diameter during reactive hyperemia was examined by a high-resolution ultrasound technique in 49 patients with hypertension and 64 normotensive subjects. Patients with hypertension had an impairment of the percentage increase in brachial arterial diameter during reactive hyperemia and an increase in thiobarbituric acid-reactive substances (TBARS) compared to normotensive subjects (percentage increase in diameter 5.6 +/- 3.0 vs. 8.0 +/- 2.5%, p < 0.001; TBARS levels 6.1 +/- 1.3 vs. 5.3 +/- 1.0 nmol/ml, p < 0.001). In patients with hypertension, there was a significant correlation between the left ventricular mass index and the percentage increase in brachial arterial diameter during reactive hyperemia (r = -0.583, p < 0.001), and the percentage increase in brachial arterial diameter during reactive hyperemia varied with the pattern of left ventricular geometry (normal ventricular geometry: 7.7 +/- 2.6%; concentric remodeling: 5.2 +/- 2.3%; eccentric hypertrophy: 4.2 +/- 1.8%; concentric hypertrophy: 2.9 +/- 2.6%). We conclude that (1) flow-mediated endothelium-dependent vasodilation in the brachial artery is impaired in patients with hypertension, (2) a relationship exists between the left ventricular mass index and flow-mediated endothelium-dependent vasodilation in the brachial artery in patients with hypertension and (3) increased oxidative stress may play a role in the endothelial dysfunction in patients with hypertension.     

Endothelial cell function during atrial fibrillation and after restoration of sinus rhythm

Beat-to-beat variation in blood flow dynamics during atrial fibrillation (AF) has been associated with evidence of endothelial dysfunction. The aim of the present work is to confirm endothelial dysfunction in patients with AF and test the hypothesis that endothelial dysfunction is reversible upon restoration of normal sinus rhythm. Endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (nitroglycerin-mediated dilation [NMD]) vasodilator function of the brachial artery were measured using high-resolution ultrasound in 46 patients with persistent AF who were scheduled for internal electrical cardioversion and in 25 control subjects. In patients who remained in sinus rhythm after cardioversion, these measurements were repeated after 24 hours (n = 32) and 1 month (n = 19). Compared with control subjects, patients (n = 32) showed lower FMD during AF (8.1 +/- 3.6% vs 12.2 +/- 3.2%, respectively, p <0.001) and similar NMD (17.0 +/- 3.5% vs 15.9 +/- 3.1%, respectively, p = 0.21). In 19 patients who remained in sinus rhythm, FMD increased at both 24 hours (8.0 +/- 3.9% vs 10.6 +/- 4.6%, p = 0.015) and 1 month (8.0 +/- 3.9% vs 13.6 +/- 5.3%, p <0.001). In contrast, NMD was not significantly altered at 24 hours or 1 month after sinus rhythm restoration (17.1 +/- 3.9% vs 17.2 +/- 4.0% vs 16.9 +/- 4.1%). In conclusion, AF is associated with impairment in endothelial function that improves after sinus rhythm restoration.     

Obstructive sleep apnea syndrome: a cardiovascular risk factor?

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is frequently associated with cardiovascular disease. We investigated endothelium-dependent and endothelium-independent nitric oxide-mediated vasodilatory function in normotensive patients with OSAS using the hand vein compliance technique. PATIENTS AND METHODS: Dose-response curves to the endothelium-dependent vasodilator bradykinin were obtained in 23 male subjects with OSAS and 12 male control subjects of comparable age, height, and weight. RESULTS: Mean (+/- SD) maximum dilation (Emax) to bradykinin was significantly lower in OSAS patients than in controls (59.8 +/- 26.0 vs. 94.8 +/- 9.5%, p < 0.0001). Mean vasodilation with nitroglycerin was not diminished in the OSAS group (90.7 +/- 30.5 vs. 100.3 +/- 12.9% in controls; n.s.). In 11 OSAS patients, a follow-up investigation was performed after at least 2 months of treatment with nasal continuous positive airway pressure (CPAP): Emax to bradykinin rose from 54.5 +/- 19.2% to 111.5 +/- 25.1% after treatment (p < 0.001). Mean vasodilation to nitroglycerin was unchanged. CONCLUSIONS: These results suggest that endothelium-dependent nitric oxide-mediated vasodilation is impaired in patients with OSAS due to an impaired function in the endothelial cells. This impairment is reversible with CPAP treatment.     

Status of home blood pressure measured in morning and evening: evaluation in normotensives and hypertensives in Japanese urban population.

To assess home blood pressure status in a Japanese urban population, we analyzed home blood pressure values in normotensive subjects determined by casual blood pressure (< 140/90 mmHg), hypertensive subjects without medication (> or = 140/90 mmHg) and treated hypertensive patients. The subjects (468 male, 232 female; mean age 41 years old) were recruited from a company located in Tokyo. Home blood pressure was measured with a semi-automatic device (Omron HEM-759P). Subjects were instructed to perform triplicate morning and evening measurements on 7 consecutive days. In the treated hypertensive group (n = 70), there was a significant difference between morning (139 +/- 12/88 +/- 9 mmHg) and evening (130 +/- 12/79 +/- 8 mmHg) home blood pressure. In the normotensive group (n = 558), however, only the diastolic blood pressure (DBP) component of the home blood pressure was significantly different between morning (115 +/- 13/72 +/- 9 mmHg) and evening (114 +/- 12/68 +/- 8 mmHg). In the nontreated hypertensive group (n = 72), casual blood pressure (145 +/- 14/92 +/- 9 mmHg) was higher than morning (138 +/- 16/89 +/- 11 mmHg) and evening (134 +/- 16/83 +/- 11 mmHg) home blood pressure, but no difference was seen between morning and evening systolic blood pressure (SBP). According to the reference value of the Japanese Society of Hypertension 2004 (SBP > or = 135 mmHg and/or DBP > or = 85 mmHg), 7.2% (systolic) and 8.7% (diastolic) of subjects in the normotensive group were classified as hypertensive by home blood pressure. Casual blood pressure in the treated hypertensive group was normal in 64.3% for SBP and 70.0% for DBP. However, their morning SBP (32.9%), morning DBP (40.0%), evening SBP (10.0%), and evening DBP (17.1%) were classified as hypertensive by home blood pressure. Furthermore, patients who were taking antihypertensive drug(s) only in the morning (n = 52) showed higher morning SBP (6 mmHg, p = 0.086) and morning DBP (6 mmHg, p = 0.005) than patients taking drug(s) by other administration schedules (n = 18), but no difference in evening home blood pressure was observed. In conclusion, a proportion of the subjects defined as normotensive by casual blood pressure were classified as hypertensive by home blood pressure in the present urban population. Furthermore, morning home blood pressure control in the treated hypertensive group classified as under control by casual blood pressure was insufficient, especially in patients who were taking medication only in the morning.     

Endothelial function fluctuates with diurnal variation in the frequency of ischemic episodes in patients with variant angina

OBJECTIVES: The aim of the present study was to investigate whether there is diurnal fluctuation in the endothelial function of patients with variant angina (VA). BACKGROUND: Coronary spasm is induced by acetylcholine and is promptly relieved by nitroglycerin. Thus, it is possible that endothelial dysfunction is involved in the pathogenesis of coronary spasm. Furthermore, the frequency of ischemic episodes is known to display diurnal variation. METHODS: Flow-mediated, endothelium-dependent vasodilation of the brachial arteries was measured in the early morning (6 AM), afternoon (2 PM) and evening (8 PM) in 20 patients with VA (mean age 54.5 years; 10 men and 10 women) and in 20 control subjects (mean age 54.2 years; 10 men and 10 women). All patients underwent 24-h ambulatory electrocardiographic monitoring during the study. RESULTS: Flow-mediated vasodilation in patients with VA was deteriorated by the early morning and improved by the afternoon (patients with VA at 8 PM vs. 6 AM vs. 2 PM: 7.8 +/- 2.1% (p < 0.01 vs. VA at 6 AM) vs. 5.4 +/- 2.3% vs. 8.8 +/- 1.9% (p < 0.01 vs. VA at 6 AM); control subjects: 9.5 +/- 2.8% vs. 9.0 +/- 2.2% vs. 9.9 +/- 1.9%, respectively). The frequency of spontaneous ischemic episodes was highest from midnight to morning and was lowest from morning to late afternoon (4 PM to midnight: 7 episodes; midnight to 8 AM: 25 episodes; 8 AM to 4 PM: 3 episodes). CONCLUSION: There is diurnal fluctuation in endothelial function, which is associated with variation in the frequency of ischemic episodes.     

Cross-sectional study of endothelial function in HIV-infected patients in Brazil

Antiretroviral therapy (ART) in HIV-infected patients has been associated with an increased risk of cardiovascular disease. This study evaluates vascular endothelial dysfunction of the peripheral circulation in Brazilian HIV-infected subjects on ART or naive to ART compared to a control group matched for age and body mass index (BMI). We performed a cross-sectional comparative study to measure postischemic peak flow-mediated dilation (FMD) of the brachial artery and the response to glyceryl trinitrate (GTN) in HIV-infected patients and healthy controls in Salvador, Bahia, Brazil. Endothelial vasomotor function was evaluated by assessing brachial artery FMD. Forty-four HIV-infected individuals (33 ARV treated and 11 ART naive) were compared to 25 healthy controls matched for age and BMI. FMD % was significantly lower for the ART-experienced patients compared to the ART-naive patients and was also significantly different from controls (ART experienced 8.2 +/- 6.0% vs. 19.3 +/- 4.8% vs. 23.3 +/- 6.1%), respectively (p < 0.0001). The cholesterol, triglyceride, and ALT levels were significantly higher in the ART-experienced group compared to the ART-naive and control subjects (p < 0.028); however, linear regression analysis revealed a statistically significant association of endothelial dysfunction as a dependent variable only with ARV treatment in HIV-infected subjects (p = 0.03). The association of endothelial dysfunction with ARV therapy in HIV-infected patients was independent of protease inhibitor-containing regimens or dyslipidemia. This dysfunction may contribute to the risk for HIV-associated atherosclerosis.     

Sleep apnea syndrome and diastolic blood pressure elevation during exercise

BACKGROUND: Several studies assessing the role of obstructive sleep apnea syndrome (OSAS) as an independent risk factor for hypertension have produced conflicting results. Although the sleep apnea syndrome is associated with hypertension, there are no references regarding the blood pressure response of normotensive OSAS patients during exercise. STUDY OBJECTIVES: The aim of this study was to investigate the relationship between diastolic blood pressure (DBP) response during exercise and the severity of OSAS. METHODS: We performed exercise testing a day after polysomnography in 17 normotensive males who were admitted for the first time because of OSAS and in 10 normal subjects who were members of the same families. During maximal incremental exercise test (bicycle ergometry) oxygen consumption (VO(2)) and the DBP were estimated at rest and at peak exercise. VO(2) was also measured when DBP were 100 and 110 mm Hg. RESULTS: At peak exercise DBP was significantly higher in OSAS patients (115.3 +/- 9.2 mm Hg) than in normal subjects (101 +/- 8.4 mm Hg, p < 0.01). OSAS patients reached a DBP of 110 mm Hg with a significantly lower VO(2) than normal subjects (1,881.5 +/- 703.4 vs. 1,972.3 +/- 108.6 ml/min, p = 0.045). VO(2) was not different between the two groups at a DBP of 100 mm Hg (1,211.2 +/- 371.7 vs. 1,536.6 +/- 267.2 ml/min, p = 0.089) but OSAS patients had a significantly lower heart rate than normals (111.2 +/- 13 vs. 118.6 +/- 27.6, p = 0.009). None of the aspects of quality of life, according to the Nottingham Health Profile Questionnaire, Part 1, were significantly different between patients and normal subjects. CONCLUSIONS: Normotensive OSAS patients develop DBP elevation at an earlier stage during exercise compared to normal subjects. This hypertensive response was not correlated with the severity (apnea-hypopnea index, oxygen desaturation parameters) of OSAS. DBP elevation could be a limiting factor of physical performance in this group of patients.     

The association of acute exercise-induced ischaemia with systemic vasodilator function in patients with peripheral arterial disease

Patients with peripheral arterial disease (PAD) frequently experience ischaemic attacks of the affected tissues during exercise. The present study assesses the association of transient exercise-induced leg ischaemia with vasodilator function of the clinically unaffected brachial artery over the course of 4 hours. Thirty male patients with symptomatic PAD and 14 age- and sex-matched healthy controls were included in the study. They performed a treadmill exercise until intolerable exercise-induced ischaemic pain occurred in the affected lower extremity, or for at most 10 min. Flow-mediated dilation (FMD) of the brachial artery was measured at baseline, 30 minutes, 2 hours and 4 hours after exercise. Baseline FMD values were significantly diminished in patients (7.03 +/- 1.99% vs 8.22 +/- 1.60% in controls, p = 0.009). A significant decrease in FMD was observed in patients after exercise (at 30 minutes: 3.92 +/- 1.78% vs 7.03 +/- 1.99% at baseline, p < 0.001; at 2 hours: 6.36 +/- 2.12% vs 7.03 +/- 1.99% at baseline, p = 0.005), followed by a gradual return to its baseline value, whereas FMD in controls non-significantly increased after exercise. The difference in the pattern of FMD change over time between patients and controls was significant (p < 0.001). This study shows that in PAD patients ischaemia during intermittent claudication is related to a transitory functional deterioration of the distant arteries. This indicates the harmful systemic effects of repeated ischaemic attacks during exercise and might explain the generalized and advanced nature of atherosclerotic disease in PAD patients.     

Large and small artery endothelial function in patients with essential hypertension--effect of ACE inhibition and beta-blockade

Hypertension has been associated with changes in endothelial function in both large muscular arteries and small resistance arteries. We evaluated the relationship between blood flow velocity and dilatation of the brachial artery following transient forearm ischemia and acetylcholine-induced relaxation in subcutaneous small arteries and the influence of antihypertensive therapy on both in patients with essential hypertension. Thirty-one previously untreated hypertensive patients were randomized in a double-blind fashion to treatment with either the angiotensin-converting enzyme (ACE) inhibitor perindopril or the beta-blocker atenolol and compared with 17 healthy normotensive controls. Before and after 1 year of treatment, while still on active medication, flow-mediated dilatation (FMD) was measured in the brachial artery using ultrasound while relaxation to acetylcholine in small arteries was tested in vitro in a myograph. FMD correlated inversely to resting brachial artery diameter (r = -0.38, p<0.05). FMD corrected for resting diameter (FMD(corr)) was lower in patients (3.0+/-0.2%) compared with controls (4.2+/-0.3%, p<0.01). In both patients and controls, FMD(corr) was related to flow velocity in a non-linear way with FMD(corr) reaching a maximum despite increasing flow velocities, and in the patients, FMD(corr) was only reduced at high flow velocities. Furthermore, patients had a reduced acetylcholine-induced relaxation in small arteries (p = 0.04). Perindopril and atenolol reduced blood pressure to similar levels and both drugs improved FMD(corr) to a similar degree without any effects on relaxation to acetylcholine in small arteries. The present study demonstrates the role of correcting for differences in baseline diameter during measurements of FMD and a non-linear relationship between flow velocity and FMD in the brachial artery. Furthermore, the results suggest different effects of antihypertensive treatment on endothelial function in large and small arteries.     

Alveolar-derived exhaled nitric oxide is reduced in obstructive sleep apnea syndrome

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular diseases, in particular systemic arterial hypertension. We postulated that intermittent nocturnal hypoxia in OSAS may be associated to decreased fractional exhaled nitric oxide (FENO) levels from distal airspaces. METHODS: Multiple flow rate measurements have been used to fractionate nitric oxide (NO) from alveolar and bronchial sources in 34 patients with OSAS, in 29 healthy control subjects, and in 8 hypertensive non-OSAS patients. The effect of 2 days of treatment with nasal continuous positive airway pressure (nCPAP) on FENO was examined in 18 patients with severe OSAS. RESULTS: We found that the mean [+/- SE] concentrations of exhaled NO at a rate of 50 mL/s was 21.8 +/- 1.9 parts per billion (ppb) in patients with OSAS, 25.1 +/- 3.3 ppb in healthy control subjects, and 15.4 +/- 1.7 ppb in hypertensive control patients. The mean fractional alveolar NO concentration (CANO) in OSAS patients was significantly lower than that in control subjects (2.96 +/- 0.48 vs 5.35 +/- 0.83 ppb, respectively; p < 0.05). In addition, CANO values were significantly lower in OSAS patients with systemic hypertension compared to those in normotensive OSAS patients and hypertensive patients without OSAS. The mean values of CANO significantly improved after nCPAP therapy (2.67 +/- 0.41 to 4.69 +/- 0.74 nL/L, respectively; p = 0.01). CONCLUSIONS: These findings suggest that alveolar FENO, and not bronchial FENO, is impaired in patients with OSAS and that this impairment is associated with an increased risk of hypertension. NO production within the alveolar space is modified by treatment with nCPAP.     

Treatment of essential arterial hypertension with enalapril does not result in normalization of endothelial dysfunction of the conduit arteries

It is assumed that endothelial dysfunction due to arterial hypertension could be improved or even normalized by antihypertensive treatment. The present study was designed to explore that assumption in patients with essential hypertension treated with an angiotensin-converting enzyme (ACE) inhibitor-enalapril. Twenty-eight patients (mean age: 55.1 years) who fulfilled the following criteria were included: essential arterial hypertension present for more than 2 years, monotherapy with enalapril for at least 1 year, adequate treatment (blood pressure in the last year <140/90 mm Hg) and absence of other factors (smoking, hypercholesterolemia, diabetes, obesity), which could importantly influence endothelial function. The flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery was assessed by high-resolution ultrasound and compared with that of 22 age-matched healthy normotensive controls. The patients and controls did not differ in regard to body mass index, lipids, and plasma glucose and insulin; there were no smokers. FMD of the brachial artery was significantly decreased in patients in comparison to controls (7.9% vs 13.5%, p<0.01). FMD in patients was inversely correlated with the duration of hypertension (r = -0.52, p<0.01) and with both systolic (r = -0.72, p<0.01) and diastolic (r = -0.43, p<0.05) blood pressure (measured after temporary withdrawal of treatment). This study showed that the adequate control of blood pressure achieved with enalapril is not followed by normalization of endothelial function, measured by FMD of the brachial artery.     

Association of cardiovascular risk factors and endothelial dysfunction in japanese hypertensive patients: implications for early atherosclerosis.

Although hypertension, hyperlipidemia, diabetes and smoking are known risk factors of atherosclerosis in Caucasians, their relative contributions to early atherosclerosis among Japanese are unknown. Decrease in flow-mediated dilation (FMD) of the brachial artery is a useful marker of endothelial dysfunction and early atherosclerosis. To evaluate the relative contribution of hypertension to early atherogenesis, we determined FMD, as well as plasma levels of tissue-type plasminogen activator (t-PA; a sensitive index of endothelial damage) and tumor necrosis factor (TNF)-a and interleukin (IL)-6 (established markers of inflammation) in normotensive and hypertensive patients under treatment. FMD was significantly reduced as the number of risk factors increased, suggesting that accumulations of risk factors were related to endothelial dysfunction. FMD was reduced in hypertensives (9.9 +/- 5.8 (SD) %) compared to normotensives (14.6 +/- 7.6, p<0.01) despite good blood pressure control (139 +/- 20/80 +/- 14 mmHg in hypertensives). Nitroglycerine-induced endothelium-independent vasodilation was not altered in hypertensives (16.0 +/- 6.3%) as compared to normotensives (16.7 +/- 5.8). Plasma t-PA, TNF-alpha, and IL-6 levels were increased in hypertensives despite good blood pressure control. Thus, hypertension alone is a high risk for early atherosclerosis. Persistent endothelial damage and moderate inflammation may increase the risk of early atherosclerosis synergistically under the presence of hypertension in Japanese.     

Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy

The aim of this study was to assess the relation between peripheral endothelial function and myocardial perfusion reserve in patients with mild heart failure due to idiopathic dilated cardiomyopathy (IDC). Myocardial perfusion and brachial artery flow mediated dilation (FMD) were measured in 20 clinically stable patients with IDC (New York Heart Association classes I to III, ejection fraction 35 +/- 9%) and 13 apparently healthy subjects who were matched for age and lipid profile. Resting and hyperemic (dipyridamole; 0.56 mg/kg/min) perfusion were measured using oxygen-15-labeled water and positron emission tomography (PET). Perfusion reserve was calculated as the ratio of hyperemic to resting perfusion. FMD was assessed by measuring the change in brachial artery diameter in response to reactive hyperemia. Patients with IDC had lower hyperemic perfusion (1.73 +/- 0.83 vs 3.01 +/- 1.20 ml/min/g, p <0.001) and perfusion reserve (2.01 +/- 0.91 vs 3.08 +/- 1.35, p <0.01) compared with healthy subjects. Brachial artery FMD, however, was not different from that of the healthy subjects. Furthermore, neither hyperemic perfusion nor perfusion reserve was correlated with FMD in the patients with IDC, whereas the healthy subjects demonstrated a positive correlation between FMD and perfusion reserve (r = 0.57; p = 0.04). Thus, abnormal myocardial perfusion characterizes patients with IDC. Myocardial perfusion reserve and peripheral endothelial function do not parallel each other in patients with IDC.     

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.     

Improved endothelium dependent vasodilation in endurance athletes and its relation with ACE I/D polymorphism.

BACKGROUND: Aerobic exercise enhances endothelium-dependent vasodilation in healthy individuals. It is thought that exercise increases nitric oxide (NO) production and decreases NO inactivation, leading to an increase in NO bioavailability. Angiotensin II and NO have important roles in maintaining vascular tone. There are polymorphisms of the angiotensin converting enzyme (ACE) gene and the presence of the deletion (D) allele has been associated with higher concentrations of circulating and tissue ACE. In this study, the relationship between endothelial function and ACE gene polymorphisms was investigated in athletes and sedentary subjects. METHODS AND RESULTS: The study group comprised 56 endurance athletes and 46 sedentary subjects who underwent brachial artery ultrasonographic examination. ACE insertion (I) and D allele frequencies were analyzed in all patients. Baseline brachial artery diameter and resting blood flow were similar in athletes and controls (p > 0.05). The flow-mediated dilation (FMD) was 8.48+/-3.65% in athletes and 5.16+/-2.5% in controls (p = 0.0001). FMD was significantly different between ACE genotypes in the athletes (p < 0.0001): it was higher in ACE II (10.5+/-1.6%) subjects than in the DI (8.4+/-2.3%) or DD (7+/-1.2%) subgroups. CONCLUSION: Regular isotonic exercise can improve endothelium-dependent vasodilation especially in those with the ACE II genotype.     

Left ventricular hypertrophy and endothelial functions in patients with essential hypertension

OBJECTIVE: In this study, we used a non-invasive method in patients with essential hypertension and without any overt clinical evidence of atherosclerosis to investigate the role of left ventricular hypertrophy (LVH) in endothelial functions. METHODS: We assessed endothelial function in 32 hypertensive patients with LVH (group 1), 28 hypertensive patients without LVH (group 2) and 29 normotensive subjects (control group). Flow-mediated (endothelium-dependent) and nitrate induced (endothelium-independent) dilatation of the brachial artery was evaluated in all groups. RESULTS: Flow-mediated dilatation was considerably higher in the control group than in group 1 and 2 (13.98 +/- 2.92%, 4.67 +/- 1.09% and 7.02 +/- 1.79% respectively, p < 0.001). In addition, endothelium-dependent dilatation was significantly lower in group 1 than in group 2 (p < 0.001), whereas nitrate induced changes were similar in all groups. CONCLUSION: Vascular endothelial functions are impaired in hypertensive patients. There may be heterogeneity of endothelial dysfunction among patients with hypertension. Presence of LVH has an additional negative effect on endothelial function in hypertensive patients.