Nitroglycerin-mediated Vasodilation Research Articles

Reply to Daiber et al. : “Doubt about an essential role for constitutive nitric oxide synthase in nitroglycerin-mediated vasodilation”

In a recent PNAS article (1) we demonstrated that endothelial NOS (eNOS) is phosphorylated at Ser-1177, an index of eNOS activation, in HUVEC and blood vessels of rodents challenged with nitroglycerin. In addition, we showed that the time scale in which this phosphorylation happens correlates with the drop in the blood pressure. We have also shown that at <10 nM concentrations nitroglycerin action depends on the endothelium and that above this dose the endothelium removal has little impact on vasodilation in isolated rat aortic rings. Contrary to the allegation by Daiber et al. (2) that our data contradict the literature are demonstrations that nitroglycerin activates eNOS (3, 4). Also, endothelium dependence of nitroglycerin effects, particularly at low concentrations, has been reported in experimental models (5) and in patients (6) with heart failure. The reading of our article reveals that we were aware that eNOS knockout animals are responsive to nitroglycerin. This has been published for some time and was referenced in our study (7). To reconcile our findings with this and other articles showing that impairment of eNOS leads to an improved response to nitroglycerin, we evaluated whether nitroglycerin modulates neuronal NOS (nNOS). Our findings demonstrated that nNOS is sensitive to nitroglycerin, which makes the statement that our article does not make any effort to reconcile our findings with the literature incorrect. We believe that considerable research is still needed to completely understand the mechanisms that lead to vasodilation and endothelial dysfunction, and our article adds to the literature, inviting the investigators of the field to consider eNOS and nNOS as possible mediators of nitroglycerin-induced vasodilation.

Coronary artery calcium score assessed by a 64 multislice computed tomography and early indexes of functional and structural vascular remodeling in cardiac syndrome X patients

Regardless of normal coronary angiograms, coronary artery calcium (CAC) can be found in cardiac syndrome X (CSX) patients. According to some data, a relationship between the CAC score and markers of early atherosclerosis in CSX has been observed. Our aim was to assess whether the extent of the CAC score assessed by multislice computed tomography (MSCT) with a 64-slice system in CSX patients is related to brachial artery reactivity, intima-media thickness (IMT), and arterial compliance indexes. High-resolution ultrasound was used to measure flow-mediated dilatation (FMD) and nitroglycerin-mediated vasodilatation, as well as the following parameters of arterial structural changes: IMT, pulse wave velocity, total arterial compliance, and stiffness index. MSCT was used to assess the presence and the quantity of CAC. The study group consisted of 46 CSX patients (mean age, 56.3 +/- 9 years), whereas the control group comprised 21 healthy subjects (mean age, 54.9 +/- 7 years). The assessment of the vascular parameters showed significantly decreased FMD and increased IMT in the CSX subjects (9.06% +/- 3.2% and 0.67 +/- 0.1 mm, respectively) in comparison to the control subjects (17.42% +/- 8.4% [P = .008] and 0.57 +/- 0.2 mm [P = .021], respectively). CAC was detectable in 19 CSX patients (41%) (CAC range according to Agatston score, 2-500; mean, 101.6; median, 26.5) and in 1 control subject (4.8%) (CAC value, 13). CSX patients with detectable CAC were characterized by a significantly higher age (P = .001), lower body mass index (P = .017), and increased stiffness index (P = .020); there were no differences in FMD and IMT values. In a multivariate logistic and linear regression analysis, age was the only risk factor independently associated with the presence of CAC (P = .001) and the log(CAC + 1) value (P = .01). In the subgroup of women, log(CAC + 1) significantly correlated with age (r = 0.587, P = .002) and stiffness index (r = 0.427, P = .024), and in a borderline significant manner, it correlated with weight (r = -0.329, P = .07) and waist-hip ratio (r = 0.315, P = .07). There were no significant correlations in the male subgroup. Low ranges of CAC are frequently detectable in CSX patients, and the results are age-related and independent of impaired early indexes of functional and structural vascular remodeling.

Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation

The physiological effects of nitroglycerin as a potent vasodilator have long been documented. However, the molecular mechanisms by which nitroglycerin exerts its biological functions are still a matter of intense debate. Enzymatic pathways converting nitroglycerin to vasoactive compounds have been identified, but none of them seems to fully account for the reported clinical observations. Here, we demonstrate that nitroglycerin triggers constitutive nitric oxide synthase (NOS) activation, which is a major source of NO responsible for low-dose (1-10 nM) nitroglycerin-induced vasorelaxation. Our studies in cell cultures, isolated vessels, and whole animals identified endothelial NOS activation as a fundamental requirement for nitroglycerin action at pharmacologically relevant concentrations in WT animals.

Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease

Background Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. The aim of this study was to detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects without apparent coronary artery disease (CAD). Methods We prospectively assessed brachial flow-mediated dilation (FMD) in 435 consecutive healthy subjects: 281 (65%) men, mean age 54 ± 12 years and body mass index 28 ± 4 kg/m 2. After overnight fasting and discontinuation of all medications for ≥ 12 h, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high resolution linear array ultrasound. Results Subjects were divided into 2 groups: below ( n = 221) and above ( n = 214) the median FMD of 10.7%, and were comparable regarding CAD risk factors, lipoproteins, fasting glucose, C-reactive protein, and concomitant medications, with a mean clinical follow-up of 32 ± 2 months. Composite cardiovascular endpoints (all-cause mortality, non-fatal myocardial infarction, heart failure or angina pectoris hospitalization, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with below median FMD of 10.7%, than above (11.8% vs 4.7%, p = 0.007, respectively). Univariate analysis demonstrated that median FMD significantly predicted cardiovascular events [odds ratio (OR) of 2.78 and 95% CI 1.35 to 5.71 ( p = 0.003)]. After multivariate analysis including conventional CAD risk factors, median FMD was the best independent predictor of long-term cardiovascular adverse events [OR of 2.70 and 95% CI 1.16 to 6.32 ( p = 0.011)]. Conclusions Brachial artery median FMD independently predicts long-term adverse cardiovascular events in healthy subjects in addition to traditional risk factor assessment.

The Acute Effect of Cardiac Pacing Mode on Endothelial Vasodilation: Prospective, Double‐Blind, Cross‐Over, Comparative Clinical Study

Compared to atrioventricular sequential pacing, ventricular demand pacing is known to have somewhat more deleterious hemodynamic effects, which probably arise from increased sympathetic tonus and inappropriate baroreceptor activation. Endothelial function is affected by various local and systemic factors including baroreceptor activity. The aim of this study was to explore whether cardiac pacing would have any effect on endothelial functions. Twelve patients (six male, mean age: 75 +/- 9 years) with previously implanted DDD or VDDcardiac pacemakers were included. All patients had stable atrial rhythms during the study. Patients were randomized to either atrial-based pacing mode (VDD or DDD) or ventricular demand pacing mode (VVI) first, and then cross-over was performed with the other pacing mode. Endothelial function was assessed by brachial artery ultrasonography. Basal diameter of the brachial artery, and both flow-mediated dilation (FMD) and endothelium-independent vasodilation with nitroglycerin were measured 1 hour after each pacing mode. Compared to atrial-based pacing mode, ventricular demand pacing was associated with a significantly worse FMD both as absolute and percentage values (0.17 +/- 0.09 mm vs 0.28 +/- 0.11 mm, P = 0.015 and 4.84 +/- 2.37 % vs 7.00 +/- 2.88 %, P = 0.028, respectively). However, there was no significant difference in nitroglycerin-mediated vasodilation values between the two pacing sessions. Acute ventricular demand pacing (VVI pacing) is clearly associated with attenuation of FMD in patients with atrial-based pacing systems. The attenuation of endothelial vasodilation might have a role in hemodynamic and clinical deterioration in patients with VVI pacemakers.

Glaucoma Is Associated with Peripheral Vascular Endothelial Dysfunction

To evaluate peripheral vascular endothelial function in patients with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG) using noninvasive endothelium-dependent flow-mediated vasodilation (FMD). Case-control study. Thirty patients with NTG, 30 with POAG, and 30 healthy age- and gender-matched controls. Participants underwent measurement of FMD and endothelium-independent nitroglycerin-mediated vasodilation (NMD) via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. All patients also underwent blood sampling for biochemistry, lipid profile, and high sensitivity C-reactive protein analysis. The association of FMD with NTG and POAG. The FMD values differed significantly between the patients with NTG, those with POAG, and controls: NTG, 2.70+/-2.25%; POAG, 5.33+/-2.81%; controls, 7.21+/-2.36%; P<0.001. In comparison with the POAG group and normal controls, the NTG group demonstrated markedly impaired FMD. The POAG group exhibited higher intermediate FMD than the NTG group (P<0.001) but significantly lower FMD than normal controls (P = 0.012). Multivariate analysis indicated that independent predictors for impaired FMD were presence of NTG, presence of POAG, and advanced age. Additionally, FMD values were significantly lower in glaucoma patients than in controls (4.02+/-2.85% vs. 7.21+/-2.36%; P<0.001). Patients with glaucoma have impaired FMD. Additionally, patients with NTG have lower FMD than those with POAG.

Anti-Cardiolipin Antibodies and Endothelial Function in Patients With Coronary Artery Disease

Endothelial dysfunction is considered an important marker in atherosclerosis, having a prognostic value. Antiphospholipid antibodies are considered prothrombotic and have recently been reported to be associated also with atherosclerosis. This study was conducted to investigate a possible association of endothelial dysfunction with various antiphospholipid autoantibodies in healthy subjects and patients with cardiovascular disease. In a single-center, prospective study, 2 groups were included. The study group included patients with cardiovascular diseases (coronary disease and/or cerebrovascular disease) and healthy subjects without apparent heart disease who were referred to the endothelial function laboratory for the assessment of endothelial function. Flow-mediated dilatation, which indicates endothelial function, and nitroglycerin-mediated vasodilatation, which indicates smooth-muscle function, were measured. The 2 groups were evaluated for autoantibodies, including anticardiolipin (aCL; immunoglobulin G [IgG], immunoglobulin M [IgM], and immunoglobulin A [IgA]), antinuclear antibody, anti-beta2-glycoprotein I (IgG, IgM, and IgA), and oxidized low-density lipoprotein. One hundred seven subjects were included in the study: 45 patients (42%) and 62 healthy controls (58%). Flow-mediated dilatation was significantly lower in patients compared with healthy controls (8.0 +/- 9.5% vs 8.0 +/- 13.5%, p = 0.012). In addition, nitroglycerin-mediated vasodilatation was nonsignificantly lower in patients than in healthy controls (8.0 +/- 13.4% vs 11.0 +/- 16.7%, p = 0.084). The mean levels of anti-beta2-glycoprotein I (IgG, IgM, and IgA), aCL (IgM and IgA), antinuclear antibody, and oxidized low-density lipoprotein were not different between groups. However, the mean level of IgG aCL was significantly higher in patients than in healthy controls. In conclusion, in accordance with previous reports of an association between aCL and atherosclerosis, patients with cardiovascular disease had endothelial dysfunction and elevated levels of aCL.

Cardiovascular and Endothelial Effects of Fish Oil Supplementation in Healthy Volunteers

Consumption of fish oil (FO) is associated with reduced adverse cardiovascular events. In a randomized, blinded, placebo-controlled trial, 26 subjects (17 men and 9 women; mean age [+/- SD] 31 +/- 3.7 years) received 1 g FO capsule (n = 14) or placebo (1 g of corn oil, n = 12) for 14 days. At day 0 and day 14, heart rate (HR), blood pressure, endothelium-dependent brachial artery flow-mediated vasodilation (EDV), and endothelium-independent nitroglycerin-mediated vasodilation (EIDV) were assessed with ultrasound. FO supplementation resulted in a significant increase in EDV (20.4% +/- 13.2% vs 9.9% +/- 5.4%; P = .036) and EIDV (32.6% +/- 16.8% vs 18.0% +/- 14.9%; P = .043). Resting HR decreased by a mean of 5.9 +/- 9.4 bpm (FO) compared with placebo (mean increase of 0.73 +/- 4.8 bpm [P = .05]). FO supplementation in healthy subjects is associated with improved endothelial function and decreased resting HR.

Vasomotor function of endothelium in patients with coronary artery disease and ventricular arrhythmias occurring during myocardial ischemia

Purpose: To compare vasomotor endothelial function in patients with coronary artery disease (CAD) with and without VA occurring during myocardial ischemia. Methods: We studied 48 patients with CAD who had electrocardiographic signs of ischemia during ergometer exercise testing. All patients were divided into 2 equal groups: group I with VA occurred at peak exercise or during recovery and group II without VA. Exercise test duration was similar in the groups I and II. None of the patients had severe arterial hypertension, diabetes mellitus or signs of heart failure. Assessment of endothelial-dependent flow-mediated vasodilation (FMD) and endothelial-independent nitroglycerin-mediated vasodilation of brachial artery (BA) was performed using high-resolution ultrasound. Plasma endothelin-1 levels were measured by immunoassay method. Results: FMD of BA was lower and duration of ischemic changes of ECG during recovery was greater in the group I compared with group II. There were no significant differences in plasma ET-1 levels among the groups I and II. Conclusions: The patients with CAD and VA occurring during ischemia have FMD impaired to a greater degree and duration of ischemic changes of ECG in recovery longer compared with ones without VA.

Smooth Muscle Dysfunction in Patients Older than 54 Years of Age with Objective Evidence of Arteriosclerosis

This investigation was designed to assess the relationship between flow-mediated vasodilatation (FMD) and nitroglycerin (NTG)-mediated vasodilatation (NMD) with atherosclerotic risk factors. FMD and NMD were measured in 75 subjects including 57 patients with atherosclerotic disease (AAA/PAOD=30/27, age 72+/-7 years) and 18 controls. Brachial response to hyperemia and NTG were measured every minute after cuff deflation and NTG administration. In the 75 subjects, responses to NTG showed a sigmoid curve. Only 2 cases reached maximal diameter within 4 minutes after NTG, and 90% of the cases reached maximal diameter at 6 minutes or later (7.5+/-2.0 minutes). In patients with atherosclerotic disease, a multiple regression analysis showed higher FMD was associated with higher NMD, and higher NMD was associated with smaller vessel size, lower systolic blood pressure, higher FMD, lower carotid maximal IMT, lower serum levels of insulin, and lower HOMA-IR. In subjects older than 54, NMD measured at 3 or 4 minutes after NTG administration would underestimate the NTG-dependent vasodilatation. NMD measured with the maximal responded diameter was associated with atherosclerotic risk factors, and it is therefore considered to be an important parameter in patients with atherosclerotic disease.

Flow‐Mediated Dilation and Gender in Patients with Coronary Artery Disease: Arterial Size Influences Gender Differences in Flow‐Mediated Dilation

The risk of atherosclerosis and its complications differs between male and female subjects. This is probably associated with gender differences in endothelial function as reflected by endothelium-dependent vasodilation. The aim of the study was to compare flow-mediated dilatation (FMD) in males and females with coronary artery disease (CAD), and to determine factors that might potentially influence FMD. Ninety-six patients with stable CAD (CCS II-III): 76 males (mean age: 57.7 +/- 10 years) and 20 postmenopausal females (mean age: 60.1 +/- 10 years) were included into the study. Clinical data, pharmacotherapy, concomitant diseases, and FMD were all assessed. FMD was measured with high-resolution ultrasound as the percent change of brachial artery diameter (BAd) after a 3-minute occlusion (%FMD), and following the administration of 0.4 mg sublingual nitroglycerin (%NTG-MD). The percentage of FMD was significantly decreased (P < 0.05), and BAd was significantly larger (P < 0.001) in males as compared to females. Clinical data, pharmacotherapy, and concomitant diseases were comparable in the study groups. In all subjects examined, %FMD was related to BAd (r =-0.415, P < 0.001) and the percentage of ejection fraction (EF%) (r = 0.325, P < 0.01) in the univariate analysis, and to BAd only (r =-0.343, P < 0.01) in the multivariate analysis. The percentage of nitroglycerine-mediated vasodilatation (NTG-MD) correlated negatively with BAd (r =-0.430, P < 0.001), and positively with EF% (r = 0.334, P < 0.01) in the univariate analysis, and with BAd (r =-0.288, P < 0.05) in the multivariate analysis. Index %FMD x BAd was comparable for male and female subjects. Males and postmenopausal females with CAD show differences in endothelium-dependent vasodilatation that seem to secondarily result from differences in the BAd. Objective comparison of %FMD is only possible between patients with the same brachial artery size.

Enhancement of endothelium‐dependent flow‐mediated vasodilation in hyperthyroidism

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. A case-control clinical study. 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. 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. This study demonstrated that endothelium-dependent FMD was increased in the hyperthyroid patients, and could be partially restored by treatment with antithyroid agents.

Endothelial Function Varies According to Insulin Resistance Disease Type

We examined the relationship between insulin resistance and vascular function in three insulin-resistant states (type 2 diabetes, non-HIV lipodystrophic diabetes, and nondiabetic polycystic ovary syndrome [PCOS]) and in healthy control subjects. The population included 12 women with type 2 diabetes, 6 with lipodystrophic diabetes, 10 with PCOS, and 19 healthy female subjects. Metabolic measures included insulin sensitivity by the homeostasis model assessment, lipids, free fatty acids, and adiponectin. High-resolution B-mode ultrasound was used to determine endothelium-dependent and -independent vasodilation. Type 2 diabetic, liposdystrophic, and PCOS subjects were insulin resistant compared with control subjects (P = 0.001). Flow-mediated vasodilation was reduced in diabetic (3.4 +/- 1.3%) compared with control (7.3 +/- 1.1%) subjects but not in lipodystrophic (7.7 +/- 1.2%) or PCOS (9.9 +/- 0.7%) subjects (P = 0.005). Nitroglycerin-mediated vasodilation was attenuated in both diabetic (15.2 +/- 2.0%) and lipodystrophic (16.7 +/- 3.6%) subjects compared with healthy control (24.6 +/- 2.4%) and PCOS (23.2 +/- 1.8%) subjects (P = 0.019). Insulin resistance, free fatty acids, adiponectin, or C-reactive protein did not associate with vascular dysfunction. Among these different types of patients with insulin resistance, we found abnormal endothelium-dependent vasodilation only in the patients with type 2 diabetes. We postulate that variations in the mechanism of insulin resistance may affect endothelial function differently than glucose homeostasis.

Radial Artery Diameter and Vasodilatory Properties After Transradial Coronary Angiography

The radial artery is proposed as an alternative conduit in coronary revascularization. During the last years the transradial approach has, in many centers, emerged as the preferred technique in percutaneous diagnostic and interventional coronary procedures. This induces a trauma to the radial artery that possibly could influence its suitability as a bypass graft. In this study we assessed by ultrasound the long-term effects of transradial coronary angiography on the radial artery diameter and vasodilatory properties. Thirty patients were examined with high resolution ultrasound 10 to 14 months after a transradial coronary angiography. Radial artery baseline diameter and response to flow-mediated (FMD) and nitroglycerin-mediated vasodilation (NMD) were examined in the right radial artery with the unexposed left radial artery as control. Right radial artery diameter was reduced compared with the left radial artery (2.58 +/- 0.38 vs 2.71 +/- 0.32 mm, p < 0.01). Both FMD and NMD were preserved in the exposed artery (FMD 8.4 +/- 8.0 vs 8.0 +/- 6.1%, NMD 15.5 +/- 6.8 vs 16.7 +/- 6.6%, both ns). Due to the reduced baseline diameter, the right radial lumen diameter remained significantly smaller after vasodilatory stimuli. Large interindividual differences were demonstrated. The radial artery diameter is diminished one year after transradial coronary angiography while vasodilatory properties are preserved. The preserved vasodilatory capacity could favorably influence the suitability of the artery as bypass graft. However, with the long-term structural changes induced by transradial angiography, use of a catheter-exposed radial artery as a conduit in coronary artery revascularization should not be strongly recommended. With ultrasound, both structure and vasodilatory properties of a catheterization-exposed radial artery may be assessed in case the artery is considered as bypass material.

The association between right coronary artery morphology and endothelial function

Background Two distinct right coronary artery (RCA) morphologies have been previously described: sigma- and C-shaped RCAs. While the C-shaped RCA was significantly associated with atherosclerosis, the sigma-shaped was not. The association of RCA morphology and vascular endothelial function has not yet been assessed. Methods To evaluate the association between the RCA's morphology and flow-mediated endothelium-dependent dilation (FMD) in patients without evidence of atherosclerotic lesions, we prospectively assessed FMD in 49 consecutive patients with non-specific chest pain, who were referred to our laboratory 30 ± 10 days after corroboration of normal coronary arteries on coronary angiography. Endothelium-dependent brachial artery FMD and endothelium-independent nitroglycerin-mediated vasodilation (NTG) were assessed using high resolution (15 MHz) linear array ultrasound. The patients were divided into 2 groups according to their RCA morphology on coronary angiograms (sigma and C) which were analyzed by 2 independent readers who were blinded to the patients' FMD results. Results The C-shaped group exhibited a significantly lower FMD compared to the sigma-shaped group (9.0 ± 4.2% vs. 14.3 ± 4.7%, p < 0.04, respectively), while NTG was the same in both groups. There were no significant group differences in other variables. Conclusions Endothelium-dependent FMD in the brachial artery is significantly greater in sigma- compared to C-shaped RCA in coronary arteries without overt atherosclerotic lesions, suggesting a potential mechanism whereby C-shaped RCA are predisposed to atherosclerosis.

Short-Term Sibutramine Therapy Is Associated With Weight Loss and Improved Endothelial Function in Obese Patients With Coronary Artery Disease

In obese patients with coronary artery disease (CAD), the vascular endothelium is usually impaired, and the modification or reversal of endothelial dysfunction may significantly enhance treatment. Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment, but its impact on endothelial function in obese patients with CAD has not yet been investigated. Eighty consecutive obese, nonhypertensive, stable patients with CAD (65 men; mean age 65 +/- 11 years, mean body mass index 32 +/- 3 kg/m2) were randomly assigned to either sibutramine 10 mg/day (n = 40) or routine treatment (n = 40; controls) for 4 months. The percentage improvement in endothelium-dependent brachial artery flow-mediated dilation (%FMD) and endothelium-independent nitroglycerin-mediated vasodilation were assessed at baseline and after 4 months using high-resolution ultrasound. At baseline, all patients had %FMD of 5.4 +/- 3.1% and percentage improvement in endothelium-independent nitroglycerin-mediated vasodilation of 9.2 +/- 2.9%, showing no significant differences. After 4 months, however, initial body weight was reduced by 11.4 +/- 1.2% in the sibutramine group compared with only 2.2 +/- 1.3% in controls (p <0.001), demonstrating a significant improvement in postintervention %FMD (8.9 +/- 2.4%, p = 0.01, compared with baseline) in the sibutramine group compared with controls (5.2 +/- 3.6%, p = 0.68, compared with baseline). No significant therapeutic effect on the percentage improvement in endothelium-independent nitroglycerin-mediated vasodilation was seen in either group (9.2 +/- 2.5% vs 9.1 +/- 3.0%, respectively, p = 0.792). In addition, sibutramine therapy was associated with significant C-reactive protein reduction compared with routine treatment (44% vs 9%, p = 0.035). Thus, short-term therapy with sibutramine, together with diet and lifestyle intervention, is associated with improved endothelial function assessed by brachial artery %FMD in nonhypertensive, stable patients with CAD.

Iron sucrose augments homocysteine-induced endothelial dysfunction in normal subjects

Intravenous iron is commonly used in conjunction with erythropoietic agents to treat anemia in patients with chronic kidney disease. Iron has been proposed to promote oxidative stress and endothelial dysfunction in vascular tissues. We studied the acute effects of intravenous iron sucrose on homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. In all, 40 healthy subjects received intravenous iron sucrose 100 mg or placebo over 30 min immediately before ingestion of 100 mg/kg of oral methionine in a double-blind, randomized study. Flow- and nitroglycerin-mediated dilation in the brachial artery, serum markers of iron stores, and homocysteine and nitrotyrosine levels were measured before and after study drug administration. Intravenous iron significantly increased transferrin saturation and non-transferrin-bound iron (NTBI) when compared with placebo. Flow-mediated dilation significantly decreased from baseline 1 h after administration of iron sucrose when compared with placebo (from 6.66+/-0.47 to 1.93+/-0.35% after iron sucrose vs from 6.00+/-0.40 to 5.61+/-0.46% after placebo, P<0.001), but did not differ between groups at 4 h (1.10+/-0.39 vs 1.33+/-0.51%). Nitroglycerin-mediated vasodilation, and homocysteine and 3-nitrotyrosine levels did not differ after administration of iron sucrose and placebo. Intravenous administration of iron sucrose in the setting of transient hyperhomocysteinemia induced by methionine ingestion significantly increased transferrin saturation and plasma levels of NTBI and significantly attenuated flow-mediated dilation in the brachial artery when compared with placebo. This potential mechanistic link between intravenous iron and endothelial dysfunction warrants further study of cardiovascular effects of intravenous iron in anemic chronic kidney disease populations.

The Changes in Atherosclerotic Markers and Adiopocytokines after Treatment with Growth Hormone for the Patients with Hypopituitarism and Growth Hormone Deficiency

Background: It is known that patients with hypopituitarism have a high mortality rate due to the presence of atherosclerosis, cardiovascul ar diseases and stroke. The aim of this study was the effect of growth hormone (GH) on the atherosclerotic markers and the adipocytokine levels. Method: The study was conducted on 13 adult patients with hypopituitarism and growth hormone deficiency (GHD), and they had been stabilized after receiving hormone replacement therapy for other insufficient pituitary hormones, other than GH, for more than o ne year. Before treatment with GH, we compared the lipid metabolism, glucose metabolism, cardiovascular risk factors and adipocytokine levels, including adiponectin, leptin, TNF-α and IL-6, between the GHD patients and 13 healthy adults who were of a similar age and gender distribution. Patients with GHD were treated with 1 U/day of GH for 6 months. We measured insulin-like growth factor- Ⅰ (IGF-Ⅰ), blood pressure, body composition, lipid metabolism, glucose metabolism and hs-CRP, cardiac function, adiponectin, leptin, TNF-α and IL-6 levels, flow mediated vasodilation (FMD) and nitroglycerin mediated vasodilation (NMD) before and after GH treatment. Results: The patients with hypopituitarism and GHD showed significantly higher levels of total cholesterol (P = 0.002), low-density lipoprotein cholesterol (LDL-C) (P = 0.036), hs-CRP (P = 0.0087) and leptin (P < 0.001) than did the normal healthy adults. However, there was no difference between the normal adults and the patients with GHD for the systolic and diastolic BP, the levels of apoA, apoB, fasting blood glucose(FBG) and HOMA-IR. In the subjects with GHD after treatment with GH, the level of fat mass (P = 0.0017), total cholesterol (P = 0.004), LDL-C (P = 0.001), leptin (P = 0.013), TNF-α (P < 0.001) and hs-CRP (P = 0.0001)

Enhanced Coronary Calcification Determined by Electron Beam CT Is Strongly Related to Endothelial Dysfunction in Patients With Suspected Coronary Artery Disease

Coronary artery calcification determined by electron beam CT (EBCT) is strongly associated with total plaque burden but is not related to systemic vascular inflammation. 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). 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). 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.

Transient impairment of flow-mediated vasodilation in patients with metabolic syndrome at moderate altitude (1700 m)

Background The influence of moderate altitude on the cardiovascular system in patients with metabolic syndrome has not been investigated sufficiently, yet. The aim of this study was to assess the effect of acute and mid-term exposure to moderate altitude (1700 m) on endothelial function in patients with metabolic syndrome. Methods Flow-mediated (FMD) and nitroglycerin-mediated vasodilation (NMD) were assessed in 18 patients with coronary risk factors on 5 occasions: (1) at location A (576 m), (2) on the first day at moderate altitude (location B, 1700 m), (3) after 3 weeks at moderate altitude, (4) and (5) again at location A (6 and 16 weeks after the stay at moderate altitude, respectively). In addition, markers of lipid metabolism, serum erythropoietin and endothelin were measured. Results FMD on the first day at moderate altitude was similar compared to baseline FMD at location A (7.0 ± 3.3 vs. 7.4 ± 4.6%; NS). A 3-week stay at moderate altitude was associated with a significant reduction in FMD (7.4 ± 4.6 vs. 3.8 ± 2.5%; p < 0.05) despite a decrease in baseline diameter (4.5 ± 0.3 vs. 4.3 ± 0.4 mm; p < 0.05). Six weeks after returning to location A, FMD was still reduced compared to baseline (4.3 ± 2.8%; p < 0.05) and after further 16 weeks, FMD returned to baseline values (5.5 ± 3.5%). However, metabolic parameters improved significantly. In contrast, NMD and endothelin levels remained unchanged. Conclusion In patients with metabolic syndrome, a sojourn of 3 weeks at moderate altitude leads to a prolonged, but reversible impairment of FMD. The discrepancy to improvement of other cardiovascular and metabolic parameters requires further investigation.