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

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

A T-786C polymorphism in 5'-flanking region of the endothelial nitric oxide synthase gene and endothelium-dependent arterial dilation in Type 2 diabetes.

OBJECTIVE: Several studies have shown that the T-786C polymorphism in 5'-flanking region of the endothelial nitric oxide synthase (eNOS) gene is associated with coronary artery disease in non-diabetic population. In the present study, we attempted to assess whether the T-786C polymorphism of eNOS gene is associated with endothelial dysfunction Type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 162 Type 2 diabetic men were studied. PCR/allele-specific probes were used to analyse the T-786C polymorphism of eNOS gene, and high resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate. RESULTS: The flow-mediated arterial dilation among subjects with T/C or C/C was 3.73+/-0.50%, which was significantly lower than that in subjects with T/T (4.15+/-0.49%) (P=0.000). On multiple linear regression analysis, the presence of C allele, mean blood pressure, low-density lipoprotein (LDL) and serum lipoprotein (a) [Lp(a)] were independent determinants for reduced endothelium-dependent arterial dilation (R2=0.175, P=0.0021). The flow-mediated arterial dilation in smokers with T/C or C/C was significantly lower than that in smokers with T/T (P<0.001), but not in non-smokers. In addition, the presence of C allele, LDL and Lp(a) were independent determinants for reduced endothelium-dependent arterial dilation (R2=0.258, P=0.0017) in smokers, but not in non-smokers. CONCLUSION: The C allele of T-786C polymorphism of eNOS gene is a genetic risk factor for endothelial dysfunction in Type 2 diabetic patients, especially among smokers.     

Endothelium-dependent and independent vasodilation studied at normoglycaemia in Type I diabetes mellitus with and without microalbuminuria

Aims/hypothesis. We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. Methods. Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. Results. Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 ± 0.3 %) compared with normoalbuminuric diabetic patients (5.4 ± 0.6 %) and control subjects (7.9 ± 0.6 %, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 ± 1.1 % vs 20.0 ± 1.2 %, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). Conclusion/interpretation. Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease. [Diabetologia (2001) 44: 593–601] Received: 6 November 2000 and in revised form: 11 January 2001     

Apolipoprotein e4 allele and endothelium-dependent arterial dilation in Type 2 diabetes mellitus without angiopathy

AIMS/HYPOTHESIS: Several studies have suggested a predisposing role of the e4 allele of apolipoprotein E (ApoE) in the development of atherosclerosis and cardiovascular disease in Type 2 diabetes. Therefore, we hypothesized that the e4 allele is also a risk factor for endothelial dysfunction. We attempted to assess whether Apo e4 allele is associated with endothelial dysfunction in the early stage of Type 2 diabetes. METHODS: We selected 255 Chinese Han Type 2 diabtetic men without angiopathy. PCR or allele-specific oligonucleotide probes were used to analyse ApoE genotypes, and high resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate. RESULTS: The flow-mediated arterial dilation among the subjects with e4/3 or e4/4 was 3.14+/-0.32%, which was lower than that in subjects with e2/2 or e3/2 (4.04+/-0.30%) ( p=0.038). The baseline vessel size, glyceryltrinitrate-induced arterial dilation and baseline flow were not different among different ApoE genotypes. On univariate analysis, reduced flow-mediated arterial dilation was related to total cholesterol, LDL, lipoprotein(a) [Lp(a)], high blood pressure, older age, family history of premature vascular disease, larger vessel size, cigarette smoking, duration of diabetes and e4 allele ( p<0.05). By multiple stepwise regression analysis, reduced flow-mediated arterial dilation was associated with cigarette smoking, LDL, Lp(a), and e4 allele ( p<0.01). CONCLUSION/INTERPRETATION: Apo e4 allele is associated with impairment of endothelium-dependent arterial dilation in the early stage of Type 2 diabetes.     

Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia

Elevated plasma levels of asymmetric dimethylarginine (ADMA) have been associated with attenuated endothelium-dependent vasodilation in hypercholesterolemic patients. However, whether lowering of plasma cholesterol concentration by hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) can reduce plasma ADMA levels is still not clear. This study was a multicenter, randomized, double-blind, placebo-controlled design including 46 patients with elevated low-density lipoprotein cholesterol levels. Patients were randomized into 2 groups: rosuvastatin 10 mg/day and placebo for 6 weeks. Plasma levels of ADMA, 8-isoprostane (as a marker of oxidative stress), homocysteine, and high-sensitivity C-reactive protein were measured at baseline and 6 weeks later. Endothelial function assessed by flow-mediated vasodilation of the brachial artery was performed in 11 patients in the rosuvastatin group and in 12 in the placebo group. Baseline characteristics of both groups were similar, and the plasma ADMA levels were significantly correlated with 8-isoprostane (r = 0.388, p = 0.008). After 6 weeks of treatment, plasma ADMA levels were significantly reduced in the rosuvastatin group (from 0.60 +/- 0.19 to 0.49 +/- 0.10 micromol/L, p <0.001). Increases in flow-mediated vasodilation were positively correlated with reductions in plasma levels of ADMA (p = 0.017) and low-density lipoprotein cholesterol (p <0.001). Thus, our findings suggest that treatment with rosuvastatin in patients with hypercholesterolemia may lead to a significant reduction in plasma ADMA levels, which appear to be related to the improvement in endothelial function by rosuvastatin.     

Glucose intolerance is associated with C-reactive protein and intima-media anatomy of the common carotid artery in patients with coronary heart disease.

AIMS: The purpose of this study was to examine the relationship between glucose intolerance and levels of hsCRP, calculated intima-media area (cIMa) of the carotid artery and flow-mediated dilation of the brachial artery in 122 patients with a myocardial infarction 1-12 months before inclusion and without known diabetes mellitus. METHODS: A standard oral glucose test (OGTT) was performed. Diabetes mellitus and impaired glucose tolerance (IGT) were defined according to the WHO criteria. Ultrasound measurement of cIMa of the carotid artery and flow-mediated dilation of the brachial artery were analyzed. RESULTS: Patients with diabetes mellitus had higher hs-CRP compared with patients with IGT and those patients with normal glucose tolerance (P < 0.05). The greater cIMa of the carotid artery in those with diabetes mellitus compared with normal subjects failed to reach conventional levels of significance (P = 0.058). hs-CRP and cIMa were associated with plasma glucose 120 min after the glucose load (P < 0.05). A multiple stepwise regression analysis, including all variables significantly associated with plasma-glucose 120 min after glucose ingestion as independent variables, revealed an independent and significant association between plasma-glucose 120 min after glucose ingestion in the OGTT and CRP (P < 0.05). No association was observed between glucose intolerance and endothelial function. CONCLUSION: Glucose intolerance was associated with hs-CRP and cIMa in patients with coronary heart disease without known diabetes mellitus. Thus, inflammation, atherosclerosis and impaired glucose tolerance are tightly interrelated disorders even in subjects without known diabetes mellitus.     

Insulin-like growth factor I (IGF-1) supplementation prevents diabetesinduced alterations in coenzymes Q<Subscript>9</Subscript> and Q<Subscript>10</Subscript>

Diabetes, which causes enhanced oxidative stress, is a multifactorial disease that leads to deleterious effects in many organ systems within the body. Ubiquinones (coenzyme Q₉ and Q₁₀) are amphipathic molecular components of the electron transport chain that function also as endogenous antioxidants and attenuate the diabetes-induced decreases in antioxidant defense mechanisms. Insulin-like growth factor 1 (IGF-1) is considered to be an “essential surviving factor”, the level and function of which are compromised in diabetes. This study investigated the impact of IGF-1 supplementation on ubiquinone levels in a rat model of type I diabetes. Adult male Sprague-Dawley rats were divided into four groups: control, control plus IGF-1, diabetic and diabetic plus IGF-1. Diabetic animals received a single intravenous injection of streptozotocin (STZ, 55 mg/kg). IGF-1 supplementation groups received a daily intraperitoneal dose of 3 mg IGF-1 per kilogram body weight for 7 weeks. Coenzyme Q₉ and Q₁₀ levels were assessed by ultraviolet detection on high pressure liquid chromatography. STZ caused a significant reduction in body weight and an elevation in blood glucose level, which were not prevented by IGF-1 supplementation. In addition Q₉ and Q₁₀ levels in diabetic liver were significantly elevated. IGF-1 supplementation prevented liver alterations in Q₁₀ but not Q₉ levels. Q₉ and Q₁₀ levels in diabetic kidney were significantly depressed, and these deleterious effects were abolished by IGF-1 treatment. These data suggest that IGF-1 antagonizes the diabetes-induced alterations in endogenous antioxidants including coenzyme Q₁₀, and hence may have a therapeutic role in diabetes. Received: 28 March 2002 / Accepted in revised form: 5 December 2002 Correspondence to J. Ren     

Biological correlates of day-to-day variation in flow-mediated dilation in individuals with Type 2 diabetes: a study of test–retest reliability

Aims/hypothesis Dysfunction of the vascular endothelium is commonly observed in Type 2 diabetes, and endothelial function may be an important outcome for clinical trials in diabetic samples. However, the most commonly used non-invasive test of endothelial function (flow-mediated dilation [FMD]) is technically challenging to perform, and no previous studies have carefully examined the reproducibility of FMD measurements in individuals with Type 2 diabetes. In this study, we tested the hypothesis that larger day-to-day changes in insulin and glucose are associated with larger fluctuations in FMD.Methods Ultrasound was used to measure the FMD (% change from baseline diameter) of the brachial artery in 18 healthy adults with Type 2 diabetes on three separate occasions, in the absence of changes to diet, activity level or medications. The CV and mean deviations between pairs of FMD scores in the same individual were used as the primary outcome variables.Results The CV for FMD (29.7%) was higher than the level traditionally accepted for biochemical assays. However, this CV estimate is within the low range of published values for FMD in healthy individuals. FMD scores were not significantly correlated with glucose or insulin levels. However, subjects with the largest variability in FMD also showed the largest fluctuations in glucose (r=0.52), insulin (r=0.47) and heart rate (r=0.48) (p0.05).Conclusions/interpretation FMD can be reliably measured in individuals with Type 2 diabetes, and population-specific data on reliability is critical for the design of adequately powered studies of endothelial function.     

Endothelial dysfunction in type 2 diabetes mellitus subjects with peripheral artery disease

We strived to characterize the endothelial function status in type 2 diabetic patients with peripheral artery disease which was detected by ankle-brachial index by utilizing high frequency ultrasounds. Predictors of endothelial dysfunction were investigated. We chose 23 type 2 diabetic patients had ankle-brachial index <0.97 (0.15-0.95; mean=0.74+/-0.20), 31 diabetic patients had ankle-brachial index >/=1.0 and 28 non-diabetic subjects for study. Older age, a longer duration of diabetes, higher systolic blood pressure, higher prevalence of history of hypertension were observed in patients with peripheral vascular disease. Type 2 diabetic patients showed impaired flow-mediated dilatation than non-diabetic and it showed more impaired in patients with peripheral vascular disease. Nitroglyerin-induced dilatation showed a trend of impairment in patients with peripheral vascular disease but did not reach statistical significance. Age (r=-0.259, P=0.019), baseline brachial artery diameter (r=-0.321, P=0.003), ankle-brachial index (r=0.259, P=0.002) and hypertension history (P=0.01) were significantly associated with flow-mediated dilatation. However, after adjusting for age, only baseline diameter and ankle-brachial index were independent predictors of flow-mediated dilatation. In conclusion, we demonstrated flow-mediated dilatation was impaired in type 2 diabetic patients and it was further impaired in patients with peripheral vascular disease. Nitroglycerin-induced dilatation showed a trend of impairment but did not reach statistical significance.     

N-acetylcysteine neither lowers plasma homocysteine concentrations nor improves brachial artery endothelial function in cardiac transplant recipients

BACKGROUND: N-acetylcysteine is a novel antioxidant that has been reported to reduce plasma homocysteine concentrations and improve endothelial function. Cardiac transplant recipients have a high incidence of coronary endothelial dysfunction and hyperhomocysteinemia, both of which may lead to the development of transplantation coronary artery disease. It was hypothesized that N-acetylcysteine would reduce plasma homocysteine concentrations and improve brachial endothelial function in cardiac transplant recipients. PATIENTS AND METHODS: A cohort of stable cardiac transplant recipients was recruited from the outpatient clinic at the Toronto General Hospital, Toronto, Ontario. Brachial artery endothelial functions were studied according to standard techniques to determine flow-mediated dilation of the brachial artery. Plasma homocysteine concentrations were assayed using high performance liquid chromatography with electrochemical detection and pulsed integrated amperometry. After baseline testing, patients were treated in an unblinded fashion with N-acetylcysteine 500 mg/day. After 10 weeks of therapy, patients returned for follow-up endothelial function and homocysteine testing. RESULTS: Thirty-one patients were initially enrolled. Two patients withdrew due to excessive gastrointestinal upset. Two patients did not return for follow-up testing. The remaining 27 patients tolerated the treatment well. At baseline, 85% of the patients had hyperhomocysteinemia (greater than 15 mol/L) with a mean plasma concentration of 18.6 4.7 mol/L. No changes in homocysteine concentrations were seen at follow-up. At baseline, the average flow-mediated dilation was only 4.7 6.3%. No changes were seen at follow-up. CONCLUSIONS: Hyperhomocysteinemia and brachial endothelial dysfunction are common in stable cardiac transplant recipients and are unaffected by supplementation with N-acetylcysteine.     

Impaired flow-mediated vasodilation in type 2 diabetes: lack of relation to microvascular dysfunction

A reduced availability of nitric oxide (NO) is an important feature of endothelial dysfunction occurring early in the course of type 2 diabetes. The measurement of flow-mediated dilation (FMD) of the brachial artery after forearm ischemia is supposed to be a non-invasive method to assess endothelial production and release of NO. The impairment of reactive hyperemia due to microvascular dysfunction in diabetes might cause an insufficient increase in shear stress stimulating the endothelial NO release, thus leading to an underestimation of FMD. Therefore, the aim of the present study was to investigate the relationship between microcirculatory disturbances and the impairment of FMD in type 2 diabetic patients. 63 type 2 diabetic patients and 44 non-diabetic control subjects were investigated. Capillary blood cell velocity (CBV) was assessed at the dorsal middle phalangeal area of the left ring finger. Lumen diameter of the brachial artery was measured by high-resolution ultrasound. Patients were investigated at rest and after 5-min suprasystolic arterial compression. Percentage change of CBV during reactive hyperemia (CBV%) and flow-mediated dilation (FMD%) of the brachial artery relative to the baseline measurement were calculated. CBV% (63.4 ± 10.7% vs. 124.0 ± 18.5%; p < 0.01) and FMD% (3.8 ± 0.8% vs. 6.9 ± 0.9%; p < 0.01) were reduced in the diabetic patients compared to their control subjects. FMD% was not related to CBV% (r = 0.14; p = 0.139). The lack of an association between the reduction of endothelium-dependent vasodilation of the brachial artery and the impairment of postocclusive microvascular hyperemia observed in the present study contradicts the assumption that a reduced FMD is only the consequence of an impaired reactive hyperemia due to microvascular dysfunction. It also lends support to the suggestion that endothelial dysfunction in conduit vessels and impaired cutaneous microvascular responses to reactive hyperemia might at least partly develop independently due to several differences in their pathogenesis.     

Statin therapy improves brachial artery vasodilator function in patients with Type 1 diabetes and microalbuminuria.

AIMS: Type 1 diabetes mellitus patients with microalbuminuria have endothelial dysfunction associated with the degree of albuminuria but not with LDL-cholesterol levels. Lipid-lowering agents such as statins may still be of benefit as they can correct endothelial dysfunction by both lipid and non-lipid mechanisms. We therefore examined the effects of atorvastatin on brachial artery endothelial dysfunction in these patients. METHODS: In a double-blind, randomized crossover study, 16 Type 1 diabetes mellitus patients with microalbuminuria received 6 weeks of atorvastatin 40 mg/day or placebo, separated by a 4-week washout. Brachial artery, endothelium-dependent, flow-mediated dilatation (FMD) and endothelium-independent, glyceryl trinitrate-mediated dilatation (GTNMD) were measured. RESULTS: Compared with placebo, atorvastatin produced a significant decrease in apolipoprotein B (34.2%), LDL-cholesterol (44.1%) (all P < 0.001), and oxidized-LDL (35.7%, P = 0.03). There was a non-significant increase in plasma cGMP (P = 0.13) on atorvastatin. FMD and GTNMD increased significantly on atorvastatin (FMD: atorvastatin +1.8 +/- 0.4%; placebo +0.2 +/- 0.4%, P = 0.007); (GTNMD: atorvastatin +1.3 +/- 0.9%; placebo -1.2 +/- 0.6%, P = 0.04). An increase in cGMP was independently correlated with an increase in FMD on atorvastatin (adjusted (R2) 0.41, P = 0.02). CONCLUSION: Atorvastatin improves endothelium-dependent and independent vasodilator function of the brachial artery in Type 1 diabetes mellitus patients with microalbuminuria. This may relate to pleiotropic effects of statins, in particular reduced oxidative stress and increased availability of nitric oxide.     

Terminalia arjuna reverses impaired endothelial function in chronic smokers

BACKGROUND: Smoking, largely through increased oxidative stress, causes endothelial dysfunction which is an early key event in atherosclerosis. Smoking cessation and antioxidant vitamin therapy are shown to have beneficial role by restoring altered endothelial physiology. The present study was aimed to determine whether Terminalia arjuna, an Indian medicinal plant with potent antioxidant constituents, would improve endothelial dysfunction in smokers. METHODS AND RESULTS: Eighteen healthy male smokers (age 28.16+/-9.45 years) and equal number of age-matched non-smoker controls participated in the study. The baseline brachial artery reactivity studies were performed using high frequency ultrasound according to standard protocol under identical conditions to determine endothelium-dependent, flow-mediated dilation and endothelium-independent nitroglycerine-mediated dilation. The two groups were matched regarding age, body mass index, blood pressure, serum cholesterol, mean resting vessel diameters and post-occlusion flow velocities (all p=NS). While flow-mediated dilation was significantly impaired amongst smokers compared to controls (4.71+/-2.22 v. 11.75+/-5.94%, p <0.005), the nitroglycerine-mediated dilation was similar in the two groups (20.35+/-3.89 v. 19.68+/-3.74%, p=NS). Subsequently the smokers were given Terminalia arjuna (500 mg q8h) or matching placebo randomly in a double blind cross-over design for two weeks each, followed by repetition of brachial artery reactivity studies to determine various parameters including flow-mediated dilation after each period. There was no significant difference as regards vessel diameter and flow velocities between the two therapies. However, the flow-mediated dilation showed significant improvement from baseline values after Terrminalia arjuna therapy but not with placebo (9.31+/-3.74 v. 5.17+/-2.42%, p <0.005). CONCLUSIONS: Smokers have impaired endothelium-dependent but normal endothelium-independent vasodilation as determined by brachial artery reactivity studies. Further, Terrminalia arjuna therapy for two weeks leads to significant regression of this endothelial abnormality amongst smokers.     

Endothelial dysfunction in Type 2 diabetic subjects with and without microalbuminuria.

AIMS: The primary aim of this study was to determine whether microalbuminuria is associated with endothelial dysfunction in Type 1 diabetes mellitus. The secondary aim was to determine whether any reported biochemical markers of cardiovascular risk are associated with endothelial dysfunction in this group. METHODS: Measurements were made of the vasodilatory responses of the brachial artery to post-ischaemic hyperaemia and to sublingual glyceryl trinitrate (GTN) (causing endothelium-dependent and endothelium-independent dilation, respectively) using a high-resolution ultrasound technique in 18 Type 1 diabetic patients with microalbuminuria, 18 age and sex-matched normoalbuminuric Type 1 diabetic patients and 18 non-diabetic control subjects. RESULTS: There was a significant reduction in flow-mediated dilation (FMD) in microalbuminuric and normoalbuminuric diabetic patients compared with control subjects (2.4% (95% confidence interval (CI) 1.0-3.8%) and 2.3% (95% CI 0.7-3.9%) respectively vs. 6.3% (95% CI 5.1-7.5%), P<0.0001) but no difference in GTN-mediated dilation (14.7% (95% CI 10.7-18.7%) and 15.2% (95% CI 11.2-19.2%) vs. 18.7% (95% CI 16.1-21.3%), P = 0.09). There was no significant difference in FMD, however, between the microalbuminuric group and normoalbuminuric group (P=0.45). FMD was not significantly associated with urinary albumin-creatinine ratio, glycosylated haemoglobin, plasma glucose, lipid or lipoprotein concentrations in diabetic patients. There was a positive correlation between active transforming growth factor (TGF)-beta concentration, a novel biochemical marker of macrovascular disease, and FMD in diabetic patients (r=0.36, P<0.05). GTN-mediated dilation was positively associated with HDL-cholesterol concentration (r = 0.49, P = 0.002) but not with other biochemical variables (including active TGF-beta concentration). Active TGF-beta concentration was not associated with degree of microalbuminuria or other biochemical parameters. CONCLUSIONS: These data suggest that endothelial dysfunction occurs in Type 1 diabetic patients regardless of urine albumin status. Endothelial dysfunction appears therefore to predate the development of microalbuminuria as a marker for the development of coronary artery disease. It is also concluded that low plasma levels of active TGF-beta are associated with an impaired endothelial response and this may provide a useful tool for identifying Type 1 diabetic patients at a greater risk of coronary artery disease.     

Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects

Coenzyme Q₁₀ is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q₁₀ increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q₁₀ resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q₁₀. Oral administration of coenzyme Q₁₀ markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q₁₀ increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q₁₀ can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.     

Acute effects of vasoactive drug treatment on brachial artery reactivity

OBJECTIVES: The goal of this study was to investigate whether concomitant therapy with vasoactive medications alters the results of noninvasive assessment of endothelial function. BACKGROUND: Ultrasound assessment of brachial artery flow-mediated dilation is emerging as a useful clinical tool. The current practice of withholding cardiac medications before ultrasound studies has unknown utility and would limit the clinical use of the methodology. METHODS: To determine whether a single dose of a vasoactive drug influences brachial reactivity, we examined flow-mediated dilation and nitroglycerin-mediated dilation in 73 healthy subjects (age 27 +/- 6 years). Studies were completed at baseline and 3 h after randomized treatment with a single oral dose of placebo, felodipine (5 mg), metoprolol (50 mg), or enalapril (10 mg). To determine if holding vasoactive therapy for 24 h before study yields different results than continuation of clinically prescribed medications, we examined vascular function in 72 patients (age 57 +/- 10 years) with coronary artery disease. Ultrasound studies were performed 24 h after the last dose and again 3 h after patients took their clinically prescribed medications. RESULTS: In healthy subjects one dose of all three drugs lowered blood pressure, and metoprolol also lowered heart rate. However, there was no significant effect of treatment on brachial artery dilation. In patients with coronary artery disease on chronic treatment, taking prescribed medications reduced blood pressure and heart rate, but had no significant effect on brachial artery dilation. CONCLUSIONS: Recent administration of commonly used nonnitrate vasoactive drugs has no significant effect on brachial reactivity. These findings suggest that current practice of withholding cardiac medications before testing endothelial function may not be necessary, making this methodology more practical for clinical use.     

Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study

Endothelium-dependent flow-mediated dilation is a homeostatic response to short-term increases in local shear stress. Flow-mediated dilation of the brachial artery in response to postischemic reactive hyperemia is impaired in patients with cardiovascular disease risk factors and may reflect local endothelial dysfunction in the brachial artery. However, previous studies have largely neglected the effect of risk factors on evoked shear stress, which is the stimulus for dilation. We evaluated brachial artery percent dilation and evoked diastolic shear stress during reactive hyperemia using high-resolution ultrasound and Doppler in 2045 participants (1107 women, mean age 61 years) in the Framingham Offspring Study. In age- and sex-adjusted models, baseline and hyperemic shear stress were related to brachial artery percent dilation. In stepwise multivariable analyses examining clinical correlates of percent dilation (without shear stress in the model), age, sex, mean arterial pressure, pulse pressure, heart rate, body mass index, lipid medication use, and hormone replacement therapy were related to percent dilation (R2=0.189; P<0.001). When hyperemic shear stress was incorporated, the overall R2 improved (R2=0.335; P<0.001), but relationships between risk factors and percent dilation were attenuated (age and mean arterial pressure) or no longer significant (all others). In contrast, risk factors were related to baseline and hyperemic shear stress in multivariable analyses. Evoked hyperemic shear stress is a major correlate of brachial artery flow-mediated dilation. The associations between many risk factors and brachial artery flow-mediated dilation may be attributable to reduced stimulus for dilation rather than impaired local conduit artery response during hyperemia.     

Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries.

AIMS AND BACKGROUND: Coronary endothelial dysfunction improves after acute oestradiol treatment in women with angina and normal coronary angiograms. We sought to analyse whether this effect is also seen in the peripheral circulation and whether it is sustained after a mid-term period of treatment. METHODS: We studied 20 women with angina, signs suggestive of myocardial ischaemia and normal coronary angiograms. In five of them, coronary and peripheral endothelial functions were studied at baseline. Brachial artery flow-mediated dilation was reanalysed after 24 h of transdermal oestradiol treatment. In the other 15 women, brachial artery vasoreactivity was studied at baseline and after a 6-week period of treatment with transdermal oestradiol and medroxyprogesterone (HRT) or placebo in a double-blinded crossover fashion. RESULTS: An abnormal coronary artery response to acetylcholine was observed in all women as well as impaired brachial flow-mediated dilation. Brachial flow-mediated dilation significantly increased after 24 h of oestradiol treatment (4.8+/-0.8% vs 0.06+/-0.6%, P<0.001). Peripheral flow-mediated dilation also increased after a 6-week period of HRT compared with baseline (4.1+/-3% vs 0.4+/-1%, P<0.01) and placebo treatment (4.1+/-3% vs 0.6+/-1.7%, P<0.01). CONCLUSION: Impaired endothelium-dependent vasodilation exists both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms. Flow-mediated dilation improves in these women after short and mid-term therapy with transdermal oestradiol irrespective of concomitant progesterone use.     

Comparison of flow-mediated dilatation of the brachial artery in coronary patients with low-density lipoprotein cholesterol levels <80 mg/dl versus patients with levels 80 to 100 mg/dl

Testing of peripheral vascular endothelial function was performed in subjects who had coronary artery disease and a low-density lipoprotein (LDL) cholesterol level <100 mg/dl. LDL cholesterol was an independent predictor of flow-mediated dilation of the brachial artery (p = 0.010). The 63 subjects who had an LDL cholesterol level <80 mg/dl had better endothelial function (flow-mediated dilation 8.4 +/- 3.8%) than did 47 subjects whose level of LDL cholesterol was 80 to 100 mg/dl (flow-mediated dilation 6.8 +/- 4.0%, p = 0.03). The beneficial effects of LDL cholesterol levels <80 mg/dl on endothelial function were more apparent in subjects who had low levels of high-density lipoprotein cholesterol than in those who had normal levels. These data support recent reports that decreasing levels of LDL cholesterol below those currently recommended provides additional benefits and suggest that this benefit may be due in part to increased endothelial function.     

Urinary albumin excretion is related to cardiovascular risk indicators,not to flow-mediated vasodilation,in apparently healthy subjects

Based on studies in diabetic and hypertensive populations it has been postulated that early endothelial dysfunction is the mechanism responsible for the increased cardiovascular risk in microalbuminuric subjects. We evaluated the relation between microalbuminuria and endothelial dysfunction, assessed as flow-mediated dilation of the brachial artery, in an apparently healthy population. Within the framework of the PREVEND Intervention Trial non-hypertensive and non-hypercholesterolemic subjects were recruited on the basis of reproducible microalbuminuria. Using high-resolution ultrasound, flow-mediated dilation and nitroglycerin-mediated dilation of the brachial artery was assessed to measure endothelium-dependent and endothelium-independent responses, respectively. For the current study subjects with diabetes mellitus, clinical atherosclerosis, and macroalbuminuria were excluded from the analyses. We studied 421 men and 233 women (mean age (SD) 50 (12)). Increasing levels of urinary albumin excretion were accompanied by a significant increase in age, percentage men, systolic and diastolic blood pressure, body mass index, and serum triglycerides, whereas there was no decrease of flow-mediated vasodilation or nitroglycerin-mediated vasodilation. Adjusted for age and sex, urinary albumin excretion was significantly related to systolic (r=0.19, P<0.001) and diastolic (r=0.16, P<0.001) blood pressure, body mass index (r=0.18, P<0.001), and triglycerides (r=0.13, P=0.001), but not to flow-mediated vasodilation (r=-0.01, P=0.8). In contrast to blood pressure, body mass index, and triglycerides, there was no relation between urinary albumin excretion and flow-mediated vasodilation in apparently healthy subjects. These data suggest that the presence of atherogenic risk factors precedes the development of endothelial dysfunction in microalbuminuric, but otherwise healthy subjects.