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     

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.     

Impaired flow-mediated vasodilatation and insulin resistance in type 2 diabetic patients with albuminuria

An elevated urinary albumin excretion is associated with an increased risk of cardiovascular disease due to atherosclerosis, but the pathophysiological mechanism underlying this association is poorly understood. We studied 217 diabetic patients, that is, 121 normoalbuminuric patients, 71 microalbuminuric patients, and 25 macroalbuminuric patients. We evaluated flow-mediated dilatation of brachial artery (%FMD, one endothelial function marker associated with endogenous NO production), von Willebrand factor (vWF, endothelial activation marker), high-sensitive CRP (hsCRP, a low-grade inflammation marker), asymmetric dimethyl arginine (ADMA, an endogenous inhibitor of NO synthesis), and insulin sensitivity by steady-state plasma glucose method. %FMD was apparently decreased in microalbuminuric and macroalbuminuric patients compared with normoalbuminuric patients (p<0.001). Moreover, %FMD was significantly correlated with the degree of albuminuria (r=-0.38, p<0.05). On the other hand, vWF and hsCRP did not show significant difference between normoalbuminuric patients and microalbuminuric patients. In diabetic patients with macroalbuminuria, ADMA was significantly elevated compared to those with normoalbuminuria. Insulin sensitivity was significantly associated with urinary albumin excretion rate. These results suggested that endothelial dysfunction which may be due to impaired NO production and insulin resistance underlie the association between diabetic nephropathy and atherosclerosis in diabetic patients.     

Insulin resistance and endothelial dysfunction in type 2 diabetes patients with or without microalbuminuria

OBJECTIVE: To evaluate the relationship between insulin resistance and endothelial function in type 2 diabetes patients with or without microalbuminuria and to explore the pathophysiological mechanisms of the increased macrovascular risk in type 2 diabetes mellitus. METHODS: Twelve type 2 diabetes patients with microalbuminuria (urinary albumin 30-300 g/mg creatinine, DM-MA) and 12 type 2 diabetes patients without microalbuminuria (urinary albumin <30 g/mg creatinine, DM-NA) were recruited, matched for their sex, age, body mass index (BMI), diabetes duration, antidiabetic therapy. Their hemoglobin (HbA1C) was less than 7.5% and the blood pressure was lower than 140/90 mmHg. None had evidence of macrovascular disease and serum cholesterol levels were normal. Twelve healthy volunteers (C) were enrolled as controls. All subjects received a hyperinsulinemic euglycemic clamp study (insulin infusion rate, 120 mU/m2/min) to assess the peripheral glucose disposal rate (GDR) in the steady state and had a high-resolution ultrasonography to measure vasodilation in the brachial artery diameter in response to reactive hyperemia (endothelium-dependent) and administration of glyceryl trinitrate (endothelium-independent). Plasma free fatty acids (FFAs), plasminogen activator inhibitor type I (PAI-1), and von Willebrand factor (vWF) were also measured. RESULTS: The GDR was lower in type 2 diabetes patients with microalbuminuria (7.90 +/- 1.79 mg/kg/min) than in patients without microalbuminuria (9.46 +/- 1.59 mg/kg/min, P<0.05), and the GDR in both diabetes groups was decreased, compared with the findings from the healthy control group (13.06 +/- 1.98 mg/kg/min, P<0.01). Plasma FFAs concentration was different among the three groups (DM-MA-1008 +/- 229 mol/l, DM-NA-675 +/- 201 mol/l, P<0.01; C-364 +/- 169 mol/l, P<0.01). Endothelium-dependent vasodilation was impaired in the microalbuminuric patients (8.0 +/- 3.8%) compared with the normoalbuminuria patients (9.7 +/- 4.3%, P>0.05) and the healthy controls (14.2 +/- 5.0, P<0.05). Plasma PAI-1 and vWF levels increased in the microalbuminuric patients (61.9 +/- 18.2 ng/ml, 126.8 (76.5-212.7) %) compared with the levels in the normoalbuminuric patients (45.4 +/- 16.3 ng/ml, 87.9 (84.2-114) %) (PAI-1, P<0.05; vWF, P>0.05) and in the healthy controls (33.6 +/- 10.6 ng/ml, 67.2 (61.5-75.4) %, both P<0.01). In addition, the partial correlation analysis revealed a significant positive correlation between GDR and endothelium-dependent vasodilation (r=0.465, P<0.01, n=36), and a negative correlation between GDR and plasma FFA levels (P<0.05). CONCLUSIONS: Compared with type 2 diabetes patients with normoalbuminuria, patients with microalbuminuria had more severe insulin resistance, more prominent endothelial dysfunction, and higher plasma FFA, PAI-1, and vWF levels. Therefore we speculate that insulin resistance and endothelial dysfunction may act within the metabolic syndrome to increase the cardiovasular risk in this subset of patients, and improving insulin resistance and endothelial dysfunction may reduce the morbidity and mortality from macrovascular complications in type 2 diabetes patients.     

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.     

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.     

Flow-mediated vasodilation of the femoral and brachial artery induced by exercise in healthy nonsmoking and smoking men.

OBJECTIVES: We sought to analyze diameter changes of conduit arteries in response to whole-body exercise and hypothesized that this response might be endothelium-dependent and, therefore, impaired in smokers. BACKGROUND: Hyperemia and coincident vasodilation are pivotal mechanisms for meeting the increased metabolic demands of active muscle tissue during physical exercise, but studies in humans are sparse. METHODS: We studied diameter and blood flow of the femoral and brachial arteries in response to a submaximal bicycle exercise test in 10 nonsmoking and 8 smoking healthy male subjects. During an exercise period of 40 min the investigated conduit arteries were periodically scanned in longitudinal sections by high-resolution ultrasound. In the same subjects flow-mediated dilation (FMD) of the brachial artery was recorded by inducing an ischemia through a forearm-occluding cuff. RESULTS: In response to exercise the diameter of the femoral artery significantly increased in both nonsmokers and smokers, with a diminished response in smokers (9.2 +/- 1.9% vs. 4.8 +/- 1.6%, p < 0.001). Flow-mediated dilation of the brachial artery induced by forearm occlusion was also reduced in smoking subjects, revealing a strong correlation between these different methods of FMD (exercise vs. forearm ischemia) (r = 0.88, p < 0.001). In contrast, blood flow increase of the femoral artery was similar in nonsmoking and smoking subjects (392 +/- 77% vs. 382 +/- 109%, p = NS). CONCLUSIONS: Conduit arteries react with a flow-mediated dilation in response to whole-body exercise. The impairment of this vasodilation observed in smokers was strongly related to a decrease of endothelium-dependent dilation induced by forearm ischemia, indicating that endothelial dysfunction represents the underlying mechanism.     

Impaired flow-mediated vasoactivity during post-prandial phase in young healthy men

Impaired flow-mediated vasodilation in large arteries is an expression of endothelial dysfunction and an established marker of early atherosclerosis. Post-prandial lipemia can induce an impairment of the endothelial function. The aim of our study was to evaluate the effects of post-prandial phase on flow-mediated vasodilation in a group of ten young (23 +/- 2 years) healthy men without cardiovascular risk factors, who underwent an oral fat-loading test. Flow-mediated vasodilation of the brachial artery and serum lipid profile were assessed under fasting conditions and 2, 4, 6 and 8 h after a high-fat meal. Triglycerides increased from 0.6 +/- 0.2 fasting to 1.1 +/- 0.5 and 1.3 +/-0.6 mmol/l at the 2nd and 4th hour (both P < 0.01), and decreased thereafter. Flow-mediated vasodilation fell significantly from 14.5 +/- 6.6% fasting to 3.5 +/- 1.5% and 4.0 +/- 2.2% at the 2nd and 4th hour (both P < 0.01), and returned to the basal values at the 6th and 8th hour. A strong inverse correlation was observed between the area under the incremental curve of post-prandial triglycerides (i.e. after subtraction of baseline triglycerides) and the area under the decremental curve of post-prandial flow-mediated vasodilation (r = -0.70, P = 0.025). No association was found between post-prandial vasodilation changes and fasting triglycerides, other lipid parameters or insulin. We conclude that a transient post-prandial impairment in brachial artery flow-mediated vasodilation is evident in young healthy men after a high-fat meal, and is closely associated with triglyceride levels. These data provide support for a role of post-prandial phase in vascular regulation in young healthy subjects.     

Effects of mental stress on flow-mediated brachial arterial dilation and influence of behavioral factors and hypercholesterolemia in subjects without cardiovascular disease

Mental and emotional arousal are known to trigger coronary events. The relation between hypercholesterolemia, behavioral factors, and mental stress-induced alterations in endothelial function are not well defined. Flow-mediated brachial arterial vasodilation has been established as a measure of arterial endothelial function. High-resolution ultrasound was used to measure mental stress-mediated, flow-mediated, and the combination of mental stress- and flow-mediated brachial artery dilation in 38 subjects, 20 of whom had total cholesterol levels > or =200 mg/dl. Mental stress was provoked by anger recall and mental arithmetic and trait hostility were assessed using the Cook-Medley scale. Under mental stress, participants with hypercholesterolemia showed less vasodilation than participants without hypercholesterolemia, even after adjustment for age and the magnitude of blood pressure response to mental stress. Mental stress attenuated flow-mediated brachial arterial vasodilation. There was an inverse relation between hostile affect and percent change in brachial artery diameter after mental stress combined with hyperemia (r = -0.57, p <0.001). Thus, hypercholesterolemia is associated with impaired vasodilation in response to mental stress. Mental stress inhibits flow-mediated vasodilation in normal subjects and those with hypercholesterolemia. The magnitude of this inhibition is associated with hostility.     

Endothelial function and aminothiol biomarkers of oxidative stress in healthy adults

Endothelial dysfunction is known to precede the development of atherosclerosis and results primarily from increased oxidative degradation of NO. We hypothesized that assessment of oxidative stress in the bloodstream will reliably predict endothelial function in healthy adults. A total of 124 healthy nonsmokers had endothelial function assessed using ultrasound measurement of brachial artery flow-mediated vasodilation. Plasma oxidative stress was estimated by measuring the levels of the reduced and oxidized forms of thiols, including glutathione (reduced glutathione and oxidized glutathione) and cysteine (cysteine and cystine), respectively, and the mixed disulfide. Among the traditional risk factors, there were significant and independent correlations between flow-mediated vasodilation and high-density lipoprotein level, body mass index, gender, and the Framingham risk score. Among the thiol markers, plasma cystine (r=-0.23; P=0.009) and the mixed disulfide (r=-0.23; P=0.01) levels correlated with endothelium-dependent but not endothelium-independent vasodilation, even after adjusting for the Framingham risk score and high-sensitivity C-reactive protein level. A higher level of oxidized metabolites was associated with worse endothelial function. In conclusion, the oxidative stress markers, cystine, and the mixed disulfide are independent predictors of endothelial function. These markers, in combination with the Framingham risk score, may help in the early identification of asymptomatic subjects with endothelial dysfunction who are at potentially increased risk for future atherosclerotic disease progression.     

Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction

RATIONALE: Patients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular diseases. Injury of endothelial cells has been advanced as an initial trigger to atherosclerosis. OBJECTIVES: To study the association between circulating apoptotic endothelial cells and vasomotor dysfunction as a function of sleep apnea. METHODS: Brachial artery flow-mediated dilation was determined in 14 subjects with documented OSA and 10 healthy control subjects at baseline and 8 weeks after continuous positive airway pressure (CPAP) therapy. Quantification of circulating apoptotic endothelial cells (CD146(+) Annexin V(+)) was performed by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Compared with healthy subjects, patients with OSA had higher numbers of circulating CD146(+) Annexin V(+) cells (39.2 +/- 13.6 cells/mL and 17.8 +/- 9.4, respectively; p < 0.001). Increased apoptotic endothelial cells correlated moderately with abnormal vascular function (r = -0.61; p = 0.001). A significant correlation was observed between CD146 Annexin V(+) cells and the apnea-hypopnea index (r = 0.56; p = 0.004). After 8 weeks of treatment with CPAP, the numbers of circulating apoptotic endothelial cells were reduced significantly from 39.2 +/- 13.6 to 22.3 +/- 12.9 apoptotic cells per milliliter (p < 0.001) and correlated with improvement in endothelium-dependent vasodilation (r = 0.49; p = 0.07). CONCLUSIONS: In patients with OSA, impairment of endothelial-dependent vasodilation correlated with the degree of endothelial cell apoptosis. CPAP therapy led to significant decline in circulating apoptotic endothelial cells. These findings provide an additional mechanism for the predisposition of patients with OSA to premature vascular disease.     

Effect of short-term weight loss on the metabolic syndrome and conduit vascular endothelial function in overweight adults

Impaired vascular endothelial function may be an important mechanism linking obesity to increased cardiovascular risk. We investigated whether short-term weight loss improves conduit artery endothelial dysfunction in overweight adults. Forty-three otherwise healthy overweight patients with a body mass index > or =27 kg/m(2) completed an open-label 3-month trial consisting of a calorie-restricted diet and 120 mg of orlistat taken 3 times daily with meals. Endothelial function and parameters of the metabolic syndrome were measured before and after intervention. Subjects lost 6.6 +/- 3.4% of their body weight. Low-density lipoprotein cholesterol, low-density lipoprotein concentration, fasting insulin, and leptin decreased significantly (all p <0.009), and C-reactive protein decreased (p = 0.22). Conduit vascular function did not change as assessed by flow-mediated dilation (3.86 +/- 3.54 vs 3.74 +/- 3.78%, p = 0.86) and nitroglycerin-mediated dilation (17.18 +/- 5.89 vs 18.87 +/- 7.11%, p = 0.13) of the brachial artery. A moderate degree of weight reduction over 3 months improved the metabolic syndrome profile but not the vascular dysfunction associated with uncomplicated obesity.     

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.     

Left ventricular mass and systolic function in African diabetic patients: association with microalbuminuria.

OBJECTIVE: To assess echocardiographic evidence of cardiomyopathy and its association with microalbuminuria in type 2 normotensive non-proteinuric diabetic patients. MATERIAL AND METHODS: Forty consecutive normotensive non-proteinuric type 2 diabetic patients were studied. Body mass index, blood pressure, urinary albumin excretion, ECG at rest and after exercise, left ventricular mass, and shortening fraction using two-dimensional and M-mode echocardiography were measured in every patient. RESULTS: Among the 40 patients studied, 17 (42.5%) presented with microalbuminuria, 16 (40.0%) with left ventricular hypertrophy, 22 (55.0%) with systolic dysfunction and 3 (7.5%) with ECG changes compatible with cardiac ischaemia. No significant difference existed between normoalbuminuric and microalbuminuric patients for age, known duration of diabetes, body mass index, systolic and diastolic blood pressure. Ventricular mass correlated to urinary albumin excretion rate (r=0.34; p=0.04) and shortening fraction to diastolic blood pressure (r = - 0.40; p=0.01). CONCLUSION: Left ventricular structure and function might be altered in African type 2 diabetic patients in the absence of hypertension, and microalbuminuria may be an early biochemical marker of these abnormalities.     

Relation of cumulative weight burden to vascular endothelial dysfunction in obesity

Although excess fat mass is linked to increased cardiovascular risk, the relation between vascular phenotype and degree of obesity in high weight categories is unknown. We examined brachial artery vasomotor responses using ultrasound in 203 consecutive patients with severe obesity (mean age 44 +/- 11 years; body mass index [BMI] 46 +/- 9 kg/m(2), range 30 to 72; and body weight 128 +/- 29 kg, range 69 to 207). We studied a unique population in which 71% of subjects were characterized as morbidly obese (BMI > or =40 kg/m(2)), which included a 31% group of super-obese subjects (BMI > or =50 kg/m(2)). Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were examined as measures of endothelium-dependent and -independent dilation, respectively, in relation to clinical, hemodynamic, and metabolic variables. Endothelial function was significantly impaired in the highest compared with the lowest tertile of body weight (FMD 6.5 +/- 4.6% vs 9.8 +/- 4.8%, p <0.001), whereas nitroglycerin-mediated dilation was similar in all groups. Univariate correlates of FMD were gender, weight, waist circumference, BMI, diastolic blood pressure, and creatinine. In multivariate analysis, weight was a strong independent significant predictor of FMD (beta = -0.23, p = 0.005) in addition to gender. Within an overweight population, cumulative weight burden remains strongly linked to progressive arterial dysfunction. In conclusion, these results suggest that cardiovascular risks intensify with higher degrees of obesity and underscore the importance of therapeutic weight loss interventions.     

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 hypertriglyceridemia is associated with peripheral vasodilation and increased basal flow in healthy young adults.

Prior studies suggest that acute elevations in plasma triglycerides alter vascular tone and impair endothelial function. To investigate the relation between acute hypertriglyceridemia and vascular function, we examined the effects of high- and low-fat meals on brachial artery reactivity in 14 healthy volunteers. Flow-mediated dilation declined from 14.7 +/- 8.3% to 10.6 +/- 6.2% after the high-fat meal only (p <0.001), and this decline was associated with a 6% increase in baseline brachial artery diameter (3.50 +/- 0.74 mm to 3.70 +/- 0.81 mm, p <0.001), but not a decrease in the arterial diameter during hyperemia. The high-fat meal increased serum triglycerides and insulin by 94% and 438%, respectively. To investigate the effects of triglyceride elevation in isolation from hyperinsulinemia, we examined vascular responses to an intravenous infusion of a triglyceride emulsion in 28 subjects. Triglyceride emulsion increased serum triglycerides 197% but had no effect on serum insulin. Brachial artery diameter increased 4%, from 3.68 +/- 0.51 mm to 3.81 +/- 0.56 mm (p <0.05), and forearm flow increased 36%, reflecting vasodilation of forearm resistance vessels. Flow-mediated dilation and nitroglycerin-mediated dilation were unaffected. The triglyceride emulsion had no direct dilator effect on rabbit aortic tissue in vitro. In conclusion, acute hypertriglyceridemia is associated with vasodilation of conduit and resistance vessels in the arm and does not impair endothelial vasodilator function per se. The dilator effect is not insulin-dependent and does not appear to be a direct effect of triglycerides on vascular tissue.     

超重和肥胖对血管内皮功能的影响

目的探讨中年人群超重或肥胖对血管内皮功能的影响.方法对609例35～55岁经健康检查无心血管病和其他疾病者,应用高分辨血管外超声法检测其肱动脉血管内皮功能,并测定总体脂含量[体重指数、脂肪百分比(%)]、局部体脂含量(腰围、臀围)和体脂分布[腰围臀围比值(腰臀比)].结果超重或肥胖组血流介导的肱动脉内径变化的百分率较对照组均明显降低,男女之间无显著性差异.相关分析显示,超重或肥胖者血流介导的血管扩张在男性中与脂肪%(r=-0.221,P＜0.001)、腰围(r=-0.135,P＜0.001)和腰臀比(r=-0.148,P＜0.01)呈负相关,女性中则与BMI(r=-0.192,P＜0.001)和脂肪%(r=-0.287,P＜0.001)呈负相关.硝酸甘油引起的血管扩张在各组间无显著性差异,亦与体脂含量及体脂分布无关.结论超重或肥胖是血管内皮功能受损的重要危险因素,血管内皮功能受损与男性体脂分布和女性体脂含量密切相关.     

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.     

2型糖尿病合并糖尿病肾病脂联素水平变化及与血管内皮功能的关系

目的探讨糖尿病肾病患者血清脂联素水平的变化,及与血管内皮功能的关系。方法 50例无明显临床大血管并发症的2型糖尿病患者,按24 h尿白蛋白排出量分为正常白蛋白尿组、微量白蛋白尿组及大量白蛋白尿组。检测血清脂联素、可溶性血管细胞黏附分子1、生物化学指标、肱动脉内皮依赖性舒张功能(FMD)、含服硝酸甘油后肱动脉内皮依赖性舒张功能(NID)、心脏结构参数及颈动脉内膜-中膜厚度。结果大量白蛋白尿组脂联素水平是正常白蛋白尿组的4倍,是微量白蛋白尿组的2倍(P<0.01和P<0.05)。微量白蛋白尿组脂联素水平比正常白蛋白尿组升高(P<0.05)。脂联素/血肌酐在三组中有同样的变化(均P<0.05)。大量白蛋白尿组和微量白蛋白尿组可溶性血管细胞黏附分子1均高于正常白蛋白尿组(P<0.01和P<0.05)。大量白蛋白尿组FMD、NID随脂联素水平的增加而下降(P<0.05)。颈动脉内膜-中膜厚度在三组间无统计学差异。脂联素与可溶性血管细胞黏附分子1、24 h尿白蛋白排出量、血肌酐、左心室后壁厚度、内膜-中膜厚度呈正相关(r值分别为0.338、0.704、0.470、0.331、0.324,P<0.05),与FMD、NID呈显著负相关(r值为-0.397、-0.413,P<0.01)。结论糖尿病肾病伴随高脂联素血症,且与血管内皮功能损害密切相关。脂联素可作为糖尿病肾病患者早期血管内皮功能障碍的预测指标。