Artery Flow-mediated Dilation Research Articles

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Recombinant human activated protein C (rhAPC) is one of the treatment panels for improving vascular dysfunction in septic patients. In a previous study, we reported that rhAPC treatment in rat endotoxemia improved vascular reactivity, although the mechanisms involved are still under debate. In the present study, we hypothesized that rhAPC may improve arterial dysfunction through its nonanticoagulant properties. Ten hours after injection of LPS in mice (50 mg/kg ip), aortic rings and mesenteric arteries were isolated and incubated with or without rhAPC for 12 h. Aortic rings were mounted in a myograph, after which arterial contractility and endothelium-dependent relaxation were measured in the presence or absence of nitric oxide synthase or cyclooxygenase inhibitors. Flow (shear stress)-mediated dilation with or without the above inhibitors was also measured in mesenteric resistance arteries. Protein expression was assessed by Western blotting. Lipopolysaccharide (LPS) reduced aortic contractility to KCl and phenylephrine as well as dilation to acetylcholine. LPS also reduced flow-mediated dilation in mesenteric arteries. In rhAPC-treated aorta and mesenteric arteries, contractility and endothelial responsiveness to vasodilator drug and shear stress were improved. rhAPC treatment also improved LPS-induced endothelial dysfunction; this effect was associated with an increase in the phosphorylated form of endothelial nitric oxide synthase and protein kinase B as well as cyclooxygenase vasodilatory pathways, thus suggesting that these pathways, together with the decrease in nuclear factor-kappaB activation and inducible nitric oxide synthase expression in the vascular wall, are implicated in the endothelial effect of rhAPC. In conclusion, ex vivo application of rhAPC improves arterial contractility and endothelial dysfunction resulting from endotoxemia in mice. This finding provides important insights into the mechanism underlying rhAPC-induced improvements on arterial dysfunction during septic shock.

Inflammation predicts accelerated brachial arterial wall changes in patients with recent-onset rheumatoid arthritis

IntroductionPatients with recent-onset rheumatoid arthritis (RA) have impaired brachial artery endothelial function compared with controls matched for age, sex and cardiovascular risk factors. The present study examined endothelium-dependent (flow-mediated dilatation (FMD)) and independent (glyceryl trinitrate (GTN)-mediated dilatation (GMD)) structural responses in early RA patients, and determined progress over one year.MethodsBrachial artery FMD and GMD and carotid intima media thickness (cIMT) were studied using ultrasound in 20 patients diagnosed with early RA in whom symptoms had been present for less than 12 months, and in 20 control subjects matched for age, sex and established cardiovascular risk factors. FMD and GMD were re-assessed after 12 months in RA patients and the change in each parameter was calculated. Data were analysed by univariate regression.ResultsMean FMD and GMD were significantly lower in early RA patients at baseline than in controls, but each parameter significantly improved in one year. FMD and GMD responses were positively associated with each other. Patients' age, C-reactive protein (CRP) level and cIMT at baseline and CRP level at one year, were negatively associated with change in brachial responses in one year.ConclusionsPatients with recent-onset RA have altered brachial artery responses signifying both functional and structural abnormalities. However, early control of inflammation may reduce arterial dysfunction and thus the tendency for atherosclerotic progression.

Changes in endothelial function and its association with plasma osteoprotegerin in hypothyroidism with exercise‐induced silent myocardial ischaemia

Hypothyroidism is associated with an increased risk for cardiovascular disease. Exercise-induced silent myocardial ischaemia (SI) is an early stage of coronary artery disease. Recently, many studies have shown that endothelial dysfunction is an early physiological event in atherosclerosis, and osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. The aim of this study was to investigate the alteration of endothelial function and its association with plasma OPG in hypothyroidism with SI. Forty-eight female postmenopausal hypothyroid patients with normal rest electrocardiography (ECG) were selected. Of these, 19 cases had SI. Twenty healthy females without SI were selected as controls. High-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate (GTN). Plasma OPG concentration was measured in duplicate by a sandwich enzyme-linked immunosorbent assay (ELISA). Flow-mediated arterial dilation (FMD) in the total hypothyroid group, the hypothyroidism with SI group and the hypothyroidism without SI group was 3.51 +/- 0.62%, 3.20 +/- 0.54% and 3.72 +/- 0.60%, respectively, significantly lower than that in the controls (5.08 +/- 0.61%) (P < 0.01). Compared with the hypothyroidism without SI group, FMD in the hypothyroidism with SI group was significantly lower (P < 0.05). Plasma OPG levels in the total hypothyroid group, patients with SI and patients without SI were significantly higher than in the control group (P < 0.05). Compared with patients without SI, OPG levels were significantly higher in patients with SI (P < 0.05). On multiple regression analysis, low density lipoprotein cholesterol (LDL-C), lipoprotein (a) [Lp(a)], C-reactive protein (CRP), OPG, TSH, free T3 (FT3) and thyroid peroxidase antibody (TPO-Ab) were found to be significant factors that were associated with FMD. Logistic analysis also showed that LDL-C, TSH, OPG, CRP and FMD were independently and significantly associated with SI in hypothyroidism. Impaired endothelial function and increased levels of OPG exist in hypothyroid patients, especially those with SI. These findings support the growing concept that endothelial dysfunction may be associated with vascular disease, and subsequently elevated plasma OPG may have a role in the development of vascular dysfunction in hypothyroid patients.

Changes in vascular and cardiac function after prolonged strenuous exercise in humans

Prolonged exercise has been shown to result in an acute depression in cardiac function. However, little is known about the effect of this type of exercise on vascular function. Therefore, the purpose of the present study was to investigate the impact of an acute bout of prolonged strenuous exercise on vascular and cardiac function and the appearance of biomarkers of cardiomyocyte damage in 15 male (32 +/- 10 yr) nonelite runners. The subjects were tested on two occasions, the day before and within an hour of finishing the London marathon (229 +/- 38 min). Function of the brachial and femoral arteries was determined using flow-mediated dilatation (FMD). Echocardiographic assessment of cardiac strain, strain rate, tissue velocities, and flow velocities during diastole and systole were also obtained. Venous blood samples were taken for later assessment of cardiac troponin I (cTnI), a biomarker of cardiomyocyte damage. Completion of the marathon resulted in a depression in femoral (P = 0.04), but not brachial (P = 0.96), artery FMD. There was no change, pre- vs. postmarathon, in vascular shear, indicating that the impaired femoral artery function was not related to hemodynamic changes. The ratio of peak early to atrial radial strain rate, a measure of left ventricular diastolic function, was reduced postmarathon (P = 0.006). Postrace cTnI was elevated in 12 of 13 runners, with levels above the recognized clinical threshold for damage in 7 of these. In conclusion, when taken together, these data suggest a transient depression in cardiac and leg vascular function following prolonged intensive exercise.

Flow-Mediated Arterial Dilation in Primary Antiphospholipid Syndrome

To investigate precocious alterations in the artery wall of patients with primary antiphospholipid syndrome (APS). We evaluated flow-mediated dilation (FMD) of the brachial artery and intima-media thickness (IMT) of carotid arteries in 16 patients and 16 healthy controls matched for age, gender, and other cardiovascular risk factors. FMD of the brachial artery was significantly lower in patients than in controls (6.3 +/- 5.2% vs 18.2 +/- 2.7; P < .005). IMT was similar in the 2 groups. FMD was significantly reduced in patients with anticardiolipin antibodies IgM. APS correlates closely with precocious atherosclerosis, and the correlation with a type of anticardiolipin antibody may be predictive of more accelerated atherosclerosis.

Diastolic Dysfunction

It has recently become firmly established that patients can experience chronic and acute heart failure with a normal ejection fraction (HFNEF).1–5 We now know this disorder is the dominant form of HF in the community, and that compared with HF with reduced ejection fraction (HFREF), it is increasing in prevalence and incidence,6 causes at least as many hospitalizations and healthcare expenditures,1,6,7 causes at least as severe chronic symptoms and reduced objectively measured exercise tolerance,4 and, once patients are hospitalized, has death rates that are similarly grim.1,6 Until recently, however, we have invested nearly all our resources into understanding the pathophysiology and treatment of HFREF. As a result, a physician managing a patient with HFREF can rely on practice guidelines that are solidly supported by dozens of large trials demonstrating substantial improvements in each of the meaningful HF outcomes: mortality, hospitalizations, exercise intolerance, and reduced quality of life. When the patient instead has HFNEF, there is relatively little information about pathophysiology or treatment to guide the physician. This fact is reflected in outcomes, which a recent study indicates are improving in patients with HFREF but worsening in those with HFNEF.6 This disconcerting imbalance is magnified by sex and age, as the large burden of HFNEF falls primarily on older women.1,2,6 Article p 2051 In the present issue of Circulation , Westermann and colleagues8 report a welcomed and important study aimed at addressing the dearth of information about the pathophysiology of HFNEF. They studied 70 very well-characterized patients with documented symptoms of HF, normal left ventricular (LV) EF, and no other detectable cause for their symptoms, including pulmonary and ischemic heart disease. The investigators used a conductance catheter to measure pressure–volume loops during supine rest, handgrip exercise, and atrial pacing to 120 bpm. They …

Vasomotion in Multiple Spontaneous Cervical Artery Dissections

The etiology of spontaneous cervical artery dissection (sCAD) is still unknown, even though an underlying arteriopathy impairing vasomotion has often been suspected. This study was undertaken to investigate: (1) spontaneous, (2) endothelial-dependent, and (3) endothelial-independent vasodilation in patients with multiple sCAD. In 19 consecutive patients with multiple carotid or vertebral artery dissections high-resolution ultrasound was used to assess spontaneous and endothelial-independent dilations (isosorbide dinitrate-mediated) in the common carotid, vertebral and brachial arteries, and endothelial-dependent dilation (flow-mediated arterial dilation) in the brachial arteries alone. The same parameters were measured in 19 healthy subjects matched for age, sex, and height (controls). Ultrasound studies were performed by one investigator, and off-line analysis by another investigator who was blinded to the clinical data and study status (patient or control). Spontaneous and endothelial-independent dilations were significantly impaired in the carotid (P=0.0006 and P<0.0001, respectively) and vertebral arteries (P=0.0121 and P=0.0047, respectively) of patients as compared with controls, whereas no statistically significant differences were found in the brachial arteries; conversely, endothelial-dependent dilation of the brachial arteries was significantly lower in patients as compared with controls (P<0.0001). Patients with multiple sCADs have a significantly impaired vasomotion, which may predispose to dissection.

Direct Association between C-reactive Protein Serum Levels and Endothelial Dysfunction in Patients with Claudication

To evaluate the relationship between C-Reactive Protein (hsCRP), a serum marker of inflammation, and endothelial dysfunction in patients with intermittent claudication. Cross-sectional study with stratified sampling on dependent variables of age, genre, hypertension, hyperlipidemia, diabetes, smoking status and ankle-brachial index (ABI) to select 156 patients from a target population of 4,100 patients with claudication. We assessed the flow-mediated arterial dilation (FMAD) as a reporter of endothelial function and plasma levels of hsCRP and fibrinogen. Patients with a FMAD<3% (range for the lowest 5% of healthy subjects) had increased levels of plasma hsCRP (6.3 vs 2.3mg/L; p<0.05) and fibrinogen (351vs 302mg/L; p<0.05) in comparison to those with FMAD>3%. There was a negative correlation between hsCRP and FMAD(r=-0.465; p<0.05). Impaired endothelial dysfunction is association with increased plasma concentrations of inflammatory markers, and both may have a role in the aetiopathogenesis of peripheral arterial disease.

Last Word on Point:Counterpoint: Cardiac denervation does/does not play a major role in exercise limitation after heart transplantation

to the editor: Over time, publications support that whether cardiac denervation plays a major role in exercise limitation after heart transplantation still remains controversial ([1][1], [2][2], [4][3]). In fact, the relative role of central and peripheral impairments on exercise limitation after

Usefulness of High-Frequency Vascular Ultrasound Imaging and Serum Inflammatory Markers to Predict Plaque Rupture in Patients With Stable and Unstable Angina Pectoris

It remains unclear what kind of morphologic and biochemical features best predict plaque rupture in patients with angina pectoris (AP). This study aimed to investigate whether combined high-frequency vascular ultrasound imaging and measurements of serum inflammatory biomarkers can predict coronary plaque ruptures in patients with AP. The study population consisted of 20 patients with stable AP and 40 patients with unstable AP. High-frequency vascular ultrasound imaging was performed in the 2 groups to measure intima-media thickness, the plaque acoustic density of the common carotid arteries, and the flow-mediated dilation of the brachial arteries. Serum lipid profile and inflammatory biomarkers were measured in all patients. Using intravascular ultrasound, a list of coronary imaging parameters was obtained. A multivariate logistic regression model was applied to calculate the odds ratio of each parameter to predict coronary plaque ruptures detected by intravascular ultrasound. Of 139 coronary artery plaques identified by intravascular ultrasound, 48 plaques (9 in stable AP and 39 in unstable AP) developed ruptures. Among measured parameters, the values of carotid intima-media thickness, coronary external elastic membrane area, plaque area, plaque burden, plaque eccentric index and remodeling index, serum high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were significantly higher in unstable AP than in stable AP (p <0.05 to 0.01). Of these parameters, carotid intima-media thickness, serum high-sensitivity C-reactive protein, and the coronary remodeling index were found to be significant predictors of coronary plaque rupture, with odds ratios of 9.51 (95% confidence interval 1.29 to 21.81), 3.02 (95% confidence interval 1.01 to 7.65), and 0.01 (95% confidence interval 0.00 to 0.34), respectively. In conclusion, combined high-frequency ultrasound imaging of coronary and carotid arteries and measurements of serum inflammatory markers are able to predict coronary plaque ruptures in patients with AP.

Effects of thyroxine replacement on lipid profile and endothelial function after thyroidectomy

Hypothyroidism is a risk factor for atherosclerotic cardiovascular disease. This study investigated the effects of L-thyroxine replacement therapy on lipid profile and endothelial function after thyroidectomy in patients with overt transient non-autoimmune hypothyroidism. Twenty-two patients with non-toxic multinodular goitre treated by total or near-total thyroidectomy and 22 healthy individuals matched for age, sex and body mass index were studied. Lipid profile and endothelial function were determined in each patient at the euthyroid phase before thyroidectomy (stage 1), the hypothyroid phase 3 weeks after surgery (stage 2), and the euthyroid phase 3 months (stage 3) and 6 months (stage 4) after the start of thyroxine treatment. The lipid profile and endothelial function deteriorated between stage 1 and stages 2 and 3. Findings at stage 4 were similar to those at stage 1. There was a positive correlation between serum thyroid-stimulating hormone (TSH) and total cholesterol (r(s) = 0.588, P < 0.001), and a negative correlation between serum TSH and flow-mediated arterial dilatation (r(s) = 0.506, P < 0.001). Total cholesterol and TSH were independent determinants of endothelial function. A 3-week hypothyroid period after thyroidectomy led to a more atherogenic lipid profile and impaired endothelial function that persisted for at least 3 months.

The study of vascular lesion using ultrasound in children with a history of Kawasaki disease

To explore the endothelial function, carotid artery stiffness index and carotid intima-media thickness in children with a history of Kawasaki disease (KD). A cohort of 204 children was studied, which comprised 51 patients with Kawasaki disease with coronary artery lesion (CAL group), 50 patients with Kawasaki disease with normal coronary arteries (normal coronary arteries group), and 103 healthy age matched children (control group). Their systemic blood pressure, fasting cholesterol concentrations, flow-mediated dilation (FMD) of the brachial artery, carotid artery stiffness index and carotid intima-media thickness (IMT) were compared. FMD of the brachial artery in CAL group (5.2% +/- 1.9%) and normal coronary arteries group (6.8% +/- 2.0%) were significantly lower than that of control group (13.2% +/- 4.1%, both P < 0. 01); carotid artery stiffness index in CAL group (4.0 +/- 0.6) was significantly greater than that of normal coronary arteries group (3.6 +/- 0.6) and control group (3.4 +/- 0.5, P = 0.05, P < 0.01); likewise, IMT in CAL group (0.447 mm +/- 0.024 mm) was significantly higher than that of normal coronary arteries group (0.426 mm +/- 0.016 mm) and control group (0.424 mm +/- 0.016 mm, both P < 0.01). In multiple linear regression analysis, age and patient grouping were significant determinants of carotid artery stiffness index, FMD and IMT. There were significant correlations between carotid artery stiffness index, FMD and IMT in both healthy group and KD group after adjustment of age. There were endothelial dysfunction and increased systemic arterial stiffness and IMT late after the acute phase of Kawasaki disease. flow-mediated dilation of the brachial artery, carotid artery stiffness index combined carotid intima-media thickness can evaluated completely the prognosis of vascular lesion in convalescence after KD.

Cytochrome P450 2C9 is involved in flow‐dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure

Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans. FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery. FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.

Endothelial Cell Apoptosis in Obstructive Sleep Apnea

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. To study the association between circulating apoptotic endothelial cells and vasomotor dysfunction as a function of sleep apnea. 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. 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). 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.

Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction

flow-mediated arterial dilation (FMAD), an indicator of endothelial function, is reduced in patients with heart failure and reduced left ventricular ejection fraction (HFREF). Many elderly patients with heart failure exhibit a normal left ventricular ejection fraction (HFNEF). It is unknown whether FMAD is severely reduced in the elderly with HFNEF. 30 participants >60 yr of age, 11 healthy, 9 with HFNEF, and 10 with HFREF, underwent a cardiovascular magnetic resonance (CMR) assessment of FMAD in the superficial femoral artery followed within 48 h by symptom-limited exercise with expired gas analysis. Elderly patients with HFREF and HFNEF had severely reduced peak oxygen consumption (Vo(2 peak); 12 +/- 2 and 13 +/- 1 ml.kg(-1).min(-1), respectively) vs. their healthy age-matched contemporaries (20 +/- 3 ml.kg(-1).min(-1)). FMAD was 3.8 +/- 1.3% (0.85 +/- 0.22 mm(2)) in patients with HFREF; it was 12.1 +/- 3.6% (3.1 +/- 1.2 mm(2)) and 13.7 +/- 5.9% (3.9 +/- 1.7 mm(2)), respectively, in patients with HFNEF and age-matched healthy older individuals. After adjustment for age and gender, the association of FMAD with Vo(2) was high in healthy and HFREF subjects (P = 0.05 and 0.02, respectively) but less so in HFNEF participants (P = 0.58). elderly patients with HFNEF do not exhibit marked reduction in leg FMAD. These data suggest that mechanisms other than impaired femoral arterial endothelial function contribute to the severe exercise intolerance experienced by these individuals.

Impaired flow-mediated dilation with age is not explained by l-arginine bioavailability or endothelial asymmetric dimethylarginine protein expression

Aging is associated with a decline in vascular endothelial function, manifesting in part as impaired flow-mediated arterial dilation (FMD), but the underlying mechanisms are uncertain. Impaired FMD may be mediated in part by a decrease in synthesis of nitric oxide by endothelial nitric oxide synthase, and in clinical populations this has been attributed to competitive inhibition of l-arginine binding sites by asymmetric dimethylarginine (ADMA). If this mechanism is involved in the age-associated decline in FMD, increasing l-arginine concentration may swing the competitive balance in favor of l-arginine binding, restoring nitric oxide synthesis, and enhancing FMD in older humans. To test this hypothesis, we measured FMD (brachial ultrasound) in 10 younger (21 +/- 1 yr) and 12 older healthy men and women (60 +/- 2 yr) following infusion of vehicle or vehicle + l-arginine. Baseline FMD in the older subjects was only approximately 60% of that in the younger subjects (P = 0.002). l-Arginine did not significantly increase FMD in either group despite 23-fold (older) and 19-fold (younger) increases in plasma l-arginine concentrations (P < 0.0001 vs. control). Protein expression (immunofluorescence) in vascular endothelial cells showed that ADMA and the enzyme isoform that controls its degradation, dimethylarginine dimethylaminohydrolase II, were not different in the younger and older subjects. Endothelium-independent vasodilation (sublingual nitroglycerine) was not different between age groups or conditions. We conclude that acutely increasing plasma concentrations of l-arginine do not significantly improve brachial artery FMD in healthy older subjects and thus does not restore the age-associated loss of FMD. Together with the finding that endothelial cell ADMA protein expression was not increased in older adults, these findings suggest that competitive inhibition of l-arginine binding sites on endothelial nitric oxide synthase by ADMA is not an important mechanism contributing to impaired conduit artery endothelium-dependent dilation with aging in healthy humans.

Impairment of endothelium‐dependent arterial dilation in Hashimoto's thyroiditis patients with euthyroidism

Recent studies have shown that immune responses contribute to atherosclerosis, and endothelial dysfunction is an important early event in atherogenesis. The aim of this study was to investigate the alteration of endothelial function in Hashimoto's thyroiditis (HT) patients with euthyroidism. Study subjects included 28 female HT patients with euthyroidism, 23 female HT patients with hypothyroidism, and 22 healthy women. High-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate (GTN). Flow-mediated arterial dilation in HT patients with euthyroidism was significantly lower (3.88%) than in controls (4.98%, P = 0.000) and higher than in HT patients with hypothyroidism (3.26%, P < 0.001). Flow-mediated arterial dilation among HT patients with hypothyroidism was significantly lower than that in controls (P = 0.000). GTN-induced arterial dilation, baseline vessel size, and baseline blood flow were not significantly different among the three groups (P > 0.05). On multiple regression analysis, anti-thyroid peroxidase antibody (TPO-Ab), TSH, free T3, low density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] were found to be significant factors associated with endothelium-dependent arterial dilation. Endothelial dysfunction exists in HT patients with euthyroidism. Autoimmune reactivity and an elevated Lp(a) level might be responsible for the endothelial dysfunction.

Magnitude and Time Course of Arterial Vascular Adaptations to Inactivity in Humans

We demonstrate that extensive arterial vascular adaptations occur within 3-8 wk of inactivity in humans. We put forth the hypothesis that the diameter decrease represents an adaptation to a lack of variation in peak shear stress. Furthermore, an enhanced flow-mediated dilation in deconditioned arteries implies that functional vascular adaptations to inactivity are not simply the inverse of adaptations to exercise.

Determinants of short-term variation in arterial flow-mediated dilatation in healthy young men

Brachial artery FMD (flow-mediated dilatation) is widely used as a marker of systemic arterial endothelial function. FMD, however, shows considerable 25% day-to-day variation that hinders its clinical use. The reasons for this variability are poorly characterized. Therefore the present study was designed to clarify factors responsible for the hourly variation in endothelial function, including consuming a low-fat meal and circadian rhythms in endogenous hormonal levels. Brachial artery FMD, along with serum glucose, triacylglycerols (triglycerides) and levels of several hormones were measured six times per day on two separate days 1 week apart. On one day, the subjects (healthy males: n=12, mean age, 24 years) ate a light breakfast and a standardized lunch (23.5% fat, 48.7% carbohydrate and 27.8% protein). On the other day, they had a similar breakfast after which they fasted. Postprandial FMD values (both after breakfast and after lunch) were similar to baseline FMD. FMD showed a 28% hourly variation and 27% weekly variation. Variation in plasma levels of insulin (P=0.02) associated negatively and DHPG (3,4-dihydroxyphenylglycol) (P=0.001), a marker of sympathetic nervous activation, associated positively with variation in FMD. The effects of DHPG and insulin on FMD were independent of changes in baseline brachial artery diameter, although DHPG was also inversely associated with baseline diameter. Eating a regular low-fat meal does not have any measurable effects on brachial artery endothelial function. These data suggest that strict requirements for fasting conditions may be unnecessary when measuring peripheral endothelial function using the ultrasound technique. Circadian variation in serum insulin and sympathetic tone are physiological determinants of endothelial function.

Prolonged deterioration of endothelial dysfunction in response to postprandial lipaemia is attenuated by vitamin C in Type 2 diabetes

Endothelial dysfunction (ED) has been described in Type 2 diabetes (T2DM). We have described previously a diminution of flow-mediated arterial dilatation and, by implication, further ED in T2DM in response to postprandial lipaemia (PPL) at 4 h. This is possibly mediated by oxidative stress/alteration of the nitric oxide (NO) pathway. T2DM subjects tend to exhibit both exaggerated and prolonged PPL. We therefore studied the relationship of PPL to the duration of ED in T2DM subjects and oxidative stress with or without the antioxidant, vitamin C. Twenty subjects with T2DM with moderate glycaemic control (mean HbA1c 8.4%) were studied. After an overnight fast, all subjects consumed a standard fat meal. Endothelial function (EF), lipid profiles, and venous free radicals were measured in the fasting, peak lipaemic phase (4 h) and postprandially to 8 h. The study was repeated in a double-blinded manner with placebo, vitamin C (1 g) therapy for 2 days prior to re-testing and with the fat meal. Oxidative stress was assessed by lipid-derived free radicals in plasma, ex vivo by electron paramagnetic resonance spectroscopy (EPR) and by markers of lipid peroxidation (TBARS). Endothelial function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery. There was a significant decrease in endothelial function in response to PPL from baseline (B) 1.3 +/- 1.3% to 4 h 0.22 +/- 1.1% (P < 0.05) and 8 h 0.7 +/- 0.9% (P < 0.05) (mean +/- sem). The endothelial dysfunction seen was attenuated at each time point with vitamin C. Baseline EF with vitamin C changed from (fasting) 3.8 +/- 0.9-2.8 +/- 0.8 (at 4 h) and 2.9 +/- 1.3 (at 8 h) in response to PPL. Vitamin C attenuated postprandial (PP) oxidative stress significantly only at the 4-h time point [301.1 +/- 118 (B) to 224.7 +/- 72 P < 0.05] and not at 8 h 301.1 +/- 118 (B) to 260 +/- 183 (P = NS). There were no changes with placebo treatment in any variable. PPL was associated with a PP rise in TG levels (in mmol/l) from (B) 1.8 +/- 1 to 2.7 +/- 1 at 4 h and 1.95 +/- 1.2 at 8 h (P = 0.0002 and 0.33, respectively). PPL is associated with prolonged endothelial dysfunction for at least 8 h after a fatty meal. Vitamin C treatment improves endothelial dysfunction at all time points and attenuates PPL-induced oxidative stress. This highlights the importance of low-fat meals in T2DM and suggests a role for vitamin C therapy to improve endothelial function during meal ingestion.