Impact of aortic stenting on peripheral vascular function and daytime systolic blood pressure in adult coarctation.

OBJECTIVES: To determine the relation of ambulatory systolic blood pressure to aortic obstruction and more extensive vascular dysfunction, assessed by central aortic, peripheral conduit arterial and resistance vessel function. METHODS: 12 adults (5 native, 7 recoarctation) were studied before, and 2 weeks and 6 months after aortic stenting. Systolic blood pressure was measured during normal daily living by 24-hour ambulatory monitoring. Central aortic function was assessed by pulse wave analysis (augmentation index). Brachial artery flow-mediated dilatation and dilatation in response to 25 mug of sublingual glyceryl trinitrate was assessed by ultrasound to measure peripheral conduit arterial and resistance vessel function. Baseline vascular measures were compared with those of 12 matched controls. RESULTS: Patients had a higher augmentation index, impaired endothelium-dependent and -independent dilatation, and forearm vascular resistance (p<0.02). After successful gradient relief by stenting, daytime ambulatory systolic blood pressure (151 (134, 166) mm Hg vs 138 (130, 150) mm Hg, p = 0.01) and the augmentation index (26 (15, 34) vs 23 (13, 30), p = 0.03) fell progressively over 6 months, but did not completely normalise. Endothelium-dependent and -independent dilatation, and forearm vascular resistance remained unchanged and impaired. CONCLUSION: Relief of aortic obstruction is associated with improvement in central aortic function and results in reduction of daytime ambulatory systolic blood pressure. Peripheral vascular dysfunction, however, remains unchanged and may contribute to residual hypertension.

Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors.

BACKGROUND: Atherosclerosis develops from childhood, but the determinants of this preclinical stage remain uncertain. We examined the relations of classic coronary risk factors, adiposity and its associated metabolic disturbances, to arterial distensibility (a marker of early arterial disease) in 13- to 15-year-olds, some of whom had previously been studied at ages 9 to 11 years. METHODS AND RESULTS: Brachial artery distensibility was measured by a noninvasive ultrasound technique in 471 British children in whom measures of adiposity, blood pressure, fasting blood lipids, and insulin had been made. All adiposity measures showed strong graded inverse relationships with distensibility. Inverse associations with distensibility were also observed for insulin resistance (homeostasis model assessment), diastolic pressure, C-reactive protein, and the number of metabolic syndrome components present, which had a graded relation to distensibility. Total and LDL cholesterol levels were also inversely related to distensibility, but less strongly than adiposity; homocysteine had no relation to distensibility. Although the relations of total and LDL cholesterol and diastolic pressure to distensibility had been present at 9 to 11 years of age, those of adiposity and insulin resistance were only apparent at 13 to 15 years. CONCLUSIONS: Adiposity and its metabolic consequences are associated with adverse changes in the arterial wall by the teenage years. The graded relation with increasing adiposity was stronger than that for cholesterol and was seen at body mass index levels well below those considered to represent "obesity." This emphasizes the importance of population-based strategies to control adiposity and its metabolic consequences in the young.

Treatment of photoaged skin with a cream containing 0.05% isotretinoin and sunscreens.

AIMS: To determine the safety and efficacy of a cream formulation of 0.05% isotretinoin with sunscreens (SPF 15) (I+S) in the treatment of photoaged skin. DESIGN AND SUBJECTS: A 6-month, multicentre, randomized, double-blind, parallel-group, vehicle-controlled study of 346 subjects with photoaged skin, as defined by the presence of fine lines in the periorbital region. The main outcome measure was profilometry measurements of replicas of the periorbital region, taken at 0 and 6 months. Subsidiary outcome measures were clinical scoring of wrinkles/fine lines at 0, 1, 3, 6 and 9 months and histopathology at 0 and 6 months. METHODS AND RESULTS: A total of 172 subjects were randomized to 0.05% I+S and 174 subjects to vehicle. Subjects used the study medication topically, once-daily for 6 months, followed by a 3-month washout period. Profilometry measurements of the distance between the highest peak and lowest valley (Rz) and the distance between all valleys and peaks from mid-line (Ra) showed that subjects using I+S had statistically significant improvement (p<0.05) compared with the vehicle group. Additionally, at all visits, VAS clinical scoring of wrinkles/fine lines showed a statistically significant difference between the groups in favour of I+S. Tolerance assessments showed that more subjects in the I+S group experienced local side effects at the start of the study; however, reports of side effects decreased over time in both groups. CONCLUSION: This study confirms that I+S improves the appearance of fine wrinkles associated with photoaged skin.

Clinical evaluation of Double Strength Isotrexin versus Benzamycin in the topical treatment of mild to moderate acne vulgaris.

BACKGROUND: Topical retinoid therapy has been shown to be an effective means of treating both the inflammatory and non-inflammatory lesions of acne vulgaris. AIM: To assess the efficacy and safety of the test product, a gel containing isotretinoin 0.1% w/w and erythromycin 4.0% w/w, with a currently used and effective treatment for mild to moderate acne vulgaris, a gel containing benzoyl peroxide 5.0% w/w and erythromycin 3.0% w/w. METHODS: This multi-centre, single-blind (investigator blind), parallel group study compared the efficacy and safety of isotretinoin/erythromycin gel (Double Strength Isotrexin) once daily against benzoyl peroxide/erythromycin gel (Benzamycin twice daily in the topical treatment of mild to moderate acne vulgaris. Patients (n = 188) with a history (mean duration 3.3 years) of facial acne vulgaris and with 15-100 inflammatory lesions and/or 15-100 non-inflammatory lesions, but not more than three nodulocystic lesions, were included. At baseline and weeks 2, 4, 8 and 12, the investigator assessed efficacy (total number and severity of inflammatory and non-inflammatory lesions and acne grade) while subjective global change assessments of facial acne from baseline and symptom-specific skin tolerance were assessed by the patient. The investigator recorded an overall global assessment of skin tolerability at week 12. Adverse events were recorded throughout. RESULTS: The treatments were comparable with regard to their effects on inflammatory and non-inflammatory lesions and acne grade. Few adverse events were considered to be treatment-related. Both the isotretinoin/erythromycin and benzoyl peroxide/erythromycin gels were generally well tolerated. Compliance was better with the isotretinoin/erythromycin gel, which had the advantages of not requiring mixing or storage in a refrigerator, and was applied once rather than twice daily. CONCLUSIONS: Isotretinoin/erythromycin gel given only once daily showed comparable efficacy with benzoyl peroxide/erythromycin given twice daily in the treatment of mild to moderate acne vulgaris of the face.

Acute administration of L-arginine does not improve arterial endothelial function in chronic renal failure.

BACKGROUND: Reduced activity of the nitric oxide (NO) pathway has been implicated in the endothelial dysfunction that occurs in patients with renal failure. NO is generated from L-arginine by NO synthase, and certain uremic toxins including asymmetrical dimethyl-L-arginine (ADMA), inhibit NO synthase and might contribute to endothelial dysfunction. We hypothesized that exogenous L-arginine might improve endothelial function in patients with renal failure by overcoming the effects of uremic toxins. METHODS: Endothelial function of the forearm resistance vasculature was assessed using plethysmography to measure the dilator response to intra-arterial acetylcholine (25 to 100 nmol/min). Endothelial function of radial and brachial arteries was assessed using vascular ultrasound to measure the dilator response to flow during reactive hyperemia (flow-mediated dilation; FMD). Studies were performed before and after administration of L-arginine by intra-arterial infusion (50 micromol/min) in 8 pre-dialysis patients or by intravenous infusion (10 g) in 18 hemodialysis patients. RESULTS: Local L-arginine did not improve the dilator response of forearm resistance vessels (AUC 23.1 +/- 6.4 pre, 23.1 +/- 5.1 post; P = 0.9) or FMD of the radial artery (6.5 +/- 1.2% pre, 6.3 +/- 0.8% post; P = 0.8). Systemic L-arginine did not improve FMD of the brachial artery (4.1 +/- 1.1% pre, 3.0 +/- 1.1% post; P = 0.07). These data demonstrate that acute local or systemic administration of L-arginine did not improve endothelial function in resistance or conduit arteries of patients with chronic renal failure. CONCLUSION: The results suggest that competitive inhibition of nitric oxide synthase (NOS) by circulating inhibitors is not the principal explanation for impaired endothelial dilator function in chronic renal failure.

Assessment of endothelial function in normal twin pregnancy.

OBJECTIVE: To assess the maternal endothelial function in normal twin pregnancy. DESIGN: Cross-sectional study. SUBJECTS: Endothelial function was investigated in 74 women with normal twin pregnancy at 11-30 weeks of gestation and the results were compared to previous reported findings in 98 women with normal singleton pregnancy and 19 non-pregnant controls. METHODS: Endothelial function was assessed by measuring the changes of the brachial artery diameter in response to reactive hyperemia (flow-mediated dilatation) using external high resolution ultrasound. RESULTS: Flow-mediated dilatation of the brachial artery in both twin and singleton pregnancies was significantly higher than in non-pregnant women (P = 0.002 and P = 0.02, respectively). However, there was no significant difference in flow-mediated dilatation between women with twin and singleton pregnancy (9.61 +/- 4.36 vs. 8.84 +/- 3.18, P = 0.38). Resting vessel size, baseline flow and reactive hyperemia did not change significantly with gestation in twin pregnancy and were similar to values in singleton pregnancies and controls. CONCLUSION: Our findings indicate that although in pregnancy endothelial function is enhanced, this change may not be affected by the number of fetoplacental units present.

Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

The effect of amlodipine on endothelial function in young adults with a strong family history of premature coronary artery disease: a randomised double blind study.

Endothelial dysfunction, an early event in atherogenesis, has been demonstrated in young asymptomatic subjects with a strong family history of premature coronary artery disease (CAD). In these subjects, preventive measures involving risk factor modification are not appropriate, and strategies employing novel antiatherogenic agents, such as the dihydropyridine calcium channel blocker, amlodipine, may be useful. Ninety-one subjects (mean age, 28.6 years; range, 18-40) with a strong family history of premature CAD and no other identified vascular risk factors were randomised to either 5 mg amlodipine (49 subjects) or placebo (42 subjects). Brachial artery flow mediated dilatation (FMD) (endothelium-dependent response) and response to glyceryltrinitrate (GTN) (direct smooth muscle dilator) were assessed non-invasively at baseline, and after 12 and 24 weeks using high-resolution vascular ultrasound. In those treated with amlodipine, mean FMD increased from 2.32+/-2.23% at baseline to 3.52+/-3.1% at 24 weeks (P<0.005). However, FMD also increased in the placebo group from 1.64+/-2.12 to 3.37+/-2.68% (P<0.002), and the difference between the FMD response in the amlodipine and placebo groups was not significant. Dilatation to GTN did not change in either group. Therefore, impaired endothelial function improved in family history subjects taking both amlodipine and placebo, but there is no difference between the groups.

Mental stress induces transient endothelial dysfunction in humans.

BACKGROUND: Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. METHODS AND RESULTS: Endothelial function was studied in 10 healthy men (aged 50. 4+/-9.6 years) and in 8 non-insulin-dependent diabetic men (aged 52. 0+/-7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 microg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0+/-2.1%) was significantly (P:<0.01) reduced at 30 and 90 minutes after mental stress (2.8+/-2.3% and 2.3+/-2.4%, respectively) and returned toward normal after 4 hours (4.1+/-2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0+/-1.5% versus 5.0+/-2.1%, respectively; P:=0.02) but showed no changes in FMD (2.7+/-1.1% after 30 minutes, 2.8+/-1.9% after 90 minutes, and 3.1+/-2.3% after 240 minutes) or GTN responses after mental stress. CONCLUSIONS: These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.

Non-invasive assessment of endothelial function in normal pregnancy.

OBJECTIVE: To assess endothelial function in normal pregnancy by non-invasive methods. METHODS: Flow-mediated dilatation of the brachial artery was measured by ultrasonography in 157 women with normal singleton pregnancies between 10 and 40 weeks' gestation and 19 non-pregnant controls. RESULTS: Flow-mediated dilatation in the non-pregnant controls was 6.42 +/- 2.45%. In pregnant women, between 10 and 30 weeks, the mean flow-mediated dilatation (8.84 +/- 3.18%) was significantly higher than the non-pregnant controls (P = 0.002), but after 30 weeks of gestation there was a decrease to prepregnancy levels. Resting vessel diameter and blood flow were significantly increased in pregnancy, mainly after 30 weeks' gestation (P < 0.001, P < 0.001, respectively). Flow-mediated dilatation was significantly correlated to resting vessel diameter and reactive hyperemia. CONCLUSION: Normal pregnancy is associated with enhanced endothelial function which is apparent from at least 10 weeks' gestation.

Acute systemic inflammation impairs endothelium-dependent dilatation in humans.

BACKGROUND: We tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation. METHODS AND RESULTS: Salmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P:=0.0099) and ACh (P:=0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal. CONCLUSIONS: S typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.

Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study.

OBJECTIVES: We sought to determine the effects of oral L-arginine and the hexamethylglutaryl coenzyme A reductase inhibitor atorvastatin on endothelial function in young patients with type I diabetes mellitus (DM). BACKGROUND: Endothelial dysfunction, a key early event in atherosclerosis, occurs in young patients with type I DM, and its reversal may benefit the progression of vascular disease. Cholesterol reduction in L-arginine improve endothelial function in nondiabetic subjects, but their effect in patients with type I DM is unknown. METHODS: In a double-blind, 2x2 factorial study, we investigated the effect of L-arginine (7 g twice daily) and atorvastatin (40 mg/day) on conduit artery vascular function in 84 normocholesterolemic young adults (mean+/-SD: age 34 years [range 18 to 46], low density lipoprotein [LDL] cholesterol 2.96+/-0.89 mmol/liter) with type I DM. Brachial artery dilation to flow (flow-mediated dilation [FMD]) and to the direct smooth muscle dilator glyceryl trinitrate (GTN) were assessed noninvasively using high resolution ultrasound at baseline and after six weeks of treatment. RESULTS: Atorvastatin resulted in a 48+/-10% decrease in serum LDL cholesterol levels, whereas L-arginine levels increased by 247+/-141% after L-arginine therapy. By analysis of covariance, treatment with atorvastatin resulted in a significant increase in FMD (p = 0.018. L-Arginine therapy had no significant effect on endothelial function, and there was no significant change in dilation to GTN after either intervention. CONCLUSIONS: In young patients with type I DM, improvement in endothelial dysfunction can be demonstrated after just six weeks of treatment with atorvastatin. In contrast to studies of hypercholesterolemia, however, L-arginine had no benefit. Treatment with atorvastatin at an early stage may have an impact on the progression of atherosclerosis in these high risk patients.

Cholesterol and arterial distensibility in the first decade of life: a population-based study.

BACKGROUND: Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years. METHODS AND RESULTS: A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient -11.8 microm. mmol(-1). L(-1), P=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (-12.9 microm. mmol(-1). L(-1), P=0. 005 and -36.9 microm/mmol/L, P=0.01). HDL and triglyceride levels showed no consistent association with distensibility. CONCLUSIONS: LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.

Exercise training enhances endothelial function in young men.

OBJECTIVES: The present study was designed to assess whether exercise training can enhance endothelium-dependent dilatation in healthy young men. BACKGROUND: Exercise has been shown to reduce cardiovascular morbidity and mortality, but the mechanisms for this benefit are unclear. Endothelial dysfunction is an early event in atherogenesis, and animal studies have shown that exercise training can enhance endothelial function. METHODS: We have examined the effect of a standardized, 10-week, aerobic and anaerobic exercise training program on arterial physiology in 25 healthy male military recruits, aged 17 to 24 (mean 20) years, of average fitness levels. Each subject was studied before starting, and after completing the exercise program. Baseline vascular reactivity was compared with that of 20 matched civilian controls. At each visit, the diameter of the right brachial artery was measured at rest, during reactive hyperemia (increased flow causing endothelium-dependent dilation) and after sublingual glyceryltrinitrate (GTN; an endothelium-independent dilator), using high-resolution external vascular ultrasound. RESULTS: At baseline, flow-mediated dilatation (FMD) and GTN-mediated dilatation were similar in the exercise and control groups (FMD 2.2+/-2.4% and 2.4+/-2.8%, respectively, p = 0.33; GTN 13.4+/-6.2 vs. 16.7+/-5.9, respectively, p = 0.53). In the military recruits, FMD improved from 2.2+/-2.4% to 3.9+/-2.5% (p = 0.01), with no change in the GTN-mediated dilation (13.4+/-6.2% vs. 13.9+/-5.8%, p = 0.31) following the exercise program. CONCLUSION: Exercise training enhances endothelium-dependent dilation in young men of average fitness. This may contribute to the benefit of regular exercise in preventing cardiovascular disease.

Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine.

OBJECTIVES: We sought to examine endothelial responses to L-arginine in three groups with isolated risk factors: hypercholesterolemia, smoking and insulin-dependent diabetes mellitus (IDDM). BACKGROUND: Endothelial dysfunction occurs early in atherosclerosis, predating clinical disease. We hypothesized that the nature of endothelial injury associated with individual cardiovascular risk factors might be different and that this might affect the response to L-arginine, the substrate for endothelial nitric oxide synthase. METHODS: We studied the effects of intravenous L-arginine on brachial artery flow-mediated dilation (FMD) and glyceryl trinitrate (GTN)-mediated dilation in 36 young subjects (18 to 40 years old) without clinical atherosclerosis: 9 each of normal control subjects, hypercholesterolemic subjects, cigarette smokers and subjects with IDDM. RESULTS: Baseline FMD was significantly impaired in hypercholesterolemic subjects (mean +/- SD 1.7 +/- 2.3%), smokers (1.6 +/- 1.8%) and diabetic subjects (1.8 +/- 1.5%) compared with that in control subjects (6.9 +/- 3.3%, p = 0.001). The response to GTN was not significantly different between the subjects with risk factors and control subjects, apart from those with IDDM, in whom it was significantly impaired (p = 0.026). After infusion of L-arginine, there was no change in FMD in control or diabetic subjects. In hypercholesterolemic subjects and smokers, FMD improved from 1.9 +/- 1.9% to 4.1 +/- 2.1% (p = 0.01) and from 2.0 +/- 1.71% to 3.1 +/- 2.5% (p = 0.02), respectively. CONCLUSIONS: FMD was impaired in all three risk factor groups; however, they responded differently to L-arginine, FMD being improved in hypercholesterolemic subjects and smokers but unchanged in diabetic subjects. These results indicate differing underlying pathophysiologies that may facilitate the design of treatment strategies for subjects with different risk factors.

Prospective randomized trial of woven versus collagen-impregnated knitted prosthetic Dacron grafts in aortoiliac surgery.

BACKGROUND: Despite the theoretical advantages of coating knitted grafts with a material designed to reduce blood loss, their performance has not been directly compared with woven grafts in a prospective randomized trial. The aim of this study was to compare the graft handling qualities and operative blood loss of the two types of arterial prosthesis, as well as complication rate and patient survival at 1 year. METHODS: A total of 267 consecutive patients having surgery for occlusive or aneurysmal disease of the aortoiliac arteries were randomized to receive woven (141 patients) or knitted collagen-impregnated Dacron (126 patients) grafts. Graft patency was assessed on discharge and at 1 year by duplex imaging. RESULTS: Mean(s.d.) intraoperative blood loss was statistically greater with woven grafts (1690(1424) ml) compared with knitted (1363(1172) ml) (P = 0.049). An insignificant 1-year increase in mean(s.d.) graft diameter of 1.2(0.2) mm was found at the distal anastomosis in the knitted group. There was no difference in graft patency between the groups and only one graft became infected. CONCLUSION: This study suggests that knitted and woven grafts have similar clinical performance and therefore the less expensive material (woven) should usually be selected unless haemorrhagic complications are anticipated.

Effect of enalapril on endothelial function in young insulin-dependent diabetic patients: a randomized, double-blind study.

OBJECTIVES: We sought to determine whether 6 months of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can improve conduit artery endothelial function in young subjects with insulin-dependent diabetes mellitus (IDDM). BACKGROUND: Endothelial dysfunction is an early event in atherogenesis and has been demonstrated in young subjects with IDDM. ACE inhibitors have been shown to enhance conduit artery endothelial function in animal experiments and in patients with established coronary atherosclerosis, although their effect in IDDM is not known. METHODS: Ninety-one subjects (mean age 30.9 years, range 18 to 44) with stable IDDM but no clinical evidence of vascular disease were randomized to receive enalapril (20 mg once daily) (46 subjects) or placebo (45 subjects) in a randomized, double-blind, parallel-group study. Brachial artery flow-mediated dilation (FMD), an endothelium-dependent stimulus, and response to glyceryl trinitrate (GTN), which acts directly on vascular smooth muscle, were assessed noninvasively by means of high resolution external vascular ultrasound at baseline and after 12 and 24 weeks of treatment. RESULTS: FMD was inversely correlated with total cholesterol (r=0.22, p=0.041) but not with any diabetic variables. Treatment with enalapril had no significant effect on FMD (p=0.67) or response to the endothelial-independent dilator GTN (p=0.45). CONCLUSIONS: These data suggest that impairment of endothelial-dependent dilation in young subjects with IDDM is not improved by treatment with the ACE inhibitor enalapril. This lack of improvement may reflect the complex nature of vascular disease in IDDM, which can affect both endothelial and smooth muscle function.

Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease.

BACKGROUND: A family history of premature coronary artery disease (CAD) in a first-degree relative is an independent risk factor for coronary disease. Both genetic and environmental influences are likely to be responsible and may interact, but their relative importance is unclear. METHODS AND RESULTS: We studied endothelial function in 50 first-degree relatives (31 men, 19 women; mean age, 25+/-8 years) of patients (men < or = 45 years, women < or = 55 years) with proven CAD. All subjects were well, lifelong nonsmokers, not diabetic, and not hypertensive and took no medications. Using high-resolution external vascular ultrasound, we measured brachial artery diameter at rest and in response to reactive hyperemia (with increased flow causing an endothelium-dependent vasodilatation) and to sublingual glyceryltrinitrate (GTN, an endothelium-independent dilator). Vascular responses were compared with those of 50 healthy control subjects matched for age and sex. Flow-mediated dilatation (FMD) was impaired in the family history group (4.9+/-4.6% versus 8.3+/-3.5% in control subjects, P<.005). In contrast, GTN caused dilatation in all subjects (family history, 17.1+/-8.8%; control subjects, 19.0+/-6.3%; P=NS), suggesting that reduced FMD was due to endothelial dysfunction. When the family history subjects were subdivided, those found to have a serum cholesterol > 4.2 mmol/L (group A, n=10) had mildly impaired FMD compared with control subjects (5.5+/-5.1% versus 8.3+/-3.5%). In others whose affected relative had coronary risk factors (group B, n=24), FMD was also only slightly reduced (6.2+/-4.8% versus 8.3+/-3.5%). In contrast, subjects with no risk factors and whose affected relative had a normal cardiovascular risk factor profile (group C, n=16) had markedly impaired FMD (2.9+/-3.7% versus 8.3+/-3.5%). Although ANOVA of the three family history subgroups did not reach statistical significance (F=2.55, P=.09), pairwise analysis showed that FMD in group C was significantly impaired compared with group B (P=.026). CONCLUSIONS: Healthy young adults with a family history of premature coronary disease may have impaired endothelium-dependent dilatation, even in the absence of other cardiovascular risk factors. Those subjects, who were free of risk factors and whose affected first-degree relative was free of risk factors, had the most impaired endothelial function, suggesting a genetic influence on early arterial physiology that may be relevant to later clinical disease.

Flow-mediated dilation in 9- to 11-year-old children: the influence of intrauterine and childhood factors.

BACKGROUND: Early life factors, particularly size at birth, may influence later risk of cardiovascular disease, but a mechanism for this influence has not been established. We have examined the relation between birth weight and endothelial function (a key event in atherosclerosis) in a population-based study of children, taking into account classic cardiovascular risk factors in childhood. METHODS AND RESULTS: We studied 333 British children aged 9 to 11 years in whom information on birth weight, maternal factors, and risk factors (including blood pressure, lipid fractions, preload and postload glucose levels, smoking exposure, and socioeconomic status) was available. A noninvasive ultrasound technique was used to assess the ability of the brachial artery to dilate in response to increased blood flow (induced by forearm cuff occlusion and release), an endothelium-dependent response. Birth weight showed a significant, graded, positive association with flow-mediated dilation (0.027 mm/kg; 95% CI, 0.003 to 0.051 mm/kg; P=.02). Childhood cardiovascular risk factors (blood pressure, total and LDL cholesterol, and salivary cotinine level) showed no relation with flow-mediated dilation, but HDL cholesterol level was inversely related (-0.067 mm/mmol; 95% CI, -0.021 to -0.113 mm/mmol; P=.005). The relation between birth weight and flow-mediated dilation was not affected by adjustment for childhood body build, parity, cardiovascular risk factors, social class, or ethnicity. CONCLUSIONS: Low birth weight is associated with impaired endothelial function in childhood, a key early event in atherogenesis. Growth in utero may be associated with long-term changes in vascular function that are manifest by the first decade of life and that may influence the long-term risk of cardiovascular disease.

Physiology and biochemistry of endothelial function in children with chronic renal failure.

Premature atherosclerosis is a major cause of morbidity and mortality in chronic renal failure (CRF). Endothelial dysfunction is a key early event in atherogenesis. The aim of this study was to assess the effect of CRF on endothelial function using physiological and biochemical measures. To focus on the effect of CRF itself, 23 children (matched with 23 controls for age and vessel diameter) were selected because they were normotensive, had normal total cholesterol (TC) levels, and were not on vasoactive drugs. Their mean (range) age was 12.0 (7.8 to 17.0) years; GFR 17.5 (8.8 to 34.5) ml/min/1.73 m2. The physiology of endothelial function in the brachial artery was assessed using high resolution ultrasound by measuring its diameter at rest, during reactive hyperemia (endothelium dependent dilation) and after sublingual glyceryl trinitrate (GTN; endothelium independent dilation). Nitric oxide (NO) metabolites and endogenous NO synthetase (eNOS) inhibitors were measured as an assessment of endothelial metabolism. Brachial artery dilation to flow [FMD, mean (SEM)%] was reduced in CRF to 4.9 (0.6) and controls 8.6 (0.6), P < 0.0001. In contrast, the response to GTN was similar in both groups: CRF 25.1 (1.6), controls 23.3 (1.2), P = 0.31. There was no difference in TC, low density lipoprotein (LDL) or high density lipoprotein (HDL) between the patients and the controls. Triglycerides (TG) were higher in the patients but within the normal range. Antibodies against oxidized LDL (ox-LDL) were high in CRF. Endogenous NOS inhibitors were high in CRF, and intermediate NO metabolites were low. There was no correlation between FMD of the brachial artery and lipid subfractions, or with NO metabolites or eNOS inhibitors. Endothelium dependent dilation of the brachial artery is impaired in children with CRF who do not have co-existing risk factors for atherosclerosis. This may represent early evidence of atherogenic vascular disease.