Jacqui Robinson

Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.

BackgroundCigarette smoking is the most important modifiable risk factor for atherosclerosis. Endothelial dysfunction is an early event in atherogenesis, and we hypothesized that smoking might be associated with endothelial damage in the systemic arteries of otherwise healthy young adults. Methods and ResultsWe studied noninvasively the brachial arteries of 200 subjects aged 15 to 57 years, all normotensive, nondiabetic with cholesterol level 5240 mg/dL and no family history of premature vascular disease: 80 control subjects aged 16 to 56 years (mean, 35), 80 current smokers aged 15 to 55 years (mean, 33), and 40 former smokers aged 25 to 57 years (mean, 38). Total lifetime amount smoked varied from 1 to 75 pack years in the smokers. Using high-resolution ultrasound, vessel diameter was measured at rest, during reactive hyperemia (with flow increase causing endothelium-dependent dilation), and after sublingual glyceryl trinitrate (GTN, an endothelium-independent vasodilator). Flow-mediated dilation (FMD) was observed in all the control subjects (10±33%; range, 4% to 22%) but was impaired or absent in the smokers (4±3.9%vo; range, 0% to 17%; P<.0001). FMD in the smokers was inversely related to lifetime dose smoked (6.6±4.0%o in very light smokers, 4.0±3.1% in light smokers, 3.2±3.2% in moderate smokers, and 2.6±1.2% in heavy smokers; P<.01). FMD for the former smokers was 5.1±4.1% (range, 0%/ to 15%). In a multivariate model adjusting for age, sex, cholesterol, smoking history, and vessel size, former smoking was associated with a higher FMD than current smoking (P=.07); when only male former and current smokers were considered, the higher FMD was significant (P=.0001) but not for female smokers (P=.24). GTN caused dilation in all subjects (control subjects, 20±5.2%; smokers, 17±5.8%; former smokers, 17.4±5.4%). Vessel diameter, baseline flow, and degree of reactive hyperemia (Doppler estimated) were similar in all groups. ConclusionsCigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent arterial dilation in asymptomatic young adults, consistent with endothelial dysfunction.

Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction.

OBJECTIVES This study attempted to assess whether coronary risk factors are associated with endothelial dysfunction in the systemic arteries of asymptomatic men and women. BACKGROUND Endothelial dysfunction is present in adults with established atherosclerosis. It is not known whether risk factors interact to produce endothelial dysfunction in clinically well subjects early in the natural history. METHODS Using high resolution ultrasound, we measured arterial diameter at rest, after reactive hyperemia (with increased flow causing endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). Arterial responses were studied noninvasively in 500 clinically well, nonhypertensive subjects (252 men, 248 women; mean [+/- SD] age 36 +/- 15 years, range 5 to 73), including 179 current and former smokers. The superficial femoral artery was studied in 46 subjects and the brachial artery in 454. RESULTS Flow-mediated dilation ranged from -1% to +17%. All arteries dilated in response to administration of nitroglycerin (17 +/- 6%), suggesting an abnormality of endothelial function in subjects with impaired flow-mediated dilation. On univariate analysis, reduced flow-mediated dilation was significantly related to hypercholesterolemia, cigarette smoking, higher blood pressure, male gender, older age, family history of premature vascular disease and larger vessel size (p < 0.01). By multiple stepwise regression analysis, reduced flow-mediated dilation was independently associated with cigarette smoking, older age, male gender and larger vessel size (p < 0.005) but not with total cholesterol level, blood pressure or family history. A composite risk factor score was independently related to flow-mediated dilation (r = -0.30, p < 0.0001), suggesting risk factor interaction. CONCLUSIONS Loss of endothelium-dependent dilation in the systemic arteries occurs in the preclinical phase of vascular disease and is associated with interaction of the same risk factors known to predispose to atherosclerosis and its complications in later life.

Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women

OBJECTIVES This study assessed whether aging is associated with progressive endothelial dysfunction, whether the pattern of any age-related decline in vascular health is different in men and women and whether any gender difference is consistent with known changes in hormonal status. BACKGROUND Coronary and cerebrovascular disease are much less common in young and middle-aged women compared with men, although the gender difference in death from atherosclerosis is less marked after the menopause. Endothelial dysfunction is an early event in atherogenesis and is important in dynamic plaque stenosis in later life. The effect of aging on endothelial function in men and women, however, is not well known. METHODS We used high resolution ultrasound to study endothelium-dependent and endothelium-independent vascular responses. Brachial artery physiology was investigated in 238 subjects (103 men, 135 women; mean [+/- SD] age 38 +/- 17 years, range 15 to 72) with no known risk factors for atherosclerosis. The responses to reactive hyperemia (flow-mediated dilation, which is endothelium dependent) and to glyceryl trinitrate (an endothelium-independent dilator) were assessed for all the subjects and then for men and women separately. RESULTS On multivariate analysis for the whole group, reduced flow-mediated dilation was related to older age (r = -0.34, p < 0.0001). In men, flow-mediated dilation was preserved in subjects aged < or = 40 years but declined thereafter at 0.21%/year. In women, flow-mediated dilation was stable until the early 50s, after which it declined at 0.49%/year (p = 0.002 compared with men). In contrast, there was no significant change in the glyceryl trinitrate response with aging in either gender. CONCLUSIONS Aging is associated with progressive endothelial dysfunction in normal humans, and this appears to occur earlier in men than in women. In women, however, a steep decline commences at around the time of the menopause. This is consistent with a protective effect of estrogens on the arterial wall.

Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults.

BACKGROUND Passive smoking has been linked to an increased risk of dying from atherosclerotic heart disease. Since endothelial dysfunction is an early feature of atherogenesis and occurs in young adults who actively smoke cigarettes, we hypothesized that passive smoking might also be associated with endothelial damage in healthy young-adult nonsmokers. METHODS We studied 78 healthy subjects (39 men and 39 women) 15 to 30 years of age (mean +/- SD, 22 +/- 4): 26 control subjects who had never smoked or had regular exposure to environmental tobacco smoke, 26 who had never smoked but had been exposed to environmental tobacco smoke for at least one hour daily for three or more years, and 26 active smokers. Using ultrasonography, we measured the brachial-artery diameter under base-line conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent dilator). RESULTS Flow-mediated dilatation was observed in all control subjects (8.2 +/- 3.1 percent; range, 2.1 to 16.7) but was significantly impaired in the passive smokers (3.1 +/- 2.7 percent; range, 0 to 9; P < 0.001 for the comparison with the controls) and in the active smokers (4.4 +/- 3.1 percent; range, 0 to 10; P < 0.001 for the comparison with the controls; P = 0.48 for the comparison with the passive smokers). In the passive smokers, there was an inverse relation between the intensity of exposure to tobacco smoke and flow-mediated dilatation (r = -0.67, P < 0.001). In contrast, dilatation induced by nitroglycerin was similar in all groups. CONCLUSIONS Passive smoking is associated with dose-related impairment of endothelium-dependent dilatation in healthy young adults, suggesting early arterial damage.

Carotid Intima-Media Thickness Is Only Weakly Correlated With the Extent and Severity of Coronary Artery Disease

BACKGROUND Intima-media thickness (IMT) of the common carotid artery (CCA), measured with external vascular ultrasound, has been widely used in clinical trials as a surrogate marker for coronary atherosclerosis. Despite this, the degree of correlation between carotid IMT and the extent and severity of coronary artery disease (CAD) is not known. METHODS AND RESULTS Common carotid IMT was measured by ultrasound in 350 consecutive subjects of age 60 +/- 10 years (range, 30 to 85 years) on the day of coronary angiography. Carotid mean IMT was 0.83 +/- 0.20 mm (range, 0.43 to 1.80 mm), and maximum IMT was 1.04 +/- 0.27 mm (range, 0.49 to 2.19 mm). Coronary angiograms were analyzed by independent observers for disease severity (number of vessels with > or = 70% stenosis), extent score, and a modified Gensini score. Mean carotid IMT was weakly but significantly correlated with CAD severity (r = .26), extent (r = .23), and modified Gensini score (r = .29, P < .0001 for all correlations). Carotid IMT was not clinically useful, however, because it was not specific or sensitive enough to identify patients with or without significant CAD. Increasing age, male sex, and presence of diabetes were all associated with a significantly (P < .01) higher CAD score than the average for any level of carotid IMT, suggesting differential effects of these traditional risk factors on the coronary and common carotid arteries. CONCLUSIONS Although carotid IMT is significantly correlated with extent and severity of CAD, the relationship is weak. This relatively poor correlation (r2 < .10) should be considered in the interpretation of clinical trials that use carotid IMT as a surrogate end point for coronary atherosclerosis.

Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.

In hypercholesterolemic rabbits, oral L-arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29+/-5 (19-40) years, with known endothelial dysfunction and LDL-cholesterol levels of 238+/-43 mg/dl. Each subject was studied before and after 4 wk of L-arginine (7 grams x 3/day) or placebo powder, with 4 wk washout, in a randomized double-blind crossover study. Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation). After oral L-arginine, plasma L-arginine levels rose from 115+/-103 to 231+/-125 micromol/liter (P<0.001), and EDD improved from 1.7+/-1.3 to 5.6+/-3.0% (P<0.001). In contrast there was no significant change in response to glyceryl trinitrate. After placebo there were no changes in endothelium-dependent or independent vascular responses. Lipid levels were unchanged after L-arginine and placebo. Dietary supplementation with L-arginine significantly improves EDD in hypercholesterolemic young adults, and this may impact favorably on the atherogenic process.

Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis

OBJECTIVES We sought to assess smooth muscle function in adults at risk for atherosclerosis. BACKGROUND Previous studies in subjects at risk for atherosclerosis have demonstrated arterial endothelial dysfunction, with reduced vasodilator responses after pharmacologic or physiologic stimulation of endothelial nitric oxide (NO). Most have also shown a slight but nonsignificant impairment of vasodilation in response to exogenous sources of NO, such as nitroglycerin (NTG). We hypothesized that NTG responses might be reduced in a large number of consecutively studied adults at risk for atherosclerosis, independent of any impaired endothelium-dependent responses, consistent with concomitant smooth muscle dysfunction. METHODS Using high resolution ultrasound, the dilator response of the brachial artery to 400 microg of sublingual NTG was measured in 800 asymptomatic subjects. Subjects were also assessed for a history of vascular risk factors, blood pressure, total serum cholesterol and flow-mediated endothelium-dependent dilation (EDD). RESULTS We studied 317 men and 483 women, 38 +/- 17 years old (mean +/- SD, range 15 to 76). The mean cholesterol level was 5.2 +/- 1.3 mmol/liter, and there were 126 smokers and ex-smokers (16 +/- 9 mean pack-years) and 105 diabetic subjects. On univariate analysis, a reduced vasodilator response to NTG was associated with high cholesterol, cigarette smoking, diabetes mellitus, increasing age, male gender, larger vessel size and reduced EDD (p < or = 0.01 for all). On multivariate analysis, diabetes, larger vessel size and reduced EDD were all independently associated with impaired NTG-related vasodilation (p < or = 0.001 for all). In the 574 nondiabetic subjects who had never smoked cigarettes, the independent relation between EDD and NTG responses was still observed (r = 0.24, p = 0.01). CONCLUSIONS The vasodilator response to exogenous NO is impaired in asymptomatic subjects with reduced EDD, consistent with smooth muscle dysfunction in adults at risk for atherosclerosis.

IMPAIRED ENDOTHELIAL FUNCTION OCCURS IN THE SYSTEMIC ARTERIES OF CHILDREN WITH HOMOZYGOUS HOMOCYSTINURIA BUT NOT IN THEIR HETEROZYGOUS PARENTS

OBJECTIVES Because endothelial dysfunction is an early event in atherogenesis, we aimed to determine whether endothelial function is normal or impaired in the systemic arteries of children with homozygous homocystinuria or in those of heterozygous adults, or both. BACKGROUND Homocystinuria is strongly associated with premature vascular disease in homozygotes, and even heterozygotes have been shown to be at increased risk from early atherosclerosis associated with hyperhomocystinemia. METHODS We conducted noninvasive studies on the superficial femoral or brachial arteries of 9 children aged 4 to 17 years (mean 11) with homozygous homocystinuria and on the brachial arteries of 14 obligate heterozygous parents age 33 to 49 years (mean 41). Each subject was matched with two control subjects. Using high resolution ultrasound, we measured vessel diameter at rest, during reactive hyperemia (with flow increase causing endothelium-dependent dilation) and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). RESULTS Flow-mediated dilation was observed in the control children (9 +/- 0.6%, range 6% to 14%) but was impaired in the children with homocystinuria (2.8 +/- 0.7%, range 0% to 7%, p < 0.0001). In contrast, nitroglycerin-mediated dilation was similar in both groups (15.7 +/- 1.6% vs. 13.1 +/- 1.2%, p = 0.27), indicating that the impaired flow-mediated dilation is secondary to endothelial dysfunction. In the heterozygous parents, both flow-mediated dilation and nitroglycerin responses (6.3 +/- 0.9%, 17 +/- 1.4%, respectively) were similar to control values (6.8 +/- 0.7%, 20.7 +/- 1.7%, p > 0.10). CONCLUSIONS Children with homozygous homocystinuria had impaired endothelial function in the systemic arteries as early as 4 years of age, representing an early event in their premature vascular disease. However, endothelial function was preserved in the heterozygous adults.

Arterial reactivity is significantly impaired in normotensive young adults after successful repair of aortic coarctation in childhood.

BACKGROUND Despite successful repair of coarctation of the aorta in childhood, adult survivors often have hypertension at rest or on exercise, and their life expectancy is shorter than normal because of premature coronary and cerebrovascular disease. This may be related to persistent structural and functional arterial abnormalities after surgery. METHODS AND RESULTS Using high-resolution ultrasound, we studied the right brachial arteries of 25 normotensive young adults who had undergone successful repair of coarctation in childhood (mean age at repair, 62 months; range, 0 to 167 months, including 8 patients operated on in infancy; mean age at study, 19 years; range, 14 to 27 years) and 50 age- and sex-matched control subjects. We assessed the degree of reactive hyperemia (RH) produced after distal cuff occlusion and release and the changes in arterial diameter in response to RH (with increased flow causing endothelium-dependent dilation) and to glyceryltrinitrate (GTN, an endothelium-independent dilator). The response of the right femoral artery to GTN was also measured in 12 coarctation subjects and 12 control subjects. Studies were performed 13.7 years (range, 7 to 21 years) after surgery. RH was significantly lower in coarctation subjects (343 +/- 130% versus 482 +/- 147%), as were endothelium-dependent dilation (3.8 +/- 3.3% versus 8.8 +/- 3.6%) and GTN response (13.3 +/- 6.0% versus 20.5 +/- 6.1%) (P < .001 for each), reflecting abnormal dilatory capacity in both the resistance and conduit arteries. In contrast, GTN-induced dilation in the femoral arteries was similar to that in control subjects (9.5 +/- 2.6% versus 10.1 +/- 4.1%, P = .70). On multivariate analysis, GTN response and systolic blood pressure at peak exercise were inversely correlated (r = -.52, P = .04). Vascular responses were not related to the age at repair. CONCLUSIONS Despite successful repair of coarctation in childhood, arterial dilation is significantly impaired in the precoarctation vascular bed of healthy young adults. This may be an important contributor to exercise-related hypertension and late morbidity or mortality.

Oral L-Arginine Inhibits Platelet Aggregation but Does Not Enhance Endothelium-Dependent Dilation in Healthy Young Men

OBJECTIVES Our aim was to assess the effect of oral L-arginine on endothelial or platelet physiology in humans. BACKGROUND L-Arginine is the substrate for nitric oxide synthesis, and in cholesterol-fed rabbits, oral L-arginine improves endothelium-dependent dilation, inhibits platelet aggregation and reduces atheroma. In hypercholesterolemic humans, intravenous L-arginine immediately improves endothelium-dependent dilation; however, the vascular effects of oral L-arginine in healthy humans have not previously been investigated. METHODS In a prospective, double-blind, randomized crossover trial, 12 healthy young men 27 to 37 years old took L-arginine (7 g three times daily) or placebo for 3 days each, separated by a washout period of 7 to 14 days. RESULTS After L-arginine, plasma levels of arginine (mean +/- SEM 303 +/- 36 vs. 128 +/- 12 mumol/liter, p = 0.01) and urea (6.7 +/- 0.5 vs. 5.2 +/- 0.2 mmol/liter, p < 0.01) were higher than levels measured after placebo, and platelet aggregation in response to adenosine diphosphate was markedly impaired (37 +/- 12% vs. 81 +/- 3%, p = 0.02). The inhibition of platelet aggregation correlated with the plasma level of L-arginine (r = 0.74, p = 0.01), and it could be completely or partially reversed by ex vivo incubation with N-monomethyl-L-arginine, a specific nitric oxide synthase inhibitor. Platelet cyclic guanosine monophosphate levels were higher after oral L-arginine than at baseline (1.91 +/- 0.46 vs. 1.38 +/- 0.40 pmol/10(9) platelets, p = 0.04). No changes were seen in fasting lipid levels, heart rate, blood pressure, endothelium-dependent dilation of the brachial artery (measured in response to reactive hyperemia, using external vascular ultrasound) (6.1 +/- 0.7% vs. 6.5 +/- 0.7%, p = NS) or in plasma levels of nitrosylated proteins (a marker of in vivo nitric oxide production) (3.5 +/- 0.5 vs. 3.3 +/- 0.4 mumol/liter, p = NS) 1 to 1.5 h after the last dose of L-arginine. CONCLUSIONS In these healthy young adult men, oral L-arginine inhibited platelet aggregation by way of the nitric oxide pathway. However, it had no effect on systemic hemodynamic variables, plasma nitrosylated protein levels or endothelium-dependent dilation. Therefore, at certain doses, oral L-arginine may result in a relatively platelet-specific increase in nitric oxide production.