A double-blind, randomized study evaluating losartan potassium monotherapy or in combination with hydrochlorothiazide versus placebo in obese patients with hypertension.

OBJECTIVES: The objective of this study was to evaluate the effects of losartan +/- hydrochlorothiazide (HCTZ) versus placebo in obese patients with systolic and diastolic hypertension. RESEARCH DESIGN AND METHODS: Randomized patients (n = 261) were non-diabetic with systolic blood pressure (SBP) > or = 140 and < or = 180 mmHg and diastolic BP (DBP) > or = 95 and < or = 115 mmHg, body mass index > 30 kg/m(2), and waist circumference > 40 (males)/> 35 (females) inches. Patients were randomized to placebo or a forced titration of losartan 50 mg titrated at 4-week intervals to losartan 100 mg, losartan 100 mg/HCTZ 12.5 mg, and losartan 100 mg/HCTZ 25 mg. Primary efficacy measurements were change from baseline in SBP and DBP at 12 weeks. Secondary measurements were change from baseline in BPs at 8 and 16 weeks, percent responders at 12 and 16 weeks, and safety/tolerability. Post-hoc analyses were BP at 4 weeks and achievement of controlled BP (SBP < 140 and/or DBP < 90 mmHg) at 12 and 16 weeks. RESULTS: Losartan 50 mg reduced BP from 151.6/99.2 mmHg at baseline to 140.1/89.8 mmHg at week 4 (post hoc), 139.5/89.6 mmHg with losartan 100 mg at week 8 (secondary), 134.3/85.9 mmHg with losartan 100 mg/HCTZ 12.5 mg at week 12 (primary), and 132.1/84.9 mmHg with losartan 100 mg/HCTZ 50 mg at week 16 (secondary) (all p < 0.05). Rates of clinical adverse experiences were similar between treatment groups. A limitation of these analyses is the relatively rapid rate of study drug titration, which may not have allowed for the evaluation of the full treatment effect at each titration step. CONCLUSIONS: We conclude that losartan alone or in combination with HCTZ was generally well tolerated and effective in the treatment of elevated systolic and diastolic BP in obese patients with hypertension.

The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes.

AIMS/HYPOTHESIS: Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. We studied the role played by total adiponectin and by the bioactive high-molecular-weight (HMW) oligomeric complexes of adiponectin in vascular function in offspring whose parents both had type 2 diabetes, a population at high risk of diabetes and atherosclerosis. METHODS: Total and %HMW adiponectin, the cytokines C-reactive protein, interleukin-6 and plasminogen activator inhibitor-1 (PAI-1), as well as lipid profiles were assayed in 19 offspring, each with two type 2 diabetic parents. Subjects underwent OGTTs and IVGTTs. Endothelium-dependent vasodilation (EDV) was assessed by brachial artery ultrasonography. RESULTS: There was a significant relationship between %HMW and total adiponectin levels (r=0.72, p=0.001). Despite an expected strong positive correlation between HDL-cholesterol and adiponectin levels (r=0.52, p=0.04), as well as HDL-cholesterol and EDV (r=0.56, p<0.02), there was no significant relationship between either total adiponectin or % HMW adiponectin and EDV. Adiponectin was inversely associated with PAI-1 (r=0.50, p=0.05), but did not correlate with the inflammatory markers C-reactive protein or interleukin-6. CONCLUSIONS/INTERPRETATION: In offspring of diabetic parents, a population at high risk of diabetes and atherosclerotic disease, there is no relationship between total or %HMW adiponectin and endothelium-dependent vasodilation. However, low adiponectin was associated with impaired fibrinolysis as manifested by increased levels of plasminogen activator inhibitor-1.

Endotelina-1 y tono vascular en sujetos con factores de riesgo aterogénico / Endothelin-1 and vascular tone in subjects with atherogenic risk factors

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Radiation therapy impairs endothelium-dependent vasodilation in humans.

OBJECTIVES: The objective of this study was to test the hypothesis that external-beam radiation induces a chronic impairment of endothelium-dependent vasodilation. BACKGROUND: Radiation therapy is used commonly in the treatment of cancer and is associated with an increased incidence of adverse vascular events related to the field of radiation, including stroke and myocardial infarction. As endothelial injury is central to the pathogenesis of vascular diseases, we hypothesized that radiotherapy induces arterial endothelial dysfunction. METHODS: Sixteen women with unilateral breast cancer who underwent standard external-beam radiation therapy to the breast and axilla >3 years before enrollment and ten healthy women were studied. Vascular ultrasonography was used to image both the artery exposed to radiation and the contralateral artery. Flow-mediated, endothelium-dependent vasodilation and endothelium-independent vasodilation to nitroglycerin of both axillary arteries were measured. RESULTS: Endothelium-dependent vasodilation was significantly impaired in the irradiated axillary arteries compared with the contralateral, nonirradiated arteries (-0.4 +/- 0.4% vs. 3.2 +/- 0.8% p < 0.001) and also compared with control subjects' arteries (-0.4 +/- 0.4% vs. 2.5 +/- 0.6%, p < 0.001). In contrast, endothelium-independent vasodilation was greater in the arteries that received radiation compared with the contralateral arteries (3.8 +/- 0.5% vs. 2.0 +/- 0.4%, p < 0.05) and also compared with control arteries (3.8 +/- 0.5% vs. 2.5 +/- 0.4%, p < 0.05). CONCLUSIONS: External beam radiation therapy impairs endothelium-dependent vasodilation of conduit arteries, implicating a decrease in the bioavailability of nitric oxide. These abnormalities may contribute to the development of arterial occlusive disease and associated clinical events.

Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo.

Arterial elasticity is determined by structural characteristics of the artery wall and by vascular smooth muscle tone. The identity of endogenous vasoactive substances that regulate elasticity has not been defined in humans. We hypothesized that NO, a vasodilator released constitutively by the endothelium, augments arterial elasticity. Seven healthy young men were studied. A 20-MHz intravascular ultrasound catheter was introduced through an arterial sheath to measure brachial artery cross-sectional area, wall thickness, and intra-arterial pressure. After control was established, indices of elasticity (pressure-area relationship, instantaneous compliance, and stress-strain, pressure-incremental elastic modulus (E(inc)), and pressure-pulse wave velocity relationships) were examined over 0 to 100 mm Hg transmural pressure obtained by inflation of an external cuff. Thereafter, the basal production of endothelium-derived NO was inhibited by N(G)-monomethyl-L-arginine (L-NMMA) (4 and 8 mg/min). Finally, nitroglycerin (2.5 and 12.5 microgram/min), an exogenous donor of NO, was given to relax the vascular smooth muscle. Elasticity was measured under all of these conditions. L-NMMA (8 mg/min) decreased brachial artery area (P=0.016) and compliance (P<0.0001) and increased E(inc) (P<0.01) and pulse wave velocity (P<0.0001). Nitroglycerin (12.5 microgram/min) increased brachial artery area (P<0.001) and compliance (P<0.001) and decreased pulse wave velocity (P=0.02). NO, an endothelium-derived vasodilator, augments arterial elasticity in the human brachial artery. Loss of constitutively released NO associated with cardiovascular risk factors may adversely affect arterial elasticity in humans.

Relationship of clinical presentation and calcification of culprit coronary artery stenoses.

Coronary artery calcification is increased in the presence of atherosclerosis. However, there is great variability in the calcification of individual coronary stenoses, and the clinical significance of this finding remains unknown. We tested the hypothesis that culprit lesions associated with myocardial infarction or unstable angina are less calcified than are stenoses associated with stable angina. The study consisted of 78 patients who underwent intravascular ultrasound imaging of culprit stenoses after the placement of a stent. Seventeen patients presented with stable angina; 43, with unstable angina; and 18, with myocardial infarction. The extent of coronary calcification was measured by the angle of its arc and was quantified with a computer-based protractor. The arc of calcium was measured in the stented area at the point of maximal calcification and also as an average of the calcification found at proximal, middle, and distal stent segments. The maximal arc of calcium decreased progressively from patients with stable angina (91+/-10 degrees ) to those with unstable angina (59+/-8 degrees ) and to those with myocardial infarction (49+/-11 degrees, P=0.014). Similarly, the average arc of calcium was greatest (32+/-7 degrees ) in patients with stable angina, less (15+/-4 degrees ) in patients with unstable angina, and least (10+/-5 degrees ) in patients with acute myocardial infarction (P=0.014). These associations remained significant after adjustment for other factors that potentially affect arterial calcification. Acute coronary syndromes are associated with a relative lack of calcium in the culprit stenoses compared with stenoses of patients with stable angina. These findings have implications for the understanding of the biology of acute coronary syndromes as well as for the identification of coronary stenoses by methods that rely solely on the presence of calcium.

Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries.

BACKGROUND: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries. METHODS AND RESULTS: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01). CONCLUSIONS: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Peripheral arterial disease detection, awareness, and treatment in primary care.

CONTEXT: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice. OBJECTIVE: To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics. DESIGN AND SETTING: The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999. PATIENTS: A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease. MAIN OUTCOME MEASURES: Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis. RESULTS: PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups. CONCLUSIONS: Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.

Medical management of peripheral arterial disease.

Peripheral arterial disease affects approximately 8-10 million people in the United States. Approximately one-third to one-half of these individuals are symptomatic. The risk factors that contribute to peripheral arterial disease are similar to those associated with other forms of atherosclerosis, including diabetes mellitus, cigarette smoking, hypercholesterolemia, high blood pressure, and hyperhomocysteinemia. Of these, diabetes and cigarette smoking pose the greatest risk for developing peripheral arterial disease. The prognosis of patients with these risk factors is limited because of their greater risks for myocardial infarction, stroke, and cardiovascular death. Cardiovascular mortality correlates inversely with the ankle/brachial index, and the risk of death is greatest in those with the most severe peripheral arterial disease. Treatment regimens to reduce cardiovascular morbidity and mortality in patients with peripheral arterial disease should include risk factor modification and antiplatelet therapy. The cardinal symptoms of peripheral arterial disease include intermittent claudication and rest pain, with the latter being indicative of critical limb ischemia. Therapeutic strategies that focus on improving the patient's quality of life, reducing the severity of claudication, and improving limb viability include supervised exercise training, pharmacotherapy, and revascularization. Two drugs-pentoxifylline and cilostazol-currently are approved by the Food and Drug Administration for the treatment of patients with claudication. Meta-analyses have suggested that, compared with placebo, pentoxifylline improves maximal walking distance by approximately 20-25%. Cilostazol is a phosphodiesterase type 3 inhibitor. In clinical trials, cilostazol has consistently improved maximal walking distance as compared with placebo, with the range of improvement being approximately 40-60%. Drugs that are currently under investigation include propionyl-L-carnitine, vasodilator prostaglandins, L-arginine, and the angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factors.

Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication.

PURPOSE: We tested the hypothesis that propionyl-L-carnitine would improve peak walking time in patients with claudication. Secondary aims of the study were to evaluate the effects of propionyl-L-carnitine on claudication onset time, functional status, and safety. SUBJECTS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 155 patients with disabling claudication from the United States (n = 72) or Russia (n = 83) received either placebo or propionyl-L-carnitine (2g/day orally) for 6 months. Subjects were evaluated at baseline and 3 and 6 months after randomization with a graded treadmill protocol at a constant speed of 2 miles per hour, beginning at 0% grade, with increments in the grade of 2% every 2 minutes until maximal symptoms of claudication forced cessation of exercise. Questionnaires were used to determine changes in functional status. RESULTS: At baseline, peak walking time was 331 +/- 171 seconds in the placebo group and 331 +/- 187 seconds in the propionyl-L-carnitine group. After 6 months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 +/- 222 seconds (a 54% increase) as compared with an improvement of 75 +/- 191 seconds (a 25% increase) for those on placebo (P <0.001). Similar improvements were observed for claudication onset time. Propionyl-L-carnitine treatment significantly improved walking distance and walking speed (by the Walking Impairment Questionnaire), and enhanced physical role functioning, reduced bodily pain, and resulted in a better health transition score (by the Medical Outcome Study SF-36 Questionnaire). The incidence of adverse events and study discontinuations were similar in the two treatment groups. CONCLUSIONS: Propionyl-L-carnitine safely improved treadmill exercise performance and enhanced functional status in patients with claudication.

Endothelial function during stimulation of renin-angiotensin system by low-sodium diet in humans.

We examined whether physiological stimulation of the endogenous renin-angiotensin system results in impaired endothelium-dependent vasodilatation in forearm resistance vessels of healthy subjects and whether this impairment can be prevented by angiotensin II type 1 receptor blockade. A low-sodium diet was administered to 27 volunteers who were randomized to concomitant treatment with losartan (100 mg once daily) or matched placebo in a double-blind fashion. Forearm blood flow was assessed by venous occlusion plethysmography at baseline and after 5 days. Endothelium-dependent and -independent vasodilation was assessed by intra-arterial infusion of methacholine and verapamil, respectively. The low-sodium diet resulted in significantly decreased urine sodium excretion (placebo: 146 +/- 64 vs. 10 +/- 9 meq/24 h, P < 0.001; losartan: 141 +/- 56 vs. 14 +/- 14 meq/24 h, P < 0.001) and increased plasma renin activity (placebo: 1.0 +/- 0.5 vs. 5.0 +/- 2.5 ng x ml(-1) x h(-1), P < 0.001; losartan: 3.8 +/- 7.2 vs. 19.1 +/- 11.2 ng x ml(-1) x h(-1), P = 0.006) in both the losartan and placebo groups. With the baseline study as the reference, the diet intervention was not associated with any significant change in endothelium-dependent vasodilation to methacholine in either the placebo (P = 0.74) or losartan (P = 0.40) group. We conclude that short-term physiological stimulation of the renin-angiotensin system does not cause clinically significant endothelial dysfunction. Losartan did not influence endothelium-dependent vasodilation in humans with a stimulated renin-angiotensin system.

Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans.

BACKGROUND: Endothelium-dependent vasodilation is impaired in patients with insulin-dependent and non-insulin-dependent diabetes mellitus and restored by vitamin C administration, implicating a causative role for oxidant stress. Hyperglycemia per se attenuates endothelium-dependent vasodilation in healthy subjects. Accordingly, this study investigated whether impaired endothelium-dependent vasodilation caused by hyperglycemia in nondiabetic humans is restored by administration of the antioxidant vitamin C. METHODS AND RESULTS: Endothelium-dependent vasodilation was measured by incremental brachial artery administration of methacholine chloride (0.3 to 10 microg/min) during euglycemia, after 6 hours of hyperglycemia (300 mg/dL) created by dextrose (50%) intra-arterial infusion, and with coadministration of vitamin C (24 mg/min) during hyperglycemia. Endothelium-dependent vasodilation was significantly diminished by hyperglycemia (P:=0.02 by ANOVA) and restored by vitamin C (P:=0.04). In contrast, endothelium-dependent vasodilation was not affected by equimolar infusions of mannitol, with and without vitamin C coinfusion (P:=NS). Endothelium-independent vasodilation was measured by incremental infusion of verapamil chloride (10 to 300 microg/min) without and with coadministration of N:(G)-monomethyl-L-arginine (L-NMMA). In the absence of L-NMMA, endothelium-independent vasodilation was not significantly altered during hyperglycemia (P:=NS) but was augmented by vitamin C (P:=0.04). The coadministration of L-NMMA eliminated the vitamin C-related augmentation in verapamil-mediated vasodilation. CONCLUSIONS: Vitamin C administration restores endothelium-dependent vasodilation impaired by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia may contribute in part to impaired vascular function through production of superoxide anion.

Proteinuria in a placebo-controlled study of basic fibroblast growth factor for intermittent claudication.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 microg/kg for 6 sequential weeks (total dose 12 microg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.

Takayasu arteritis.

Takayasu arteritis is a severe inflammatory vascular disorder that can involve the thoracic or abdominal aorta and their branches as well as the pulmonary artery. It has a much higher incidence in women than in men, and is most frequently found in Asia, although known in North America, Europe, Africa, and the Middle East. Clinical presentation depends on the location and severity of the aortic branch lesions. Diagnosis is difficult, and treatment options include corticosteroids, percutaneous transluminal angioplasty, or surgical bypass. The case of an Indian woman requiring bypass surgery is presented here, with indications for diagnostic and treatment strategy in other patients.

Percutaneous interventions for lower-extremity peripheral atherosclerotic disease.

Patients with peripheral arterial disease frequently develop symptoms of claudication that interfere with ambulation and adversely affect quality of life, and some develop critical limb ischemia. Many of these patients have coexisting coronary artery disease, and surgical revascularization poses risks of perioperative myocardial infarction and cardiovascular death. Peripheral catheter-based interventions are a feasible alternative. Percutaneous treatment can preserve the surgical option and is often used as an adjunct to surgery by addressing inflow stenoses and limiting the extent of surgical reconstruction that is necessary. Iliac artery balloon angioplasty has been shown to have a high rate of initial procedural success and long-term patency, and the use of stents is promising, especially in cases complicated by flow-limiting dissection or significant residual stenosis. Percutaneous revascularization of the femoropopliteal arteries has shown high restenosis rates and stents should be confined, at present, to flow-limiting dissections or inadequate results from balloon angioplasty alone. The indication for percutaneous revascularization below the knee is typically limited to those patients with critical limb ischemia who are at high risk for surgical reconstruction; short-term results with modern equipment have been promising and can salvage ischemic limbs.

Venous thromboembolism occurs frequently in patients undergoing brain tumor surgery despite prophylaxis.

Most Neurosurgical Service patients at our hospital receive venous thromboembolism prophylaxis. In 1995-96, the rate of clinically overt venous thromboembolism was 3.7% among patients undergoing neurosurgery. However, rates were much higher when craniotomy was undertaken for brain tumor. Of 497 who underwent craniotomy for primary (429) or metastatic (68) brain tumor, 47 (9.5%) developed clinically overt venous thromboembolism: 7.5% after primary brain tumor resection and 19% after craniotomy for metastatic cancer. The high rate of venous thromboembolism in craniotomy patients with brain tumor warrants study of alternative measures for preventing thrombus, such as prophylaxis with low molecular weight heparin.

Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function.

BACKGROUND: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.

Nitric oxide and pulmonary hypertension.

The constitutive release of NO by the endothelium plays a key role in maintaining normal low basal pulmonary vascular tone and countering hypoxic vasoconstrictive tone in many mammals and in humans. Many, but not all, studies have suggested that reduced availability of NO contributes to the increased pulmonary vascular resistance that occurs in experimental models and in humans with pulmonary hypertension. Potential mechanisms limiting the activity of NO include L-arginine deficiency and a reduction in eNOS expression or message stability. Inhaled NO therapy may overcome some of these abnormalities, improving oxygenation and reducing pulmonary artery pressure in patients with primary and secondary forms of pulmonary hypertension.

Plasma concentrations of interleukin-6 and abdominal aortic diameter among subjects without aortic dilatation.

Previous studies suggest that cytokine-induced tissue inflammation may participate in the pathogenesis of abdominal aortic aneurysms. Serum inflammatory markers may reflect arterial inflammation in asymptomatic phases of the aneurysmal disease. We studied 120 outpatients (62 men; age, 65+/-9 years) by ultrasound evaluation of the abdominal aorta to evaluate the association of circulating levels of interleukin-6 (IL-6) with abdominal aortic diameter in subjects with normal aortic size. Aortic diameter was measured at the infrarenal level and indexed for body surface area. Seven patients with abdominal aortic dilatation (indexed aortic diameter, >1.3 cm/m2) were also identified. Plasma concentrations of IL-6, serum amyloid A (SAA), C-reactive protein (CRP), total homocysteine, and lipids were measured. Among the 113 subjects without aortic dilatation, indexed aortic diameter was positively associated with serum levels of IL-6 (P<0.01), SAA (P<0.01), and total homocysteine (P=0.01). IL-6 levels increased in a stepwise fashion among dichotomized groups of aortic size (low and high aortic diameters) and peaked in patients with aortic dilatation (2.3+/-1.2 versus 2. 7+/-0.9 versus 3.2+/-0.9 pg/mL, respectively; P for trend=0.039). None of the serum lipid measurements correlated with abdominal aortic diameter. Although CRP levels were associated with SAA levels (r=0.60; P<0.001), associations between CRP and aortic diameter were nonsignificant. In multivariate analysis, levels of IL-6 (P=0.02), SAA (P=0.001), and total homocysteine (P<0.001) were independent correlates of indexed aortic diameter. In conclusion, circulating levels of IL-6, SAA, and total homocysteine may reflect processes involved in the early phases of abdominal aortic aneurysm formation, before dilation of the abdominal aorta is established. These data support a role for chronic inflammation in the progression of asymptomatic aortic disease.