A comparison of self-reported risk and protective factors and the death implicit association test in the prediction of future suicide attempts in adolescent emergency department patients.

BACKGROUND: Concerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings. METHODS: A total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics. RESULTS: A few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84-0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85-0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52-0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55-0.79). CONCLUSIONS: In pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT.

Clopidogrel, prasugrel or ticagrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention.

BACKGROUND: Guidelines recommend prasugrel or ticagrelor instead of clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI). AIM: We sought to describe the trends in uptake of the newer agents and analyse the clinical characteristics and short-term outcomes of patients treated with clopidogrel, prasugrel or ticagrelor. METHODS: We analysed the temporal trends of antiplatelet use since the availability of prasugrel (2009-2013) in patients with ACS from the Melbourne Interventional Group registry. To assess clinical characteristics and outcomes, we included 1850 patients from 2012 to 2013, corresponding to the time all three agents were available. The primary outcome was major adverse cardiovascular events (MACE). The safety end-point was in-hospital bleeding. RESULTS: For the period of 2009-2013, the majority of patients were treated with clopidogrel (72%) compared with prasugrel (14%) or ticagrelor (14%). There was a clear trend towards ticagrelor by the end of 2013. Patients treated with clopidogrel were more likely to present with non-ST-elevation ACS, be older, and have more comorbidities. There was no difference in unadjusted 30-day mortality (0.9 vs 0.5 vs 1.0%, P = 0.76), myocardial infarction (2 vs 1 vs 2%, P = 0.52) or MACE (3 vs 3 vs 4%, P = 0.57) between the three agents. There was no difference in in-hospital bleeding (3 vs 2 vs 2%, P = 0.64). CONCLUSION: Prasugrel and ticagrelor are increasingly used in ACS patients treated with PCI, predominantly in a younger cohort with less comorbidity. Although antiplatelet therapy should still be individualised based on the thrombotic and bleeding risk, our study highlights the safety of the new P2Y12 inhibitors in contemporary Australian practice.

Pre-treatment with dual antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention.

BACKGROUND: Although dual antiplatelet therapy is the standard of care in non-ST-segment elevation acute coronary syndromes (NSTEACS), it remains unclear when a second antiplatelet agent should be initiated. We sought to assess the safety and efficacy of pre-treatment with clopidogrel in patients with NSTEACS undergoing percutaneous coronary intervention (PCI). METHODS: We analysed baseline clinical and procedural characteristics of 6817 patients with NSTEACS who underwent PCI from the Melbourne Interventional Group registry from 2005 to 2012. Patients were included in the pre-treatment group if clopidogrel was administered prior to cardiac catheterisation. We assessed 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events. The safety endpoint was in-hospital bleeding. RESULTS: Of the 6817 patients, only 2951 (43%) received pre-treatment with clopidogrel. Patients in the pre-treatment group were more likely to present with unstable angina (70.8% vs 68.2%, P = 0.02) and have a history of MI (35.6% vs 23.6%, P < 0.01) but were less likely to have PCI within 24 h of admission (17.2% vs 25.2%, P < 0.01). There was no difference between the groups in 30-day mortality (0.9% vs 1.4%, P = 0.06), MI (2.0% vs 2.2%, P = 0.52) or major adverse cardiovascular event (3.7% vs 4.2%, P = 0.25). There was no difference in bleeding complications (1.9% vs 1.9%, P = 0.94). CONCLUSIONS: Pre-treatment with dual antiplatelet therapy in NSTEACS is not routine clinical practice in Australia. Pre-treatment appears safe but is not associated with improved short-term clinical outcomes.

Trends in door-to-balloon time and outcomes following primary percutaneous coronary intervention for ST-elevation myocardial infarction: an Australian perspective.

BACKGROUND: Guidelines for patients with ST-elevation myocardial infarction include a door-to-balloon time (DTBT) of ≤90 min for primary percutaneous coronary intervention. AIM: The aim of this study was to assess temporal trends (2006-2010) in DTBT and determine if a reduction in DTBT was associated with improved clinical outcomes. METHODS: We compared annual median DTBT in 1926 STEMI patients undergoing primary percutaneous coronary intervention from the Melbourne Interventional Group registry. ST-elevation myocardial infarction presenting >12 h and rescue percutaneous coronary intervention was excluded. Major adverse cardiac events were analysed according to DTBT (dichotomised as ≤90 min vs >90 min). A multivariable analysis for predictors of mortality (including DTBT) was performed. RESULTS: Baseline demographics, clinical and procedural characteristics were similar in the STEMI cohort across the 5 years, apart from an increase in out-of-hospital cardiac arrest (3.6% in 2006 vs 9.4% in 2010, P < 0.0001) and cardiogenic shock (7.7-9.6%, P = 0.07). The median DTBT (interquartile range) was reduced from 95 (74-130) min in 2006 to 75 (51-100) min in 2010 (P < 0.01). In this period, the proportion of patients achieving a DTBT of ≤90 min increased from 45% to 67% (P < 0.01). Lower mortality and major adverse cardiac event rates were observed with DTBT ≤90 min (all P < 0.01). Multivariable analysis showed that a DTBT of ≤90 min was associated with improved clinical outcomes at 12 months (odds ratio 0.48; 95% confidence interval 0.33-0.73, P < 0.01). CONCLUSION: There has been a decline in median DTBT in the Melbourne Interventional Group registry over 5 years. DTBT of ≤90 min is associated with improved clinical outcomes at 12 months.

Effectiveness of systematic foot and mouth disease mass vaccination campaigns in Argentina.

The objective of this paper is to evaluate the effectiveness of systematic mass vaccination campaigns against foot and mouth disease in Argentina. The analysis was based on an estimation of the proportion of protected animals and protected farms in vaccinated populations, as reflected by levels of antibodies measured in liquid-phase enzyme-linked immunosorbent assay. The analysis was carried out in 49 animal health districts in Buenos Aires province, using data collected from four cross-sectional studies, in 2004, 2007, 2008 and 2011. Cattle were assigned to one of two categories on the basis of correlation between serological titres and expected percentage protection: non-adequately protected (expected protection < 75%) and adequately protected (expected protection ≥ 75%). The proportions of adequately protected cattle and significantly non-adequately protected farms were estimated and compared among sampled locations. Protection was variable among the districts; cattle aged one to two years showed higher levels of protection than cattle six to 12 months old, and the proportion of protected cattle was higher in the more recent studies. The results of the analysis will allow the national animal health service to investigate in depth those districts where protection was lower than the regional background protection. The authors propose that this methodology could be used to evaluate the effectiveness of vaccination campaigns in other countries or zones where systematic foot and mouth disease mass vaccination campaigns are undertaken.

Ephedrine activates brown adipose tissue in lean but not obese humans.

AIMS/HYPOTHESIS: Brown adipose tissue (BAT) activation increases energy consumption and may help in the treatment of obesity. Cold exposure is the main physiological stimulus for BAT thermogenesis and the sympathetic nervous system, which innervates BAT, is essential in this process. However, cold-induced BAT activation is impaired in obese humans. To explore the therapeutic potential of BAT, it is essential to determine whether pharmacological agents can activate BAT. METHODS: We aimed to determine whether BAT can be activated in lean and obese humans after acute administration of an orally bioavailable sympathomimetic. In a randomised, double-blinded, crossover trial, we administered 2.5 mg/kg of oral ephedrine to nine lean (BMI 22 ± 1 kg/m²) and nine obese (BMI 36 ± 1 kg/m²) young men. On a separate day, a placebo was administered to the same participants. BAT activity was assessed by measuring glucose uptake with [¹8F]fluorodeoxyglucose and positron emission tomography-computed tomography imaging. RESULTS: BAT activity was increased by ephedrine compared with placebo in the lean, but unchanged in the obese, participants. The change in BAT activity after ephedrine compared with placebo was negatively correlated with various indices of body fatness. CONCLUSIONS/INTERPRETATION: BAT can be activated via acute, oral administration of the sympathomimetic ephedrine in lean, but not in obese humans.

Do we need cardiac arrest centres in Australia?

The mortality rate post admission to hospital after successful resuscitation from out-of-hospital cardiac arrest is high, with significant variation between regions and individual institutions. While prehospital factors such as age, bystander cardiopulmonary resuscitation and total cardiac arrest time are known to influence outcome, several aspects of post-resuscitative care including therapeutic hypothermia, coronary intervention and goal-directed therapy may also influence patient survival. Regional systems of care have improved provider experience and patient outcomes for those with ST elevation myocardial infarction and life-threatening traumatic injury. In particular, hospital factors such as hospital size and interventional cardiac care capabilities have been found to influence patient mortality. This paper reviews the evidence supporting the possible development and implementation of Australian cardiac arrest centres.

Principles, current status and clinical implications of ischaemic heart disease assessment by cardiac magnetic resonance imaging.

Cardiac magnetic resonance imaging (CMR) has matured into a robust, accurate and highly reproducible imaging modality for the assessment of cardiac function and ischaemic heart disease. The unique physical properties of CMR permit depiction of pathology-specific tissue contrast based on differences in tissue composition, such as myocardial oedema, necrosis and fibrosis. This can be imaged at high spatial resolution allowing characterisation of the acuity of an ischaemic event, the presence and extent of myocardial ischaemia, necrosis and viability. Prognostically important information obtained from CMR evaluation of ischaemic heart disease, such as left ventricular ejection fraction, infarct size and transmurality, infarct location and the presence of intraventricular mechanical dyssynchrony may be used to guide coronary revascularisation, device and medical therapies.

Clinical outcomes of drug-eluting stent use in patients with ST elevation myocardial infarction.

AIM: Randomised trials using drug-eluting stents (DES) in ST elevation myocardial infarction (STEMI) have shown mixed results, and excluded patients at the highest risk of adverse outcomes. We aimed to determine the real world clinical outcomes of DES and compare these with bare-metal stents (BMS) in an unrestricted observational study of patients presenting with STEMI. METHODS: 564 consecutive patients undergoing primary PCI for STEMI were prospectively enrolled in the Melbourne Interventional Group registry (August 2004 to May 2006). The choice of using DES was at the operator's discretion, yet restricted to patients considered at highest risk of restenosis [e.g. diabetes, long lesions (>20 mm) and small target vessels (<2.5 mm)]. Clinical, procedural, and 12-month outcomes of patients receiving DES were evaluated and compared to BMS. RESULTS: DES were used in 45% of patients presenting with STEMI. The rates of cardiogenic shock were similar in the DES and BMS groups (10.2 vs. 11%, p=0.71). In-hospital outcomes were not significantly different with respect to death (4.7 vs. 7.2%, p=0.23), major adverse cardiac events (MACE) (10.6 vs. 11.3%, p=0.80) or stent thrombosis (1.7 vs. 0.3%, p=0.71). At 12 months, target vessel revascularisation (TVR) in patients with DES was 10.2% vs. 7.2% in BMS (p=0.22). On propensity score adjusted multivariate analyses, the only independent predictor of 12-month MACE was presentation with cardiogenic shock (OR 2.59, 95% C.I 1.04-6.45), and the only predictor of 12-month TVR was reference vessel diameter ≤2.5 mm (OR 2.16, 95% C.I 1.06-4.33). DES use was not independently predictive of lower TVR, MACE rates or mortality. Late stent thrombosis rates were similar (DES 3.2 vs. BMS 3.8%, p=0.65). CONCLUSIONS: Drug-eluting stents are frequently used in Australia in the high-risk setting of STEMI. While target vessel revascularisation rates were moderate in this high-risk group, there was no increased mortality, reinfarction or stent thrombosis compared to bare-metal stents.

A description of cattle movements in two departments of Buenos Aires province, Argentina.

We present a descriptive analysis of cattle movement information retrieved from the Argentinean animal movement database for two departments in the province of Buenos Aires during 2004. For each quarter of the year (January to March, April to June, July to September, and October to December) we report the number of on- and off-farm movement events for the purpose of finishing. Our analyses show that the distribution of the number of finishing-related movement events per farm was skewed, with the majority of farms reporting at least 1 and less than 5% of farms of reporting greater than 15 finishing related movement events throughout the year. The frequency of finishing-related movement events varied over time, with a 1.2-1.8-fold increase in reported movement events from April to September, compared with the rest of the year. These analyses indicate that cattle movement patterns in these departments are dependent on the relative mix of constituent cattle enterprise types. Departments with a mixture of breeding and finishing enterprises behave as potential recipients and distributors of infectious disease, whereas departments comprised of primarily finishing enterprises are predominantly recipients of infectious disease, rather than distributors. Data integrity audits of the Argentinean animal movement database, on a regular or intermittent basis, should allow the presence of bias in these data to be quantified in greater detail.

Gut transport of a molybdenum/ascorbic acid complex.

BACKGROUND: Relatively little work has been done on the absorption of trace elements in the mammalian small intestine. Recently, studies have demonstrated that a molybdenum/ascorbic acid complex has shown some promise as a potentially orally administered insulin-mimetic agent. However, the transport mechanism of the molybdenum/ascorbic acid complex is unknown. In this study we examine some aspects of the movement of the complex across the intestinal wall using measurements of elemental molybdenum as an indicator because it is not possible to measure the complex directly. METHODS: Everted rat small intestine sacs were used to determine some aspects of the transport of the complex across the intestine. Intestinal sacs from five rats were incubated in a medium containing 1 g/L of the molybdenum complex. Sacs from a further five rats had 1 mmol/L of 2,4-dinitrophenol, a known inhibitor of oxidative phosphorylation, added to the incubation medium. In a second experiment, everted sacs from five rats were also incubated in media containing one of six concentrations of the molybdenum complex (0.5, 1, 2, 4, 8 or 10 g/L). RESULTS: There was no significant difference between transport rates of groups with or without 2,4-dinitrophenol in the incubation medium, suggesting that the predominant mechanism of molybdenum transport is energy-independent. There was a significant positive, linear increase in the transport rate with increasing concentration of the molybdenum complex. CONCLUSION: These data suggest that the predominant mechanism of this molybdenum/ascorbic acid complex transport in the small intestine is non-saturable and therefore not protein-mediated.

The foundation and launch of the Melbourne Interventional Group: a collaborative interventional cardiology project.

The Melbourne Interventional Group (MIG) is a voluntary collaborative venture of interventional cardiologists practicing at 12 major public and private hospitals in Victoria, designed to record data pertaining to percutaneous coronary interventions (PCI) and perform long-term follow-up. The potential advantages of collaboration involve large-scale analysis of current interventional strategies (e.g. drug-eluting stents, evaluation of new technologies and cost-effective analysis), provide a basis for multi-centred clinical trials and allow comparison of clinical outcomes with cardiac surgery. The established registry documents demographic, clinical and procedural characteristics of consecutive patients undergoing PCI and permits analysis of those characteristics at 30 days and 12 months. The registry is co-ordinated by the Centre of Clinical Research Excellence (CCRE), a research body within the Department of Epidemiology and Preventive Medicine (Monash University, Melbourne). The eventual goal of MIG is to provide a contemporary appraisal of Australian interventional cardiology practice, with opportunities to improve in-hospital and long-term outcomes of patients with coronary artery disease.

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Nitric oxide (NO) has been implicated as an important signalling molecule in the contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control. The current study sought to determine whether acute infusion of the NO donor, sodium nitroprusside (SNP), increases leg glucose uptake at rest in patients with type 2 diabetes. METHODS: Fifteen male patients with type 2 diabetes (aged 54+/-4 years, mean+/-SD) were entered into a randomised, cross-over design study, examining the effect of a 30-min intra-femoral infusion of SNP on leg glucose uptake. Comparison was made with a 30-min infusion of verapamil, titrated to elicit similar leg blood flow responses to SNP. Leg blood flow was measured by thermodilution in the femoral vein, and leg glucose uptake was calculated as the product of leg blood flow and the femoral arterio-venous (A-V) glucose concentration gradient. RESULTS: The two drugs increased leg blood flow to a similar extent (p=0.50). Both leg A-V glucose concentration gradient (SNP 0.12+/-0.05, verapamil -0.06+/-0.04 mmol/l; mean+/- SEM, p=0.03) and leg glucose uptake (SNP 0.17+/-0.09, verapamil -0.09+/-0.06 mmol/min; p=0.03) were higher with the SNP treatment than with verapamil. These results occurred independently of any significant difference in plasma insulin concentration between drugs (p=0.56). CONCLUSIONS/INTERPRETATION: Acute infusion of SNP resulted in greater glucose uptake relative to verapamil. NO may therefore be an important mediator of peripheral glucose disposal and a potential therapeutic target in patients with type 2 diabetes.

Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery.

Black Americans have increased morbidity and mortality rates from cardiovascular disease, greater prevalence of hypertension, and altered responses to vasodilator medications compared with those of white Americans. Hypertension and black race have been linked to impaired vascular function in the microcirculation. To examine these effects and their interaction in the conduit vasculature, we examined vasomotor responses of the brachial artery by using high-resolution vascular ultrasound in 228 subjects (48% hypertensive, 54% black). Subjects had no history of diabetes mellitus and were matched for age and gender. Flow-mediated dilation (8.5+/-5.3% versus 11.7+/-6.3%, P<0.001) and nitroglycerin-mediated vasodilation (14.9+/-6.0 versus 18.5+/-7.8, P=0.003) were both impaired in hypertensive compared with normotensive individuals. Multivariate analysis identified higher systolic blood pressure (P=0.003) and larger baseline vessel (P<0.001) size as independent predictors of lower flow-mediated dilation. Race did not significantly influence flow-mediated dilation. In contrast, blacks had a greater vasodilator response to nitroglycerin compared with whites (17.7+/-7.5% versus 15.0+/-6.2%, respectively; P=0.02). By multivariate analysis, black race (P=0.004), smaller vessel size (P=0.001), lower serum glucose (P=0.02), lower systolic blood pressure (P=0.02), and lower serum total cholesterol (P=0.04) were independent predictors of higher nitroglycerin-mediated dilation. Thus, hypertension is associated with impaired NO-mediated vasodilation in the conduit brachial artery. Overall, race did not influence flow-mediated dilation, but black race was associated with an enhanced response to sublingual nitroglycerin. This later observation provides further evidence of racial differences in the responses to medical therapy that may be relevant to the treatment of patients with cardiovascular disease.

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

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

Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease.

BACKGROUND: Epidemiological studies suggest that tea consumption decreases cardiovascular risk, but the mechanisms of benefit remain undefined. Endothelial dysfunction has been associated with coronary artery disease and increased oxidative stress. Some antioxidants have been shown to reverse endothelial dysfunction, and tea contains antioxidant flavonoids. Methods and Results-- To test the hypothesis that tea consumption will reverse endothelial dysfunction, we randomized 66 patients with proven coronary artery disease to consume black tea and water in a crossover design. Short-term effects were examined 2 hours after consumption of 450 mL tea or water. Long-term effects were examined after consumption of 900 mL tea or water daily for 4 weeks. Vasomotor function of the brachial artery was examined at baseline and after each intervention with vascular ultrasound. Fifty patients completed the protocol and had technically suitable ultrasound measurements. Both short- and long-term tea consumption improved endothelium- dependent flow-mediated dilation of the brachial artery, whereas consumption of water had no effect (P<0.001 by repeated-measures ANOVA). Tea consumption had no effect on endothelium-independent nitroglycerin-induced dilation. An equivalent oral dose of caffeine (200 mg) had no short-term effect on flow-mediated dilation. Plasma flavonoids increased after short- and long-term tea consumption. CONCLUSIONS: Short- and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. This finding may partly explain the association between tea intake and decreased cardiovascular disease events.

Effect of acute and chronic tea consumption on platelet aggregation in patients with coronary artery disease.

Epidemiological studies suggest that tea consumption is associated with a decreased risk of cardiovascular events, but the mechanisms of benefit remain undefined. Platelet aggregation is a precipitating event in cardiovascular disease, and tea contains antioxidant flavonoids that are known to decrease platelet aggregation in vitro. To test the effect of tea consumption on platelet aggregation, we randomized 49 patients with coronary artery disease to either 450 mL of black tea or water consumed initially, followed by 900 mL of tea or water daily for 4 weeks in a crossover design. Ex vivo platelet aggregation in platelet-rich plasma was assessed in response to ADP and thrombin receptor-activating peptide at baseline and 2 hours and 4 weeks after beverage consumption. We observed dose-dependent platelet aggregation in response to each agonist, and neither relation was altered by acute or chronic tea consumption. Plasma flavonoids increased with acute and chronic tea consumption, indicating adequate absorption of tea flavonoids. In conclusion, these results demonstrate that acute and chronic black tea consumption does not affect ex vivo platelet aggregation in patients with coronary artery disease. These findings suggest that an effect of tea flavonoids on platelet aggregation is unlikely to be the explanation for the reduction in risk of cardiovascular events noted in epidemiological studies.

Iron chelation improves endothelial function in patients with coronary artery disease.

BACKGROUND: Some epidemiological studies have shown that increased iron stores are associated with increased cardiovascular events. Redox-active iron may contribute to lipid peroxidation, endothelial cell activation, and generation of reactive oxygen species (especially hydroxyl radical, via Fenton chemistry). Increased oxidative stress is associated with impaired action of endothelium-derived nitric oxide in patients with atherosclerosis. METHODS AND RESULTS: To test the hypothesis that reducing vascular iron stores would reverse endothelial dysfunction, we examined the effects of the iron chelator deferoxamine (500 mg intra-arterially over 1 hour) on vasomotor function in forearm resistance vessels of patients with coronary artery disease by venous occlusion plethysmography. Patients with coronary artery disease had impaired endothelium-dependent vasodilation in response to methacholine compared with healthy control subjects (P<0.001). Deferoxamine infusion decreased serum iron levels (P<0.001). Deferoxamine improved the blood flow response to methacholine in patients with coronary artery disease (P<0.01 by 2-way repeated-measures ANOVA) but had no effect on the response to sodium nitroprusside. In normal volunteers, deferoxamine had no effect on the response to methacholine. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine abolished augmentation of the methacholine response associated with deferoxamine. The hydroxyl radical scavenger mannitol had no effect on the methacholine response. CONCLUSIONS: Deferoxamine improved nitric oxide-mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.

Effect of anti-oxidant treatment and cholesterol lowering on resting arterial tone, metabolic vasodilation and endothelial function in the human forearm: a randomized, placebo-controlled study.

1. The aim of the present study was to determine whether anti-oxidant therapy with vitamin E and/or cholesterol-lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in 26 young, otherwise healthy volunteers (mean (+/-SD) age 29+/-7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double-blinded in a 2 x 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma alpha-tocopherol from 39.5+/-9.6 to 75.7+/-33.8 micromol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9+/-1.7 to 4.9+/-0.8 mmol/L and low- density lipoprotein (LDL) from 4.8+/-1.7 to 3.0+/-0.7 mmol/L (both P < 0.001), although total and LDL-cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1+/-0.3 to 2.4+/-0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1+/-4.2 to 36.1+/-3.4 units (P = 0.01), but the reduction in resting FBF with L-NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E-simvastatin groups. NG-Monomethyl-L-arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO-dependent pathways. Metabolic vasodilation and responses to the NO-mediated vasodilators ACh and SNP were not favourably affected by anti-oxidant or cholesterol-lowering therapy, either alone or in combination.