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    ABSTRACT: The risk of acute myocardial infarction in firefighters is increased during fire suppression duties, and is likely to reflect a combination of factors including extreme physical exertion and heat exposure. We assess the effects of physical exertion and heat exposure on vascular function and thrombosis in firefighters.
    Journal of the American College of Cardiology 05/2014; 63(12):A1.
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    ABSTRACT: Urocortin 2 and urocortin 3 are endogenous peptides with an emerging role in cardiovascular pathophysiology. We assessed their pharmacodynamic profile and examined the role of the endothelium in mediating their vasomotor effects in vivo in man. Eighteen healthy male volunteers (23±4 years) were recruited into a series of double-blind, randomized crossover studies using bilateral forearm venous occlusion plethysmography during intra-arterial urocortin 2 (3.6 to 120 pmol/min), urocortin 3 (1.2 to 36 nmol/min), and substance P (2 to 8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole), and nitric oxide synthase (L-NMMA). Urocortins 2 and 3 evoked arterial vasodilatation (P<0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L-NMMA reduced vasodilatation to substance P and urocortin 2 (P≤0.001 for both) but had little effect on urocortin 3 (P>0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P>0.05 for all). In the presence of all 3 inhibitors, urocortin 2- and urocortin 3-induced vasodilatation was attenuated (P<0.001 for all) to a greater extent than with L-NMMA alone (P≤0.005). Urocortins 2 and 3 cause potent and prolonged arterial vasodilatation without tachyphylaxis. These vasomotor responses are at least partly mediated by endothelial nitric oxide and cytochrome P450 metabolites of arachidonic acid. The role of urocortins 2 and 3 remains to be explored in the setting of human heart failure, but they have the potential to have major therapeutic benefits. http://www.clinicaltrials.gov//. Unique identifier: NCT01096706 and NCT01296607.
    Journal of the American Heart Association. 12/2013; 2(1):e004267.
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    ABSTRACT: Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (NO) bioavailability in mediating these effects. In 2 randomized double-blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air. Study 1: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (ACh; 5 to 20 μg/min) and sodium nitroprusside (SNP; 2 to 8 μg/min) in the presence of the NO clamp (NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) 8 μg/min coinfused with the NO donor SNP at 90 to 540 ng/min to restore basal blood flow). Study 2: Blood pressure, arterial stiffness, and cardiac output were measured during systemic NO synthase inhibition with intravenous l-NMMA (3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68±48 versus 41±32 nmol/L; P=0.006) despite similar l-NMMA-induced reductions in basal blood flow (-20.6±14.7% versus -21.1±14.6%; P=0.559) compared to air. In the presence of the NO clamp, ACh and SNP caused dose-dependent vasodilatation that was not affected by diesel exhaust inhalation (P>0.05 for both). Following exposure to diesel exhaust, l-NMMA caused a greater increase in blood pressure (P=0.048) and central arterial stiffness (P=0.007), but reductions in cardiac output and increases in systemic vascular resistance (P>0.05 for both) were similar to those seen with filtered air. Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced NO generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced NO bioavailability. URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00845767 and NCT01060930.
    Journal of the American Heart Association. 12/2013; 2(1):e004309.
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    ABSTRACT: To determine the optimal T1 mapping approach to assess myocardial fibrosis at 3T. T1 mapping was performed at 3T using the modified look-locker-inversion sequence in 20 healthy volunteers and 20 patients with aortic stenosis (AS). Pre- and post-contrast myocardial T1, the partition coefficient (λ; ΔRmyocardium/ΔRblood, where ΔR = 1/post-contrast T1 - 1/pre-contrast T1), and extracellular volume fraction [ECV; λ (1 - haematocrit)] were assessed. After establishing the optimal time point and myocardial region for analysis, we compared the reproducibility of these T1 measures and their ability to differentiate asymptomatic patients with AS from healthy volunteers. There was no segmental variation across the ventricle in any of the T1 measures evaluated. λ and ECV did not vary with time, while post-contrast T1 was relatively constant between 15 and 30 min. Thus, mid-cavity myocardium at 20 min was used for subsequent analyses. ECV displayed excellent intra-, inter-observer, and scan-rescan reproducibility [intra-class correlation coefficients (ICC) 1.00, 0.97, and 0.96, respectively], as did λ (ICC 0.99, 0.94, 0.93, respectively). Moreover, ECV and λ were both higher in patients with AS compared with controls (ECV 28.3 ± 1.7 vs. 26.0 ± 1.6%, P < 0.001; λ 0.46 ± 0.03 vs. 0.44 ± 0.03, P = 0.02), with the former offering improved differentiation. In comparison, scan-rescan reproducibilities for pre- and post-contrast myocardial T1 were only modest (ICC 0.72 and 0.56) with no differences in values observed between cases and controls (both P> 0.05). ECV appears to be the most promising measure of diffuse myocardial fibrosis at 3T based upon its superior reproducibility and ability to differentiate disease from health.
    European Heart Journal – Cardiovascular Imaging 11/2013;
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    ABSTRACT: Therapeutic inhibition of neutrophil-derived elastases holds promise with powerful treatment effects observed in various preclinical models of lung, bowel and skin inflammation and ischaemia-reperfusion injury relevant to myocardial infarction, stroke and transplant medicine. This brief review considers recent studies eliciting the complex interaction between neutrophil-derived elastases and endogenous inhibitors that determines elastase-mediated inflammation in humans. Translating results of preclinical studies with neutrophil elastase inhibitors remains challenging. Future clinical studies will harness developments in drug delivery and utilize more specific markers of neutrophil elastase activity to inform on the efficacy of inhibition. A summary of recently published and ongoing clinical trials with synthetic inhibitors sivelestat and AZD9668 and recombinant elafin is provided. Clinical trials with neutrophil elastase inhibitors in lung and cardiovascular disease are ongoing, and future studies will incorporate novel delivery approaches and be directed by specific markers of neutrophil-derived elastase activity to target inhibition to the sites of inflammatory tissue injury.
    Current opinion in hematology 11/2013; 21(1).
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    ABSTRACT: The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG). In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001). (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. Chief Scientist Office Scotland and British Heart Foundation.
    The Lancet 11/2013;
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    ABSTRACT: While glucocorticoids (GC) are known to be present in the zebrafish embryo little is known about their physiological roles at this stage. We hypothesised that GC play key roles in stress response, hatching and swim activity during early development. To test this, whole embryo cortisol (WEC) and corticosteroid-related genes were measured in embryos from 6 to 120 hours post fertilisation (hpf) by ELISA. Stress response was assessed by change in WEC following stirring, hypoxia or brief electrical impulses applied to the bathing water. The impact of pharmacological and molecular glucocorticoid manipulation on the stress-response, spontaneous hatching and swim activity at different stages of development was also assessed. WEC levels demonstrated a biphasic pattern during development with a decrease from 0 to 36 hpf followed by a progressive increase towards 120hpf. This was accompanied by a significant and sustained increase in the expression of genes encoding cyp11b1 (glucocorticoid biosynthesis), 11βhsd2 (glucocorticoid metabolism) and gr (glucocorticoid receptor) from 48 to 120hpf. Metyrapone (Met) an inhibitor of 11β hydroxylase (encoded by cyp11b1) and cyp11b1 morpholino knockdown significantly reduced basal and stress-induced WEC levels at 72 and 120hpf but not at 24 hpf. Spontaneous hatching and swim activity were significantly affected by manipulation of GC action from approximately 48 hpf onwards. We have identified a number of key roles of GC in zebrafish embryos contributing to adaptive physiological responses under adverse conditions. The ability to alter GC action in the zebrafish embryo also highlights its potential value for GC research.
    The Journal of Physiology 10/2013;
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    ABSTRACT: Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) Class II OP insecticide poisoning. Patient data were derived from two studies, a cohort study (using a bolus treatment of 1 g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2 g pralidoxime over 20 min, followed by an infusion of 0.5 g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by two diethyl-OP insecticides, chlorpyrifos and quinalphos; however, unlike AChE reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1 g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO Class II OP poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful.
    Toxicological Sciences 09/2013;
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    Journal of the American College of Cardiology 09/2013;
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    ABSTRACT: The mechanisms through which ω-3 fatty acids reduce adverse cardiac events remain uncertain. We aimed to investigate the effect of ω-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in patients with coronary heart disease. Randomised, double-blind, placebo-controlled, cross-over trial. Academic cardiac centre. 20 male patients with a previous myocardial infarction. ω-3 Fatty acid supplementation (2 g/day for 6 weeks) versus olive oil placebo. Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 patients during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. All vasodilators caused dose-dependent increases in FBF (p<0.0001). ω-3 Fatty acid supplementation did not affect endothelium-dependent vasodilation with acetylcholine and substance P compared with placebo (p=0.5 and 0.9). Substance P caused a dose-dependent increase in plasma t-PA concentrations (p<0.0001), which was not affected by ω-3 fatty acid supplementation (p=0.9). ω-3 Fatty acids did not affect platelet-monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. We have demonstrated that dietary supplementation with ω-3 fatty acids does not affect endothelial vasomotor function, endothelial t-PA release, or platelet and monocyte activation in patients with coronary heart disease. Cardiac benefits conferred by ω-3 fatty acids in coronary heart disease are unlikely to be mediated through effects on these systems.
    BMJ Open 09/2013; 3(9):e003054.
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