Showing papers by "David E. Newby published in 2013"

Late Outgrowth Endothelial Cells Resemble Mature Endothelial Cells and Are Not Derived from Bone Marrow

Abstract: A decade of research has sought to identify circulating endothelial progenitor cells (EPC) in order to harness their potential for cardiovascular regeneration. Endothelial outgrowth cells (EOC) most closely fulfil the criteria for an EPC, but their origin remains obscure. Our aim was to identify the source and precursor of EOC and to assess their regenerative potential compared to mature endothelial cells. EOC are readily isolated from umbilical cord blood (6/6 donors) and peripheral blood mononuclear cells (4/6 donors) but not from bone marrow (0/6) or peripheral blood following mobilization with granulocyte-colony stimulating factor (0/6 donors). Enrichment and depletion of blood mononuclear cells demonstrated that EOC are confined to the CD34 1 CD133 2 CD146 1 cell fraction. EOC derived from blood mononuclear cells are indistinguishable from mature human umbilical vein endothelial cells (HUVEC) by morphology, surface antigen expression, immunohistochemistry, real-time polymerase chain reaction, proliferation, and functional assessments. In a subcutaneous sponge model of angiogenesis, both EOC and HUVEC contribute to de novo blood vessel formation giving rise to a similar number of vessels (7.0 6 2.7 vs. 6.6 6 3.7 vessels, respectively, n 5 9). Bone marrow-derived outgrowth cells isolated under the same conditions expressed mesenchymal markers rather than endothelial cell markers and did not contribute to blood vessels in vivo. In this article, we confirm that EOC arise from CD34 1 CD133 2 CD146 1 mononuclear cells and are similar, if not identical, to mature endothelial cells. Our findings suggest that EOC do not arise from bone marrow and challenge the concept of a bone marrowderived circulating precursor for endothelial cells. STEM CELLS 2013;31:338–348

Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation?

Abstract: Aims The pathophysiology of aortic stenosis shares many similarities with atherosclerosis and skeletal bone formation. Using non-invasive imaging, we compared aortic valve calcification and inflammation activity with that measured in atherosclerosis and bone. Methods and results Positron emission and computed tomography was performed using 18F-sodium fluoride (18F-NaF, calcification) and 18F-fluorodeoxyglucose (18F-FDG, inflammation) in 101 patients with calcific aortic valve disease (81 aortic stenosis and 20 aortic sclerosis). Calcium scores and positron emission tomography tracer activity (tissue-to-background ratio; TBR) were measured in the aortic valve, coronary arteries, thoracic aorta, and bone. Over 90% of the cohort had coexistent calcific atheroma, yet correlations between calcium scores were weak or absent (valve vs. aorta r 2 = 0.015, P = 0.222; valve vs. coronaries r 2 = 0.039, P = 0.049) as were associations between calcium scores and bone mineral density (BMD vs. valve r 2 = 0.000, P = 0.766; vs. aorta r 2 = 0.052, P = 0.025; vs. coronaries r 2 = 0.016, P = 0.210). 18F-NaF activity in the valve was 28% higher than in the aorta (TBR: 2.66 ± 0.84 vs . 2.11 ± 0.31, respectively, P < 0.001) and correlated more strongly with the severity of aortic stenosis ( r 2 = 0.419, P < 0.001) than 18F-NaF activity outwith the valve (valve vs. aorta r 2 = 0.167, P < 0.001; valve vs. coronary arteries r 2 = 0.174, P < 0.001; valve vs. bone r 2 = 0.001, P = 0.806). In contrast, 18F-FDG activity was lower in the aortic valve than the aortic atheroma (TBR: 1.56 ± 0.21 vs . 1.81 ± 0.24, respectively, P < 0.001) and more closely associated with uptake outwith the valve (valve vs. aorta r 2 = 0.327, P < 0.001). Conclusion In patients with aortic stenosis, disease activity appears to be determined by local calcific processes within the valve that are distinct from atherosclerosis and skeletal bone metabolism. Trial Registration: ClinicalTrials.gov number: [NCT01358513][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01358513&atom=%2Fehj%2F34%2F21%2F1567.atom

Inhibition of galectin-3 reduces atherosclerosis in apolipoprotein E-deficient mice

Abstract: Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and stroke. Galectin-3 is a carbohydrate-binding lectin implicated in the pathophysiology of CVD and is highly expressed within atherosclerotic lesions in mice and humans. The object of this present study was to use genetic deletion and pharmacological inhibition in a well-characterized mouse model of atherosclerosis to determine the role of galectin-3 in plaque development. Apolipoprotein-E/galectin-3 knockout mice were generated and fed a high-cholesterol "western" diet. Galectin-3 deletion had no consistent effect on the serum lipid profile but halved atherosclerotic lesion formation in the thoracic aorta (57% reduction), the aortic arch (50% reduction) and the brachiocephalic arteries. The aortic plaques were smaller, with reduced lipid core and less collagen. In apolipoprotein E-deficient (ApoE(-/-)) mice, there was a switch from high inducible nitric oxide expression in early lesions (6 weeks) to arginase-1 expression in later lesions (20 weeks), which was reversed in ApoE(-/-)/gal-3(-/-) mice. Administration of modified citrus pectin, an inhibitor of galectin-3, during the latter stage of the disease reduced plaque volume. We conclude that inhibiting galectin-3 causes decreased atherosclerosis. Strategies to inhibit galectin-3 function may reduce plaque progression and potentially represent a novel therapeutic strategy in the treatment of atherosclerotic disease.

Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice

Abstract: Objective: Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE �/� ) mice. Methods: ApoE �/� mice were fed a ‘Western diet’ (8 weeks) to induce ‘complex’ atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 μL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery. Results: Brachiocephalic atherosclerotic plaques were larger in ApoE �/� mice treated with DEP (59±10%) than in controls (32±7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4±0.2 vs 1.8±0.2; P = 0.048) and buried fibrous layers (1.2±0.2 vs 0.4±0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation. Conclusions: Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.

Exposure to wood smoke increases arterial stiffness and decreases heart rate variability in humans

Abstract: Background: Emissions from biomass combustion are a major source of indoor and outdoor air pollution, and are estimated to cause millions of premature deaths worldwide annually. Whilst adverse respiratory health effects of biomass exposure are well established, less is known about its effects on the cardiovascular system. In this study we assessed the effect of exposure to wood smoke on heart rate, blood pressure, central arterial stiffness and heart rate variability in otherwise healthy persons. Methods: Fourteen healthy non-smoking subjects participated in a randomized, double-blind crossover study. Subjects were exposed to dilute wood smoke (mean particle concentration of 314±38 μg/m 3 ) or filtered air for three hours during intermittent exercise. Heart rate, blood pressure, central arterial stiffness and heart rate variability were measured at baseline and for one hour post-exposure. Results: Central arterial stiffness, measured as augmentation index, augmentation pressure and pulse wave velocity, was higher after wood smoke exposure as compared to filtered air (p < 0.01 for all), and heart rate was increased (p < 0.01) although there was no effect on blood pressure. Heart rate variability (SDNN, RMSSD and pNN50; p = 0.003, p < 0.001 and p < 0.001 respectively) was decreased one hour following exposure to wood smoke compared to filtered air. Conclusions: Acute exposure to wood smoke as a model of exposure to biomass combustion is associated with an immediate increase in central arterial stiffness and a simultaneous reduction in heart rate variability. As biomass is used for cooking and heating by a large fraction of the global population and is currently advocated as a sustainable alternative energy source, further studies are required to establish its likely impact on cardiovascular disease. Trial registration: ClinicalTrials.gov, NCT01488500

Sustained Cardiovascular Actions of APJ Agonism During Renin-Angiotensin System Activation and in Patients with Heart Failure

Abstract: Background— To assess cardiovascular actions of APJ agonism during prolonged (Pyr1)apelin-13 infusion and renin–angiotensin system activation. Methods and Results— Forty-eight volunteers and 12 patients with chronic stable heart failure attended a series of randomized placebo–controlled studies. Forearm blood flow, cardiac index, left ventricular dimensions, and mean arterial pressure were measured using bilateral venous occlusion plethysmography, bioimpedance cardiography, transthoracic echocardiography, and sphygmomanometry, respectively, during brief local (0.3–3.0 nmol/min) and systemic (30–300 nmol/min) or prolonged systemic (30 nmol/min) (Pyr1)apelin-13 infusions in the presence or absence of renin–angiotensin system activation with sodium depletion or angiotensin II coinfusion. During sodium depletion and angiotensin II coinfusion, (Pyr1)apelin-13–induced vasodilatation was preserved ( P 0.05 for all). Prolonged 6-hour (Pyr1)apelin-13 infusion caused a sustained increase in cardiac index with increased left ventricular ejection fraction in patients with chronic heart failure (ANOVA; P <0.001 for all). Conclusions— APJ agonism has sustained cardiovascular effects that are preserved in the presence of renin–angiotensin system activation or heart failure. APJ agonism may hold major promise to complement current optimal medical therapy in patients with chronic heart failure. Clinical Trial Registration— URL: . Unique identifiers: [NCT00901719][1], [NCT00901888][2], [NCT01049646][3], [NCT01179061][4]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00901719&atom=%2Fcirchf%2F6%2F3%2F482.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00901888&atom=%2Fcirchf%2F6%2F3%2F482.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01049646&atom=%2Fcirchf%2F6%2F3%2F482.atom [4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01179061&atom=%2Fcirchf%2F6%2F3%2F482.atom

The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol

Abstract: Chronic obstructive pulmonary disease (COPD) often coexists with other chronic diseases and comorbidities that can markedly influence patients' health status and prognosis This is particularly true for cardiovascular disease (CVD) However, there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases The "Study to Understand Mortality and Morbidity in COPD" (SUMMIT) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD SUMMIT is a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial of 16 000 patients with moderate COPD randomly assigned to once daily treatment with fluticasone furoate/vilanterol (100/25 μg), fluticasone furoate (100 μg), vilanterol (25 μg) or matched placebo; mortality is the primary end-point The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point This article describes the design of the SUMMIT study

Cardiovascular Effects of a Novel SIRT1 Activator, SRT2104, in Otherwise Healthy Cigarette Smokers

Abstract: Background We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers. Methods and Results Twenty-four otherwise healthy cigarette smokers participated in a randomized double-blind, placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra-arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328±748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (−11.6±20 versus 6±21 mg/dL), low-density lipoprotein cholesterol (−10±17 versus 3±21 mg/dL), and triglyceride (−39.8±77 versus 13.3±57 mg/dL) concentrations ( P 0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014. Conclusions SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers. Clinical Trial Registration . Unique identifier: [NCT01031108][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01031108&atom=%2Fahaoa%2F2%2F3%2Fe000042.atom

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study

Abstract: Objective The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. Design and setting and patients A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10 mg) or saline placebo. Main outcome measures Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24 h after study intervention. Results Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254±15 vs 0.12±0.02 pg/ml; p<0.0001), but not saline infusion. Etanercept treatment reduced neutrophil

Altered Nitric Oxide Bioavailability Contributes to Diesel Exhaust Inhalation‐Induced Cardiovascular Dysfunction in Man

Abstract: Background Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric o ...

Effect of ω-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in male cigarette smokers

Abstract: Objective The effects of ω-3 fatty acids on endothelial function, fibrinolysis and platelet function are uncertain. We investigated the effects of ω-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in healthy cigarette smokers; a group at increased risk of myocardial infarction. Design, setting, participants Twenty cigarette smokers were recruited into a randomised, double-blind, placebo-controlled, crossover trial of ω-3 fatty acid supplementation. Intervention ω-3 fatty acid supplements (2 g/day) or placebo for a 6-week period. Main outcome measures Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 smokers during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. Results All vasodilators caused dose-dependent increases in FBF (p −1 vs 3.6±1.1 IU ml −1 ; p=0.029). ω-3 fatty acids did not affect platelet-monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. Conclusions We have demonstrated for the first time that ω-3 fatty acids augment acute endothelial t-PA release and improve endothelial vasomotor function in cigarette smokers. Improved endogenous fibrinolysis and endothelial function may represent important mechanisms through which ω-3 fatty acids confer potential cardiovascular benefits.

Endothelial progenitor cells, atheroma burden and clinical outcome in patients with coronary artery disease

Abstract: Objective We wished to determine the effect of an acute coronary syndrome (ACS) on putative endothelial progenitor cell (EPC) populations, and define their relationship to coronary artery disease (CAD) severity and clinical outcome, in order to clarify their clinical relevance. Design and setting A prospective cohort study conducted in a tertiary referral cardiac centre. Patients Two-hundred-and-one patients undergoing coronary angiography for suspected angina or ACS. Main outcome measures Putative EPC populations were determined by flow cytometry. CAD was quantified using the Gensini scoring system. Survival free from revascularisation, recurrent myocardial infarction and death were determined at 3 years. Results Circulating CD34 + VEGFR-2 + and CD34 + VEGFR-2 + CD133 + cells were rare ( 0.1 for all). By contrast, CD34 + CD45 − cells were increased in patients with CAD compared with those with normal coronary arteries (p=0.008) and correlated with atheroma burden (r=0.44, p + CD45 − cells were associated with a shorter cumulative event-free survival (p + VEGFR-2 + Tie-2 + ) and endothelial cell-colony forming units were increased in patients with ACS (p Conclusions Traditional EPC populations, CD34 + VEGFR-2 + and CD34 + VEGFR-2 + CD133 + are not related to the extent of CAD or clinical outcome. However, CD34 + CD45 − cells are increased in patients with CAD and predict future cardiovascular events. It is likely that CD34 + CD45 − concentrations reflect the extent of vascular injury and atheroma burden.

Forced expiratory volume in one second predicts length of stay and in-hospital mortality in patients undergoing cardiac surgery: a retrospective cohort study.

Abstract: Objective: An aging population and increasing use of percutaneous therapies have resulted in older patients with more co-morbidity being referred for cardiac surgery. Objective measurements of physiological reserve and severity of co-morbid disease are required to improve risk stratification. We hypothesised that FEV1 would predict mortality and length of stay following cardiac surgery. Methods: We assessed clinical outcomes in 2,241 consecutive patients undergoing coronary artery bypass grafting and/or valve surgery from 2001 to 2007 in a regional cardiac centre. Generalized linear models of the association between FEV1 and length of hospital stay and mortality were adjusted for age, sex, height, body mass index, socioeconomic status, smoking, cardiovascular risk factors, long-term use of bronchodilators or steroids for lung disease, and type and urgency of surgery. FEV1 was compared to an established risk prediction model, the EuroSCORE. Results: Spirometry was performed in 2,082 patients (93%) whose mean (SD) age was 67 (10) years. Median hospital stay was 3 days longer in patients in the lowest compared to the highest quintile for FEV1, 1.35-fold higher (95% CI 1.20–1.52; p<0.001). The adjusted odds ratio for mortality was increased 2.11-fold (95% CI 1.45–3.08; p<0.001) per standard deviation decrement in FEV1 (800 ml). FEV1 improved discrimination of the EuroSCORE for mortality. Similar associations were found after excluding people with known pulmonary disease and/or airflow limitation on spirometry. Conclusions: Reduced FEV1 strongly predicted increased length of stay and in-hospital mortality following cardiac surgery. FEV1 is a widely available measure of physiological health that may improve risk stratification of complex patients undergoing cardiac surgery and should be evaluated for inclusion in new prediction tools.

On the prediction of monocyte deposition in abdominal aortic aneurysms using computational fluid dynamics

Abstract: In abdominal aortic aneurysm disease, the aortic wall is exposed to intense biological activity involving inflammation and matrix metalloproteinase-mediated degradation of the extracellular matrix. These processes are orchestrated by monocytes and rather than affecting the aorta uniformly, damage and weaken focal areas of the wall leaving it vulnerable to rupture. This study attempts to model numerically the deposition of monocytes using large eddy simulation, discrete phase modelling and near-wall particle residence time. The model was first applied to idealised aneurysms and then to three patient-specific lumen geometries using three-component inlet velocities derived from phase-contrast magnetic resonance imaging. The use of a novel, variable wall shear stress-limiter based on previous experimental data significantly improved the results. Simulations identified a critical diameter (1.8 times the inlet diameter) beyond which significant monocyte deposition is expected to occur. Monocyte adhesion occurred proximally in smaller abdominal aortic aneurysms and distally as the sac expands. The near-wall particle residence time observed in each of the patient-specific models was markedly different. Discrete hotspots of monocyte residence time were detected, suggesting that the monocyte infiltration responsible for the breakdown of the abdominal aortic aneurysm wall occurs heterogeneously. Peak monocyte residence time was found to increase with aneurysm sac size. Further work addressing certain limitations is needed in a larger cohort to determine clinical significance.

High sensitivity cardiac troponin in patients with chest pain

Abstract: This article describes how high sensitivity troponin assays can be used to diagnose acute myocardial infarction in patients with chest pain

Effect of PSI-697, a novel P-selectin inhibitor, on platelet-monocyte aggregate formation in humans

Abstract: Background Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P-selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P-selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P-selectin antagonist PSI-697 on platelet–monocyte aggregate formation in humans. Methods and Results In a double-blind, randomized, placebo-controlled crossover study, healthy smokers were randomized to receive either oral PSI-697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI-697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor-activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration-dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% ( P 0.05). P-selectin-blocking antibody (CLB-Thromb6), but not PSI-697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro ( P <0.001). Conclusions The novel small-molecule P-selectin antagonist PSI-697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established. Clinical Trial Registration URL: Unique identifier: 2007-005695-14.

Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers

Abstract: Background 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. Methods and Results 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 0.05). 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). Conclusions 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. Clinical Trial Registration /. Unique identifier: [NCT01096706][1] and [NCT01296607][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01096706&atom=%2Fahaoa%2F2%2F1%2Fe004267.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01296607&atom=%2Fahaoa%2F2%2F1%2Fe004267.atom

Impact of Scotland's comprehensive, smoke-free legislation on stroke.

Abstract: Background: Previous studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overall and by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006. Methods and Findings: A negative binomial regression model was used to determine whether the introduction of smokefree legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age-group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p,0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential confounders. Conclusions: Following introduction of national, comprehensive smoke-free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke.

Association between Exposure to Environmental Tobacco Smoke and Biomarkers of Oxidative Stress Among Patients Hospitalised with Acute Myocardial Infarction

Abstract: Objective To determine whether exposure to environmental tobacco smoke was associated with oxidative stress among patients hospitalised for acute myocardial infarction. Design An existing cohort study of 1,261 patients hospitalised for acute myocardial infarction. Setting Nine acute hospitals in Scotland. Participants Sixty never smokers who had been exposed to environmental tobacco smoke (admission serum cotinine ≥3.0 ng/mL) were compared with 60 never smokers who had not (admission serum cotinine ≤0.1 ng/mL). Intervention None. Main outcome measures Three biomarkers of oxidative stress (protein carbonyl, malondialdehyde (MDA) and oxidised low-density lipoprotein (ox-LDL)) were measured on admission blood samples and adjusted for potential confounders. Results After adjusting for baseline differences in age, sex and socioeconomic status, exposure to environmental tobacco smoke was associated with serum concentrations of both protein carbonyl (beta coefficient 7.96, 95% CI 0.76, 15.17, p = 0.031) and MDA (beta coefficient 10.57, 95% CI 4.32, 16.81, p = 0.001) but not ox-LDL (beta coefficient 2.14, 95% CI −8.94, 13.21, p = 0.703). Conclusions Exposure to environmental tobacco smoke was associated with increased oxidative stress. Further studies are requires to explore the role of oxidative stress in the association between environmental tobacco smoke and myocardial infarction.

What can we learn about valvular heart disease from PET/CT?

Abstract: Valvular heart disease is a major cause of morbidity and mortality, and with an aging population, its prevalence is increasing. Here, we review the evolving use of positron emission tomography/computed tomography in valvular heart disease, with particular focus on calcific aortic stenosis and infective endocarditis. In principle, the activity of any pathological process can be studied, as long as an appropriate radiotracer can be developed. We will review some of the early data using established tracers in the above and other conditions, providing discussion as to the future research and clinical roles of these techniques. Furthermore, we will discuss the potential impact of novel tracers that are currently under development or testing in preclinical models. It is hoped that such advanced imaging might improve the diagnosis, treatment and outlook for patients with valvular heart disease.

Effect of ω-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in patients with a previous myocardial infarction: a randomised controlled trial

Abstract: Objective 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. Design Randomised, double-blind, placebo-controlled, cross-over trial. Setting Academic cardiac centre. Participants 20 male patients with a previous myocardial infarction. Intervention ω-3 Fatty acid supplementation (2 g/day for 6 weeks) versus olive oil placebo. Outcome measures 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. Results All vasodilators caused dose-dependent increases in FBF (p Conclusions 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.

Imaging of inflammation and calcification in aortic stenosis.

Abstract: Aortic stenosis is a common clinical condition that is set to increase in prevalence with an ageing population. However, reliable methods for predicting disease progression and effective medical therapies are lacking. Inflammation and calcification are believed to have a key role but until recently the relative contributions of these processes at the different stages of the disease process were unknown. Recent studies have suggested that combined positron emission tomography and computed tomography (PET/CT) is a feasible and reproducible method for measuring the degree of inflammation and calcification in the valves of patients with aortic stenosis. For the first time this provides us with a potential method of measuring disease activity, which might then allow prediction of progression and act as a surrogate endpoint in studies of novel therapies. In this review, we will examine the basis for PET/CT scanning and discuss the studies that have investigated its use in aortic stenosis. We will cover the work that is still required in order to validate this technique and how it might impact on future clinical research and practice. Finally, we will examine alternative imaging methods that might also provide insight in to the underlying pathogenesis of this important and common clinical condition.