Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

BACKGROUND: Elevated levels of osteoprotegerin, a secreted tumor necrosis factor-related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6 months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial. METHODS AND RESULTS: The associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non-coronary artery bypass grafting major bleeding during 1 year of follow-up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21-1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C-reactive protein, troponin T, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and growth differentiation factor-15). The corresponding rates of non-coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36-1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09-1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1 month resulted in an HR of 1.09 (95% CI, 0.89-1.33); for major bleeding after 1 month, the HR was 1.33 (95% CI, 0.91-1.96). CONCLUSIONS: In patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872

Legumain in acute coronary syndromes: A substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial

Background The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. Methods and Results Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow‐up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04–1.21), P=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02–1.19; P=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44–0.88; P=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37–0.88; P=0.0114). Conclusions Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00391872

Prevalence and relevance of abnormal glucose metabolism in acute coronary syndromes : insights from the PLATelet inhibition and patient outcomes (PLATO) trial

Diabetes mellitus (DM) and abnormal glucose metabolism are associated with cardiovascular (CV) disease. We investigated the prevalence and prognostic importance of dysglycaemia in patients with acute coronary syndromes (ACS) in the PLATelet inhibition and patient Outcomes (PLATO) trial. Diabetes was defined as known diabetes or HbA1c ≥ 6.5% or non-fasting glucose ≥ 11.1 mmol/L on admission, prediabetes as HbA1c ≥ 5.7% but < 6.5%, and no diabetes as HbA1c < 5.7%. The primary endpoint was the composite of CV death, spontaneous myocardial infarction type 1 (sMI) or stroke at 12 months. Multivariable Cox regression models, adjusting for baseline characteristics, and biomarkers NT-proBNP and troponin I, were used to explore the association between glycaemia and outcome. On admission, 16,007 (86.1%) patients had HbA1c and/or glucose levels available and were subdivided into DM 38.5% (6160) (1501 patients had no previous DM diagnosis), prediabetes 38.8% (6210), and no DM 22.7% (3637). Kaplan Meier event rates at 12 months for CV death, sMI or stroke per subgroups were 14.5% (832), 9.0% (522), and 8.5% (293), respectively with multivariable adjusted HRs, versus no diabetes, for diabetes: 1.71 (1.50–1.95) and for prediabetes 1.03 (0.90–1.19). Corresponding event rates for CV death were 6.9% (391), 3.4% (195) and 3.0% (102), respectively, with adjusted HRs for patients with DM of: 1.92 (1.42–2.60) and for prediabetes 1.02 (0.79–1.32). Abnormal glucose metabolism is common in ACS patients, but only patients with definite DM have an increased CV risk, indicating that prediabetes is not immediately associated with worse CV outcomes

Realistic forest stand reconstruction from terrestrial LiDAR for radiative transfer modelling

Forest biophysical variables derived from remote sensing observations are vital for climate research. The combination of structurally and radiometrically accurate 3D "virtual" forests with radiative transfer (RT) models creates a powerful tool to facilitate the calibration and validation of remote sensing data and derived biophysical products by helping us understand the assumptions made in data processing algorithms. We present a workflow that uses highly detailed 3D terrestrial laser scanning (TLS) data to generate virtual forests for RT model simulations. Our approach to forest stand reconstruction from a co-registered point cloud is unique as it models each tree individually. Our approach follows three steps: (1) tree segmentation; (2) tree structure modelling and (3) leaf addition. To demonstrate this approach, we present the measurement and construction of a one hectare model of the deciduous forest in Wytham Woods (Oxford, UK). The model contains 559 individual trees. We matched the TLS data with traditional census data to determine the species of each individual tree and allocate species-specific radiometric properties. Our modelling framework is generic, highly transferable and adjustable to data collected with other TLS instruments and different ecosystems. The Wytham Woods virtual forest is made publicly available through an online repository

Interleukin‐18 in patients with acute coronary syndromes

Background We aimed to assess associations between circulating IL‐18 concentrations and cardiovascular outcomes in patients with acute coronary syndromes (ACS). Hypothesis and Methods Plasma IL‐18 concentrations were measured at admission, discharge, 1 month, and 6 months in patients with ACS in the PLATelet inhibition and patient Outcomes (PLATO) trial. Associations with outcomes were evaluated with Cox regression models on the composite of CV death, spontaneous myocardial infarction (sMI), or stroke; and on CV death or sMI separately, including adjustment for clinical risk factors and biomarkers (cTnT‐hs, NT‐proBNP, cystatin C, CRP‐hs, and GDF‐15). Results Median IL‐18 concentrations at baseline, discharge, 1 month, and 6 months were 237, 283, 305, and 320 ng/L (n = 16 636). Male sex, obesity, diabetes, and plasma levels of cystatin C, GDF‐15, and CRP‐hs were independently associated with higher IL‐18 levels. Higher baseline IL‐18 levels were associated with the composite endpoint and with CV death (hazard ratio [HR] 1.05, 95% confidence interval [95% CI] 1.02‐1.07 and HR 1.10, 95% CI 1.06‐1.14, respectively, per 25% increase of IL‐18 levels). Associations remained significant after adjustment for clinical variables but became non‐significant after adjustment for all biomarkers (HR 1.01, 95% CI 0.98‐1.04 and HR 1.04, 95% CI 1.00‐1.08, respectively). There were no associations with sMI. Conclusions In ACS patients, IL‐18 concentrations increased after the acute event and remained increased for 6 months. Baseline IL‐18 levels were significantly associated with CV mortality, independent of clinical characteristics and indicators of renal/cardiac dysfunction but this association was attenuated after adjustment for multiple biomarkers

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Clinicians' management strategies for patients with dyspepsia: a qualitative approach

BACKGROUND: Symptoms from the upper gastrointestinal tract are frequently encountered in clinical practice and may be of either organic or functional origin. For some of these conditions, according to the literature, certain management strategies can be recommended. For other conditions, the evidence is more ambiguous. The hypothesis that guided our study design was twofold: Management strategies and treatments suggested by different clinicians vary considerably, even when optimal treatment is clear-cut, as documented by evidence in the literature. Clinicians believe that the management strategies of their colleagues are similar to their own. METHODS: Simulated case histories of four patients with symptoms from the upper gastrointestinal tract were presented to 27 Swedish clinicians who were specialists in medical gastroenterology, surgery, and general practice and worked at three hospitals in the southern part of Sweden. The patients' histories contained information on the patient's sex and age and the localisation of the symptoms, but descriptions of subjective symptoms and findings from examinations differed from history to history. Interviews containing open-ended questions were conducted. RESULTS: For the same patient, the management strategies and treatments suggested by the clinicians varied widely, as did the strategies suggested by clinicians in the same speciality. Variation was more pronounced if the case history noted symptoms but no organic findings than if the case history noted unambiguous findings and symptoms. However, even in cases with a consensus in the scientific literature on treatment, the variations in clinicians' opinion on management were pronounced. CONCLUSION: Despite these variations, the clinicians believed that the decisions made by their colleagues would be similar to their own. The overall results of this study indicate that we as researchers must make scientific evidence comprehensible and communicate evidence so that clinicians are able to interpret and implement it in practice. Of particular significance is that scientific evidence leads to an evidence-based care which is effective clinical practice and to the promotion of health from the perspective of the patient, together with cost-effectiveness as a priority

Safety and efficacy of the 5-lipoxygenase-activating protein inhibitor AZD5718 in patients with recent myocardial infarction: The phase 2a FLAVOUR study

Background: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. Methods: Patients 7–28 days after myocardial infarction (±ST elevation), with coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4- and 12-week cohorts. Change in urine leukotriene E4 (uLTE4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. Results: Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE4 levels of >80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths. </p

Long-term changes (1990–2015) in the atmospheric deposition and runoff water chemistry of sulphate, inorganic nitrogen and acidity for forested catchments in Europe in relation to changes in emissions and hydrometeorological conditions

The international Long-Term Ecological Research Network (ILTER) encompasses hundreds of long-term research/monitoring sites located in a wide array of ecosystems that can help us understand environmental change across the globe. We evaluated long-term trends (1990–2015) for bulk deposition, throughfall and runoff water chemistry and fluxes, and climatic variables in 25 forested catchments in Europe belonging to the UNECE International Cooperative Programme on Integrated Monitoring of Air Pollution Effects on Ecosystems (ICP IM). Many of the IM sites form part of the monitoring infrastructures of this larger ILTER network. Trends were evaluated for monthly concentrations of non-marine (anthropogenic fraction, denoted as x) sulphate (xSO4) and base cations x(Ca + Mg), hydrogen ion (H+), inorganic N (NO3 and NH4) and ANC (Acid Neutralising Capacity) and their respective fluxes into and out of the catchments and for monthly precipitation, runoff and air temperature. A significant decrease of xSO4 deposition resulted in decreases in concentrations and fluxes of xSO4 in runoff, being significant at 90% and 60% of the sites, respectively. Bulk deposition of NO3 and NH4 decreased significantly at 60–80% (concentrations) and 40–60% (fluxes) of the sites. Concentrations and fluxes of NO3 in runoff decreased at 73% and 63% of the sites, respectively, and NO3 concentrations decreased significantly at 50% of the sites. Thus, the LTER/ICP IM network confirms the positive effects of the emission reductions in Europe. Air temperature increased significantly at 61% of the sites, while trends for precipitation and runoff were rarely significant. The site-specific variation of xSO4 concentrations in runoff was most strongly explained by deposition. Climatic variables and deposition explained the variation of inorganic N concentrations in runoff at single sites poorly, and as yet there are no clear signs of a consistent deposition-driven or climate-driven increase in inorganic N exports in the catchments.Long-term changes (1990–2015) in the atmospheric deposition and runoff water chemistry of sulphate, inorganic nitrogen and acidity for forested catchments in Europe in relation to changes in emissions and hydrometeorological conditionsacceptedVersio