Marie Fisk

Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease

Abstractp38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.

Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.

Background Empyema is an increasingly frequent clinical problem worldwide, and has substantial morbidity and mortality. Our objectives were to identify the clinical, surgical and microbiological features, and management outcomes, of empyema. Methods A retrospective observational study over 12 years (1999–2010) was carried out at The Heart Hospital, London, United Kingdom. Patients with empyema were identified by screening the hospital electronic ‘Clinical Data Repository’. Demographics, clinical and microbiological characteristics, underlying risk factors, peri-operative blood tests, treatment and outcomes were identified. Univariable and multivariable statistical analyses were performed. Results Patients (n = 406) were predominantly male (74.1%); median age = 53 years (IQR = 37–69). Most empyema were community-acquired (87.4%) and right-sided (57.4%). Microbiological diagnosis was obtained in 229 (56.4%) patients, and included streptococci (16.3%), staphylococci (15.5%), Gram-negative organisms (8.9%), anaerobes (5.7%), pseudomonads (4.4%) and mycobacteria (9.1%); 8.4% were polymicrobial. Most (68%) cases were managed by open thoracotomy and decortication. Video-assisted thoracoscopic surgery (VATS) reduced hospitalisation from 10 to seven days (P = 0.0005). All-cause complication rate was 25.1%, and 28 day mortality 5.7%. Predictors of early mortality included: older age (P = 0.006), major co-morbidity (P = 0.01), malnutrition (P = 0.001), elevated red cell distribution width (RDW, P<0.001) and serum alkaline phosphatase (P = 0.004), and reduced serum albumin (P = 0.01) and haemoglobin (P = 0.04). Conclusions Empyema remains an important cause of morbidity and hospital admissions. Microbiological diagnosis was only achieved in just over 50% of cases, and tuberculosis is a notable causative organism. Treatment of empyema with VATS may reduce duration of hospital stay. Raised RDW appears to associate with early mortality.

Quantification of lung PET images: challenges and opportunities.

Millions of people are affected by respiratory diseases, leading to a significant health burden globally. Because of the current insufficient knowledge of the underlying mechanisms that lead to the development and progression of respiratory diseases, treatment options remain limited. To overcome this limitation and understand the associated molecular changes, noninvasive imaging techniques such as PET and SPECT have been explored for biomarker development, with 18F-FDG PET imaging being the most studied. The quantification of pulmonary molecular imaging data remains challenging because of variations in tissue, air, blood, and water fractions within the lungs. The proportions of these components further differ depending on the lung disease. Therefore, different quantification approaches have been proposed to address these variabilities. However, no standardized approach has been developed to date. This article reviews the data evaluating 18F-FDG PET quantification approaches in lung diseases, focusing on methods to account for variations in lung components and the interpretation of the derived parameters. The diseases reviewed include acute respiratory distress syndrome, chronic obstructive pulmonary disease, and interstitial lung diseases such as idiopathic pulmonary fibrosis. Based on review of prior literature, ongoing research, and discussions among the authors, suggested considerations are presented to assist with the interpretation of the derived parameters from these approaches and the design of future studies.

The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial

Background Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis. Objectives This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l). Methods This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Results We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups. Conclusions In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.

Surrogate markers of cardiovascular risk and chronic obstructive pulmonary disease

Cardiovascular disease is a common comorbidity and cause of mortality in chronic obstructive pulmonary disease. A better understanding of mechanisms of cardiovascular risk in chronic obstructive pulmonary disease patients is needed to improve clinical outcomes. We hypothesized that such patients have increased arterial stiffness, wave reflections, and subclinical atherosclerosis compared with controls and that these findings would be independent of smoking status and other confounding factors. A total of 458 patients with a diagnosis of chronic obstructive pulmonary disease and 1657 controls (43% were current or ex-smokers) with no airflow limitation were matched for age, sex, and body mass index. All individuals underwent assessments of carotid–femoral (aortic) pulse wave velocity, augmentation index, and carotid intima–media thickness. The mean age of the cohort was 67±8 years and 58% were men. Patients with chronic obstructive pulmonary disease had increased aortic pulse wave velocity (9.95±2.54 versus 9.27±2.41 m/s; P<0.001), augmentation index (28±10% versus 25±10%; P<0.001), and carotid intima–media thickness (0.83±0.19 versus 0.74±0.14 mm; P<0.001) compared with controls. Chronic obstructive pulmonary disease was associated with increased levels of each vascular biomarker independently of physiological confounders, smoking, and other cardiovascular risk factors. In this large case-controlled study, chronic obstructive pulmonary disease was associated with increased arterial stiffness, wave reflections, and subclinical atherosclerosis, independently of traditional cardiovascular risk factors. These findings suggest that the cardiovascular burden observed in this condition may be mediated through these mechanisms and supports the concept that chronic obstructive pulmonary disease is an independent risk factor for cardiovascular disease.

Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study

Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator—fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II–IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ2). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor.

Longitudinal follow-up of quadriceps strength and function in a COPD cohort after 3 years

Skeletal muscle weakness is a distinct extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD), which is associated with a poor prognosis [1] and may represent a novel therapeutic target [2]. However, there are only sparse longitudinal data from prospective studies on skeletal muscle weakness and its relationship with disease progression in COPD. Previous studies have been cross-sectional in nature, and have failed to correlate data with baseline measures of exercise performance or systemic inflammation. The short physical performance battery may be a useful endpoint in assessing impact on skeletal muscle dysfunction http://ow.ly/xf8z30dOFMz

Comparison of analysis approaches for multi-level vascular imaging data.

Analysis methods for clinical trials with imaging endpoints are not well established. Here we will present and compare methods to analyse vascular inflammation as measured by 18F-FDG PET/CT imaging. These methods have been developed for the EVOLUTION trial: An Evaluation of Losmapimod in patients with Chronic Obstructive Pulmonary Disease (COPD) with systemic inflammation stratified using fibrinogen (EudraCT Number 2011-004936-75), a randomised, double-blind, placebo-controlled trial. Patients were randomised to 7.5 mg losmapimod or matching placebo tablets twice daily for four months. Vascular inflammation was assessed by 18F-FDG PET/CT scan at baseline and following treatment. Each scan covers up to six vessel segments per participant (left carotid, right carotid, and four aortic segments) and each segment is analysed in “slices”, generating a three-level data structure: participants, vessels, slices. For each slice, the mean and maximum inflammation level is recorded (as measured by the tissue-to-background ratio of the 18F-FDG tracer). Here, we consider three analysis approaches to assess the treatment effect. 1: Data are pooled by vessel and by patient, by considering the change in the mean (or max) inflammation. 2: The most inflamed vessel segment in each patient is identified at baseline and followed-up in each patient. 3: A multi-level model incorporates the complete data set and data structure. Through comparing these analysis approaches, we aim to identify a method which provides an accurate measure of the treatment effect, and a straightforward interpretation.

P67 Outcomes from surgical management of pleural infection: 12-year experience from a tertiary cardiothoracic centre

Introduction and Objectives Thoracic empyema affects >65 000 patients/year in the US and UK. Up to 50% require surgical drainage, and 15% die. We describe clinical features, microbiology, risk factors and surgical outcomes from referrals to a regional specialist cardiothoracic centre over 12 year. Methods Patients were identified by searching the hospital Clinical Data Repository for a diagnosis of ‘pyothorax’ from 1999 to 2010. A retrospective observational study was conducted using case note and database review. Results 406 distinct empyemas were identified. Patients were predominantly male (n=301, 74.1%), with median age of 53 years (IQR=37–69). Pyothorax predominantly developed secondary to community-acquired pneumonia, although 51 (12.6%) were hospital-acquired; 70 (17.2%) were receiving steroids or immunosuppressants, 35 (8.6%) had concurrent malignancy, 33 (8.1%) were diabetic and 14 (3.4%) patients were HIV-infected. Empyemas were right-sided in 233 (57.3%, p=0.03); four were bilateral. A causative organism was identified in 229 (56.4%) patients. Positive cultures were obtained from sputum in 59 (14.5%), pleural fluid in 174 (42.9%) and blood in 61 (15.0%) patients. Organisms identified included Streptococcus milleri (n=18, 4.4%), Streptococcus pneumoniae (n=39, 9.6%), other streptococci (n=10, 2.5%), Enterobacteraciae (n=12, 3.0%), anaerobes (n=32, 7.9%), methicillin-sensitive Staphylococcus aureus (n=36, 8.9%), methicillin-resistant Staphylococcus aureus (n=25, 6.2%), Enterococcus (n=14, 3.4%), Mycobacterium tuberculosis (n=36, 8.9%), non-tuberculous mycobacteria (n=1, 0.2%), other bacteria (n=25, 6.2%), and fungi (n=9, 2.2%); 34 (8.4%) cultures were polymicrobial. 277 (68.2%) patients were managed by open thoracotomy. 116 (28.6%) underwent video-assisted thoracoscopic surgery (VATS), of whom 17 (14.7%) were converted to open. Three (0.7%) required a Clagett window; 10 (2.5%) were managed with tube thoracostomy alone. A significant trend towards increased use of VATS over time was noted (p=0.0002). All-cause complication rate was 20.7%, and 28-day mortality was 5.7%. Low preoperative haemoglobin was predictive of mortality (p=0.04), but admission and peak C-reactive protein were not. Conclusions In this large series of empyemas from a tertiary referral centre, microbiological diagnosis was achieved in only half the patients. The identification of tuberculosis in 36 cases means routine screening for mycobacteria is necessary. Use of VATS has increased significantly, and mortality was lower than previously reported and associated with preoperative anaemia.