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Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease (CVD) and concomitant disease leads to reduced quality of life, increased hospitalisations and worse survival. Acute pulmonary exacerbations are an important contributor to COPD burden and are associated with increased cardiovascular (CV) events. Both COPD and CVD represent a significant global disease impact and understanding the relationship between the two could potentially reduce this burden. The association between CVD and COPD could be a consequence of (1) shared risk factors (environmental and/or genetic) (2) shared pathophysiological pathways (3) coassociation from a high prevalence of both diseases (4) adverse effects (including pulmonary exacerbations) of COPD contributing to CVD and (5) CVD medications potentially worsening COPD and vice versa. CV risk in COPD has traditionally been associated with increasing disease severity, but there are other relevant COPD subtype associations including radiological subtypes, those with frequent pulmonary exacerbations and novel disease clusters. While the prevalence of CVD is high in COPD populations, it may be underdiagnosed, and improved risk prediction, diagnosis and treatment optimisation could lead to improved outcomes. This state-of-the-art review will explore the incidence/prevalence, COPD subtype associations, shared pathophysiology and genetics, risk prediction, and treatment of CVD in COPD.

Thrombotic events that frequently occur in COVID-19 are predominantly venous thromboemboli (VTE) and are associated with increasing disease severity and worse clinical outcomes. Distinctive microvascular abnormalities in COVID-19 include endothelial inflammation, disruption of intercellular junctions and microthrombi formation. A distinct COVID-19-associated coagulopathy along with increased cytokines and activation of platelets, endothelium and complement occur in COVID-19, which is more frequent with worsening disease severity. This proinflammatory milieu may result in immunothrombosis, a host defence mechanism that can become dysregulated, leading to excess formation of immunologically mediated thrombi which predominantly affect the microvasculature. The haemostatic and immune systems are intricately linked, and multifactorial processes are likely to contribute to VTE and immunothrombosis in COVID-19. This state-of-the-art review will explore the pathobiological mechanisms of immunothrombosis and VTE in COVID-19 focusing on: COVID-19-associated coagulopathy, pathology, endothelial dysfunction and haemostasis, the immune system and thrombosis, genetic associations and additional thrombotic mechanisms. An understanding of the complex interplay between these processes is necessary for developing and assessing how new treatments affect VTE and immunothrombosis in COVID-19.

Introduction Recent studies have demonstrated that metabolomic profiling can identify metabolites and pathways which may have importance in the pathobiology of pulmonary arterial hypertension. However, the plasma metabolome in chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic vascular occlusions without pulmonary hypertension (CTED) has not been well characterised. Objective To profile circulating metabolites in CTEPH and CTED and assess metabolite gradients across the pulmonary circulation. Methods In the patient group, multisite blood sampling was performed at the time of right heart catheterisation. Blood samples were collected from the superior vena cava, pulmonary artery and radial artery. Venous blood samples from patients were compared to healthy controls to identify the metabolites present and to assess the difference between health and disease. Additionally, in the disease group, transpulmonary gradients were assessed by analysis of fold change in metabolite concentration between paired samples from the pulmonary artery and radial artery. Untargeted, semi-quantitative metabolic profiling of plasma was performed using the Metabolon DiscoveryHD4™ platform (Metabolon, NC, USA), utilising 2 ultra-high performance liquid chromatography methods, coupled with tandem mass spectrometry. Kruskal-Wallis analysis was used to compare metabolites between disease and control, with false discovery rate correction for multiple testing. Results The disease group included patients with a spectrum of chronic pulmonary vascular occlusions (Table 1). A total of 1375 metabolites were detected in 70 venous plasma samples analysed from 43 patients and 27 healthy controls. Amongst endogenous metabolites, 266 showed a significant difference between disease and control. In the disease group there were increases in acylcarnitine metabolites, long chain fatty acids, polyamines, glycogen metabolites and primary bile acid metabolites compared to healthy controls. There was a reduction in lysolipids, plasmalogens, aminosugars, branched chain amino acid metabolites, glutathione metabolites and a number of steroids (Table 1). Analysis of transpulmonary gradients revealed primarily a reduction in metabolite concentration across the pulmonary circulation. This included depletion of energy substrates, lysolipids, lysoplasmalogens and acylcholines. Conclusions This pilot study of circulating metabolites in patients with CTEPH, CTED and healthy controls reveals differences between health and disease in several biological pathways. Measurement of the transpulmonary gradient of metabolites indicated predominant clearance of circulating metabolites associated with energy metabolism and cell turnover. These findings require confirmation in a larger population.

Introduction Pre-test probability (PTP) scores are widely used to risk stratify pulmonary emboli (PE). A multitude of scores exist; however diagnosing PE remains challenging. We aim to identify whether patients were correctly PTP scored and what effect rescoring with the correct information has on predicting PE. We will identify the effect different PTP scores have on the likelihood of PE. Methods We conducted a retrospective study of inpatient computer tomography pulmonary angiograms (CTPA) within a large teaching hospital over a 1-year period. We recorded the originally submitted PTP score (modified Wells score), D-Dimer result and the CTPA outcome (PE-positive or negative cohorts). The accuracy of the PTP score was assessed from the original clinical information; rescoring when appropriate. We also rescored using alternative PTP systems (Geneva and simplified BTS). We analysed whether any factor or PTP scores could predict the presence of PE. Results 202 CTPAs were performed (70, 35% PE positive; 131, 65% PE negative). Baseline characteristics did not differ (age, gender, requesting team, inflammatory markers, mortality). PE was more likely with a higher D-dimer (682 vs. 853; p Table 1 ). Geneva score did not accurately predict PE (2.3 vs. 2.5; p=0.25); whereas the simplified BTS score did (0.9 vs. 1.3; p Conclusions Patients without a PE were significantly more likely to have an incorrect PTP score. Clinicians may have poor concordance with scoring to meet CTPA requesting criteria. The originally calculated PTP score was not predictive of PE. However, when scores were adjusted with the correct information, a higher PTP score was predictive of PE. Simple PTP scoring systems performed well compared with more complex versions. PTP scores are only effective at predicting PE when used accurately; this may not occur in practise.

Introduction Vitamin D binding protein (DBP) plays a role in macrophage activation and neutrophil chemotaxis, both functions being relevant to COPD and airway infection. We have shown previously that DBP is present in the COPD lung and relates directly to macrophage activation.1 Transcription of DBP is stimulated by inflammatory cytokines,2 which tend to be raised in exacerbations. DBP is also cleaved from its binding site on neutrophils by the action of neutrophil elastase.3 We reasoned that DBP would be elevated in the lung and systemic circulation during exacerbations of COPD compared to the stable state. Methods 20 patients with a known diagnosis of COPD were studied in the stable state and at the start of an exacerbation. Circulating CRP, elastase, AAT and DBP were measured at each time point, together with sol phase DBP, AAT and CRP, where sufficient sample was available (n=9). All clinical parameters were studied in the stable state only. Relationships between exacerbation and stable state were sought using pair-wise tests for each individual, whilst group relationships between DBP, CRP and elastase were sought using Spearman9s rank correlation. Results No significant differences between stable state and exacerbation were seen for circulating or sol phase DBP (both p>0.4). Circulating CRP and AAT were significantly higher in exacerbation (mean difference 3.95, p Conclusions The level of local and systemic inflammation, with consequent elastase release, during a COPD exacerbation is insufficient to alter DBP levels. As such it is unlikely that DBP-derived macrophage activation is important in their pathogenesis or resolution.