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18F-GP1 is a novel radiotracer that binds to the platelet glycoprotein IIb/IIIa receptor and can image in vivo venous and arterial thrombi including deep vein thrombosis and pulmonary thromboemboli (1-3). We performed 18F-GP1 positron emission tomography-computed tomography (PET-CT) in 6 patients recovering from coronavirus disease (COVID)-19 with concomitant pulmonary embolism (median age 56 [interquartile range 53-60] years, 1 female, 5 requiring supplemental oxygen, no intensive care admissions) and undertook 18F-GP1 autoradiography of post-mortem lung tissue in 3 patients who had died from COVID-19 (4).All patients demonstrated increased pulmonary 18F-GP1 uptake at a median of 69 (interquartile range 56-98) days after index presentation despite ongoing therapeutic oral anticoagulation. Focal intravascular uptake in persistent pulmonary embolism (A) was seen, as described previously (5). However, we also noted parenchymal uptake in regions of consolidation (B), as well as systemic uptake in an occluded saphenous vein coronary artery bypass graft and left ventricular thrombus which was subsequently confirmed on echocardiography (C). 18F-GP1 autoradiography also demonstrated focal and specific uptake co-localising to intravascular thrombus in patients with confirmed diffuse alveolar damage (D).Protracted systemic and pulmonary thrombosis may be a feature of COVID-19 that can persist despite systemic therapeutic anticoagulation. 18F-GP1 is able to detect pulmonary and systemic arterial thrombosis and has potential applications across a broad range of pathologies.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk. Objectives: Determine whether AECOPD events are associated with increased risk of subsequent CVD. Methods: We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD. Measurements and Main Results: Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7–5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6–14.9). Conclusions: In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676).

Cardiovascular disease is a common comorbidity in patients with chronic obstructive pulmonary disease. Although β-blockers can be used safely in patients with chronic obstructive pulmonary disease, concerns remain regarding safety and efficacy interactions in patients using concomitant inhaled long-acting β-agonists.To compare the differential effects of long-acting β-agonist or inhaled corticosteroid use on clinical outcomes in patients with heightened cardiovascular risk treated and not treated with β-blockers.We examined data from 16,485 participants in the SUMMIT study (Study to Understand Mortality and Morbidity in COPD) who were randomized to once-daily inhaled fluticasone furoate, vilanterol, fluticasone furoate/vilanterol combination, or placebo and examined the associations between treatment allocation and lung function, chronic obstructive pulmonary disease exacerbations, cardiovascular events, and all-cause mortality, stratified by baseline β-blocker therapy.Baseline β-blocker therapy was used by 31% (n = 5,159) of SUMMIT participants. There was no evidence of an interaction between baseline β-blocker therapy and the association between inhaled treatments and forced expiratory volume in 1 second at 3 months (P = 0.27), 6 months (P = 0.14), or 12 months (P = 0.33). The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the vilanterol-alone group were 58 ml (95% confidence interval, 38-78) in those receiving baseline β-blocker therapy and 51 ml (95% confidence interval, 38-65) in those not receiving baseline β-blocker therapy. The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the combination fluticasone furoate/vilanterol group were 85 ml (95% confidence interval, 65-105) in those receiving baseline β-blocker therapy and 68 ml (95% confidence interval, 54-82) in those not receiving baseline β-blocker therapy. Overall, there was no evidence of interaction by randomized treatment, including vilanterol alone or in combination with fluticasone furoate, for chronic obstructive pulmonary disease exacerbations (P = 0.18), cardiovascular composite events (P = 0.33), and all-cause mortality (P = 0.41).There is no evidence to suggest that baseline β-blocker therapy reduces the respiratory benefits or increases the cardiovascular risk of inhaled long-acting β-agonists in patients with chronic obstructive pulmonary disease and heightened cardiovascular risk. Clinical trial registered with www.clinicaltrials.gov (NCT01313676).

Rationale: Many patients with chronic obstructive pulmonary disease (COPD) have an accelerated loss of lung function. It is unclear whether drug treatment can modify this in patients with moderately severe disease.Objectives: In a prespecified analysis of the key secondary outcome in SUMMIT (Study to Understand Mortality and Morbidity), we investigated whether the inhaled corticosteroid fluticasone furoate (FF; 100 μg), the long-acting β-agonist vilanterol (VI; 25 μg), or their combination (FF/VI) modified the rate of decline in FEV1 compared with placebo. We also investigated how baseline covariates affected this decline.Methods: Spirometry was measured every 12 weeks in this event-driven, randomized, placebo-controlled trial of 16,485 patients with moderate COPD and heightened cardiovascular risk. An average of seven spirometric assessments per subject among the 15,457 patients with at least one on-treatment measurement were used in the analysis of rate of FEV1 decline. All statistical comparisons are c...

Inhaled corticosteroids have been shown to decrease exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Their effects in patients with milder airflow obstruction remain unclear.This was an analysis of exacerbations in the SUMMIT (Study to Understand Mortality and Morbidity) study.In a double-blind, randomized controlled trial, once-daily inhaled placebo, fluticasone furoate (FF; 100 μg), vilanterol (VI; 25 μg), or the combination of FF/VI was administered. The primary outcome was all-cause mortality. Exacerbations of COPD were an additional predefined endpoint. A total of 1,368 centers in 43 countries and 16,485 patients with moderate COPD and heightened cardiovascular risk were included in the study.Compared with placebo, FF/VI reduced the rate of moderate and/or severe exacerbations by 29% (95% confidence interval [CI], 22-35; P 0.001) and the rate of hospitalized exacerbations by 27% (95% CI, 13-39; P 0.001). These relative effects were similar regardless of whether subjects had a history of exacerbation in the year before the study or an FEVPatients with moderate chronic airflow obstruction experienced a reduction in exacerbations with FF/VI compared with placebo, irrespective of a history of exacerbations or baseline FEV

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Exposure to air pollution containing diesel exhaust particulate (DEP) is linked to adverse cardiovascular events. This study tested the hypothesis that DEP not only causes direct endothelial cell injury, but also induces indirect endothelial cell activation via the release of soluble proinflammatory cytokines from macrophages. Human umbilical vein endothelial cells (HUVECs) and monocyte-derived macrophages (MDMs) were incubated with DEP (1-100 μg/ml; 24 h). Supernatants were analyzed for monocyte chemotactic protein (MCP)-1, IL6, IL8, and TNF-α. Indirect actions of DEP were investigated by incubating HUVECs with conditioned media from DEP-exposed MDMs in the presence and absence of the TNF-α inhibitor, etanercept. A modified Boyden chamber assay was used to determine whether HUVECs treated in this manner induced monocyte chemotaxis. Direct incubation with DEP induced a modest increase in MCP-1 concentration, but had no effect on IL-6 or IL-8 release from HUVECs. In contrast, direct treatment of MDMs with DEP had no effect on MCP-1, but elevated IL-8 and TNF-α concentrations. Incubation with conditioned media from DEP-exposed MDMs caused a dramatic amplification in MCP-1 and IL-6, but not IL-8, release from HUVECs. The potentiation of HUVEC activation was suppressed by TNF-α inhibition. MCP-1- and IL-6-containing HUVEC supernatants caused increased monocyte chemotaxis that was not inhibited by anti-MCP-1 antibodies. We conclude that DEP has only modest direct endothelial effects. In contrast, proinflammatory cytokines released from particle-laden MDMs appear to exacerbate endothelial activation after DEP exposure.

Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), which may in part be attributable to abnormalities of systemic vascular function. It is unclear whether such associations relate to the presence of COPD or prior smoking habit.To undertake a comprehensive assessment of vascular function in patients with COPD and healthy control subjects matched for smoking history.Eighteen men with COPD were compared with 17 healthy male control subjects matched for age and lifetime cigarette smoke exposure. Participants were free from clinically evident cardiovascular disease.Pulse wave velocity and pulse wave analysis were measured via applanation tonometry at carotid, radial, and femoral arteries. Blood flow was measured in both forearms using venous occlusion plethysmography during intrabrachial infusion of endothelium-dependent vasodilators (bradykinin, 100-1,000 pmol/min; acetylcholine, 5-20 microg/min) and endothelium-independent vasodilators (sodium nitroprusside, 2-8 microg/min; verapamil, 10-100 microg/min). Tissue plasminogen activator (t-PA) was measured in venous plasma before and during bradykinin infusions. Patients with COPD have greater arterial stiffness (pulse wave velocity, 11 +/- 2 vs. 9 +/- 2 m/s; P = 0.003; augmentation index, 27 +/- 10 vs. 21 +/- 6%; P = 0.028), but there were no differences in endothelium-dependent and -independent vasomotor function or bradykinin-induced endothelial t-PA release (P0.05 for all).COPD is associated with increased arterial stiffness independent of cigarette smoke exposure. However, this abnormality is not explained by systemic endothelial dysfunction. Increased arterial stiffness may represent the mechanistic link between COPD and the increased risk for cardiovascular disease associated with this condition.

Rationale: More patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes than of respiratory causes, and patients with COPD have increased morbidity and mortality from stroke and coronary heart disease. Arterial stiffness independently predicts cardiovascular risk, is associated with atheromatous plaque burden, and is increased in patients with COPD compared with control subjects matched for cardiovascular risk factors. Elastin fragmentation and changes in collagen are found in the connective tissue of both emphysematous lungs and stiff arteries, but it is not known whether the severity of arterial stiffness in patients with COPD is associated with the severity of emphysema. Objectives: To identify whether the extent of arterial stiffness is associated with emphysema severity. Methods: We performed a cross-sectional study in 157 patients with COPD. Measurements and Main Results: We measured pulse wave velocity (a validated measure of arterial stiffness), blood pressure, smoking pack-years, glucose, cholesterol, and C-reactive protein in 157 patients with COPD. We assessed emphysema using quantitative computed tomography scanning in a subgroup of 73 patients. We found that emphysema severity was associated with arterial stiffness (r = 0.471, P < 0.001). The association was independent of smoking, age, sex, FEV1% predicted, highly sensitive C-reactive protein and glucose concentrations, cholesterol–high-density lipoprotein ratio, and pulse oximetry oxygen saturations. Conclusions: Emphysema severity is associated with arterial stiffness in patients with COPD. Similar pathophysiological processes may be involved in both lung and arterial tissue and further studies are now required to identify the mechanism underlying this newly described association.

Rationale: Exposure to combustion-derived air pollution is associated with an early (1–2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans.Objectives: To investigate the vascular and systemic effects of diesel exhaust in humans 24 hours after inhalation.Methods: Fifteen healthy men were exposed to diesel exhaust (particulate concentration, 300 μg/m3) or filtered air for 1 hour in a double-blind, randomized, crossover study. Twenty-four hours after exposure, bilateral forearm blood flow, and inflammatory and fibrinolytic markers were measured before and during unilateral intrabrachial bradykinin (100–1,000 pmol/min), acetylcholine (5–20 μg/min), sodium nitroprusside (2–8 μg/min), and verapamil (10–100 μg/min) infusions.Measurements and Main Results: Resting forearm blood flow, blood pressure, and basal fibrinolytic markers were si...

RATIONALE: Increased exposure to particulate air pollution (PM(10)) is a risk factor for death and hospitalization with cardiovascular disease. It has been suggested that the nanoparticulate component of PM(10) is capable of translocating into the circulation with the potential for direct effects on the vasculature. OBJECTIVE: The study's aim was to determine the extent to which inhaled technetium-99m ((99m)Tc)-labeled carbon nanoparticles (Technegas) were able to access the systemic circulation. METHODS AND MAIN RESULTS: Ten healthy volunteers inhaled Technegas and blood samples were taken sequentially over the following 6 h. Technegas particles were 4-20 nm in diameter and aggregated to a median particle diameter of approximately 100 nm. Radioactivity was immediately detected in blood, with levels increasing over 60 min. Thin-layer chromatography of whole blood identified a species that moved with the solvent front, corresponding to unbound (99m)Tc-pertechnetate, which was excreted in urine. There was no evidence of particle-bound (99m)Tc at the origin. gamma Camera images demonstrated high levels of Technegas retention (95.6 +/- 1.7% at 6 h) in the lungs, with no accumulation of radioactivity detected over the liver or spleen. CONCLUSIONS: The majority of (99m)Tc-labeled carbon nanoparticles remain within the lung up to 6 h after inhalation. In contrast to previous published studies, thin-layer chromatography did not support the hypothesis that inhaled Technegas carbon nanoparticles pass directly from the lungs into the systemic circulation.