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Research question: Is withholding anticoagulation for patients with isolated or incidental subsegmental pulmonary embolism clinically and cost-effective compared with full anticoagulation for 3 months? Background: There has been an increase in the diagnosis of subsegmental pulmonary embolism since the advent of computed tomography pulmonary angiogram to investigate patients with suspected pulmonary embolism. Subsegmental pulmonary embolism is not often detectable with older nuclear medicine-based diagnostic imaging for ventilation/perfusion mismatch. The case fatality of pulmonary embolism has reduced as subsegmental pulmonary embolism diagnoses from computed tomography pulmonary angiogram have increased. There is growing equipoise about the optimal treatment for patients with subsegmental pulmonary embolism, given that full anticoagulation has significant risks of bleeding and subsegmental pulmonary embolism was not often diagnosed previously with ventilation/perfusion scanning and therefore most likely left predominantly untreated prior to the introduction of computed tomography pulmonary angiogram scanning. Objectives: Determine whether withholding anticoagulation for isolated or incidental subsegmental pulmonary embolism (i.e. subsegmental pulmonary embolism with no coexisting deep-vein thrombosis) reduces the harms of recurrent thromboembolism and major bleeding compared with 3 months of full anticoagulation at 3, 6 and 12 months. Determine the rate of complications of anticoagulation therapy (predominantly bleeding) in patients with isolated subsegmental pulmonary embolism. Determine whether not treating isolated subsegmental pulmonary embolism is acceptable to clinicians and patients. Determine the reclassification rate of subsegmental pulmonary embolism diagnoses made by general reporting radiologists when reviewed by specialist respiratory radiologists and develop a set of rules to improve general radiologists' diagnoses of subsegmental pulmonary embolism. Assess cost-effectiveness of not treating patients with isolated subsegmental pulmonary embolism with anticoagulation, taking a health service perspective. Methods: Prospective individually randomised open controlled trial with blinded end-point committee assessment for outcomes, powered for non-inferiority for recurrent venous thromboembolism and for superiority for bleeding events. An internal pilot phase is included for feasibility and acceptability of no anticoagulation. We planned to recruit 1466 patients from at least 50 acute hospital sites. Allowing for a dropout rate of 15%, this would have given us 90% power to detect a reduction in major and clinically relevant non-major bleeding from 7.3% in the anticoagulation arm to 3% in the intervention arm. We were powered to determine that a strategy of no anticoagulation was non-inferior to anticoagulation with an upper margin of a 2.3% increase in recurrent venous thromboembolism from an expected rate of 2% in those who receive full anticoagulation. We also planned to undertake a study comparing acute reporting radiologists' diagnoses of subsegmental pulmonary embolism from all computed tomography pulmonary angiograms with specialist respiratory radiologists. This would have allowed us to determine safety in the pilot study (i.e. patients with pulmonary embolism that was in fact larger than subsegmental would have been identified) and develop guidance for subsegmental pulmonary embolism diagnosis for general radiologists. Patients with lived experience of thrombosis contributed to all aspects of the trial design and were part of the Trial Management Group. Progress of study: The STOPAPE trial was stopped prematurely due to a low recruitment rate in the wake of the COVID pandemic and prioritisation of recovery of the National Institute for Health and Care Research research portfolio. There are no outcome data available for this trial. Separate NIHR Library publications will detail the linked qualitative study examining the views of patients and clinicians around withholding anticoagulation for isolated subsegmental pulmonary embolism as well as presenting all collected data of recruited patients. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128073. A plain language summary of this research article is available on the NIHR Journals Library Website https://doi.org/10.3310/HRCW7937.
Pulmonary embolism is a potentially serious condition, whereby blood clots cause a blockage of the blood supply to the lungs. The diagnosis of pulmonary embolism is made with a scan of the lungs, by showing areas where blood cannot get through the vessels easily due to blood clots. The treatment of pulmonary embolism includes anticoagulant medication ('blood thinners') that is taken over months and includes warfarin, an injectable form of heparin and directly acting oral anticoagulants. These medications work by preventing new clots from forming while the body's own mechanisms break down the clots. As the scanning technology for pulmonary embolism has become more sensitive, smaller clots are being diagnosed. However, small pulmonary embolisms may not cause any symptoms and may be found incidentally on scans performed for other reasons. In these situations, it is unclear whether treatment is required for the pulmonary embolism. These clots in smaller blood vessels away from the centre of the lungs (subsegmental pulmonary embolism) may be removed by the body's own mechanisms for dissolving clots without needing medications. Anticoagulant medication can cause side effects in some patients such as bleeding. For the anticoagulant medication to be appropriate in these smaller pulmonary embolisms, the benefits from preventing future blood clots (pulmonary embolism and deep-vein thrombosis) would need to outweigh the potential risks from the medication side effects. The STOPAPE study aimed to answer this question by testing whether we can safely withhold anticoagulation from patients diagnosed with subsegmental pulmonary embolism. Although we aimed to enrol 1466 patients in the trial with half getting usual care of anticoagulation and half getting no anticoagulation, we could not recruit patients quickly enough to the trial and, as a result, we could not continue with the STOPAPE study. This study protocol is published to help future research teams that wish to answer this research question.
ABSTRACT
Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.
Subject(s)
Genome-Wide Association Study , Hypertension, Pulmonary , Pulmonary Embolism , Humans , Pulmonary Embolism/genetics , Pulmonary Embolism/complications , Hypertension, Pulmonary/genetics , Male , Female , Middle Aged , Chronic Disease , Genomics , Genetic Predisposition to Disease , Adult , Case-Control Studies , Aged , Venous Thrombosis/geneticsABSTRACT
Aim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD. Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE. Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001). Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.
Subject(s)
Cardiovascular Diseases , Heart Failure , Myocardial Infarction , Pulmonary Disease, Chronic Obstructive , Stroke , alpha 1-Antitrypsin Deficiency , Humans , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Prevalence , Quality of Life , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/epidemiology , Heart Failure/diagnosis , Heart Failure/epidemiology , Myocardial Infarction/diagnosis , Myocardial Infarction/epidemiology , Stroke/diagnosis , Stroke/epidemiologyABSTRACT
Lung disease progression in alpha-1 antitrypsin deficiency (AATD) is heterogenous and manifests in different ways. Blood biomarkers are an attractive method of monitoring diseases as they are easy to obtain and repeatable. In non-AATD COPD, blood biomarker panels have predicted disease severity, progression, and mortality. We measured a panel of seven serum biomarkers in 200 AATD patients and compared levels between those with COPD and those without. We assessed whether biomarkers were associated with baseline lung function parameters (FEV1 and TLco) or absolute change in these parameters. In total, 111 patients with a severely deficient genotype of AATD (PiZZ) and COPD were included in the analyses. Pearson's correlation coefficient was measured for biomarker correlations and models were compared using ANOVA. CRP and CCL18 were significantly higher in the serum of AATD COPD versus AATD with no COPD. Biomarkers were not predictive of cross-sectional lung function measurements, however, CC16 was significantly associated with an absolute change in TLco (p = 0.018). An addition of biomarkers to the predictive model for TLco added significant value over covariates alone (R2 0.13 vs. 0.02, p = 0.028). Our findings suggest that CC16 is predictive of emphysema progression in AATD COPD. Proteomics data may reveal alternative candidate biomarkers and further work should include the use of longitudinal biomarker measurements.
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Purpose: Alpha 1 antitrypsin deficiency (AATD) is a genetic risk factor for chronic obstructive pulmonary disease (COPD). Whilst testing for the condition is relatively simple, there is a disconnect in published literature between genetic epidemiology and numbers of patients known to specialists. This makes planning services for patients difficult. We aimed to estimate the number of patients likely to have lung disease eligible for specific AATD therapy within the UK. Patients and Methods: The THIN database was used to determine the prevalence of AATD and symptomatic COPD. This, and published rates of AATD were used to extrapolate THIN data to the population size of the UK to give an indicative population size for symptomatic AATD patients who have lung disease. The Birmingham AATD registry was used to describe age at diagnosis, rate of lung disease and symptomatic lung disease for patients with PiZZ (or equivalent) AATD, together with the time from symptom onset to diagnosis, in order to aid interpretation of the THIN data and improve modeling. Results: THIN data showed COPD prevalence of 3%, and AATD prevalence of 0.005-0.2%, depending on how stringently AATD diagnostic codes were applied. The majority of Birmingham AATD patients were diagnosed between the ages 46-55, whilst patients recorded in THIN tended to be older. The rate of COPD was similar in the THIN and Birmingham patients diagnosed with AATD. Modelling to the size of the UK demonstrated a likely symptomatic AATD population of between 3016 and 9866 people. Conclusion: AATD is likely to be under-diagnosed in the UK. Based on projected patient numbers an expansion to specialist services is desirable, in particular if specific therapy for AATD such as augmentation were to be introduced to the healthcare system.
Subject(s)
Pulmonary Disease, Chronic Obstructive , alpha 1-Antitrypsin Deficiency , Humans , Middle Aged , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/therapy , Prevalence , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/epidemiology , alpha 1-Antitrypsin Deficiency/genetics , Risk Factors , United Kingdom/epidemiologyABSTRACT
INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. METHODS: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. RESULTS: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. CONCLUSIONS: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).
Subject(s)
Angiopoietin-2 , C-Reactive Protein , Hypertension, Pulmonary , Humans , Biomarkers , Endarterectomy/adverse effects , Hemodynamics , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/metabolism , Vascular Endothelial Growth Factor AABSTRACT
BACKGROUND: The incidence of subsegmental pulmonary embolism (SSPE) has increased with improvements in imaging technology. There is clinical equipoise for SSPE treatment, with conflicting evidence of improved mortality or reduced venous thromboembolism recurrence with anticoagulation. SSPE studies have significant heterogeneity and often lack adequately matched disease comparator groups. OBJECTIVES: To determine the prevalence, management, and outcomes of SSPE and compare them to patients with main, lobar, segmental, and no pulmonary embolism (PE). PATIENTS/METHODS: All adult patients undergoing CT pulmonary angiography (CTPA) between 2013 and 2019, at 3 UK hospitals were included in the study. CTPA reports were text mined for language relating to PE, and then further manually screened for the presence and anatomical location of PE. Patient groups were propensity matched by age, sex, and year of CTPA prior to analysis. 3-month outcomes of major bleeding, VTE recurrence, and death were recorded. RESULTS: 79 (3.8%) SSPEs were identified from 2,055 diagnoses of PE, and 14,300 CTPA reports. 44 (56%) of SSPEs were single artery emboli, 25 (32%) were multiple unilateral emboli, and 10 (13%) were multiple bilateral emboli. Mortality, VTE recurrence and major bleeding were similar at 3 months across all groups. 87.3% of SSPE imaging reports had an additional radiological diagnosis, with pleural effusion (30%), consolidation (19%), and cardiomegaly (19%) being the most common. CONCLUSION: The prevalence of SSPE was 3.8% of all PEs and there were a substantial number of additional radiological findings in the SSPE group that may have accounted for their symptoms.
Subject(s)
Pulmonary Embolism , Subacute Sclerosing Panencephalitis , Venous Thromboembolism , Adult , Humans , Venous Thromboembolism/diagnostic imaging , Venous Thromboembolism/drug therapy , Venous Thromboembolism/epidemiology , Prevalence , Subacute Sclerosing Panencephalitis/drug therapy , Anticoagulants/therapeutic use , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/drug therapy , Hemorrhage/drug therapyABSTRACT
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.
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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.
Subject(s)
COVID-19/complications , Cytokines/blood , Pandemics , SARS-CoV-2 , Venous Thromboembolism/immunology , COVID-19/blood , COVID-19/epidemiology , Global Health , Humans , Incidence , Venous Thromboembolism/blood , Venous Thromboembolism/etiologyABSTRACT
INTRODUCTION: The purpose of the quality standards document is to provide healthcare professionals, commissioners, service providers and patients with a guide to standards of care that should be met for outpatient management of pulmonary embolism in the UK, together with measurable markers of good practice. Quality statements are based on the British Thoracic Society (BTS) Guideline for the Initial Outpatient Management of Pulmonary Embolism. METHODS: Development of BTS Quality Standards follows the BTS process of quality standard production based on the National Institute for Health and Care Excellence process manual for the development of quality standards. RESULTS: Six quality statements have been developed, each describing a standard of care for the outpatient management of pulmonary embolism in the UK, together with measurable markers of good practice. DISCUSSION: BTS Quality Standards for Outpatient Management of Pulmonary Embolism form a key part of the range of supporting materials that the society produces to assist in the dissemination and implementation of a guideline's recommendations.
Subject(s)
Practice Guidelines as Topic , Pulmonary Embolism/therapy , Disease Management , Humans , Outpatients , Quality Assurance, Health Care , Societies, Medical , United KingdomABSTRACT
BACKGROUND: Pulmonary endarterectomy (PEA) is the recommended treatment for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) score is an internationally validated patient-reported outcome (PRO) measure for CTEPH. It assesses three domains: activity, quality of life (QoL) and symptoms. We assessed PROs in patients with CTEPH undergoing PEA. METHODS: This retrospective observational study of consecutive CTEPH patients undergoing PEA at the UK national PEA centre between 2006 and 2017 assessed change in CAMPHOR score from baseline (pre-PEA) until up to 5â years post-PEA. CAMPHOR scores were compared between 1) those with and without clinically significant residual pulmonary hypertension and 2) those undergoing PEA and propensity-matched CTEPH patients who were not operated on. The minimally clinically important difference (MCID) was calculated using an anchor-based method. RESULTS: Out of 1324 CTEPH patients who underwent PEA, 1053 (80%) had a CAMPHOR score recorded pre-PEA, 934 (71%) had a score recorded within a year of PEA and 784 (60%) had both. There were significant improvements between pre- and post-PEA in all three CAMPHOR domains (median±interquartile range activity -5±7, QoL -4±8, symptoms -7±8; all p<0.0001). Improvements in CAMPHOR score were greater and more sustained in those without clinically significant residual pulmonary hypertension. CTEPH patients undergoing PEA had better CAMPHOR scores than those not operated on. The MCID in CAMPHOR score was -3±5 for activity, -4±7 for QoL and -6±7 for symptoms. CONCLUSIONS: PROs are markedly improved by PEA in patients with CTEPH, more so in those without clinically significant residual pulmonary hypertension.
Subject(s)
Hypertension, Pulmonary , Pulmonary Embolism , Chronic Disease , Endarterectomy , Humans , Hypertension, Pulmonary/surgery , Patient Reported Outcome Measures , Pulmonary Artery/surgery , Pulmonary Embolism/complications , Pulmonary Embolism/surgery , Quality of Life , Treatment OutcomeABSTRACT
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, few data exist on the safety and efficacy of vitamin K antagonists (VKAs) in CTEPH and none for direct oral anticoagulants (DOACs). OBJECTIVES: To evaluate outcomes and complication rates in CTEPH following pulmonary endarterectomy (PEA) for individuals receiving VKAs or DOACs. METHODS: Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Postoperative outcomes, recurrent venous thromboembolism (VTE), and bleeding events were obtained from patient medical records. RESULTS: Seven hundred ninety-four individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (standard deviation: 702) days. Significant improvements in hemodynamics and functional status were observed in both groups following PEA (P < .001). Major bleeding events were equivalent (P = 1) in those treated with VKAs (0.67%/person-year) and DOACs (0.68%/person-year). The VTE recurrence was proportionately higher (P = .008) with DOACs (4.62%/person-year) than VKAs (0.76%/person-year), although survival did not differ. CONCLUSIONS: Post-PEA functional and hemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates significantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH.
Subject(s)
Hypertension, Pulmonary , Venous Thromboembolism , Administration, Oral , Anticoagulants/adverse effects , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/drug therapy , Retrospective Studies , Venous Thromboembolism/complications , Venous Thromboembolism/diagnosis , Venous Thromboembolism/drug therapy , Vitamin K/therapeutic useABSTRACT
While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5â µm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a prioriHigher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3â µg·m-3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3â µg·m-3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000â m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.
Subject(s)
Air Pollution/adverse effects , Pulmonary Arterial Hypertension/epidemiology , Traffic-Related Pollution/adverse effects , Adult , Aged , Air Pollution/analysis , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Nitrogen Dioxide/adverse effects , Nitrogen Dioxide/analysis , Particulate Matter/adverse effects , Particulate Matter/analysis , Prospective Studies , Pulmonary Arterial Hypertension/etiology , Traffic-Related Pollution/analysis , United Kingdom/epidemiologyABSTRACT
Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted ß -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (ßâ¯+75.5%, 95% CI 44.8-113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for â¼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.
Subject(s)
ADAMTS13 Protein/genetics , Hypertension, Pulmonary/physiopathology , Pulmonary Embolism/physiopathology , von Willebrand Factor/analysis , Adult , Aged , Aged, 80 and over , Biomarkers , Case-Control Studies , Chronic Disease , Endarterectomy , Female , Humans , Hypertension, Pulmonary/genetics , Linear Models , Male , Middle Aged , Multivariate Analysis , Pulmonary Embolism/genetics , Thrombosis/genetics , Thrombosis/physiopathologySubject(s)
Biomarkers/blood , Familial Primary Pulmonary Hypertension/enzymology , Leukocyte Elastase/antagonists & inhibitors , Pulmonary Artery/enzymology , Thromboembolism/enzymology , alpha 1-Antitrypsin/blood , Case-Control Studies , Chronic Disease , Familial Primary Pulmonary Hypertension/blood , Familial Primary Pulmonary Hypertension/diagnosis , Female , Humans , Male , Middle Aged , Thromboembolism/blood , Thromboembolism/diagnosisABSTRACT
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
Subject(s)
Adenosine Triphosphatases/chemistry , Aquaporin 1/chemistry , Familial Primary Pulmonary Hypertension/genetics , Growth Differentiation Factors/chemistry , Membrane Transport Proteins/chemistry , Mutation , SOXF Transcription Factors/chemistry , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Adult , Aquaporin 1/genetics , Aquaporin 1/metabolism , Base Sequence , Bone Morphogenetic Protein Receptors, Type II/genetics , Bone Morphogenetic Protein Receptors, Type II/metabolism , Case-Control Studies , Familial Primary Pulmonary Hypertension/diagnosis , Familial Primary Pulmonary Hypertension/metabolism , Familial Primary Pulmonary Hypertension/pathology , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Growth Differentiation Factor 2 , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , HEK293 Cells , Humans , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Models, Molecular , Prognosis , SOXF Transcription Factors/genetics , SOXF Transcription Factors/metabolism , Signal Transduction , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Whole Genome SequencingSubject(s)
Age Factors , Endarterectomy , Hypertension, Pulmonary/surgery , Patient Selection , Thromboembolism/surgery , Adult , Aged , Aged, 80 and over , Chronic Disease , Female , Humans , Hypertension, Pulmonary/etiology , Male , Middle Aged , Pulmonary Artery/surgery , Thromboembolism/complications , Treatment OutcomeABSTRACT
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.