Publications
395 results found
Garfield B, McFadyen C, Briar C, et al., 2021, Potential for personalised application of inhaled nitric oxide in COVID-19 pneumonia, British Journal of Anaesthesia, Vol: 126, Pages: E72-E75, ISSN: 0007-0912
Lewis RA, Armstrong I, Bergbaum C, et al., 2021, EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study, EUROPEAN RESPIRATORY JOURNAL, Vol: 57, ISSN: 0903-1936
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- Citations: 21
Mahomed AS, Burke-Gaffney A, Ghazaly MM, et al., 2021, SOX17-SILENCED HUMAN PULMONARY ARTERY ENDOTHELIAL CELLS MARKEDLY INDUCE CXCL10 AND CXCL11 EXPRESSION, Publisher: BMJ PUBLISHING GROUP, Pages: A55-A55, ISSN: 0040-6376
Schwiening M, Pandya D, Swietlik EM, et al., 2021, PATTERNS OF CYTOKINES AND GROWTH FACTORS IN PULMONARY ARTERIAL HYPERTENSION PATIENTS WITH BMPR2 MUTATIONS AND PAH PATIENTS WITHOUT DRIVING MUTATIONS AND THEIR INFLUENCE ON SURVIVAL, Publisher: BMJ PUBLISHING GROUP, Pages: A55-A56, ISSN: 0040-6376
Panselinas I, Toe QK, Clementson K, et al., 2021, HEPCIDIN AND INTERLEUKIN-6 DOWNREGULATE BMPR2 AND DYSREGULATE BMPR2 DOWNSTREAM PATHWAYS; IMPLICATIONS FOR PULMONARY ARTERY HYPERTENSION, Publisher: BMJ PUBLISHING GROUP, Pages: A56-A56, ISSN: 0040-6376
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- Citations: 1
Swietlik EM, Greene D, Zhu N, et al., 2021, Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension., Circulation: Genomic and Precision Medicine, Vol: 14, Pages: 57-70, ISSN: 2574-8300
Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Trenk L, Lammers AE, Radke R, et al., 2021, Neurological complications in aortic coarctation: Results of a Nationwide analysis based on 11,907 patients, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 322, Pages: 114-120, ISSN: 0167-5273
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- Citations: 2
Piccari L, Bernardo RJ, Rodríguez-Chiaradía D, et al., 2021, Pulmonary vasodilator treatment in pulmonary hypertension due to left heart or lung disease: time for a high-definition picture?, Pulm Circ, Vol: 11, ISSN: 2045-8932
Price LC, Garfield B, Bleakley C, et al., 2020, Rescue therapy with thrombolysis in patients with severe COVID-19 ARDS, Pulmonary Circulation, Vol: 10, Pages: 1-5, ISSN: 2045-8940
Acute respiratory distress syndrome (ARDS) in patients with Coronavirus disease 19 (COVID-19) is associated with an unusually high incidence of pulmonary embolism (PE) and microthrombotic disease, with evidence for reduced fibrinolysis. We describes even patients requiring invasive ventilation for COVID-19 ARDS with pulmonary thromboembolic disease, pulmonary hypertension ± severe right ventricular (RV) dysfunction on echocardiography, who were treated with alteplaseas fibrinolytic therapy. All patients were non-smokers, 6 (86%) were male and median age was 56.7 (50-64) years. They had failed approaches including therapeutic anticoagulation, prone ventilation (n=4), inhaled nitric oxide (n=5) and nebulised epoprostenol (n=2). The median duration of mechanical ventilation prior to thrombolysis was 7 (5-11) days.Systemic alteplase was administered to 6 patients (50mg or 90mg bolus over 120 minutes) at 16 (10-22) days after symptom onset. All received therapeutic heparin pre-and post-thrombolysis, without intracranial haemorrhageor other major bleeding. Alteplase improvedPaO2/FiO2(PF) ratio (from 97.0 (86.3-118.6) to 135.6 (100.7-171.4), p=0.03) and ventilatory ratio (from 2.76 (2.09 -3.49) to 2.36 (1.82 –3.05), p=0.011) at twenty-four hours.Echocardiographic parameters at 2 (1-3) days (n=6) showed RVSP was 63 (50.3-75) then 57 (49-66) mmHgpost-thrombolysis (p=0.26), TAPSE was unchanged (from 18.3 (11.9-24.5) to 20.5 (15.4-24.2) mm, p=0.56)and RV fractional area change (from 15.4 (11.1-35.6) to 31.2 (16.4-33.1) %, p=0.09). At7 (1-13) days after thrombolysis,using DECT imaging(n=3),average relative peripheral lung enhancement increased from 12.6 to 21.6% (p=0.06).Conclusion:Thrombolysis improved PF ratio and ventilatory ratio at 24h as rescue therapy in patients with RV dysfunction due to COVID-19 ARDS despite maximum therapy
Castro-Verdes M, Gkouma A, Wort J, et al., 2020, Corona Virus Disease 2019 in situ arterial and venous thrombosis in critically ill patients: a case series, European Heart Journal: Case Reports, Vol: 4, Pages: 1-7, ISSN: 2514-2119
BackgroundCorona Virus Disease 2019 (COVID-19) pneumonitis associated with severe respiratory failure carries a high mortality. Coagulopathy has emerged as a significant contributor to thrombotic complications.Case summaryWe describe two cases of severe COVID-19 pneumonitis refractory to conventional mechanical ventilation and proning position, transferred to our specialist centre for cardiorespiratory failure. Cross-sectional imaging demonstrated concurrent venous and aortic thrombosis with end-organ ischaemic changes. One patient received thrombolysis with a partial response. This could not be offered to the other patient due to a recent haemorrhagic event. Both patients died of multi-organ failure in the hospital.DiscussionConcurrent aortic and venous thromboses are rare. This finding in COVID-19 cases, who were both critically ill patients, likely reflects the strongly thrombogenic nature of this illness which ultimately contributed to poor outcomes. The absence of deep vein thrombosis or a potential systemic source of embolism suggests in situ thrombosis. Further, the management of anticoagulation and thrombolysis is challenging in patients where an attendant bleeding risk exists.
Wort SJ, Arachchillage DJ, McCabe C, et al., 2020, Covid-19 pneumonia and pulmonary vascular disease: A UK Centre perspective, Respiratory Medicine and Research, Vol: 78, Pages: 1-2, ISSN: 2590-0412
Price LC, Kouranos V, Dimopoulos K, et al., 2020, Sarcoidosis-associated Pulmonary Hypertension: A London Cohort, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Sathianandan S, Rawal B, Price L, et al., 2020, Dynamic oxygen-enhanced magnetic resonance imaging-based quantification of pulmonary hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Lewis R, Armstrong I, Bergbaum C, et al., 2020, EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multi-centre study, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 3
Panselinas I, Toe QK, Clementson K, et al., 2020, Pulmonary artery endothelial cell exposure to hepcidin affects BMP-signalling; relevance to vascular remodelling in PAH, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Price L, Brame A, Martinez G, et al., 2020, Perioperative management of patients with Pulmonary Hypertension undergoing Non-Cardiac Surgery: A Systemic Review and UK Consensus Statement, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Piccari L, Vitulo P, Wort SJ, et al., 2020, Impact of borderline (BL) pulmonary hypertension (PH) in chronic lung diseases (CLD), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Otero-Nunez P, Rhodes C, Wharton J, et al., 2020, Multi-omic profiling in pulmonary arterial hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Rhodes C, Otero-Núñez P, Wharton J, et al., 2020, Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 586-594, ISSN: 1073-449X
Rationale: Idiopathic and hereditary pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA-sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signalling pathways and stratify patients more robustly according to clinical risk. Objectives: Using a three-stage design of RNA discovery, RNA validation/model construction and model validation to define a set of PAH-associated RNAs and a single summarising RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomisation (MR) analysis. Methods: RNA-sequencing was performed on whole blood samples from 359 patients with idiopathic, heritable and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known eQTL and summary statistics from a PAH GWAS. Measurements and Main Results: We identified 507 genes with differential RNA expression in PAH patients compared to controls. A model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (p=4.66x10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI:0.129-0.776, p=0.012). Conclusions: A whole blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.
Sofianopoulou E, Church C, Coghlan G, et al., 2020, Deprivation and prognosis in patients with pulmonary arterial hypertension: missing the effect of deprivation on a rare disease?, European Respiratory Journal, Vol: 56, ISSN: 0903-1936
Upton PD, Park JES, De Souza PM, et al., 2020, The endothelial protective factors, BMP9 and BMP10, inhibit CCL2 release by human vascular endothelial cells, Journal of Cell Science, Vol: 133, ISSN: 0021-9533
Bone morphogenetic protein (BMP)-9 and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor, ALK1, and the type II receptors, the activin type-IIA and bone morphogenetic type II receptors. We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and may influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of Chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte-macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. This was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.
Patel BV, Arachchillage DJ, Ridge CA, et al., 2020, Pulmonary angiopathy in severe COVID-19: physiologic, imaging and hematologic observations, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 690-699, ISSN: 1073-449X
Rationale: Clinical and epidemiologic data in coronavirus disease 2019 (Covid-19) have accrued rapidly since the outbreak but few address the underlying pathophysiology. Objectives: To ascertain the physiologic, hematologic and imaging basis of lung injury in severe Covid-19 pneumonia. Methods: Clinical, physiologic and laboratory data were collated. Radiologic (computed tomography pulmonary angiography [CTPA, n=39] and dual-energy CT [DECT, n=20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence/extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography (TEG). Measurements and Results: In 39 consecutive patients (M:F 32:7; mean age, 53±10 years [range 29-79 years]; black and ethnic minority, n=25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead-space (dynamic compliance, 33.7±14.7 mls/cmH2O; Murray Lung Injury Score, 3.14±0.53; mean ventilatory ratios, 2.6±0.8) with evidence of hypercoagulability and fibrinolytic ‘shutdown’. The mean CT extent (±SD) of normally-aerated lung, ground-glass opacification and dense parenchymal opacification were 23.5±16.7%, 36.3±24.7% and 42.7±27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]), were present in all patients (wedge-shaped, n=3; mottled, n= 9; mixed pattern, n=6). Conclusions: Physiologic, hematologic and imaging data show not only the presence of a hypercoagulable phenotype in severe Covid-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.
Price LC, McCabe C, Garfield B, et al., 2020, Thrombosis and COVID-19 pneumonia: the clot thickens!, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936
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- Citations: 115
Shlobin OA, Kouranos V, Barnett SD, et al., 2020, Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: results from an international registry, EUROPEAN RESPIRATORY JOURNAL, Vol: 55, ISSN: 0903-1936
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- Citations: 41
McCabe C, Dimopoulos K, Pitcher A, et al., 2020, Chronic thromboembolic disease following pulmonary embolism: time for a fresh look at old clot, EUROPEAN RESPIRATORY JOURNAL, Vol: 55, ISSN: 0903-1936
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- Citations: 7
Peacock AJ, Ling Y, Johnson MK, et al., 2020, Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?, Pulmonary Circulation, Vol: 10, Pages: 1-8, ISSN: 2045-8940
Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease). Patients with ‘IPAH lung disease’ have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ‘IPAH no lung disease’. We described the outcome of the cohort of patients with ‘IPAH no lung disease’ in a previous paper. Here, we have compared incident ‘IPAH lung disease’ patients with ‘IPAH no lung disease’ patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001–2009. Compared with ‘IPAH no lung disease’ (n = 355), ‘IPAH lung disease’ patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ‘IPAH lung disease’ and ‘IPAH no lung disease’. However, survival of ‘IPAH lung disease’ was lower than ‘IPAH no lung disease’ (one year survival: 72% compared with 93%). This survival was significantly w
Hodgson J, Swietlik EM, Salmon RM, et al., 2020, Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 575-585, ISSN: 1073-449X
OBJECTIVES: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating bone morphogenetic protein, BMP9, which is a ligand for the BMP type 2 receptor (BMPR2). Here we determine the functional impact of GDF2 mutations and characterised plasma BMP9 and BMP10 levels in patients with idiopathic PAH. METHODS: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signalling and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in PAH patients with GDF2 mutations, and controls. Levels were also measured in a larger cohort of controls (n=120) and idiopathic PAH patients (n=260). MAIN RESULTS: We identified novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. PAH patients carrying these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between PAH patients and controls, BMP10 levels were lower in PAH females. A subset of PAH patients had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. CONCLUSIONS: Our findings demonstrate that GDF2 mutations result in BMP9 loss-of-function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signalling in PAH.
Connolly M, Garfield B, Crosby A, et al., 2020, miR-1-5p targets TGF-βR1 and is suppressed in the hypertrophying hearts of rats with pulmonary arterial hypertension, PLoS One, Vol: 15, ISSN: 1932-6203
The microRNA miR-1 is an important regulator of muscle phenotype including cardiac muscle. Down-regulation of miR-1 has been shown to occur in left ventricular hypertrophy but its contribution to right ventricular hypertrophy in pulmonary arterial hypertension are not known. Previous studies have suggested that miR-1 may suppress transforming growth factor-beta (TGF-β) signalling, an important pro-hypertrophic pathway but only indirect mechanisms of regulation have been identified. We identified the TGF-β type 1 receptor (TGF-βR1) as a putative miR-1 target. We therefore hypothesized that miR-1 and TGF-βR1 expression would be inversely correlated in hypertrophying right ventricle of rats with pulmonary arterial hypertension and that miR-1 would inhibit TGF-β signalling by targeting TGF-βR1 expression. Quantification of miR-1 and TGF-βR1 in rats treated with monocrotaline to induce pulmonary arterial hypertension showed appropriate changes in miR-1 and TGF-βR1 expression in the hypertrophying right ventricle. A miR-1-mimic reduced enhanced green fluorescent protein expression from a reporter vector containing the TGF-βR1 3’- untranslated region and knocked down endogenous TGF-βR1. Lastly, miR-1 reduced TGF-β activation of a (mothers against decapentaplegic homolog) SMAD2/3-dependent reporter. Taken together, these data suggest that miR-1 targets TGF-βR1 and reduces TGF-β signalling, so a reduction in miR-1 expression may increase TGF-β signalling and contribute to cardiac hypertrophy.
Nashat H, Kempny A, Harries C, et al., 2020, A single-centre, placebo-controlled, double-blind randomised cross-over study of nebulised iloprost in patients with Eisenmenger syndrome: A pilot study, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 299, Pages: 131-135, ISSN: 0167-5273
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- Citations: 10
Bax S, Jacob J, Ahmed R, et al., 2020, Right ventricle to left ventricle ratio at CTPA predicts mortality in interstitial lung disease, Chest, Vol: 157, Pages: 89-98, ISSN: 0012-3692
INTRODUCTION: Patients with interstitial lung disease (ILD) may develop pulmonary hypertension (PH), often disproportionate to ILD severity. Right ventricle to left ventricle diameter ratio (RV:LV) measured at CT pulmonary angiography (CTPA), has been shown to provide valuable information in pulmonary arterial hypertension patients and to predict death or deterioration in acute pulmonary embolism. METHODS: Demographics, ILD subtype, echocardiography and detailed CTPA measurements were collected in consecutive patients undergoing both CTPA and right heart catheterisation (RHC) at the Royal Brompton Hospital between 2005 and 2015. Fibrosis severity was formally scored using CT criteria. RV:LV ratio at CTPA was evaluated by three different methods. Cox-proportional hazard analysis was used to assess the relation of CTPA-derived parameters to predict death or lung transplantation. RESULTS: 92 patients were included: 64% male, mean age 65±11 years, with FVC 57±20% (predicted), TLCOc 22±8% (predicted) and KCOc 51±17% (predicted). PH was confirmed at RHC in 78%. Of all CTPA-derived measures, an RV:LV ratio ≥1.0 strongly predicted mortality or transplantation at univariate analysis (HR 3.26, 95%CI:1.49-7.13, p=0.003), whereas invasive haemodynamic data did not. The RV:LV ratio remained an independent predictor at multivariate analysis (HR: 3.19, CI:1.44-7.10, p=0.004), adjusting for an ILD diagnosis of IPF and CT derived ILD severity. CONCLUSION: An increased RV:LV ratio measured at CTPA provides a simple, non-invasive method of risk stratification in patients with suspected ILD-PH. This should prompt closer follow up, more aggressive treatment and consideration of lung transplantation.
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