358 results found
Dawes TJW, McCabe C, Dimopoulos K, et al., 2022, Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study, RESPIROLOGY, ISSN: 1323-7799
Humbert M, Kovacs G, Hoeper MM, et al., 2022, 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG), European Heart Journal, Pages: 1-114, ISSN: 0195-668X
Diller GP, Vidal MLB, Kempny A, et al., 2022, A framework of deep learning networks provides expert-level accuracy for the detection and prognostication of pulmonary arterial hypertension, EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING, Vol: 23, Pages: 1447-1456, ISSN: 2047-2404
Prapa M, Lago-Docampo M, Swietlik EM, et al., 2022, First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease., Am J Respir Crit Care Med
RATIONALE: Despite the increased recognition of TBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. METHODS: We assembled a multi-center cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients with BMPR2 causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR). RESULTS: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared to loss-of-function (p = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (p = 0.005) and increased incidence of interstitial lung disease (p = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (p = 0.022) although age had a significant effect in the hazard model (p = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p = 0.009) compared to the BMPR2 and no identified causal variant groups. CONCLUSIONS: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Jones RJ, De Bie EMDD, Groves E, et al., 2022, Autoimmunity is a significant feature of idiopathic pulmonary arterial hypertension., American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 81-93, ISSN: 1073-449X
RATIONALE: Autoimmunity is thought to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear if this is causative or a bystander of disease and if it carries any prognostic or treatment significance. OBJECTIVE: To study autoimmunity in IPAH using a large cross-sectional cohort. METHODS: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry and the profile of serum immunoglobulins was generated using a standardised multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 controls. Additional GST-fusion array and ELISA data were used to identify a serum autoantibody to BMPR2. Clustering analyses and clinical correlations were employed to determine associations between immunogenicity and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Flow cytometric immune profiling demonstrates IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: 'high autoantibody', 'low autoantibody', and a small 'intermediate' cluster exhibiting high levels of RNP-complex. The high autoantibody cluster had worse haemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. CONCLUSIONS: This study establishes aberrant immune regulation and presence of autoantibodies as a key feature in the profile of a significant proportion of IPAH patients and is associated with clinical outcomes. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Nikkho SM, Richter MJ, Shen E, et al., 2022, Clinical significance of pulmonary hypertension in interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's innovative drug development initiative-Group 3 pulmonary hypertension, PULMONARY CIRCULATION, Vol: 12, ISSN: 2045-8932
McFadyen C, Garfield B, Mancio J, et al., 2022, Use of sildenafil in patients with severe COVID-19 pneumonitis, British Journal of Anaesthesia, Vol: 129, Pages: E18-E21, ISSN: 0007-0912
Toshner M, Church C, Harbaum L, et al., 2022, Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension (vol 59, 2002463, 2022), EUROPEAN RESPIRATORY JOURNAL, Vol: 60, ISSN: 0903-1936
Schwiening M, Swietlik EM, Pandya D, et al., 2022, Different Cytokine Patterns in BMPR2-Mutation-Positive Patients and Patients With Pulmonary Arterial Hypertension Without Mutations and Their Influence on Survival, CHEST, Vol: 161, Pages: 1651-1656, ISSN: 0012-3692
Kariotis S, Jammeh E, Swietlik EM, et al., 2022, Longitudinal Analysis of Three Major Risk-Associated Transcriptomic Subgroups Within the IPAH Classification, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Gupta R, Baughman RP, Nathan SD, et al., 2022, The six-minute walk test in sarcoidosis associated pulmonary hypertension: Results from an international registry, Virtual International Conference of the American-Thoracic-Society, Publisher: W B SAUNDERS CO LTD, ISSN: 0954-6111
Rhodes C, Wharton J, Swietlik E, et al., 2022, Using the plasma proteome for risk stratifying patients with pulmonary arterial hypertension, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1102-1111, ISSN: 1073-449X
Rationale: N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH.Objectives: Identify prognostic proteins in PAH which complement NT-proBNP and clinical risk scores.Methods: An aptamer-based assay (SomaScan-V4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable or drug-induced-PAH from the UK National Cohort of PAH (n=357) and the French EFORT study (n=79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute walk distance (6-MWD) and NT-proBNP entered LASSO modelling and the best combination in a single score was evaluated against clinical targets in EFORT.Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-MWD in the UK Cohort. A weighted combination score of 6 proteins was validated at baseline (5-year mortality, AUC:0.73, 95%CI:0.63-0.85) and follow-up in EFORT (AUC:0.84, 95%CI:0.75-0.94, p=9.96x10-6). The protein score risk-stratified patients independent of established clinical targets and risk equations. The addition of the 6-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC:0.762 (0.702-0.821) to 0.818 (0.767-0.869) by ROC analysis (p=0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response.
Piccari L, Wort SJ, Meloni F, et al., 2022, The Effect of Borderline Pulmonary Hypertension on Survival in Chronic Lung Disease, RESPIRATION, Vol: 101, Pages: 717-727, ISSN: 0025-7931
Toe QK, Issitt T, Mahomed A, et al., 2022, Human pulmonary artery endothelial cells upregulate ACE2 expression in response to iron-regulatory elements: Potential implications for SARS-CoV-2 infection, PULMONARY CIRCULATION, Vol: 12, ISSN: 2045-8932
Constantine A, Rhodes CJ, Ricci P, et al., 2022, PLASMA PROTEIN PROFILE IN EISENMENGER SYNDROME AND OTHER FORMS OF PH: ASSOCIATION WITH MARKERS OF RV REMODELLING, ACC.22, Publisher: ELSEVIER SCIENCE INC, Pages: 1364-1364, ISSN: 0735-1097
Constantine A, Dimopoulos K, Jenkins P, et al., 2021, Use of pulmonary arterial hypertension therapies in Fontan patients: current practice across the United Kingdom, Journal of the American Heart Association, Vol: 11, Pages: 1-19, ISSN: 2047-9980
Background: The Fontan circulation is a successful operative strategy for abolishing cyanosis and chronic volume overload in congenital heart disease (CHD) patients with single ventricle physiology. ‘Fontan failure’ is a major cause of poor quality of life and mortality in these patients. We assessed the number and clinical characteristics of adult Fontan patients receiving pulmonary arterial hypertension (PAH) therapies across specialist centers in the UK.Methods and Results: We identified all adult patients with a Fontan-type circulation under active follow-up in 10 specialist CHD centers in England and Scotland between 2009 and 2019. Patients on PAH therapies were matched to untreated patients. A survey of experts was also performed. Of 1538 Fontan patients followed in specialist centers, only 76 (4.9%) received PAH therapies during follow-up. The vast majority (90.8%) were treated with a phosphodiesterase-5 inhibitor. In 33% of patients, PAH therapies were started after surgery or during hospital admission. In the matched cohort, treated patients were more likely to be significantly limited, have ascites, history of protein losing enteropathy, or receive loop diuretics (p<0.0001 for all), also reflecting survey responses indicating that failing Fontan is an important treatment target. After a median 12[11-15] months, functional class was more likely to improve in the treated group (p=0.01), with no other changes in clinical parameters or safety issues. Conclusions: PAH therapies are used in adult Fontan patients followed in specialist centers, targeting individuals with very advanced disease or complications. Follow-up suggests stabilization of the clinical status after 12 months of therapy.
Kariotis S, Jammeh E, Swietlik EM, et al., 2021, Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood, Nature Communications, Vol: 12, Pages: 1-14, ISSN: 2041-1723
Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.
Vidal MLB, Kempny A, Li W, et al., 2021, Deep Learning Networks Trained on Routine Echocardiography Images Provide Expert Level Prognostication in Patients With Pulmonary Hypertension: A Study on 408 Patients From an Expert Centre, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Vidal MLB, Kempny A, Li W, et al., 2021, Utility of a Novel Ensemble Based Deep Learning Network for the Automatic Detection of Pulmonary Hypertension and Right Ventricular Dilatation: A Study Based on Data From 783 Individuals From Two Tertiary Centres, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Mahomed AS, Burke-Gaffney A, Toe Q, et al., 2021, Effects of varying shear stress profiles on the regulation of pulmonary artery endothelial cell gene expression: a focus on selected mediators of vascular tone, inflammation and angiogenesis, Publisher: OXFORD UNIV PRESS, Pages: 1892-1892, ISSN: 0195-668X
Wustmann K, Constantine A, Davies JE, et al., 2021, Prognostic implications of pulmonary wave reflection and reservoir pressure in patients with pulmonary hypertension, International Journal of Cardiology: Congenital Heart Disease, Vol: 5, Pages: 1-8, ISSN: 2666-6685
BackgroundRight ventricular (RV) coupling to the pulmonary circulation influences the response of the RV to the increased afterload caused by pulmonary hypertension (PH), which ultimately determines prognosis. A methodology that accounts for pulsatile flow is required when assessing ventriculo-arterial coupling. We applied wave intensity analysis (WIA) methods to assess the compliance of the main pulmonary artery (PA) in patients with or without PH and compared this to PA distensibility, RV function and clinical outcomes.MethodsHigh-fidelity blood pressure and Doppler flow velocity tracings were obtained simultaneously during cardiac catheterisation for suspected PH. RV volumes, main PA distensibility and ventriculo-arterial coupling (Emax/Ea) were analysed using cardiovascular magnetic resonance.ResultsThe study included 17 PH patients and 6 controls. Wave speed, reservoir and excess pressure were higher in PH patients compared to controls (p < 0.01 for all). Waveforms relating to RV ejection, microvascular wave reflection and late systolic proximal deceleration were higher in PH patients compared to controls (p < 0.01 for all) and related to echocardiographic findings, including PA Doppler notching and shortened acceleration time. Wave speed, reservoir pressure and excess pressure were strongly correlated to main PA distensibility, RV function and Emax/Ea. A higher total pressure integral was associated with an increased risk of death (all-cause mortality).ConclusionThe reservoir-excess pressure model, in combination with conventional clinical imaging, provides valuable information on the pathophysiology of PH that standard haemodynamic parameters do not. Future studies should further investigate the prognostic implications of WIA in PH, and its potential role in clinical practice.
Wilkins M, McKie M, Law M, et al., 2021, EXPRESS: Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH): A phase I/II design comprising dose finding and single arm efficacy Short title: Imatinib for PAH, Pulmonary Circulation, Vol: 11, Pages: 1-12, ISSN: 2045-8940
Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon’s two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm−5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm−5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm−5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.
Toshner M, Church C, Harbaum L, et al., 2021, Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH, European Respiratory Journal, Vol: 59, Pages: 1-11, ISSN: 0903-1936
Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg-1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
Jansen K, Constantine A, Condliffe R, et al., 2021, Pulmonary arterial hypertension in adults with congenital heart disease: markers of disease severity, management of advanced heart failure and transplantation, Expert Review of Cardiovascular Therapy, Vol: 19, Pages: 837-855, ISSN: 1477-9072
Introduction:Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a progressive, life-limiting disease. Areas covered:In this paper, we review the classification and pathophysiology of PAH-CHD, including the mechanisms of disease progression and multisystem effects of disease. We evaluate current strategies of risk stratification and the use of biological markers of disease severity, and review principles of management of PAH-CHD. The indications, timing and the content of advanced heart failure assessment and transplant listing are discussed, along with a review of the types of transplant and other forms of available circulatory support in this group of patients. Finally, the integral role of advance care planning and palliative care is discussed. Expert opinion/commentary:All patients with PAH-CHD should be followed up in expert centers, where they can receive appropriate risk assessment, PAH therapy and supportive care. Referral for transplant assessment should be considered if there continue to be clinical high-risk features, persistent symptoms or acute heart failure decompensation despite appropriate PAH specific therapy. Expert management of PAH-CHD patients, therefore, requires vigilance for these features, along with a close relationship with local advanced heart failure services and a working knowledge of listing criteria, which may disadvantage congenital heart disease patients.
Samaranayake CB, Warren C, Siewers K, et al., 2021, Impact of cyanosis on ventilatory responses during stair climb exercise in Eisenmenger syndrome and idiopathic pulmonary arterial hypertension, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 341, Pages: 84-87, ISSN: 0167-5273
Samaranayake C, Garfield B, Seitler S, et al., 2021, Right ventricular assist devices for mechanical circulatory support in acute massive pulmonary embolism: a single centre experience, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Samaranayake C, Mccabe C, Slader S, et al., 2021, A case-control study on direct oral anticoagulants versus warfarin for acute pulmonary embolism in obese patients, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Dawes T, Dimopoulos K, Mccabe C, et al., 2021, Survival effects of pulmonary vasodilators in group 3 pulmonary hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Samaranayake C, Luo Y, Siewers K, et al., 2021, Impact of cyanosis on ventilatory kinetics during stairclimbing in pulmonary arterial hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Samaranayake CB, McCabe C, Wort SJ, et al., 2021, Sarcoidosis associated pulmonary hypertension: an update, CURRENT OPINION IN PULMONARY MEDICINE, Vol: 27, Pages: 285-295, ISSN: 1070-5287
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