339 results found
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.
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, 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/).
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
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
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, 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
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, 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
Church C, Gin-Sing W, Grady D, et al., 2021, Establishing expert consensus for the optimal approach to holistic risk-management in pulmonary arterial hypertension: a Delphi process and narrative review, EXPERT REVIEW OF RESPIRATORY MEDICINE, Vol: 15, Pages: 1493-1503, ISSN: 1747-6348
Hoeper MM, Al-Hiti H, Benza RL, et al., 2021, Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial, LANCET RESPIRATORY MEDICINE, Vol: 9, Pages: 573-584, ISSN: 2213-2600
Bergbaum C, Samaranayake CB, Pitcher A, et al., 2021, A case series on the use of steroids and mycophenolate mofetil in idiopathic and heritable pulmonary veno-occlusive disease: is there a role for immunosuppression?, EUROPEAN RESPIRATORY JOURNAL, Vol: 57, ISSN: 0903-1936
Vidal MLB, Diller G-P, Kempny A, et al., 2021, UTILITY OF DEEP LEARNING ALGORITHMS IN DIAGNOSING AND AUTOMATIC PROGNOSTICATION OF PULMONARY ARTERIAL HYPERTENSION BASED ON ROUTINE ECHOCARDIOGRAPHIC IMAGING, 70th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 1670-1670, ISSN: 0735-1097
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, Martinez G, Brame A, et al., 2021, Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement, BRITISH JOURNAL OF ANAESTHESIA, Vol: 126, Pages: 774-790, ISSN: 0007-0912
Bleakley C, Singh S, Garfield B, et al., 2021, Right ventricular dysfunction in critically ill COVID-19 ARDS, International Journal of Cardiology, Vol: 327, Pages: 251-258, ISSN: 0167-5273
AIMS: Comprehensive echocardiography assessment of right ventricular (RV) impairment has not been reported in critically ill patients with COVID-19. We detail the specific phenotype and clinical associations of RV impairment in COVID-19 acute respiratory distress syndrome (ARDS). METHODS: Transthoracic echocardiography (TTE) measures of RV function were collected in critically unwell patients for associations with clinical, ventilatory and laboratory data. RESULTS: Ninety patients (25.6% female), mean age 52.0 ± 10.8 years, veno-venous extracorporeal membrane oxygenation (VVECMO) (42.2%) were studied. A significantly higher proportion of patients were identified as having RV dysfunction by RV fractional area change (FAC) (72.0%,95% confidence interval (CI) 61.0-81.0) and RV velocity time integral (VTI) (86.4%, 95 CI 77.3-93.2) than by tricuspid annular plane systolic excursion (TAPSE) (23.8%, 95 CI 16.0-33.9), RVS' (11.9%, 95% CI 6.6-20.5) or RV free wall strain (FWS) (35.3%, 95% CI 23.6-49.0). RV VTI correlated strongly with RV FAC (p ≤ 0.01). Multivariate regression demonstrated independent associations of RV FAC with NTpro-BNP and PVR. RV-PA coupling correlated with PVR (univariate p < 0.01), as well as RVEDAi (p < 0.01), and RVESAi (p < 0.01), and was associated with P/F ratio (p 0.026), PEEP (p 0.025), and ALT (p 0.028). CONCLUSIONS: Severe COVID-19 ARDS is associated with a specific phenotype of RV radial impairment with sparing of longitudinal function. Clinicians should avoid interpretation of RV health purely on long-axis parameters in these patients. RV-PA coupling potentially provides important additional information above standard measures of RV performance in this cohort.
Mumby S, Perros F, Hui C, et al., 2021, Extracellular matrix degradation pathways and fatty acid metabolism regulate distinct pulmonary vascular cell types in Pulmonary Arterial Hypertension, Pulmonary Circulation, Vol: 11, Pages: 1-16, ISSN: 2045-8940
Pulmonary arterial hypertension (PAH) describes a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between PAH and controls using both human pulmonary microvascular endothelial (HPMEC) and pulmonary artery smooth muscle cells (HPASMC). HPMEC and HPASMC from PAH patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalization, we examined differentially expressed genes (DEGs) and applied gene set enrichment analysis (GSEA) to the DEGs to identify putative activated pathways.HPMEC displayed 1008 significant (p≤0.0001) DEGs in PAH samples compared to controls. In HPASMC there were 229 significant (p≤0.0001) DEGs between PAH and controls. Pathway analysis revealed distinctive differences: HPMEC display down-regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal- and cell- adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in PAH pathogenesis. In contrast pathways in HPASMC were mainly up-regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell-cell and adherens junction interactions suggesting a more energy-driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in PAH pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression.
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
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
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
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