Publications by authors named "David Kiely"

147 Publications

Assessing pulmonary hypertension severity in lung disease is a key step to improving outcomes: embrace resistance and don't be pressurised to go with the flow.

Eur Respir J 2021 08 26;58(2). Epub 2021 Aug 26.

Dept of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1183/13993003.02008-2021DOI Listing
August 2021

Current strategies for managing chronic thromboembolic pulmonary hypertension: results of the worldwide prospective CTEPH Registry.

ERJ Open Res 2021 Jul 16;7(3). Epub 2021 Aug 16.

Royal Papworth Hospital, Cambridge, UK.

Background: Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context.

Methods: 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation-perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation.

Results: Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA).

Conclusions: The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO.
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http://dx.doi.org/10.1183/23120541.00850-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365143PMC
July 2021

Pulmonary hypertension phenotypes in patients with systemic sclerosis.

Eur Respir Rev 2021 Sep 17;30(161). Epub 2021 Aug 17.

Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK

Pulmonary hypertension (PH) commonly affects patients with systemic sclerosis (SSc) and is associated with significant morbidity and increased mortality. PH is a heterogenous condition and several different forms can be associated with SSc, including pulmonary arterial hypertension (PAH) resulting from a pulmonary arterial vasculopathy, PH due to left heart disease and PH due to interstitial lung disease. The incidence of pulmonary veno-occlusive disease is also increased. Accurate and early diagnosis to allow optimal treatment is, therefore, essential. Recent changes to diagnostic haemodynamic criteria at the 6th World Symposium on Pulmonary Hypertension have resulted in therapeutic uncertainty regarding patients with borderline pulmonary haemodynamics. Furthermore, the optimal pulmonary vascular resistance threshold for diagnosing PAH and the role of exercise in identifying early disease require further elucidation. In this article we review the epidemiology, diagnosis, outcomes and treatment of the spectrum of pulmonary vascular phenotypes associated with SSc.
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http://dx.doi.org/10.1183/16000617.0053-2021DOI Listing
September 2021

Integrated Cardiopulmonary MRI Assessment of Pulmonary Hypertension.

J Magn Reson Imaging 2021 Aug 5. Epub 2021 Aug 5.

Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

Pulmonary hypertension (PH) is a heterogeneous condition that can affect the lung parenchyma, pulmonary vasculature, and cardiac chambers. Accurate diagnosis often requires multiple complex assessments of the cardiac and pulmonary systems. MRI is able to comprehensively assess cardiac structure and function, as well as lung parenchymal, pulmonary vascular, and functional lung changes. Therefore, MRI has the potential to provide an integrated functional and structural assessment of the cardiopulmonary system in a single exam. Cardiac MRI is used in the assessment of PH in most large PH centers, whereas lung MRI is an emerging technique in patients with PH. This article reviews the current literature on cardiopulmonary MRI in PH, including cine MRI, black-blood imaging, late gadolinium enhancement, T mapping, myocardial strain analysis, contrast-enhanced perfusion imaging and contrast-enhanced MR angiography, and hyperpolarized gas functional lung imaging. This article also highlights recent developments in this field and areas of interest for future research including cardiac MRI-based diagnostic models, machine learning in cardiac MRI, oxygen-enhanced H imaging, contrast-free H perfusion and ventilation imaging, contrast-free angiography and UTE imaging. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.
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http://dx.doi.org/10.1002/jmri.27849DOI Listing
August 2021

Prevalence of metachronous contralateral mature ovarian teratoma: A systematic review.

Pediatr Blood Cancer 2021 Nov 31;68(11):e29237. Epub 2021 Jul 31.

University Hospital Southampton NHS Foundation Trust, Southampton, UK.

There is increasing recognition that contralateral metachronous tumor may occur following treatment of unilateral mature ovarian teratoma. We aimed to define this risk to guide appropriate surveillance strategies. We undertook a systematic review of three large medical databases (Ovid Medline, Embase, and Cochrane Controlled Trials Register) to April 2020 using a defined search strategy. From 1831 articles retrieved, 23 were included, reporting 1101 girls with unilateral mature ovarian teratomas. The intensity and duration of follow-up varied between studies, with only five reporting close surveillance. Overall prevalence of metachronous contralateral mature teratoma was 2.1%, with a prevalence per study of 0%-23% (median 0%). Prevalence was higher (7%) among studies with more robust surveillance. These data suggest a small but real risk of metachronous contralateral tumors. Surveillance ultrasonography is proportionate and indicated alongside further prospective data collection to record the natural history and impact of surveillance in greater detail.
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http://dx.doi.org/10.1002/pbc.29237DOI Listing
November 2021

A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach.

EBioMedicine 2021 Jul 26;69:103444. Epub 2021 Jun 26.

Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield, UK. Electronic address:

Background: Pulmonary arterial hypertension (PAH) is a rare but life shortening disease, the diagnosis of which is often delayed, and requires an invasive right heart catheterisation. Identifying diagnostic biomarkers may improve screening to identify patients at risk of PAH earlier and provide new insights into disease pathogenesis. MicroRNAs are small, non-coding molecules of RNA, previously shown to be dysregulated in PAH, and contribute to the disease process in animal models.

Methods: Plasma from 64 treatment naïve patients with PAH and 43 disease and healthy controls were profiled for microRNA expression by Agilent Microarray. Following quality control and normalisation, the cohort was split into training and validation sets. Four separate machine learning feature selection methods were applied to the training set, along with a univariate analysis.

Findings: 20 microRNAs were identified as putative biomarkers by consensus feature selection from all four methods. Two microRNAs (miR-636 and miR-187-5p) were selected by all methods and used to predict PAH diagnosis with high accuracy. Integrating microRNA expression profiles with their associated target mRNA revealed 61 differentially expressed genes verified in two independent, publicly available PAH lung tissue data sets. Two of seven potentially novel gene targets were validated as differentially expressed in vitro in human pulmonary artery smooth muscle cells.

Interpretation: This consensus of multiple machine learning approaches identified two miRNAs that were able to distinguish PAH from both disease and healthy controls. These circulating miRNA, and their target genes may provide insight into PAH pathogenesis and reveal novel regulators of disease and putative drug targets.

Funding: This work was supported by a National Institute for Health Research Rare Disease Translational Research Collaboration (R29065/CN500) and British Heart Foundation Project Grant (PG/11/116/29288).
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http://dx.doi.org/10.1016/j.ebiom.2021.103444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243351PMC
July 2021

Outcomes following emergency fixation of torted and non-torted testes.

J Pediatr Urol 2021 May 25. Epub 2021 May 25.

Department of Paediatric Surgery, Queen's Medical Centre, Nottingham University Hospitals Trust, Clifton Boulevard, Nottingham, NG7 2UH, UK.

Introduction: Scrotal exploration is a frequently performed emergency procedure in children. It is a subject of debate as to whether and how a non-torted testis should be fixed, with a wide variation in practice across the UK. This study aims to ascertain whether the method of testicular fixation (if any) impacts on patient outcomes.

Methods: A review of all emergency scrotal explorations performed in children under the age of 18 between 2008 and 2018 in a tertiary Paediatric Surgery unit was undertaken. Patients were categorised by initial fixation method, chi squared analysis was used to compare complication and reoperation rates.

Results: 522 boys were taken to theatre, 424 had a unilateral procedure and 98 had bilateral; after 35 orchidectomies, 585 testes were left in situ. The most frequent diagnosis at operation was torted testicular appendage (n = 278, 53%), followed by testicular torsion (n = 79, 15%). The number of testes by category of fixation were: 72 no documented fixation, 130 dartos pouch only, 34 absorbable sutures, 346 non-absorbable sutures and 3 unspecified sutures. There was no difference in the reattendance rate between groups after outliers were removed (p = 0.72). Thirty-seven patients experienced complications, most commonly ongoing pain. Nine patients required an ipsilateral reoperation, 25 underwent a contralateral operation at a later date. The complication rate appeared to be higher in the no fixation group compared to the dartos (p = 0.02) and sutured groups (p = 0.048). Testes in the no fixation group had a higher reoperation rate compared to the sutured group (p = 0.002).

Conclusions: The present study is a detailed analysis of a wide variety of emergency testicular fixation methods in a large cohort, including the routine fixation of non-torted testes. Whilst there appears to be a benefit to using sutured or dartos fixation, this merits cautious interpretation. It is likely that influences on complications and reoperations are multifactorial and cannot be attributed solely to the method of testicular fixation. Adoption of a standardised approach to emergency fixation of testes within or across institutions may be a potential avenue for future studies.
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http://dx.doi.org/10.1016/j.jpurol.2021.05.016DOI Listing
May 2021

Establishing expert consensus for the optimal approach to holistic risk-management in pulmonary arterial hypertension: a Delphi process and narrative review.

Expert Rev Respir Med 2021 Jun 1:1-11. Epub 2021 Jun 1.

Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom.

: Pulmonary arterial hypertension (PAH) is associated with significant morbidity and reduced life expectancy. Various medical therapies, together with non-medical therapies such as exercise training, have been shown to improve outcomes for patients. We performed a Delphi consensus process to establish optimal approaches to optimizing patient care.: A steering group of PAH experts formulated 38 statements grouped into 6 themes: burden of PAH, risk-stratification, the role of clinical phenotyping in the management of PAH, assessing clinical response to treatment, maximizing the medical treatment pathway and the role of other management options. An online survey was sent to PAH health-care professionals throughout the UK to assess consensus with these statements. Consensus was defined as high if ≥70% and very high if ≥90% of the respondents agreed with a statement. A narrative review for each theme was then performed: Consensus was very high in 27 (71%) statements, high in 7 (18%) statements and was not achieved in 4 (11%) statements.: Based on the consensus scores, the steering group derived 13 recommendations which, if implemented, should result in improved holistic care of patients with PAH.
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http://dx.doi.org/10.1080/17476348.2021.1931129DOI Listing
June 2021

Cardiovascular magnetic resonance predicts all-cause mortality in pulmonary hypertension associated with heart failure with preserved ejection fraction.

Int J Cardiovasc Imaging 2021 May 12. Epub 2021 May 12.

Sheffield Teaching Hospitals NHS Foundation Trust, London, England.

This study aimed to determine the prognostic value of cardiovascular magnetic resonance (CMR) in patients with heart failure with preserved ejection fraction and associated pulmonary hypertension (pulmonary hypertension-HFpEF). Patients with pulmonary hypertension-HFpEF were recruited from the ASPIRE registry and underwent right heart catheterisation (RHC) and CMR. On RHC, the inclusion criteria was a mean pulmonary artery pressure (MPAP) ≥ 25 mmHg and pulmonary arterial wedge pressure > 15 mmHg and, on CMR, a left atrial volume > 41 ml/m with left ventricular ejection fraction > 50%. Cox regression was performed to evaluate CMR against all-cause mortality. In this study, 116 patients with pulmonary hypertension-HFpEF were identified. Over a mean follow-up period of 3 ± 2 years, 61 patients with pulmonary hypertension-HFpEF died (53%). In univariate regression, 11 variables demonstrated association to mortality: indexed right ventricular (RV) volumes and stroke volume, right ventricular ejection fraction (RVEF), indexed RV mass, septal angle, pulmonary artery systolic/diastolic area and its relative area change. In multivariate regression, only three variables were independently associated with mortality: RVEF (HR 0.64, P < 0.001), indexed RV mass (HR 1.46, P < 0.001) and IV septal angle (HR 1.48, P < 0.001). Our CMR model had 0.76 area under the curve (P < 0.001) to predict mortality. This study confirms that pulmonary hypertension in patients with HFpEF is associated with a poor prognosis and we observe that CMR can risk stratify these patients and predict all-cause mortality. When patients with HFpEF develop pulmonary hypertension, CMR measures that reflect right ventricular afterload and function predict all-cause mortality.
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http://dx.doi.org/10.1007/s10554-021-02279-zDOI Listing
May 2021

Pulmonary Hypertension in Association with Lung Disease: Quantitative CT and Artificial Intelligence to the Rescue? State-of-the-Art Review.

Diagnostics (Basel) 2021 Apr 9;11(4). Epub 2021 Apr 9.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK.

Accurate phenotyping of patients with pulmonary hypertension (PH) is an integral part of informing disease classification, treatment, and prognosis. The impact of lung disease on PH outcomes and response to treatment remains a challenging area with limited progress. Imaging with computed tomography (CT) plays an important role in patients with suspected PH when assessing for parenchymal lung disease, however, current assessments are limited by their semi-qualitative nature. Quantitative chest-CT (QCT) allows numerical quantification of lung parenchymal disease beyond subjective visual assessment. This has facilitated advances in radiological assessment and clinical correlation of a range of lung diseases including emphysema, interstitial lung disease, and coronavirus disease 2019 (COVID-19). Artificial Intelligence approaches have the potential to facilitate rapid quantitative assessments. Benefits of cross-sectional imaging include ease and speed of scan acquisition, repeatability and the potential for novel insights beyond visual assessment alone. Potential clinical benefits include improved phenotyping and prediction of treatment response and survival. Artificial intelligence approaches also have the potential to aid more focused study of pulmonary arterial hypertension (PAH) therapies by identifying more homogeneous subgroups of patients with lung disease. This state-of-the-art review summarizes recent QCT developments and potential applications in patients with PH with a focus on lung disease.
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http://dx.doi.org/10.3390/diagnostics11040679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070579PMC
April 2021

Critical care outcomes in patients with pre-existing pulmonary hypertension: insights from the ASPIRE registry.

ERJ Open Res 2021 Apr 6;7(2). Epub 2021 Apr 6.

Dept of Critical Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Pulmonary hypertension (PH) is a life-shortening condition characterised by episodes of decompensation precipitated by factors such as disease progression, arrhythmias and sepsis. Surgery and pregnancy also place additional strain on the right ventricle. Data on critical care management in patients with pre-existing PH are scarce. We conducted a retrospective observational study of a large cohort of patients admitted to the critical care unit of a national referral centre between 2000-2017 to establish acute mortality, evaluate predictors of in-hospital mortality and establish longer term outcomes in survivors to hospital discharge. 242 critical care admissions involving 206 patients were identified. Hospital survival was 59.3%, 94% and 92% for patients admitted for medical, surgical or obstetric reasons, respectively. Medical patients had more severe physiological and laboratory perturbations than patients admitted following surgical or obstetric interventions. Higher APACHE II (Acute Physiology and Chronic Health Evaluation) score, age and lactate, and lower oxygen saturation measure by pulse oximetry/inspiratory oxygen fraction ( / ) ratio, platelet count and sodium level were identified as independent predictors of hospital mortality. An exploratory risk score, OPALS (oxygen ( / ) ≤185; platelets ≤196×10·L; age ≥37.5 years; lactate ≥2.45 mmol·L; sodium ≤130.5 mmol·L), identified medical patients at increasing risk of hospital mortality. One (11%) out of nine patients who were invasively ventilated for medical decompensation and 50% of patients receiving renal replacement therapy left hospital alive. There was no significant difference in exercise capacity or functional class between follow-up and pre-admission in patients who survived to discharge. These data have clinical utility in guiding critical care management of patients with known PH. The exploratory OPALS score requires validation.
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http://dx.doi.org/10.1183/23120541.00046-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021802PMC
April 2021

Myocardial T1-mapping and extracellular volume in pulmonary arterial hypertension: A systematic review and meta-analysis.

Magn Reson Imaging 2021 06 18;79:66-75. Epub 2021 Mar 18.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; Department of Clinical Radiology, Sheffield Teaching Hospitals, Sheffield, UK; Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK.

Introduction: Elevated myocardial T-mapping and extracellular volume (ECV) measured on cardiac MR (CMR) imaging is associated with myocardial abnormalities such as oedema or fibrosis. This meta-analysis aims to provide a summary of T-mapping and ECV values in pulmonary arterial hypertension (PAH) and compare their values with controls.

Methods: We searched CENTRAL, MEDLINE, Embase, and Web of Science in August 2020. We included CMR studies reporting T-mapping or ECV values in adults with any type of PAH. We calculated the mean difference of T-values and ECV between PAH and controls.

Results: We included 12 studies with 674 participants. T-values were significantly higher in PAH with the highest mean difference (MD) recorded at the RV insertion points (RVIP) (108 milliseconds (ms), 95% confidence intervals (CI) 89 to 128), followed by the RV free wall (MD 91 ms, 95% CI 56 to 126). The pooled mean T-value in PAH at the RVIP was 1084, 95% CI (1071 to 1097) measured using 1.5 Tesla Siemens systems. ECV was also higher in PAH with an MD of 7.5%, 95% CI (5.9 to 9.1) at the RV free wall.

Conclusion: T mapping values in PAH patients are on average 9% higher than healthy controls when assessed under the same conditions including the same MRI system, magnetic field strength or sequence used for acquisition. The highest T and ECV values are at the RVIP. T mapping and ECV values in PH are higher than the values reported in cardiomyopathies and were associated with poor RV function and RV dilatation.
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http://dx.doi.org/10.1016/j.mri.2021.03.011DOI Listing
June 2021

Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Ann Am Thorac Soc 2021 06;18(6):981-988

National Heart and Lung Institute and.

Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. To evaluate the safety and efficacy of parenteral iron replacement in PAH. In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 μg/L or iron <10.3 μmol/L or transferrin saturations <16.4%. Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).
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http://dx.doi.org/10.1513/AnnalsATS.202009-1131OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456720PMC
June 2021

Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study.

Thorax 2021 Oct 25;76(10):1032-1035. Epub 2021 Feb 25.

Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, UK.

End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test-retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen's d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (logNT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen's d 0.81), whereas the effect size for the 6 min walk test (Cohen's d 0.22) and logNT-proBNP (Cohen's d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216078DOI Listing
October 2021

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

Br J Anaesth 2021 04 19;126(4):774-790. Epub 2021 Feb 19.

Adult Intensive Care Unit, Royal Brompton Hospital, London, UK.

Background: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death.

Methods: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research.

Results: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning.

Conclusions: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.
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http://dx.doi.org/10.1016/j.bja.2021.01.005DOI Listing
April 2021

Patterns of thromboembolic pulmonary vascular disease in COVID-19.

Pulm Circ 2021 Jan-Mar;11(1):2045894020979198. Epub 2021 Jan 21.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

SARS-CoV-2 (COVID-19) is associated with increased thrombosis. Here, we demonstrate patterns of pulmonary vascular disease in COVID-19 including classical acute pulmonary embolism and subsegmental perfusion defects in the absence of acute pulmonary embolism suggestive of microvascular thrombosis.
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http://dx.doi.org/10.1177/2045894020979198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829513PMC
January 2021

Bayesian Inference Associates Rare Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Circ Genom Precis Med 2020 Dec 15. Epub 2020 Dec 15.

Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay & AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire & INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.

- 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. - 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. - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor () 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 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 . Four additional PAH cases with rare likely loss-of-function variants in were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. - The Bayesian inference approach allowed us to independently validate , 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 being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
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http://dx.doi.org/10.1161/CIRCGEN.120.003155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892262PMC
December 2020

Adults' experiences of living with pulmonary hypertension: a thematic synthesis of qualitative studies.

BMJ Open 2020 12 7;10(12):e041428. Epub 2020 Dec 7.

South Wales Clinical Psychology Training Programme, Cardiff University, Cardiff, South Glamorgan, UK.

Objectives: Pulmonary hypertension is a life-shortening disease that has a considerable impact on quality of life. Improving our understanding of how individuals are affected and cope with the disease will help to improve services and outcomes. This review synthesises the published qualitative research that has listened to adults discuss their experiences of living with the disease.

Design: A comprehensive systematic search of four databases was conducted in May 2020: Web of Science, PubMed, PsycINFO and Cochrane Library. Suitable studies were evaluated using the Critical Appraisal Skills programme. Findings from the studies were extracted and subjected to a thematic synthesis.

Results: Nineteen articles were identified reflecting the experiences of over 1900 individuals impacted by pulmonary hypertension from Europe, North and South America and Asia. Ten studies did not report participant's WHO functional class of pulmonary hypertension, which resulted in comparing experiences between different severity difficult. All studies met the majority of the quality assessment items. Six descriptive themes emerged discussing participant's experiences of diagnosis, treatment, prognosis, healthcare professionals, impact and coping with pulmonary hypertension. Four higher order analytical themes were developed from the descriptive themes, reflecting: (i) uncertainties and anxiety that participants encountered related to pulmonary hypertension; (ii) lack of recognition of the impact of the condition; (iii) frustration at the paucity of awareness of pulmonary hypertension in society and healthcare settings and (iv) participant's accounts of transitioning through different stages of living with the disease.

Conclusions: These findings form the first synthesis of experiences of life in individuals impacted by pulmonary hypertension and illustrate the multifaceted impact of the condition. The voices of numerous groups are missing from the literature highlighting the need for additional research. The results have implications for clinical practice emphasising the role of educational and psychological therapies to support those with the disease.
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http://dx.doi.org/10.1136/bmjopen-2020-041428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722804PMC
December 2020

Mild parenchymal lung disease is still lung disease.

Eur Respir J 2020 11 26;56(5). Epub 2020 Nov 26.

Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK.

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http://dx.doi.org/10.1183/13993003.03727-2020DOI Listing
November 2020

Cardiac Magnetic Resonance in Pulmonary Hypertension-an Update.

Curr Cardiovasc Imaging Rep 2020 7;13(12):30. Epub 2020 Nov 7.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Glossop Road, Sheffield, S10 2JF UK.

Purpose Of Review: This article reviews advances over the past 3 years in cardiac magnetic resonance (CMR) imaging in pulmonary hypertension (PH). We aim to bring the reader up-to-date with CMR applications in diagnosis, prognosis, 4D flow, strain analysis, T mapping, machine learning and ongoing research.

Recent Findings: CMR volumetric and functional metrics are now established as valuable prognostic markers in PH. This imaging modality is increasingly used to assess treatment response and improves risk stratification when incorporated into PH risk scores. Emerging techniques such as myocardial T mapping may play a role in the follow-up of selected patients. Myocardial strain may be used as an early marker for right and left ventricular dysfunction and a predictor for mortality. Machine learning has offered a glimpse into future possibilities. Ongoing research of new PH therapies is increasingly using CMR as a clinical endpoint.

Summary: The last 3 years have seen several large studies establishing CMR as a valuable diagnostic and prognostic tool in patients with PH, with CMR increasingly considered as an endpoint in clinical trials of PH therapies. Machine learning approaches to improve automation and accuracy of CMR metrics and identify imaging features of PH is an area of active research interest with promising clinical utility.
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http://dx.doi.org/10.1007/s12410-020-09550-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648000PMC
November 2020

Cardiac-MRI Predicts Clinical Worsening and Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis.

JACC Cardiovasc Imaging 2021 05 30;14(5):931-942. Epub 2020 Sep 30.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom; Department of Clinical Radiology, Sheffield Teaching Hospitals, Sheffield, United Kingdom; INSIGNEO, Institute for In Silico Medicine, University of Sheffield, United Kingdom.

Objectives: This meta-analysis evaluates assessment of pulmonary arterial hypertension (PAH), with a focus on clinical worsening and mortality.

Background: Cardiac magnetic resonance (CMR) has prognostic value in the assessment of patients with PAH. However, there are limited data on the prediction of clinical worsening, an important composite endpoint used in PAH therapy trials.

Methods: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Science databases were searched in May 2020. All CMR studies assessing clinical worsening and the prognosis of patients with PAH were included. Pooled hazard ratios of univariate regression analyses for CMR measurements, for prediction of clinical worsening and mortality, were calculated.

Results: Twenty-two studies with 1,938 participants were included in the meta-analysis. There were 18 clinical worsening events and 8 deaths per 100 patient-years. The pooled hazard ratios show that every 1% decrease in right ventricular (RV) ejection fraction is associated with a 4.9% increase in the risk of clinical worsening over 22 months of follow-up and a 2.1% increase in the risk of death over 54 months. For every 1 ml/m increase in RV end-systolic volume index or RV end-diastolic volume index, the risk of clinical worsening increases by 1.3% and 1%, respectively, and the risk of mortality increases by 0.9% and 0.6%. Every 1 ml/m decrease in left ventricular stroke volume index or left ventricular end-diastolic volume index increased the risk of death by 2.5% and 1.8%. Left ventricular parameters were not associated with clinical worsening.

Conclusions: This review confirms CMR as a powerful prognostic marker in PAH in a large cohort of patients. In addition to confirming previous observations that RV function and RV and left ventricular volumes predict mortality, RV function and volumes also predict clinical worsening. This study provides a strong rationale for considering CMR as a clinically relevant endpoint for trials of PAH therapies.
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http://dx.doi.org/10.1016/j.jcmg.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525356PMC
May 2021

Outcome Measures Used in Studies of Rehabilitation in Pulmonary Hypertension.

Ann Am Thorac Soc 2021 02;18(2):321-335

Department of Nursing, Faculty of Health, Psychology and Social Care, Manchester Metropolitan University, Manchester, United Kingdom.

The evidence base for rehabilitation in pulmonary hypertension is expanding, but adoption in clinical practice is limited. The World Health Organization International Classification for Functioning, Disability and Health identifies three health domains: Body Functions/Structures, Activity and Participation in society. To ensure that the wider impact of rehabilitation in pulmonary hypertension is accurately assessed, it is important that study endpoints reflect all three domains. A systematic review of the literature was conducted to identify studies of rehabilitation in patients with pulmonary hypertension from 2006 to 2019. Searches across five databases yielded 2,564 articles, of which 34 met eligibility criteria; 50 different outcome measures (mean = 5, minimum = 1, maximum = 9) were identified. When mapped onto the World Health Organization International Classification for Functioning, Disability and Health, 48% of instances of outcome usage were measures of Body Functions/Structure, 33% were measures of Activity, and 18% were measures of Participation. Measures of Participation were not included in seven studies (21%). Studies of rehabilitation in pulmonary hypertension have focused primarily on measures of Body Functions/Structure; the impact in other health domains is not well characterized. Greater inclusion of outcome measures reflecting Activity and Participation in society is needed to allow assessment of the wider impact of rehabilitation in patients with pulmonary hypertension.
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http://dx.doi.org/10.1513/AnnalsATS.202005-541OCDOI Listing
February 2021

Maximal Exercise Testing Using the Incremental Shuttle Walking Test Can Be Used to Risk-Stratify Patients with Pulmonary Arterial Hypertension.

Ann Am Thorac Soc 2021 01;18(1):34-43

Sheffield Pulmonary Vascular Disease Unit, Sheffield Teaching Hospitals National Health Service Foundation Trust, Royal Hallamshire Hospital, Sheffield, United Kingdom.

Exercise capacity predicts mortality in pulmonary arterial hypertension (PAH), but limited data exist on the routine use of maximal exercise testing. This study evaluates a simple-to-perform maximal test (the incremental shuttle walking test) and its use in risk stratification in PAH. Consecutive patients with pulmonary hypertension were identified from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) registry (2001-2018). Thresholds for levels of risk were identified at baseline and tested at follow-up, and their incorporation into current risk stratification approaches was assessed. Of 4,524 treatment-naive patients with pulmonary hypertension who underwent maximal exercise testing, 1,847 patients had PAH. A stepwise reduction in 1-year mortality was seen between levels 1 (≤30 m; 32% mortality) and 7 (340-420 m; 1% mortality) with no mortality for levels 8-12 (≥430 m) in idiopathic and connective tissue disease-related PAH. Thresholds derived at baseline of ≤180 m (>10%; high risk), 190-330 m (5-10%; intermediate risk), and ≥340 m (<5%; low risk of 1-yr mortality) were applied at follow-up and also accurately identified levels of risk. Thresholds were incorporated into the REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) 2.0 risk score calculator and French low-risk approach to risk stratification, and distinct categories of risk remained.: We have demonstrated that maximal exercise testing in PAH stratifies mortality risk at baseline and follow-up. This study highlights the potential value of the incremental shuttle walking test as an alternative to the 6-minute walking test, combining some of the advantages of maximal exercise testing and maintaining the simplicity of a simple-to-perform field test.
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http://dx.doi.org/10.1513/AnnalsATS.202005-423OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780966PMC
January 2021

Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension.

Circulation 2020 10 23;142(15):1464-1484. Epub 2020 Jul 23.

Pulmonary Hypertension Research Group, Center de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (J.O., K.H., T.S., W-H.W., S.B-B., E.T., S.M., V.N., K.G., F.M., J.P., R.P., S.P., O.B., S.B.).

Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown.

Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes.

Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines.

Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047626DOI Listing
October 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 multicentre study.

Eur Respir J 2021 02 25;57(2). Epub 2021 Feb 25.

Pulmonary Vascular Disease Unit, Royal Papworth Hospital, Cambridge, UK.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.
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http://dx.doi.org/10.1183/13993003.00124-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905834PMC
February 2021

Age-associated changes in 4D flow CMR derived Tricuspid Valvular Flow and Right Ventricular Blood Flow Kinetic Energy.

Sci Rep 2020 06 18;10(1):9908. Epub 2020 Jun 18.

Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK.

Assessment of right ventricular (RV) diastolic function is not routinely carried out. This is due to standard two-dimensional imaging techniques being unreliable. Four-dimensional flow (4D flow) derived right ventricular blood flow kinetic energy assessment could circumvent the issues of the current imaging modalities. It also remains unknown whether there is an association between right ventricular blood flow kinetic energy (KE) and healthy ageing. We hypothesise that healthy ageing requires maintaining normal RV intra-cavity blood flow as quantified using KE method. The main objective of this study was to investigate the effect of healthy ageing on tricuspid through-plane flow and right ventricular blood flow kinetic energy. In this study, fifty-three healthy participants received a 4D flow cardiovascular magnetic resonance (CMR) scan on 1.5 T Philips Ingenia. Cine segmentation and 4D flow analysis were performed using dedicated software. Standard statistical methods were carried out to investigate the associations. Both RV E-wave KEi (r = -0.3, P = 0.04) and A-wave KEi (r = 0.42, P < 0.01) showed an association with healthy ageing. Additionally, the right ventricular blood flow KEi E/A ratio demonstrated the strongest association with healthy ageing (r = -0.53, P < 0.01) when compared to all RV functional and haemodynamic parameters. Furthermore, in a multivariate regression model, KEi E/A ratio and 4D flow derived tricuspid valve stroke volume demonstrated independent association to healthy ageing (beta -0.02 and 0.68 respectively, P < 0.01). Ageing is independently associated with 4D flow derived tricuspid stroke volume and RV blood flow KE E/A ratio. These novel 4D flow CMR derived imaging markers have future potential for RV diastolic assessment.
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http://dx.doi.org/10.1038/s41598-020-66958-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303161PMC
June 2020

BNP/NT-proBNP in pulmonary arterial hypertension: time for point-of-care testing?

Eur Respir Rev 2020 Jun 15;29(156). Epub 2020 May 15.

Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK

Despite the advent of new therapies and improved outcomes in patients with pulmonary arterial hypertension (PAH), it remains a life-shortening disease and the time to diagnosis remains unchanged. Strategies to improve outcomes are therefore currently focused on earlier diagnosis and a treatment approach aimed at moving patients with PAH into a category of low-risk of 1-year mortality. B-type natriuretic peptide (BNP; or brain natriuretic peptide) and N-terminal prohormone of BNP (NT-proBNP) are released from cardiac myocytes in response to mechanical load and wall stress. Elevated levels of BNP and NT-proBNP are incorporated into several PAH risk stratification tools and screening algorithms to aid diagnosis of systemic sclerosis. We have undertaken a systematic review of the literature with respect to the use of BNP and NT-proBNP in PAH and the use of these biomarkers in the diagnosis and risk stratification of PAH, their relation to pulmonary haemodynamics and the potential for point-of-care testing to improve diagnosis and prognosis.
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http://dx.doi.org/10.1183/16000617.0009-2020DOI Listing
June 2020

Editorial: Pulmonary Hypertension: Mechanisms and Management, History and Future.

Front Med (Lausanne) 2020 21;7:125. Epub 2020 Apr 21.

Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, United Kingdom.

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http://dx.doi.org/10.3389/fmed.2020.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186409PMC
April 2020

Whole-Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome.

Am J Respir Crit Care Med 2020 08;202(4):586-594

Department of Infection, Immunity & Cardiovascular Disease, and.

Idiopathic and heritable 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 signaling pathways and stratify patients more robustly according to clinical risk. To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis. 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 expression quantitative trait loci and summary statistics from a PAH genome-wide association study. We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival ( = 4.66 × 10) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776;  = 0.012). 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.
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http://dx.doi.org/10.1164/rccm.202003-0510OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427383PMC
August 2020
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