Publications by authors named "Shahin Moledina"

30 Publications

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Practice patterns of pulmonary hypertension secondary to left heart disease among pediatric pulmonary hypertension providers.

Pulm Circ 2021 Jan-Mar;11(1):2045894021991446. Epub 2021 Feb 9.

Department of Pediatric Cardiology, Ramon y Cajal University Hospital, Madrid, Spain.

Development of pulmonary hypertension (PH) in patients with left side heart disease (LHD) is a predictor of poor prognosis. The use of pulmonary vasodilators in PH associated with LHD (PH-LHD) is controversial. In this study, we describe the practice patterns regarding the use of pulmonary vasodilators in PH-LHD among a group of international pediatric PH specialists. A survey was distributed to the members of three pediatric PH networks: PPHNet, PVRI, and REHIPED. The survey queried participants on the rationale, indications, and contraindications of the use of pulmonary vasodilators in children with PH-LHD. Forty-seven PH specialists from 39 PH centers completed the survey. Participants included PH specialists from North America (57%), South America (15%), and Europe (19%). The majority of participants (74%) recommended the use of pulmonary vasodilators only in patients with combined pre-capillary and post-capillary pulmonary hypertension. Participants required the presence of clinical symptoms or signs of heart failure (68%) or right ventricular dysfunction by echocardiography (51%) in order to recommend pulmonary vasodilator therapy. There was no agreement regarding hemodynamic criteria used to recommend pulmonary vasodilators or the etiologies of LHD considered contraindications for using pulmonary vasodilators to manage PH-LHD. Of the available PH-targeted drugs, most participants preferred the use of phosphodiesterase-5-inhibitors for this indication. In conclusion, the practice of recommending pulmonary vasodilators in PH-LHD is highly variable among international pediatric PH specialists. Most specialists of those surveyed (57% in North America) would consider the use of pulmonary vasodilators in PH-LHD only if pre-capillary pulmonary hypertension and right ventricular dysfunction are present.
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http://dx.doi.org/10.1177/2045894021991446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879002PMC
February 2021

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

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

Department of Medicine, Department of Haematology, University of Cambridge & NIHR BioResource for Translational Research, Cambridge, United Kingdom.

- 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

Pulmonary Vasodilator Therapy in Children with Single Ventricle Physiology: Effects on Saturation and Pulmonary Arterial Pressure.

Pediatr Cardiol 2020 Dec 30;41(8):1651-1659. Epub 2020 Jul 30.

Great Ormond Street Hospital for Children, London, UK.

In children with single ventricle physiology, increased pulmonary vascular resistance may impede surgical progression or result in failing single ventricle physiology. The use of pulmonary vasodilators has been suggested as a potential therapy. However, knowledge on indication, dosage, and effect is limited. A retrospective case notes review of all (n = 36) children with single ventricle physiology, treated with pulmonary vasodilators by the UK Pulmonary Hypertension Service for Children 2004-2017. Therapy was initiated in Stage 1 (n = 12), Glenn (n = 8), or TCPC (n = 16). Treatment indications were high mean pulmonary arterial pressure, cyanosis, reduced exercise tolerance, protein-losing enteropathy, ascites, or plastic bronchitis. Average dose of sildenafil was 2.0 mg/kg/day and bosentan was 3.3 mg/kg/day. 56% had combination therapy. Therapy was associated with a reduction of the mean pulmonary arterial pressure from 19 to 14 mmHg (n = 17, p < 0.01). Initial therapy with one or two vasodilators was associated with an increase in the mean saturation from 80 to 85%, (n = 16, p < 0.01). Adding a second vasodilator did not give significant additional effect. 5 of 12 patients progressed from Stage 1 to Glenn, Kawashima, or TCPC, and 2 of 8 from Glenn to TCPC during a mean follow-up time of 4.7 years (0-12.8). Bosentan was discontinued in 57% and sildenafil in 14% of treated patients and saturations remained stable. Pulmonary vasodilator therapy was well tolerated and associated with improvements in saturation and mean pulmonary arterial pressure in children with single ventricle physiology. It appears safe to discontinue when no clear benefit is observed.
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http://dx.doi.org/10.1007/s00246-020-02424-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695650PMC
December 2020

Repair of isolated atrial septal defect in infants less than 12 months improves symptoms of chronic lung disease or shunt-related pulmonary hypertension.

Cardiol Young 2020 Apr 16;30(4):511-520. Epub 2020 Mar 16.

Cardiorespiratory Unit, Great Ormond Street Hospital for Children, London, UK.

Introduction: Infants with isolated atrial septal defects are usually minimally symptomatic, and repair is typically performed after infancy. Early repair may be considered if there is high pulmonary blood flow and reduced respiratory reserve or early signs of pulmonary hypertension. Our aim was to review the characteristics and outcomes of a cohort of patients who underwent infant repair at our institute.

Methods: The study included 56 infants (28 female, 19 trisomy 21) with isolated atrial septal defect (age: 8 months (1.5-12), weight: 6 kg (2.8-7.5), echo Qp/Qs: 1.9 ± 0.1) who underwent surgical closure (20 fenestrated). Three groups were identified: 1) chronic lung disease and pulmonary hypertension (group A: n = 28%); 2) acutely unwell infants with pulmonary hypertension but no chronic lung disease (group B: n = 20, 36%); and 3) infants with refractory congestive heart failure without either pulmonary hypertension or chronic lung disease (group C: n = 9, 16%).

Results: Post-operatively, pulmonary hypertension infants (47/56) showed improvement in tricuspid annular plane systolic excursion z-score (p < 0.001) and right ventricular systolic/diastolic duration ratio (p < 0.05). All ventilator (14.3%) or oxygen-dependent (31.6%) infants could be weaned within 2 weeks after repair. One year later, weight z-score increased in all patients and by +1 in group A, +1.3 in group B and +2 in group C. Over a median follow-up of 1.4 years, three patients died, four patients continued to have pulmonary hypertension evidence and two remained on targeted pulmonary hypertension therapy.

Conclusion: Atrial septal defect repair within the first year may improve the clinical status and growth in infants with early signs of pulmonary hypertension or those requiring respiratory support and facilitate respiratory management.
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http://dx.doi.org/10.1017/S1047951120000463DOI Listing
April 2020

Characterization of Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2020 03;201(5):575-585

Department of Medicine and.

Recently, rare heterozygous mutations in were identified in patients with pulmonary arterial hypertension (PAH). encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Here we determined the functional impact of mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. Missense BMP9 mutant proteins were expressed and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with variants and in control subjects. Levels were also measured in a larger cohort of control subjects ( = 120) and patients with idiopathic PAH ( = 260). We identified a novel rare variation at the and loci, including copy number variation. , BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of mutations. Our findings demonstrate that mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.
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http://dx.doi.org/10.1164/rccm.201906-1141OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047445PMC
March 2020

Recommendations from the Association for European Paediatric and Congenital Cardiology for training in pulmonary hypertension.

Cardiol Young 2019 Nov 26;29(11):1323-1327. Epub 2019 Sep 26.

Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany.

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient's age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group "pulmonary hypertension, heart failure and transplantation" has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.
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http://dx.doi.org/10.1017/S104795111900235XDOI Listing
November 2019

Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway.

Pediatr Pulmonol 2019 10 16;54(10):1516-1526. Epub 2019 Jul 16.

M3C-Paediatric Cardiology, Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France.

Objective: While pulmonary arterial hypertension (PAH) is rare in infants and children, it results in substantial morbidity and mortality. In recent years, prognosis has improved, coinciding with the introduction of new PAH-targeted therapies, although much of their use in children is off-label. Evidence to guide the treatment of children with PAH is less extensive than for adults. The goal of this review is to discuss the treatment recommendations for children with PAH, as well as the evidence supporting the use of prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (PDE5i) in this setting.

Data Sources: Nonsystematic PubMed literature search and authors' expertise.

Study Selection: Articles were selected concentrating on the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway in PAH. The methodology of an ongoing study evaluating the sGC stimulator riociguat in children with PAH is also described.

Results: Despite recent medical advances, improved therapeutic strategies for pediatric PAH are needed. The efficacy and tolerability of riociguat in adults with PAH have been well trialed.

Conclusion: The pooling of data across trials, supplemented by registry data, will help to confirm the safety and tolerability of prostanoids, ERAs, and PDE5i in children. Ongoing studies will clarify the place of sGC stimulators in the treatment strategy for pediatric PAH.
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http://dx.doi.org/10.1002/ppul.24442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771736PMC
October 2019

Pharmacology of the single isomer, esuberaprost (beraprost-314d) on pulmonary vascular tone, IP receptors and human smooth muscle proliferation in pulmonary hypertension.

Biochem Pharmacol 2019 08 31;166:242-252. Epub 2019 May 31.

Institute of Cardiovascular Science, University College London, London, UK. Electronic address:

Background And Purpose: Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays.

Experimental Approach: Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively.

Key Results: Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP receptor-dependent vasoconstriction at high concentrations ≥ 1000 nM, but contractions were 50% lower compared to beraprost. In HEK-293-IP cells, esuberaprost was 26-fold more potent (EC 0.4 nM) at increasing cAMP than beraprost. In human PASMCs, esuberaprost was 40-fold more potent than beraprost at inhibiting cell proliferation (EC 3 nM versus 120 nM), contrasting the 5-fold potency difference for cAMP elevation. Antiproliferative effects of esuberaprost appeared more dependent on NO than on the IP receptor. In PAs from patients with pulmonary hypertension, esuberaprost, caused some relaxation whereas beraprost instead produced a weak contraction.

Conclusions And Implications: Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.
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http://dx.doi.org/10.1016/j.bcp.2019.05.026DOI Listing
August 2019

Traffic exposures, air pollution and outcomes in pulmonary arterial hypertension: a UK cohort study analysis.

Eur Respir J 2019 05 30;53(5). Epub 2019 May 30.

Dept of Medicine, University of Cambridge, Cambridge, UK.

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 μm (PM), nitrogen dioxide (NO) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined Higher estimated exposure to PM was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3 μg·m; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3 μg·m; p=0.009). No associations were found between NO exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM exposure may independently predict shorter transplant-free survival.
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http://dx.doi.org/10.1183/13993003.01429-2018DOI Listing
May 2019

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

Authors:
Christopher J Rhodes Ken Batai Marta Bleda Matthias Haimel Laura Southgate Marine Germain Michael W Pauciulo Charaka Hadinnapola Jurjan Aman Barbara Girerd Amit Arora Jo Knight Ken B Hanscombe Jason H Karnes Marika Kaakinen Henning Gall Anna Ulrich Lars Harbaum Inês Cebola Jorge Ferrer Katie Lutz Emilia M Swietlik Ferhaan Ahmad Philippe Amouyel Stephen L Archer Rahul Argula Eric D Austin David Badesch Sahil Bakshi Christopher Barnett Raymond Benza Nitin Bhatt Harm J Bogaard Charles D Burger Murali Chakinala Colin Church John G Coghlan Robin Condliffe Paul A Corris Cesare Danesino Stéphanie Debette C Gregory Elliott Jean Elwing Melanie Eyries Terry Fortin Andre Franke Robert P Frantz Adaani Frost Joe G N Garcia Stefano Ghio Hossein-Ardeschir Ghofrani J Simon R Gibbs John Harley Hua He Nicholas S Hill Russel Hirsch Arjan C Houweling Luke S Howard Dunbar Ivy David G Kiely James Klinger Gabor Kovacs Tim Lahm Matthias Laudes Rajiv D Machado Robert V MacKenzie Ross Keith Marsolo Lisa J Martin Shahin Moledina David Montani Steven D Nathan Michael Newnham Andrea Olschewski Horst Olschewski Ronald J Oudiz Willem H Ouwehand Andrew J Peacock Joanna Pepke-Zaba Zia Rehman Ivan Robbins Dan M Roden Erika B Rosenzweig Ghulam Saydain Laura Scelsi Robert Schilz Werner Seeger Christian M Shaffer Robert W Simms Marc Simon Olivier Sitbon Jay Suntharalingam Haiyang Tang Alexander Y Tchourbanov Thenappan Thenappan Fernando Torres Mark R Toshner Carmen M Treacy Anton Vonk Noordegraaf Quinten Waisfisz Anna K Walsworth Robert E Walter John Wharton R James White Jeffrey Wilt Stephen J Wort Delphine Yung Allan Lawrie Marc Humbert Florent Soubrier David-Alexandre Trégouët Inga Prokopenko Richard Kittles Stefan Gräf William C Nichols Richard C Trembath Ankit A Desai Nicholas W Morrell Martin R Wilkins

Lancet Respir Med 2019 03 5;7(3):227-238. Epub 2018 Dec 5.

Department of Medicine, Imperial College London, London, UK. Electronic address:

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.

Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.

Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.

Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.

Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
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http://dx.doi.org/10.1016/S2213-2600(18)30409-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391516PMC
March 2019

Prostanoid EP₂ Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells.

Int J Mol Sci 2018 Aug 12;19(8). Epub 2018 Aug 12.

Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP₂ receptor, the role of which is unknown in PAH. We hypothesised that EP₂ receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP₂ receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP₂ (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP₂ receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP₂ receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP₂ receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP₂ receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.
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http://dx.doi.org/10.3390/ijms19082372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121445PMC
August 2018

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Nat Commun 2018 04 12;9(1):1416. Epub 2018 Apr 12.

Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-018-03672-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897357PMC
April 2018

Phenotypic Characterization of Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

Circulation 2017 11 28;136(21):2022-2033. Epub 2017 Sep 28.

Department of Medicine, University of Cambridge, UK (C.H., M.B., M.H., J.M., C.T., K.Y., M.N., M.T., S. Gräf, N.W.M.)

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 () are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene () are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.

Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in and biallelic variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.

Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in were identified in 130 patients (14.8%). Biallelic mutations in were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without mutations. However, radiological assessment alone could not accurately identify biallelic mutation carriers. Patients with PAH with biallelic mutations had a shorter survival.

Conclusions: Biallelic mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700414PMC
November 2017

Filamin A (FLNA) mutation-A newcomer to the childhood interstitial lung disease (ChILD) classification.

Pediatr Pulmonol 2017 10 12;52(10):1306-1315. Epub 2017 Sep 12.

Department of Clinical Radiology, Great Ormond Street Hospital, London, UK.

Aim: Interstitial lung disease (ILD) in infants represents a rare and heterogenous group of disorders, distinct from those occurring in adults. In recent years a new entity within this category is being recognized, namely filamin A (FLNA) mutation related lung disease. Our aims are to describe the clinical and radiological course of patients with this disease entity to aid clinicians in the prognostic counseling and management of similar patients they may encounter.

Method: A retrospective case note review was conducted of all patients treated at our institution (a specialist tertiary referral childrens' center) for genetically confirmed FLNA mutation related lung disease. The clinical presentation, evolution, management and radiological features were recorded and a medical literature review of Medline indexed articles was conducted.

Results: We present a case series of four patients with interstitial lung disease and genetically confirmed abnormalities within the FLNA gene. Their imaging findings all reveal a pattern of predominantly upper lobe overinflation, coarse pulmonary lobular septal thickening and diffuse patchy atelectasis. The clinical outcomes of our patients have been variable ranging from infant death, lobar resection and need for supplemental oxygen and bronchodilators.

Conclusion: The progressive nature of the pulmonary aspect of this disorder and need for early aggressive supportive treatment make identification crucial to patient management and prognostic counseling.
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http://dx.doi.org/10.1002/ppul.23695DOI Listing
October 2017

Pulmonary arterial hypertension in children after neonatal arterial switch operation.

Heart 2017 08 23;103(16):1244-1249. Epub 2017 Jan 23.

Center for Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Objectives: Paediatric pulmonary arterial hypertension (PAH) after neonatal arterial switch operation (ASO) for transposition of the great arteries (TGA) is a clinically recognised entity with an estimated incidence of 0.6%-1.0%. Nevertheless, a clinical characterisation is lacking. We present an international cohort of children with PAH after neonatal ASO for TGA and describe epidemiology and clinical course.

Methods: Data were collected of children with PAH after neonatal ASO (≤6 weeks after birth) for simple TGA without residual shunt defects, identified in four national paediatric PAH networks in Europe and one US referral centre.

Results: Twenty-five children were identified between 1989 and 2014. In 17 children (68%), PAH was detected <1 year after ASO. In the remaining children, PAH was detected after median 64 months (IQR 19.5, 94.5). Nineteen children (96%) received PAH-targeted therapies. During follow-up after ASO (median 5.2 years), eight children died, four underwent lung transplantation and two received a Potts shunt. 1-year and 5-year Potts shunt- and transplantation-free survival after ASO was 100% and 73%. From first PAH detection, this was 100% and 58%, respectively, which did not differ between children with early (<1 year after ASO) or late PAH detection.

Conclusions: The occurrence of PAH after ASO for TGA represents a specific association. PAH onset may be early or late after ASO, with similar fatal course from first PAH detection. Mechanisms leading to PAH in this association are unknown, but may include abnormal prenatal pulmonary haemodynamics and/or genetic susceptibility. Routine, lifelong follow-up for children who undergo ASO for TGA should include screening for PAH.
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http://dx.doi.org/10.1136/heartjnl-2016-310624DOI Listing
August 2017

Magnetic Resonance-Augmented Cardiopulmonary Exercise Testing: Comprehensively Assessing Exercise Intolerance in Children With Cardiovascular Disease.

Circ Cardiovasc Imaging 2016 Dec;9(12)

From the Centre for Cardiovascular Imaging, UCL Institute of Cardiovascular Science, London, United Kingdom (N.J.B., E.O.A., G.T.K., M.H.C., J.A.S., V.M.); Great Ormond Street Hospital, London, United Kingdom (N.J.B., G.T.K., M.H.C., J.A.S., S.M., V.M.); and Bart's Heart Centre, London, United Kingdom (E.O.A., B.P.).

Background: Conventional cardiopulmonary exercise testing can objectively measure exercise intolerance but cannot provide comprehensive evaluation of physiology. This requires additional assessment of cardiac output and arteriovenous oxygen content difference. We developed magnetic resonance (MR)-augmented cardiopulmonary exercise testing to achieve this goal and assessed children with right heart disease.

Methods And Results: Healthy controls (n=10) and children with pulmonary arterial hypertension (PAH; n=10) and repaired tetralogy of Fallot (n=10) underwent MR-augmented cardiopulmonary exercise testing. All exercises were performed on an MR-compatible ergometer, and oxygen uptake was continuously acquired using a modified metabolic cart. Simultaneous cardiac output was measured using a real-time MR flow sequence and combined with oxygen uptake to calculate arteriovenous oxygen content difference. Peak oxygen uptake was significantly lower in the PAH group (12.6±1.31 mL/kg per minute; P=0.01) and trended toward lower in the tetralogy of Fallot group (13.5±1.29 mL/kg per minute; P=0.06) compared with controls (16.7±1.37 mL/kg per minute). Although tetralogy of Fallot patients had the largest increase in cardiac output, they had lower resting (3±1.2 L/min per m) and peak (5.3±1.2 L/min per m) values compared with controls (resting 4.3±1.2 L/min per m and peak 6.6±1.2 L/min per m) and PAH patients (resting 4.5±1.1 L/min per m and peak 5.9±1.1 L/min per m). Both the PAH and tetralogy of Fallot patients had blunted exercise-induced increases in arteriovenous oxygen content difference. However, only the PAH patients had significantly reduced peak values (6.9±1.3 mlO2/100 mL) compared with controls (8.4±1.4 mlO2/100 mL; P=0.005).

Conclusions: MR-augmented cardiopulmonary exercise testing is feasible in both healthy children and children with cardiac disease. Using this novel technique, we have demonstrated abnormal exercise patterns in oxygen uptake, cardiac output, and arteriovenous oxygen content difference.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.005282DOI Listing
December 2016

Cardiac catheterization in children with pulmonary hypertensive vascular disease: consensus statement from the Pulmonary Vascular Research Institute, Pediatric and Congenital Heart Disease Task Forces.

Pulm Circ 2016 Mar;6(1):118-25

Stollery Children's Hospital, Edmonton, Alberta, Canada; on behalf of the PVRI Pediatric Task Force members Steven Abman, Vera Aiello, Rolf Berger, Patricia Cortez, Jeffrey Fineman, Marilyne Lévy, Marlene Rabinovitch, J. Usha Raj, Irwin Reiss, Julio Sandoval, Kurt Stenmark, and Rao Sureshi.

Cardiac catheterization is important in the diagnosis and risk stratification of pulmonary hypertensive vascular disease (PHVD) in children. Acute vasoreactivity testing provides key information about management, prognosis, therapeutic strategies, and efficacy. Data obtained at cardiac catheterization continue to play an important role in determining the surgical options for children with congenital heart disease and clinical evidence of increased pulmonary vascular resistance. The Pediatric and Congenital Heart Disease Task Forces of the Pulmonary Vascular Research Institute met to develop a consensus statement regarding indications for, conduct of, acute vasoreactivity testing with, and pitfalls and risks of cardiac catheterization in children with PHVD. This document contains the essentials of those discussions to provide a rationale for the hemodynamic assessment by cardiac catheterization of children with PHVD.
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http://dx.doi.org/10.1086/685102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809667PMC
March 2016

Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

Heart 2016 May;102 Suppl 2:ii86-100

Department of Paediatric Cardiology, German Paediatric Heart Centre, Sankt Augustin, Germany.

Unlabelled: : The European Paediatric Pulmonary Vascular Disease (PVD) Network is a registered, non-profit organisation that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of paediatric pulmonary hypertensive vascular disease, including specific forms such as pulmonary arterial hypertension (PAH)-congenital heart disease, pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, persistent PH of the newborn, and related cardiac dysfunction.

Methods: The writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2015) and held five face-to-face meetings with votings. Clinical trials, guidelines, and reviews limited to paediatric data were searched using the terms 'pulmonary hypertensioń' and 5-10 other keywords, as outlined in the other nine articles of this special issue. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on paediatric data only, or on adult studies that included >10% children.

Results: A total of 9 original consensus articles with graded recommendations (COR/LOE) were developed, and are summarised here. The topics included diagnosis/monitoring, genetics/biomarker, cardiac catheterisation, echocardiography, cardiac magnetic resonance/chest CT, associated forms of PH, intensive care unit/ventricular assist device/lung transplantation, and treatment of paediatric PAH.

Conclusions: The multipaper expert consensus statement of the European Paediatric PVD Network provides a specific, comprehensive, detailed but practical framework for the optimal clinical care of children with PH.
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http://dx.doi.org/10.1136/heartjnl-2015-309132DOI Listing
May 2016

Cardiac MR and CT imaging in children with suspected or confirmed pulmonary hypertension/pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.

Heart 2016 May;102 Suppl 2:ii30-5

National Paediatric Pulmonary Hypertension Service UK, Great Ormond Street Hospital for Children, London, UK.

Childhood pulmonary hypertension (PH) is a heterogenous disease associated with considerable morbidity and mortality. Invasive assessment of haemodynamics is crucial for accurate diagnosis and guidance of medical therapy. However, adequate imaging is increasingly important in children with PH to evaluate the right heart and the pulmonary vasculature. Cardiac MR (CMR) and computed tomography (CT) represent important non-invasive imaging modalities that may enable comprehensive assessment of right ventricular (RV) function and pulmonary haemodynamics. Here, we present graded consensus recommendations for the evaluation of children with PH by CMR and CT. The article provides a structured approach for the use of CMR and CT imaging, emphasises non-invasive variables of RV function, myocardial tissue and afterload parameters that may be useful for initial diagnosis and monitoring. Furthermore, assessment of pulmonary perfusion and characterisation of the lung parenchyma provides structural information about processes that may cause or be due to PH.
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http://dx.doi.org/10.1136/heartjnl-2015-308246DOI Listing
May 2016

Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort.

Circulation 2016 May 6;133(18):1761-71. Epub 2016 Apr 6.

From Papworth Hospital, Cambridge, United Kingdom (J.E.C., K.P., M.T., E.S., C.T., A. Ponnaberanam, K.S., D.T., J.D., S.T., C.N., N.S., D.P.T., J.P.-Z.); MRC Biostatistics Unit, Cambridge, United Kingdom (L.S.); Royal Hallamshire Hospital, Sheffield, United Kingdom (D.G.K., R.C., C.E.); Respiratory Medicine Department, University of Warmia and Mazury, Poland (E.S.); Hammersmith Hospital, London, United Kingdom (D.G., S. Gibbs, L.H.); Freeman Hospital, Newcastle, United Kingdom (P.C., J.L.); Golden Jubilee Hospital, Glasgow, United Kingdom (M.J., A. Peacock); Royal United Hospital, Bath, United Kingdom (R.M.-R.); Royal Free Hospital, London, United Kingdom (B.S., G.C.); Royal Brompton Hospital, London, United Kingdom (K.D., J.W.); Mater Misericordiae University Hospital, Dublin, Ireland (S. Gaine); and Great Ormond Street Hospital, London, United Kingdom (S.M.).

Background: Chronic thromboembolic pulmonary hypertension results from incomplete resolution of pulmonary emboli. Pulmonary endarterectomy (PEA) is potentially curative, but residual pulmonary hypertension following surgery is common and its impact on long-term outcome is poorly understood. We wanted to identify factors correlated with poor long-term outcome after surgery and specifically define clinically relevant residual pulmonary hypertension post-PEA.

Methods And Results: Eight hundred eighty consecutive patients (mean age, 57 years) underwent PEA for chronic thromboembolic pulmonary hypertension. Patients routinely underwent detailed reassessment with right heart catheterization and noninvasive testing at 3 to 6 months and annually thereafter with discharge if they were clinically stable at 3 to 5 years and did not require pulmonary vasodilator therapy. Cox regressions were used for survival (time-to-event) analyses. Overall survival was 86%, 84%, 79%, and 72% at 1, 3, 5, and 10 years for the whole cohort and 91% and 90% at 1 and 3 years for the recent half of the cohort. The majority of patient deaths after the perioperative period were not attributable to right ventricular failure (chronic thromboembolic pulmonary hypertension). At reassessment, a mean pulmonary artery pressure of ≥30 mm Hg correlated with the initiation of pulmonary vasodilator therapy post-PEA. A mean pulmonary artery pressure of ≥38 mm Hg and pulmonary vascular resistance ≥425 dynes·s(-1)·cm(-5) at reassessment correlated with worse long-term survival.

Conclusions: Our data confirm excellent long-term survival and maintenance of good functional status post-PEA. Hemodynamic assessment 3 to 6 months and 12 months post-PEA allows stratification of patients at higher risk of dying of chronic thromboembolic pulmonary hypertension and identifies a level of residual pulmonary hypertension that may guide the long-term management of patients postsurgery.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.019470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860739PMC
May 2016

Left ventricular diastolic dysfunction in pulmonary hypertension predicts functional capacity and clinical worsening: a tissue phase mapping study.

J Cardiovasc Magn Reson 2015 Dec 29;17:116. Epub 2015 Dec 29.

UCL Medical School, Royal Free Campus, Rowland Hill Street, London, UK.

Background: The function of the right and left ventricles is intimately related through a shared septum and pericardium. Therefore, right ventricular (RV) disease in pulmonary hypertension (PH) can result in abnormal left ventricular (LV) myocardial mechanics. To assess this, we implemented novel cardiovascular magnetic resonance (CMR) tissue phase mapping (TPM) to assess radial, longitudinal and tangential LV myocardial velocities in patients with PH.

Methods: Respiratory self-gated TPM was performed using a rotating golden-angle spiral acquisition with retrospective cardiac gating. TPM of a mid ventricular slice was acquired in 40 PH patients and 20 age- and sex-matched healthy controls. Endocardial and epicardial LV borders were manually defined, and myocardial velocities calculated using in-house software. Patients without proximal CTEPH (chronic thromboembolic PH) and not receiving intravenous prostacyclin therapy (n = 34) were followed up until the primary outcome of disease progression (death, transplantation, or progression to intravenous therapy) or the end of the study. Physicians who determined disease progression were blinded to CMR data. Conventional ventricular volumetric indices and novel TPM metrics were analyzed for prediction of 6-min walk distance (6MWD) and disease progression.

Results: Peak longitudinal (p < 0.0001) and radial (p = 0.001) early diastolic (E) wave velocities were significantly lower in PH patients compared with healthy volunteers. Reversal of tangential E waves was observed in all patients and was highly discriminative for the presence of PH (p < 0.0001). The global radial E wave (β = 0.41, p = 0.017) and lateral wall radial systolic (S) wave velocities (β = 0.33, p = 0.028) were the only independent predictors of 6MWD in a model including RV ejection fraction (RVEF) and LV stroke volume. Over a median follow-up period of 20 months (IQR 7.9 months), 8 patients commenced intravenous therapy and 1 died. Global longitudinal E wave was the only independent predictor of clinical worsening (6.3× increased risk, p = 0.009) in a model including RVEF and septal curvature.

Conclusions: TPM metrics of LV diastolic function are significantly abnormal in PH. More importantly, abnormal LV E wave velocities are the only independent predictors of functional capacity and clinical worsening in a model that includes conventional metrics of biventricular function.
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http://dx.doi.org/10.1186/s12968-015-0220-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696235PMC
December 2015

Feasibility and safety of cardiopulmonary exercise testing in children with pulmonary hypertension.

Cardiol Young 2016 Aug 16;26(6):1144-50. Epub 2015 Sep 16.

3Cardiorespiratory Unit,Great Ormond Street Hospital,London,United Kingdom.

Background: Cardiopulmonary exercise testing helps prognosticate and guide treatment in adults with pulmonary hypertension. Concerns regarding its feasibility and safety limit its use in children with pulmonary hypertension. We aimed to assess the feasibility and safety of cardiopulmonary exercise testing in a large paediatric pulmonary hypertension cohort.

Methods: We reviewed all consecutive cardiopulmonary exercise tests performed between March, 2004 and November, 2013. The exclusion criteria were as follows: height <120 cm, World Health Organization class IV, history of exercise-induced syncope, or significant ischaemia/arrhythmias. Significant events recorded were as follows: patient-reported symptoms, arrhythmias, electrocardiogram abnormalities, and abnormal responses of arterial O2 saturation.

Results: A total of 98 children underwent 167 cardiopulmonary exercise tests. The median age was 14 years (inter-quartile range 10-15 years). Peak oxygen uptake was 20.4±7.3 ml/kg/minute, corresponding to 51.8±18.3% of the predicted value. Peak respiratory quotient was 1.08±0.16. All the tests except two were maximal, being terminated prematurely for clinical reasons. Baseline Oxygen saturation was 93.3±8.8% and was 81.2±19.5% at peak exercise. A drop in arterial O2 saturation >20% was observed in 23.5% of the patients. Moreover, five patients (3.0%) experienced dizziness, one requiring termination of cardiopulmonary exercise testing; five children (3.0%) experienced chest pain, with early cardiopulmonary exercise test termination in one patient. No significant arrhythmias or electrocardiogram changes were observed.

Conclusion: Exercise testing in non-severely symptomatic children with pulmonary hypertension is safe and practical, and can be performed in a large number of children with pulmonary hypertension in a controlled environment with an experienced team. Side-effects were not serious and were resolved promptly with test termination.
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http://dx.doi.org/10.1017/S1047951115001961DOI Listing
August 2016

Noninvasive pulmonary artery wave intensity analysis in pulmonary hypertension.

Am J Physiol Heart Circ Physiol 2015 Jun 6;308(12):H1603-11. Epub 2015 Feb 6.

Centre for Cardiovascular Imaging, Institute of Cardiovascular Science, University College London and Great Ormond Street Hospital for Children, London, United Kingdom;

Pulmonary wave reflections are a potential hemodynamic biomarker for pulmonary hypertension (PH) and can be analyzed using wave intensity analysis (WIA). In this study we used pulmonary vessel area and flow obtained using cardiac magnetic resonance (CMR) to implement WIA noninvasively. We hypothesized that this method could detect differences in reflections in PH patients compared with healthy controls and could also differentiate certain PH subtypes. Twenty patients with PH (35% CTEPH and 75% female) and 10 healthy controls (60% female) were recruited. Right and left pulmonary artery (LPA and RPA) flow and area curves were acquired using self-gated golden-angle, spiral, phase-contrast CMR with a 10.5-ms temporal resolution. These data were used to perform WIA on patients and controls. The presence of a proximal clot in CTEPH patients was determined from contemporaneous computed tomography/angiographic data. A backwards-traveling compression wave (BCW) was present in both LPA and RPA of all PH patients but was absent in all controls (P = 6e(-8)). The area under the BCW was associated with a sensitivity of 100% [95% confidence interval (CI) 63-100%] and specificity of 91% (95% CI 75-98%) for the presence of a clot in the proximal PAs of patients with CTEPH. In conclusion, WIA metrics were significantly different between patients and controls; in particular, the presence of an early BCW was specifically associated with PH. The magnitude of the area under the BCW showed discriminatory capacity for the presence of proximal PA clot in patients with CTEPH. We believe that these results demonstrate that WIA could be used in the noninvasive assessment of PH.
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http://dx.doi.org/10.1152/ajpheart.00480.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469876PMC
June 2015

Repair of congenital heart disease with associated pulmonary hypertension in children: what are the minimal investigative procedures? Consensus statement from the Congenital Heart Disease and Pediatric Task Forces, Pulmonary Vascular Research Institute (PVRI).

Pulm Circ 2014 Jun;4(2):330-41

Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada ; Leader of the Pediatric Task Force, PVRI.

Standardization of the diagnostic routine for children with congenital heart disease associated with pulmonary arterial hypertension (PAH-CHD) is crucial, in particular since inappropriate assignment to repair of the cardiac lesions (e.g., surgical repair in patients with elevated pulmonary vascular resistance) may be detrimental and associated with poor outcomes. Thus, members of the Congenital Heart Disease and Pediatric Task Forces of the Pulmonary Vascular Research Institute decided to conduct a survey aimed at collecting expert opinion from different institutions in several countries, covering many aspects of the management of PAH-CHD, from clinical recognition to noninvasive and invasive diagnostic procedures and immediate postoperative support. In privileged communities, the vast majority of children with congenital cardiac shunts are now treated early in life, on the basis of noninvasive diagnostic evaluation, and have an uneventful postoperative course, with no residual PAH. However, a small percentage of patients (older at presentation, with extracardiac syndromes or absence of clinical features of increased pulmonary blood flow, thus suggesting elevated pulmonary vascular resistance) remain at a higher risk of complications and unfavorable outcomes. These patients need a more sophisticated diagnostic approach, including invasive procedures. The authors emphasize that decision making regarding operability is based not only on cardiac catheterization data but also on the complete diagnostic picture, which includes the clinical history, physical examination, and all aspects of noninvasive evaluation.
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http://dx.doi.org/10.1086/675995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070778PMC
June 2014

Real-time magnetic resonance assessment of septal curvature accurately tracks acute hemodynamic changes in pediatric pulmonary hypertension.

Circ Cardiovasc Imaging 2014 Jul 25;7(4):706-13. Epub 2014 Apr 25.

From the Centre for Cardiovascular Imaging, UCL Institute of Cardiovascular Science, London, United Kingdom (B.P., M.A.Q., J.A.S., A.M.T., V.M.); Cardiorespiratory Division, Great Ormond Street Hospital for Children, London, United Kingdom (I.S.-N., G.D., S.M.); Adult Congenital Heart Disease Department, The Heart Hospital, University College London Hospitals, London, United Kingdom (B.P.); Pediatric Respiratory Medicine, The Royal Brompton Hospital, London, United Kingdom (A.M.); INSERM, U947, Nancy, France (F.O.); and IADI, Universite de Lorraine, Nancy, France (F.O.).

Background: This study assesses the relationship between septal curvature and mean pulmonary artery pressure and indexed pulmonary vascular resistance in children with pulmonary hypertension. We hypothesized that septal curvature could be used to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics.

Methods And Results: Fifty patients with a median age of 6.7 years (range, 0.45-16.5 years) underwent combined cardiac catheterization and cardiovascular magnetic resonance. The majority had idiopathic pulmonary arterial hypertension (n=30); the remaining patients had pulmonary hypertension associated with repaired congenital heart disease (n=17) or lung disease (n=3). Mean pulmonary artery pressure and pulmonary vascular resistance were acquired at baseline and during vasodilation. Septal curvature was measured using real-time cardiovascular magnetic resonance. There was a strong correlation between mean pulmonary artery pressure and SCmin at baseline and during vasodilator testing (r=-0.81 and -0.85, respectively; P<0.01). A strong linear relationship also existed between pulmonary vascular resistance and minimum septal curvature indexed to cardiac output both at baseline and during vasodilator testing (r=-0.88 and -0.87, respectively; P<0.01). Change in septal curvature metrics moderately correlated with absolute change in mean pulmonary artery pressure and pulmonary vascular resistance, respectively (r=0.58 and -0.74; P<0.01). Septal curvature metrics were able to identify vasoresponders with a sensitivity of 83% (95% confidence interval, 0.36-0.99) and a specificity of 91% (95% confidence interval, 0.77-0.97), using the Sitbon criteria. Idiopathic pulmonary arterial hypertension subgroup analysis revealed 3 responders with ΔSCmin values of 0.523, 0.551, and 0.568. If the middle value of 0.551 is taken as a cutoff, the approximate sensitivity would be 67% and the specificity would be 93%.

Conclusions: Septal curvature metrics are able to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics during vasodilator testing. This suggests that septal curvature could be used for continuing assessment of load in pulmonary hypertension.
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http://dx.doi.org/10.1161/CIRCIMAGING.113.001156DOI Listing
July 2014

Prognostic significance of cardiac magnetic resonance imaging in children with pulmonary hypertension.

Circ Cardiovasc Imaging 2013 May 9;6(3):407-14. Epub 2013 Apr 9.

Centre for Cardiovascular Imaging, UCL Institute of Cardiovascular Science, Unuiversity College London, UK.

Background: There are very few validated prognostic markers in pediatric pulmonary hypertension. Cardiac MRI is a useful, noninvasive method for determining prognosis in adults. The present study is the first to assess its prognostic value in children.

Methods And Results: A total of 100 children with pulmonary hypertension (median, 10.4 years; range, 0.5-17.6 years) were evaluated (idiopathic, n=60; repaired congenital heart disease, n=22; miscellaneous, n=18). In all patients, ventricular volumes and great vessel flow were measured. Volumetric data were obtained using retrospectively gated cine imaging (n=37) or real-time imaging (n=63), depending on the patient's ability to hold his or her breath. During a median follow-up of 1.9 years, 11 patients died and 3 received lung transplantation. Of the cardiac MR parameters measured, right ventricular ejection fraction and left ventricular stroke volume index were most strongly predictive of survival on univariate analysis (2.6- and 2.5-fold increase in mortality for every 1-SD decrease, respectively; P<0.05). These results were reflected in good separation of tertile-based Kaplan-Meier survival curves for these variables.

Conclusions: Cardiac MR measures correlate with clinical status and prognosis in children with pulmonary hypertension. Cardiac MR is feasible and may be useful in clinical decision making in pediatric pulmonary hypertension.
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http://dx.doi.org/10.1161/CIRCIMAGING.112.000082DOI Listing
May 2013

Fractal branching quantifies vascular changes and predicts survival in pulmonary hypertension: a proof of principle study.

Heart 2011 Aug 8;97(15):1245-9. Epub 2011 Feb 8.

Great Ormond Street Hospital, London, UK.

Objectives: To develop a non-invasive method of assessing disease severity in pulmonary hypertension by quantifying the overall degree of vascular pruning using fractal geometry.

Design: A retrospective analysis of ECG-gated CT pulmonary angiograms.

Setting: A single national referral centre for the investigation and treatment of children with pulmonary hypertension.

Patients: Consecutive CT pulmonary angiograms in children and young adults (mean age 10.3 years, range 0.7-19.1) with pulmonary arterial hypertension assessed between January 2007 and April 2009.

Main Outcome Measures: The fractal dimension (FD) of skeletonised CT pulmonary angiograms was calculated using the box counting method. The FD was compared with pulmonary vascular resistance, the percentage of predicted 6-min walk distance, WHO functional class and survival.

Results: Diagnostic plots confirmed that the pulmonary artery angiograms were all fractal. The FD correlated negatively with the pulmonary vascular resistance index (r=-0.55, p=0.01, n=21) and with WHO functional class (p<0.01, n=31) while it correlated positively with the percentage of predicted 6-min walk distance (r=0.43, p=0.04, n=24). A lower FD was associated with poorer survival (HR 5.6; 95% CI 1.2 to 25; p=0.027) for every SD reduction in FD.

Conclusion: The FD derived from CT can be used to quantify vascular changes in pulmonary hypertension. This non-invasive technique may be useful in monitoring disease progression and response to therapy.
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http://dx.doi.org/10.1136/hrt.2010.214130DOI Listing
August 2011

Pulmonary hypertension in children with Evans syndrome.

Pediatr Hematol Oncol 2008 Mar;25(2):93-8

Department of Haematology, Great Ormond Street Hospital, London, UK.

Evans syndrome is a rare cause of hemolysis in pediatric patients. The authors describe two severely affected patients who had previously been heavily treated, and who subsequently developed severe pulmonary hypertension. Both patients were successfully managed by a combination of immunosuppression and anti-pulmonary hypertension treatment. The first patient to present, case A, received an allogeneic bone marrow transplant with subsequent cure of both Evans syndrome and pulmonary hypertension and is now on a weaning dose of sildenafil. Case B is being worked up for allogeneic bone marrow transplantation. The authors speculate that the pulmonary hypertension was caused by the underlying immune dysregulation and hemolysis and that Evans syndrome joins the list of other hemolytic anemias that cause pulmonary hypertension, such as sickle cell disease, thalassemia, and paroxysmal nocturnal hemoglobinuria. However, they suggest a vasculitic process as the main cause.
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http://dx.doi.org/10.1080/08880010801888253DOI Listing
March 2008