Imperial College London

Professor Martin Wilkins

Faculty of MedicineNational Heart & Lung Institute

Professor of Clinical Pharmacology
 
 
 
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Contact

 

+44 (0)20 3313 6101m.wilkins Website

 
 
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Assistant

 

Mrs Elizabeth O'Brien +44 (0)20 3313 6101

 
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Location

 

NIHR Imperial Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

241 results found

Alhathli E, Julian T, Girach ZUA, Thompson AAR, Rhodes C, Gräf S, Errington N, Wilkins MR, Lawrie A, Wang D, Cooper-Knock Jet al., 2024, Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension, Journal of the American Heart Association, Vol: 13, ISSN: 2047-9980

BACKGROUND: Pulmonary arterial hypertension (PAH) exhibits phenotypic heterogeneity and variable response to therapy. The metabolome has been implicated in the pathogenesis of PAH, but previous works have lacked power to implicate specific metabolites. Mendelian randomization (MR) is a method for causal inference between exposures and outcomes. METHODS AND RESULTS: Using genome-wide association study summary statistics, we implemented MR analysis to test for potential causal relationships between serum concentration of 575 metabolites and PAH. Five metabolites were causally associated with the risk of PAH after multiple testing correction. Next, we measured serum concentration of candidate metabolites in an independent clinical cohort of 449 patients with PAH to check whether metabolite concentrations are correlated with markers of disease severity. Of the 5 candidates nominated by our MR work, serine was negatively associated and homostachydrine was positively associated with clinical severity of PAH via direct measurement in this independent clinical cohort. Finally we used conditional and orthogonal approaches to explore the biology underlying our lead metabolites. Rare variant burden testing was carried out using whole exome sequencing data from 578 PAH cases and 361 675 controls. Multivariable MR is an extension of MR that uses a single set of instrumental single-nucleotide polymorphisms to measure multiple exposures; multivariable MR is used to determine interdependence between the effects of different exposures on a single outcome. Rare variant analysis demonstrated that loss-of-function mutations within activating transcription factor 4, a transcription factor responsible for upregulation of serine synthesis under conditions of serine starvation, are associated with higher risk for PAH. Homostachydrine is a xenobiotic metabolite that is structurally related to l-proline betaine, which has previously been linked to modulation of inflammation and tissue

Journal article

Yogeswaran A, Gall H, Fünderich M, Wilkins MR, Howard L, Kiely DG, Lawrie A, Hassoun PM, Sirenklo Y, Torbas O, Sweatt AJ, Zamanian RT, Williams PG, Frauendorf M, Arvanitaki A, Giannakoulas G, Saleh K, Sabbour H, Cajigas HR, Frantz R, Al Ghouleh I, Chan SY, Brittain E, Annis JS, Pepe A, Ghio S, Orfanos S, Anthi A, Majeed RW, Wilhelm J, Ghofrani HA, Richter MJ, Grimminger F, Sahay S, Tello K, Seeger W, PVRI-GoDeep-Consortiumet al., 2024, Comparison of contemporary risk scores in all groups of pulmonary hypertension - a PVRI GoDeep meta-registry analysis., Chest

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). While various risk models were developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH group 1-4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among incident PH patients enrolled in the multicenter worldwide PVRI-GoDeep meta-registry. Analyses were performed across PH groups 1-4 and further subgroups to evaluate the predictive value of PAH-risk scores, including REVEAL Lite 2, REVEAL 2.0, ESC/ERS 2022, COMPERA 3-strata and COMPERA 4-strata. RESULTS: 8565 patients were included in the study, of whom 3537 patients were assigned to group 1 PH while 1807, 1635, and 1586 patients were diagnosed with group 2, group 3, and group 4 PH. Pulmonary hemodynamics were impaired with median mPAP of 42 [33,52]mmHg and PVR of 7 [4,11]WU. All risk scores were prognostic in the entire PH population and in each of the PH groups 1-4. The REVEAL scores, when used as continuous prediction models, possessed the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided sub-differentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, 1.4.4; 3.1, 3.2; group 2 with isolated post-capillary-PH versus combined pre-/post-capillary-PH; patients of all groups with concomitant cardiac comorbidities; severe [> 5 WU] versus non-severe PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH-centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common group

Journal article

Liley J, Newnham M, Bleda M, Bunclark K, Auger W, Barbera JA, Bogaard H, Delcroix M, Fernandes TM, Howard L, Jenkins D, Lang I, Mayer E, Rhodes C, Simpson M, Southgate L, Trembath R, Wharton J, Wilkins MR, Gräf S, Morrell N, Pepke Zaba J, Toshner Met al., 2024, Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism., Am J Respir Crit Care Med

RATIONALE: Chronic Thromboembolic Pulmonary Hypertension involves formation and non-resolution of thrombus, dysregulated inflammation, angiogenesis and the development of a small vessel vasculopathy. OBJECTIVES: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. METHODS: We conducted a genome-wide association study on 1907 European cases and 10363 European controls. We co-analysed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism and idiopathic pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our co-analysis we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2 and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. CONCLUSIONS: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations to pulmonary embolism and to deep vein thrombosis.

Journal article

Woolf B, Perry JA, Hong CC, Wilkins MR, Toshner M, Gill D, Burgess S, Rhodes CJet al., 2024, Multi-biobank summary data Mendelian randomisation does not support a causal effect of IL-6 signalling on risk of pulmonary arterial hypertension., Eur Respir J

Journal article

UK HFpEF Collaborative Group, 2024, Rationale and design of the United Kingdom Heart Failure with Preserved Ejection Fraction Registry., Heart, Vol: 110, Pages: 359-365

OBJECTIVE: Heart failure with preserved ejection fraction (HFpEF) is a common heterogeneous syndrome that remains imprecisely defined and consequently has limited treatment options and poor outcomes. METHODS: The UK Heart Failure with Preserved Ejection Fraction Registry (UK HFpEF) is a prospective data-enabled cohort and platform study. The study will develop a large, highly characterised cohort of patients with HFpEF. A biobank will be established. Deep clinical phenotyping, imaging, multiomics and centrally held national electronic health record data will be integrated at scale, in order to reclassify HFpEF into distinct subgroups, improve understanding of disease mechanisms and identify new biological pathways and molecular targets. Together, these will form the basis for developing diagnostics and targeted therapeutics specific to subgroups. It will be a platform for more effective and efficient trials, focusing on subgroups in whom targeted interventions are expected to be effective, with consent in place to facilitate rapid recruitment, and linkage for follow-up. Patients with a diagnosis of HFpEF made by a heart failure specialist, who have had natriuretic peptide levels measured and a left ventricular ejection fraction >40% are eligible. Patients with an ejection fraction between 40% and 49% will be limited to no more than 25% of the cohort. CONCLUSIONS: UK HFpEF will develop a rich, multimodal data resource to enable the identification of disease endotypes and develop more effective diagnostic strategies, precise risk stratification and targeted therapeutics. TRIAL REGISTRATION NUMBER: NCT05441839.

Journal article

Tai Y-Y, Yu Q, Tang Y, Sun W, Kelly NJ, Okawa S, Zhao J, Schwantes-An T-H, Lacoux C, Torrino S, Al Aaraj Y, El Khoury W, Negi V, Liu M, Corey CG, Belmonte F, Vargas SO, Schwartz B, Bhat B, Chau BN, Karnes JH, Satoh T, Barndt RJ, Wu H, Parikh VN, Wang J, Zhang Y, McNamara D, Li G, Speyer G, Wang B, Shiva S, Kaufman B, Kim S, Gomez D, Mari B, Cho MH, Boueiz A, Pauciulo MW, Southgate L, Trembath RC, Sitbon O, Humbert M, Graf S, Morrell NW, Rhodes CJ, Wilkins MR, Nouraie M, Nichols WC, Desai AA, Bertero T, Chan SYet al., 2024, Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension., Sci Transl Med, Vol: 16

Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.

Journal article

Ulrich A, Wu Y, Draisma H, Wharton J, Swietlik EM, Cebola I, Vasilaki E, Balkhiyarova Z, Jarvelin M-R, Auvinen J, Herzig K-H, Coghlan JG, Lordan J, Church C, Howard LS, Pepke-Zaba J, Toshner M, Wort SJ, Kiely DG, Condliffe R, Lawrie A, Gräf S, Morrell NW, Wilkins MR, Prokopenko I, Rhodes CJet al., 2024, Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension., Nat Commun, Vol: 15

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10-7) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10-4). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

Journal article

Varian F, Dick J, Battersby C, Roman S, Ablott J, Watson L, Binmahfooz S, Zafar H, Colgan G, Cannon J, Suntharalingam J, Lordan J, Howard L, McCabe C, Wort J, Price L, Church C, Hamilton N, Armstrong I, Hameed A, Hurdman J, Elliot C, Condliffe R, Wilkins M, Webb A, Adlam D, Benza RL, Rahimi K, Shojaei-Shahrokhabadi M, Lin NX, Wason JMS, McIntosh A, McConnachie A, Middleton JT, Thompson R, Kiely DG, Toshner M, Rothman Aet al., 2024, Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies., Pulm Circ, Vol: 14, ISSN: 2045-8932

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Journal article

Welch CL, Aldred MA, Balachandar S, Dooijes D, Eichstaedt CA, Gräf S, Houweling AC, Machado RD, Pandya D, Prapa M, Shaukat M, Southgate L, Tenorio-Castano J, ClinGen PH VCEP, Chung WK, International Consortium for Genetic Studies in Pulmonary Arterial Hypertension PAH-ICON at the Pulmonary Vascular Research Institute PVRIet al., 2023, Defining the clinical validity of genes reported to cause pulmonary arterial hypertension, Genetics in Medicine, Vol: 25, ISSN: 1098-3600

PURPOSE: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. METHODS: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. RESULTS: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. CONCLUSION: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

Journal article

Chen C-N, Hajji N, Yeh F-C, Rahman S, Ali S, Wharton J, Baxan N, Zhao L, Xie C-Y, Chen Y-G, Frid MG, Chelladurai P, Pullamsetti SS, Stenmark KR, Wilkins MR, Zhao Let al., 2023, Restoration of Foxp31 Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 208, Pages: 879-895, ISSN: 1073-449X

Journal article

Shah M, Inacio M, Lu C, Schiratti P-R, Zheng S, Clement A, Simoes Monteiro de Marvao A, Bai W, King A, Ware J, Wilkins M, Mielke J, Elci E, Kryukov I, McGurk K, Bender C, Freitag D, O'Regan Det al., 2023, Environmental and genetic predictors of human cardiovascular ageing, Nature Communications, Vol: 14, Pages: 1-15, ISSN: 2041-1723

Cardiovascular ageing is a process that begins early in life and leads to a progressive change instructure and decline in function due to accumulated damage across diverse cell types, tissues andorgans contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence andend-organ damage, however the genetic architecture of cardiovascular ageing is not known. Herewe use machine learning approaches to quantify cardiovascular age from image-derived traits ofvascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing is found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated bycardiometabolic risk factors and we also identify prescribed medications that are potential modifiersof ageing. Through large-scale modelling of ageing across multiple traits our results reveal insightsinto the mechanisms driving premature cardiovascular ageing and reveal potential molecular targetsto attenuate age-related processes.

Journal article

Yeh F-C, Chen C-N, Xie C-Y, Baxan N, Zhao L, Ashek A, Sabrin F, Lawrie A, Wilkins M, Zhao Let al., 2023, TLR7/8 activation induces autoimmune vasculopathy and causes severe pulmonary arterial hypertension, European Respiratory Journal, Vol: 62, ISSN: 0903-1936

Journal article

Williams GJ, Al-Baraikan A, Rademakers FE, Ciravegna F, van de Vosse FN, Lawrie A, Rothman A, Ashley EA, Wilkins MR, Lawford PV, Omholt SW, Wisløff U, Hose DR, Chico TJA, Gunn JP, Morris PDet al., 2023, Wearable technology and the cardiovascular system: the future of patient assessment, The Lancet: Digital Health, Vol: 5, Pages: e467-e476, ISSN: 2589-7500

The past decade has seen a dramatic rise in consumer technologies able to monitor a variety of cardiovascular parameters. Such devices initially recorded markers of exercise, but now include physiological and health-care focused measurements. The public are keen to adopt these devices in the belief that they are useful to identify and monitor cardiovascular disease. Clinicians are therefore often presented with health app data accompanied by a diverse range of concerns and queries. Herein, we assess whether these devices are accurate, their outputs validated, and whether they are suitable for professionals to make management decisions. We review underpinning methods and technologies and explore the evidence supporting the use of these devices as diagnostic and monitoring tools in hypertension, arrhythmia, heart failure, coronary artery disease, pulmonary hypertension, and valvular heart disease. Used correctly, they might improve health care and support research.

Journal article

Guignabert C, Savale L, Boucly A, Thuillet R, Tu L, Ottaviani M, Rhodes CJ, De Groote P, Prevot G, Bergot E, Bourdin A, Howard LS, Fadel E, Beurnier A, Roche A, Jevnikar M, Jais X, Montani D, Wilkins MR, Sitbon O, Humbert Met al., 2023, Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension, CIRCULATION, Vol: 147, Pages: 1809-1822, ISSN: 0009-7322

Journal article

Walters R, Vasilaki E, Aman J, Chen C-N, Wu Y, Liang OD, Ashek A, Dubois O, Zhao L, Sabrin F, Cebola I, Ferrer J, Morrell NW, Klinger JR, Wilkins MR, Zhao L, Rhodes CJet al., 2023, <i>SOX17</i> Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension, CIRCULATION, Vol: 147, Pages: 1606-1621, ISSN: 0009-7322

Journal article

Boucly A, Tu L, Guignabert C, Rhodes C, De Groote P, Prevot G, Bergot E, Bourdin A, Beurnier A, Roche A, Jevnikar M, Jais X, Montani D, Wilkins MR, Humbert M, Sitbon O, Savale Let al., 2023, Cytokines as prognostic biomarkers in pulmonary arterial hypertension, EUROPEAN RESPIRATORY JOURNAL, Vol: 61, ISSN: 0903-1936

Journal article

Hirsch K, Nolley S, Ralph DD, Zheng Y, Altemeier WA, Rhodes CJ, Morrell NW, Wilkins MR, Leary PJ, Rayner SGet al., 2023, Circulating markers of inflammation and angiogenesis and clinical outcomes across subtypes of pulmonary arterial hypertension, JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol: 42, ISSN: 1053-2498

Journal article

Alzaydi M, Abdul Salam V, Whitwell H, Russomanno G, Glynos A, Capece D, Szabadkai G, Wilkins M, Wojciak Stothard B, Wojciak-Stothard Bet al., 2023, Intracellular chloride channels regulate endothelial metabolic reprogramming in pulmonary arterial hypertension, American Journal of Respiratory Cell and Molecular Biology, Vol: 63, Pages: 103-115, ISSN: 1044-1549

Mitochondrial fission and a metabolic switch from oxidative phosphorylation to glycolysis are key features of vascular pathology in pulmonary arterial hypertension (PAH) and are associated with exuberant endothelial proliferation and apoptosis. The underlying mechanisms are poorly understood. We describe the contribution of two intracellular chloride channel proteins CLIC1 and CLIC4, both highly expressed in PAH and cancer, to mitochondrial dysfunction and energy metabolism in PAH endothelium. Pathological overexpression of CLIC proteins induces mitochondrial fragmentation, inhibits mitochondrial cristae formation and induces metabolic shift towards glycolysis in human pulmonary artery endothelial cells, consistent with changes observed in patient-derived cells. Interactions of CLIC proteins with structural components of the inner mitochondrial membrane offer mechanistic insights. Endothelial CLIC4 excision and mitofusin 2 supplementation have protective effects in human PAH cells and pre-clinical PAH. This study is first to demonstrate the key role of endothelial intracellular chloride channels in the regulation of mitochondrial structure, biogenesis, and metabolic reprogramming in expression of the PAH phenotype.

Journal article

Ali MK, Tian X, Zhao L, Schimmel K, Rhodes CJ, Wilkins MR, Nicolls MR, Spiekerkoetter EFet al., 2023, PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension, CELLS, Vol: 12

Journal article

Aman J, Morrell NW, Rhodes CJ, Wilkins MR, Bogaard HJet al., 2022, The SOX17 phenotype in pulmonary arterial hypertension: lessons for pathobiology and clinical management, European Respiratory Journal, Vol: 60, ISSN: 0903-1936

Worldwide collaborative efforts to understand the genetic architecture of pulmonary arterial hypertension (PAH) have identified several gene variants and mutations in the past 5 years. With subsequent deep phenotyping, the clinical picture associated with these mutations is becoming more clear. For example, following the identification of pathogenic mutations in TBX4 and KDR [1, 2], histopathological and clinical phenotypes were described, with specific characteristics like small patella and bronchial diverticulosis for TBX4 and low diffusing capacity of the lung for carbon monoxide and interstitial changes for KDR [3–5]. Just as mutations identify key players in pathophysiology, the clinical and histopathological characterisation of mutation carriers provides insights into the cellular processes involved.

Journal article

Kariotis S, Jammeh E, Swietlik EM, Pickworth JA, Rhodes CJ, Otero P, Wharton J, Iremonger J, Dunning MJ, Pandya D, Mascarenhas TS, Errington N, Thompson AAR, Romanoski CE, Rischard F, Garcia JGN, Yuan JX-J, An T-HS, Desai AA, Coghlan G, Lordan J, Corris PA, Howard LS, Condliffe R, Kiely DG, Church C, Pepke-Zaba J, Toshner M, Wort S, Graf S, Morrell NW, Wilkins MR, Lawrie A, Wang Det al., 2022, Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood, Nature Communications, Vol: 13, Pages: 1-1, ISSN: 2041-1723

Journal article

Wojciak-Stothard B, Ainscough AJ, Smith TJ, Haensel M, Rhodes CJ, Fellows A, Whitwell HJ, Vasilaki E, Grey K, Freeman A, Howard LS, Wharton J, Dunmore B, Upton PD, Wilkins MR, Edel Jet al., 2022, An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis, Communications Biology, Vol: 5, Pages: 1-15, ISSN: 2399-3642

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.

Journal article

Constantine A, Rhodes CJ, Ricci P, Li W, Price LC, Mccabe C, Wharton J, Wilkins MR, Howard LS, Dimopoulos K, Wort SJet al., 2022, Correlation between right ventricular dysfunction and plasma protein profile in pulmonary hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Radegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery J-L, Noordegraaf AV, Delcroix M, Rosenkranz S, Schwerzmann M, Anh-Tuan D-X, Bush A, Abdelhamid M, Aboyans V, Arbustini E, Asteggiano R, Barbera J-A, Beghetti M, Cikes M, Condliffe R, de Man F, Falk V, Fauchier L, Gaine S, Galie N, Gin-Sing W, Granton J, Grunig E, Hassoun PM, Hellemons M, Jaarsma T, Kjellstrom B, Klok FA, Konradi A, Koskinas KC, Kotecha D, Lang I, Lewis BS, Linhart A, Lip GYH, Lochen M-L, Mathioudakis AG, Mindham R, Moledina S, Naeije R, Nielsen JC, Olschewski H, Opitz I, Petersen SE, Prescott E, Rakisheva A, Reis A, Ristic AD, Roche N, Rodrigues R, Selton-Suty C, Souza R, Swift AJ, Touyz RM, Ulrich S, Wilkins MR, Wort SJet al., 2022, 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG), European Heart Journal, Pages: 1-114, ISSN: 0195-668X

Journal article

Majeed RW, Wilkins MR, Howard L, Hassoun PM, Anthi A, Cajigas HR, Cannon J, Chan SY, Damonte V, Elwing J, Foerster K, Frantz R, Ghio S, Al Ghouleh I, Hilgendorff A, Jose A, Juaneda E, Kiely DG, Lawrie A, Orfanos SE, Pepe A, Pepke-Zaba J, Sirenko Y, Swett AJ, Torbas O, Zamanian RT, Marquardt K, Michel-Backofen A, Antoine T, Wilhelm J, Barwick S, Krieb P, Fuenderich M, Fischer P, Gall H, Ghofrani H-A, Grimminger F, Tello K, Richter MJ, Seeger Wet al., 2022, Pulmonary vascular research institute GoDeep: a meta-registry merging deep phenotyping datafrom international PH reference centers, Pulmonary Circulation, Vol: 12, ISSN: 2045-8940

The Pulmonary Vascular Research Institute GoDeep meta-registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta-registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty-nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface-based automated retrospective and prospective data transfer, GoDeep aims to provide in-depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

Journal article

Wilkins MR, 2022, Pulmonary Hypertension Dissecting a Complex Phenotype, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 80, Pages: 719-721, ISSN: 0735-1097

Journal article

Jones RJ, De Bie EMDD, Groves E, Zalewska KI, Swietlik EM, Treacy CM, Martin JM, Polwarth G, Li W, Guo J, Baxendale HE, Coleman S, Savinykh N, Coghlan JG, Corris PA, Howard LS, Johnson MK, Church C, Kiely DG, Lawrie A, Lordan JL, Mackenzie Ross RV, Pepke Zaba J, Wilkins MR, Wort SJ, Fiorillo E, Orrù V, Cucca F, Rhodes CJ, Gräf S, Morrell NW, McKinney EF, Wallace C, Toshner M, UK National PAH Cohort Study Consortiumet al., 2022, Autoimmunity is a significant feature of idiopathic pulmonary arterial hypertension., American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 81-93, ISSN: 1073-449X

RATIONALE: Autoimmunity is thought to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear if this is causative or a bystander of disease and if it carries any prognostic or treatment significance. OBJECTIVE: To study autoimmunity in IPAH using a large cross-sectional cohort. METHODS: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry and the profile of serum immunoglobulins was generated using a standardised multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 controls. Additional GST-fusion array and ELISA data were used to identify a serum autoantibody to BMPR2. Clustering analyses and clinical correlations were employed to determine associations between immunogenicity and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Flow cytometric immune profiling demonstrates IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: 'high autoantibody', 'low autoantibody', and a small 'intermediate' cluster exhibiting high levels of RNP-complex. The high autoantibody cluster had worse haemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. CONCLUSIONS: This study establishes aberrant immune regulation and presence of autoantibodies as a key feature in the profile of a significant proportion of IPAH patients and is associated with clinical outcomes. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Journal article

Rhodes C, Wharton J, Swietlik E, Harbaum L, Girerd B, Coghlan G, Lordan J, Church C, Pepke-Zaba J, Toshner M, Wort SJ, Kiely D, Condliffe R, Lawrie A, Graf S, Montani D, Boucly A, Sitbon O, Humbert M, Howard LS, Morrell NW, Wilkins MRet al., 2022, Using the plasma proteome for risk stratifying patients with pulmonary arterial hypertension, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1102-1111, ISSN: 1073-449X

Rationale: N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH.Objectives: Identify prognostic proteins in PAH which complement NT-proBNP and clinical risk scores.Methods: An aptamer-based assay (SomaScan-V4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable or drug-induced-PAH from the UK National Cohort of PAH (n=357) and the French EFORT study (n=79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute walk distance (6-MWD) and NT-proBNP entered LASSO modelling and the best combination in a single score was evaluated against clinical targets in EFORT.Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-MWD in the UK Cohort. A weighted combination score of 6 proteins was validated at baseline (5-year mortality, AUC:0.73, 95%CI:0.63-0.85) and follow-up in EFORT (AUC:0.84, 95%CI:0.75-0.94, p=9.96x10-6). The protein score risk-stratified patients independent of established clinical targets and risk equations. The addition of the 6-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC:0.762 (0.702-0.821) to 0.818 (0.767-0.869) by ROC analysis (p=0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response.

Journal article

Thanaj M, Mielke J, McGurk K, Bai W, Savioli N, Simoes Monteiro de Marvao A, Meyer H, Zeng L, Sohler F, Lumbers T, Wilkins M, Ware J, Bender C, Rueckert D, MacNamara A, Freitag D, O'Regan Det al., 2022, Genetic and environmental determinants of diastolic heart function, Nature Cardiovascular Research, Vol: 1, Pages: 361-371, ISSN: 2731-0590

Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends onmyocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processesand is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiacmotion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wideassociation study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomericfunction under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes wereindependent predictors of diastolic function and we found a causal relationship between genetically-determined ventricularstiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolicfunction that are relevant for identifying causal relationships and potential tractable targets.

Journal article

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