Kiely, D.G.

Lawrie, A.

Thompson, A.A.R.

Wild, J.M.

Wilkins, M.R.

Frontiers in Medicine

English

Thompson, AA Roger

Wilkins, Martin R

Wild, Jim M

Kiely, David G

Lawrie, Allan

Spiral - Imperial College Digital Repository

EDITORIALpublished: 21 April 2020doi: 10.3389/fmed.2020.00125Frontiers in Medicine | www.frontiersin.org 1 April 2020 | Volume 7 | Article 125Edited and reviewed by:Argyrios Tzouvelekis,Alexander Fleming BiomedicalSciences Research Center, Greece*Correspondence:A. A. Roger Thompsonr.thompson@sheffield.ac.ukSpecialty section:This article was submitted toPulmonary Medicine,a section of the journalFrontiers in MedicineReceived: 04 December 2019Accepted: 20 March 2020Published: 21 April 2020Citation:Thompson AAR, Wilkins MR, Wild JM,Kiely DG and Lawrie A (2020) Editorial:Pulmonary Hypertension:Mechanisms and Management,History and Future. Front. Med. 7:125.doi: 10.3389/fmed.2020.00125Editorial: Pulmonary Hypertension:Mechanisms and Management,History and FutureA. A. Roger Thompson 1,2*, Martin R. Wilkins 3, Jim M. Wild 1,4,5, David G. Kiely 1,2,5 andAllan Lawrie 1,51Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, United Kingdom,2 Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust,Sheffield, United Kingdom, 3Department of Medicine and National Heart and Lung Institute, Imperial College London,London, United Kingdom, 4 POLARIS, Academic Unit of Radiology, Department of Infection, Immunity and CardiovascularDisease, University of Sheffield, Sheffield, United Kingdom, 5 INSIGNEO Institute for in silico Medicine, The University ofSheffield, Sheffield, United KingdomKeywords: pulmonary hypertension, screening tools, biomarkers, heart failure, therapeutics, imagingEditorial on the Research TopicPulmonary Hypertension: Mechanisms and Management, History and FutureFrom pulmonary hypertension observed at high altitude to pulmonary hypertension associatedwith left heart disease, this Frontiers Research Topic illustrates the diversity of clinical andpathological phenotypes associated with elevated pressure in the pulmonary circulation. The topicarticles highlight the breadth of ongoing research into understanding this multi-faceted diseaseand are based on the content of a symposium that drew inspiration from the work of the Britishpathologist, Donald Heath, who published his manuscript on hypertensive pulmonary vasculardisease after working as junior doctor in Sheffield (1, 2).Despite advances in therapy over the last two decades, most forms of pulmonary hypertension(PH) have a poor prognosis. The greatest improvements in outcome have been observed in patientswith CTEPH (3) where surgery may provide a cure, and pulmonary arterial hypertension (PAH)where younger patients with idiopathic disease (IPAH) in the UK now have a 5-year survival inexcess of 80% (4). Intuitively, earlier diagnosis and institution of treatment may slow vascularremodeling and improve outcomes. However, despite increased awareness and the availabilityof new therapies the time from symptom onset to diagnosis remains unchanged at 2–3 years,suggesting that new approaches need to be taken to improve disease detection (5). This highlightsthe importance of identifying easily performed and scalable tests that can be deployed in theinvestigative pathway. Three of the studies in this Research Topic highlighted different modalitiesused in the diagnosis of pulmonary hypertension: exercise, serological biomarkers, and imaging.Billings et al. reported the utility of exercise testing in newly diagnosed, treatment naïve patientswith pulmonary hypertension. Although this was a large retrospective study, only a small numberof patients (1% of 895) were diagnosed while in WHO FC I. These data are consistent with earlyvascular changes preceding the development of symptoms and highlight the need for effectiveand sensitive screening tools for early disease. Billings et al. provide evidence that an incrementalshuttle walk distance (ISWD) of <80% predicted identified 8 out of 9 patients with pulmonaryhypertension in WHO FC I, while diffusing capacity (DLCO) measurements, using a cut-off of80% predicted, only identified 4 of these patients. Further work is required to assess whetherthe simple and adaptable incremental shuttle walk test is a suitable field walking test to identifyexercise limitation and to aid screening of high-risk populations, perhaps in combination withother biomarkers.Thompson et al. Pulmonary Hypertension; Mechanisms and ManagementOne such high risk group are those with connectivetissue diseases, particularly systemic sclerosis (6). Hickey et al.discuss putative blood-based or lung tissue biomarkers for theidentification of systemic sclerosis patients who have developedpulmonary hypertension. A significant issue with potentialbiomarkers is heterogeneity of patient phenotype even withinthis sub-group of PAH patients (7). Notably, the contribution ofco-morbid interstitial lung disease is difficult to unravel. Hickeyet al. also point out limitations associated with NT-proBNP,perhaps the foremost blood-based biomarker for PH in clinicaluse. While NT-proBNP features as an important component ofearly screening algorithms for SSc-PAH (8), it lacks specificityand carries the inherent disadvantage that the right ventricularstrain, driving its release, is not a feature of early disease.The third study with a focus on enhancing diagnosis, Chinet al., reports a strong correlation between CT measurement ofpulmonary artery diameter and mean pulmonary artery pressurein the presence or absence of interstitial lung disease. Thisreport implies that use of simple CT parameters could helppredict presence of pulmonary hypertension in patients withlung disease, contrasting with previous reports suggesting thatPA diameter was a less useful indicator of PH in patientswith interstitial lung disease. Nonetheless, however useful ourpredictive tools, the armory of treatment of PH in these patientswith interstitial lung disease remains frustratingly empty.Work on the role of hypoxia in vascular remodeling offerspotential promise for patients with PH associated with lungdisease. At a molecular level, the importance of hypoxiainducible factors in vascular cell phenotypes is becoming clearer.These oxygen sensors, the discovery of which was recentlyacknowledged by the 2019 Nobel prize award to three HIF-biologists, are discussed in a review by Young et al. and thespecific impact of altitude hypoxia on the pulmonary circulationis highlighted.While hypoxia has a defining role in PH associatedwith hypoxia and lung disease, the relevance of hypoxia at earlystages of the pathogenesis of other forms of PH is less clear.One important mediator of vascular remodeling with apotentially ubiquitous role across all forms of PH is neutrophilelastase. Neutrophils are considered the dominant source ofelastase in vivo but as noted by Taylor et al., they are a relativelyunderstudied cell in PH. Nonetheless, an excess of neutrophils(or high neutrophil to lymphocyte ratio) is reportedly correlatedwith poor outcomes in patients with PH (9) and inhibition ofneutrophil elastase reversed disease in mouse models (10). Theeffect of elastase on turnover of the vascular extracellular matrix,and specifically changes resulting in stiffening of the large andsmall pulmonary vessels, is the subject of the review by Sunand Chan. Recent work from this group has shown that changesin arterial stiffness precede proliferative remodeling and thatmechanosensitive pathways play important roles in regulatingvascular cell expansion (11).The complexity of pro-proliferative signaling in thepulmonary vasculature is further illustrated by the role ofTRAIL, reviewed by Braithwaite et al.. Cleavage of TRAIL,a transmembrane protein, results in a soluble cytokine thatcan signal via a number of cell surface receptors but canalso bind to decoy receptors. TRAIL canonically inducesapoptosis in cancer cells and in virus-infected epithelial cellsbut paradoxically promotes vascular smooth muscle cellproliferation. These contrasting effects are mediated by atleast two distinct signaling pathways and but exactly how celland context-specific effects of TRAIL are mediated requiresfurther study. Notably, the importance of TRAIL in infection,fibrosis and cancer might complicate therapeutic targeting ofthis pathway. However, other mediators known to interactwith TRAIL, such as osteoprotegerin, have shown therapeuticpromise (12).Mechanistic insights are increasingly being generated byomics studies (13, 14) and this burgeoning field is reviewedby Hemnes. Blood-based or genetic signatures to enhancethe granularity of patient classification or simply to facilitatediagnosis would have great utility, although relatively smallpatient numbers limit power and validation of predictivesignatures. Furthermore, identifying whether omics arecapable of detecting changes that precede pulmonary vascularremodeling will be challenging. Nonetheless, omics approachescould not only be used to stratify or diagnose PH but could alsoprovide more personalized treatment approaches. Followinginteresting work on patients with positive vasodilator responses(15), Hemnes suggests using omics data to identify signaturesdefining a good response with other treatments. The conceptof enriching clinical studies using specific omics signaturesand then refining those signatures based on clinical response isproposed. Such strategies might increase the efficiency of laterphase clinical trials.While the majority of topic articles focus on the pulmonarycirculation, Charalampopoulos et al. provide a comprehensiveoverview of PH due to left heart disease. Echocardiographicfeatures that favor left heart disease over PAH are highlighted andthe authors discuss studies reporting use of fluid challenges orexercise during right heart catheterization to identify occult leftheart disease. The question of whether pulmonary vasodilatorshave any role in these patients or in patients with combinedpre- and post-capillary pulmonary hypertension is the subjectof ongoing clinical trials (e.g., SERENADE, NCT02246634) butunfortunately for this large group of patients, there is as yet, noclear answer.The final review in the topic, by Middleton et al., notes thelack of specific guidelines for arrhythmia management in PAH.Indeed, there is a paucity of data on arrhythmia prevalenceand on how frequently arrhythmia contributes to death inPAH patients. Deterioration in the context of atrial arrhythmiais a common clinical scenario that is potentially reversible.Therefore, exciting advances in monitoring technology,including wearable or implantable monitors, are an importantavenue for future research. Indeed, our group are examining theutility of invasive pulmonary artery pressure and implantablerhythm monitors.The broad and systematic approaches covered by themanuscripts included in this Research Topic highlight many ofthe current challenges to improve patient outcome and well-being in PH. Earlier diagnosis of patients with PH remains amajor challenge. Despite advances in treatment and increasingawareness of the disease over the last 2–3 decades, many patientsFrontiers in Medicine | www.frontiersin.org 2 April 2020 | Volume 7 | Article 125Thompson et al. Pulmonary Hypertension; Mechanisms and Managementarrive at specialist centers after a significant diagnostic delay (16).While not reviewed in this topic, recent work from our centerhas sought to improve this issue by highlighting the potentialuse of artificial intelligence to interrogate routine healthcare datain order to identify patients at high risk of idiopathic PAHat an earlier stage (5). Furthermore, the topic only alludes tothe use of novel tools to phenotype these high-risk patients.Multi-omic profiling and imaging of cardiac and lung structureand function (17, 18) including the use of emerging techniquessuch as hyperpolarised gases (19) or 4-dimensional magneticresonance imaging (20) will likely hold the key to developingmore sensitive and specific assessment tools. Such tools shouldgenerate new insights into molecular targets that alter vascularremodeling and could provide better clinical trial endpoints forassessment of treatment efficacy. The development of biomarkersand imaging tools using patients with earlier disease should bea priority for improving the treatment of PH in the precisionmedicine era.AUTHOR CONTRIBUTIONSAT and AL drafted the editorial with input from MW, JW,and DK.FUNDINGAT is supported by a British Heart Foundation IntermediateClinical Fellowship (FS/18/13/33281). AL is supported by BritishHeart Foundation Senior Basic Science Research Fellowship(FS/13/48/30453).ACKNOWLEDGMENTSThe authors gratefully acknowledge topic contributors and thesponsorship of the topic by Actelion, a Janssen PharmaceuticalCompany. The sponsor played no role in the writing ofthis editorial.REFERENCES1. Heath D. Travellers on a Hidden River. J Med Biogr. (1998) 6:105–113.doi: 10.1177/0967772098006002082. Heath D, Whitaker W. Hypertensive pulmonary vascular disease. Circulation.(1956) 14:323–43. doi: 10.1161/circ.14.3.3233. Quadery SR, Swift AJ, Billings CG, Thompson AAR, Elliot CA,Hurdman J, et al. The impact of patient choice on survival in chronicthromboembolic pulmonary hypertension. Eur Respir J. (2018) 52:1800589.doi: 10.1183/13993003.00589-20184. National Audit of Pulmonary Project Board. National Audit of PulmonaryHypertension, 10th Annual Report - NHS Digital. (2019). Available onlineat: https://digital.nhs.uk/data-and-information/publications/statistical/national-pulmonary-hypertension-audit/2019 (accessed November 24,2019).5. Bergemann R, Allsopp J, Jenner H, Drage E, Samyshkin Y, SchmittC, et al. High levels of healthcare utilization prior to diagnosis inidiopathic pulmonary arterial hypertension support the feasibility of anearly diagnosis algorithm: the SPHInX project. Pulm Circ. (2018) 8:1–9.doi: 10.1177/20458940187986136. Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, et al. ASPIREregistry: Assessing the Spectrum of Pulmonary hypertension Identified at a.Eur Respir J. (2012) 39:945–55. doi: 10.1183/09031936.000784117. Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A,Elliot CA, et al. idiopathic and systemic sclerosis-associated pulmonaryarterial hypertension: a comparison of demographic, hemodynamic,and MRI characteristics and outcomes. Chest. (2017) 152:92–102.doi: 10.1016/j.chest.2017.02.0108. Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, KhannaD, et al. Evidence-based detection of pulmonary arterial hypertension insystemic sclerosis: the DETECT study. Ann Rheum Dis. (2014) 73:1340–9.doi: 10.1136/annrheumdis-2013-2033019. Harbaum L, Baaske KM, Simon M, Oqueka T, Sinning C, Glatzel A,et al. Exploratory analysis of the neutrophil to lymphocyte ratio in patientswith pulmonary arterial hypertension. BMC Pulm Med. (2017) 17:72.doi: 10.1186/s12890-017-0407-510. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Completereversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor.Nat Med. (2000) 6:698–702. doi: 10.1038/7628211. Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q,et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysisto drive pulmonary hypertension. J Clin Invest. (2016) 126:3313–35.doi: 10.1172/JCI8638712. Arnold ND, Pickworth JA, West LE, Dawson S, Carvalho JA, Casbolt H,et al. A therapeutic antibody targeting osteoprotegerin attenuates severeexperimental pulmonary arterial hypertension. Nat Commun. (2019) 10:5183.doi: 10.1038/s41467-019-13139-913. Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W,et al. Identification of rare sequence variation underlying heritablepulmonary arterial hypertension. Nat Commun. (2018) 9:1416.doi: 10.1038/s41467-018-03672-414. Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, HadinnapolaC, Watson G, et al. Plasma metabolomics implicates modifiedtransfer RNAs and altered bioenergetics in the outcomes ofpulmonary arterial hypertension. Circulation. (2017) 135:460–75.doi: 10.1161/CIRCULATIONAHA.116.02460215. Hemnes AR, Trammell AW, Archer SL, Rich S, Yu C, Nian H, et al. Peripheralblood signature of vasodilator-responsive pulmonary arterial hypertension.Circulation. (2015) 131:401–9. doi: 10.1161/CIRCULATIONAHA.114.01331716. Armstrong I, Billings C, Kiely DG, Yorke J, Harries C, Clayton S, et al. Thepatient experience of pulmonary hypertension: a large cross-sectional study ofUK patients. BMC Pulm Med. (2019) 19:67. doi: 10.1186/s12890-019-0827-517. Swift AJ, Capener D, Johns C, Hamilton N, Rothman A, Elliot C, et al.Magnetic resonance imaging in the prognostic evaluation of patients withpulmonary arterial hypertension. Am J Respir Crit Care Med. (2017) 196:228–39. doi: 10.1164/rccm.201611-2365OC18. Johns CS, Kiely DG, Rajaram S, Hill C, Thomas S, KarunasaagararK, et al. Diagnosis of pulmonary hypertension with cardiac MRI:derivation and validation of regression models. Radiology. (2019) 290:61–68.doi: 10.1148/radiol.201818060319. Arai TJ, Horn FC, Sá RC, RaoMR, Collier GJ, Theilmann RJ, et al. Comparisonof quantitative multiple-breath specific ventilation imaging using colocalized2D oxygen-enhanced MRI and hyperpolarized 3 He MRI. J Appl Physiol.(2018) 125:1526–35. doi: 10.1152/japplphysiol.00500.201720. Fidock B, Barker N, Balasubramanian N, Archer G, Fent G, Al-Mohammad A, et al. A systematic review of 4D-Flow MRI derived mitralregurgitation quantification methods. Front Cardiovasc Med. (2019) 6:103.doi: 10.3389/fcvm.2019.00103Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2020 Thompson,Wilkins,Wild, Kiely and Lawrie. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Medicine | www.frontiersin.org 3 April 2020 | Volume 7 | Article 125

Editorial: pulmonary hypertension: mechanisms and management, history and future

White Rose Research Online

This is a repository copy of Editorial : pulmonary hypertension : mechanisms and management, history and future.White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/160355/Version: Published VersionArticle:Thompson, A.A.R. orcid.org/0000-0002-0717-4551, Wilkins, M.R., Wild, J.M. orcid.org/0000-0002-7246-8660 et al. (2 more authors) (2020) Editorial : pulmonary hypertension : mechanisms and management, history and future. Frontiers in Medicine, 7. 125. https://doi.org/10.3389/fmed.2020.00125eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. EDITORIALpublished: 21 April 2020doi: 10.3389/fmed.2020.00125Frontiers in Medicine | www.frontiersin.org 1 April 2020 | Volume 7 | Article 125Edited and reviewed by:Argyrios Tzouvelekis,Alexander Fleming BiomedicalSciences Research Center, Greece*Correspondence:A. A. Roger Thompsonr.thompson@sheffield.ac.ukSpecialty section:This article was submitted toPulmonary Medicine,a section of the journalFrontiers in MedicineReceived: 04 December 2019Accepted: 20 March 2020Published: 21 April 2020Citation:Thompson AAR, Wilkins MR, Wild JM,Kiely DG and Lawrie A (2020) Editorial:Pulmonary Hypertension:Mechanisms and Management,History and Future. Front. Med. 7:125.doi: 10.3389/fmed.2020.00125Editorial: Pulmonary Hypertension:Mechanisms and Management,History and FutureA. A. Roger Thompson 1,2*, Martin R. Wilkins 3, Jim M. Wild 1,4,5, David G. Kiely 1,2,5 andAllan Lawrie 1,51Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, United Kingdom,2 Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust,Sheffield, United Kingdom, 3Department of Medicine and National Heart and Lung Institute, Imperial College London,London, United Kingdom, 4 POLARIS, Academic Unit of Radiology, Department of Infection, Immunity and CardiovascularDisease, University of Sheffield, Sheffield, United Kingdom, 5 INSIGNEO Institute for in silico Medicine, The University ofSheffield, Sheffield, United KingdomKeywords: pulmonary hypertension, screening tools, biomarkers, heart failure, therapeutics, imagingEditorial on the Research TopicPulmonary Hypertension: Mechanisms and Management, History and FutureFrom pulmonary hypertension observed at high altitude to pulmonary hypertension associatedwith left heart disease, this Frontiers Research Topic illustrates the diversity of clinical andpathological phenotypes associated with elevated pressure in the pulmonary circulation. The topicarticles highlight the breadth of ongoing research into understanding this multi-faceted diseaseand are based on the content of a symposium that drew inspiration from the work of the Britishpathologist, Donald Heath, who published his manuscript on hypertensive pulmonary vasculardisease after working as junior doctor in Sheffield (1, 2).Despite advances in therapy over the last two decades, most forms of pulmonary hypertension(PH) have a poor prognosis. The greatest improvements in outcome have been observed in patientswith CTEPH (3) where surgery may provide a cure, and pulmonary arterial hypertension (PAH)where younger patients with idiopathic disease (IPAH) in the UK now have a 5-year survival inexcess of 80% (4). Intuitively, earlier diagnosis and institution of treatment may slow vascularremodeling and improve outcomes. However, despite increased awareness and the availabilityof new therapies the time from symptom onset to diagnosis remains unchanged at 2–3 years,suggesting that new approaches need to be taken to improve disease detection (5). This highlightsthe importance of identifying easily performed and scalable tests that can be deployed in theinvestigative pathway. Three of the studies in this Research Topic highlighted different modalitiesused in the diagnosis of pulmonary hypertension: exercise, serological biomarkers, and imaging.Billings et al. reported the utility of exercise testing in newly diagnosed, treatment naïve patientswith pulmonary hypertension. Although this was a large retrospective study, only a small numberof patients (1% of 895) were diagnosed while in WHO FC I. These data are consistent with earlyvascular changes preceding the development of symptoms and highlight the need for effectiveand sensitive screening tools for early disease. Billings et al. provide evidence that an incrementalshuttle walk distance (ISWD) of <80% predicted identified 8 out of 9 patients with pulmonaryhypertension in WHO FC I, while diffusing capacity (DLCO) measurements, using a cut-off of80% predicted, only identified 4 of these patients. Further work is required to assess whetherthe simple and adaptable incremental shuttle walk test is a suitable field walking test to identifyexercise limitation and to aid screening of high-risk populations, perhaps in combination withother biomarkers.Thompson et al. Pulmonary Hypertension; Mechanisms and ManagementOne such high risk group are those with connectivetissue diseases, particularly systemic sclerosis (6). Hickey et al.discuss putative blood-based or lung tissue biomarkers for theidentification of systemic sclerosis patients who have developedpulmonary hypertension. A significant issue with potentialbiomarkers is heterogeneity of patient phenotype even withinthis sub-group of PAH patients (7). Notably, the contribution ofco-morbid interstitial lung disease is difficult to unravel. Hickeyet al. also point out limitations associated with NT-proBNP,perhaps the foremost blood-based biomarker for PH in clinicaluse. While NT-proBNP features as an important component ofearly screening algorithms for SSc-PAH (8), it lacks specificityand carries the inherent disadvantage that the right ventricularstrain, driving its release, is not a feature of early disease.The third study with a focus on enhancing diagnosis, Chinet al., reports a strong correlation between CT measurement ofpulmonary artery diameter and mean pulmonary artery pressurein the presence or absence of interstitial lung disease. Thisreport implies that use of simple CT parameters could helppredict presence of pulmonary hypertension in patients withlung disease, contrasting with previous reports suggesting thatPA diameter was a less useful indicator of PH in patientswith interstitial lung disease. Nonetheless, however useful ourpredictive tools, the armory of treatment of PH in these patientswith interstitial lung disease remains frustratingly empty.Work on the role of hypoxia in vascular remodeling offerspotential promise for patients with PH associated with lungdisease. At a molecular level, the importance of hypoxiainducible factors in vascular cell phenotypes is becoming clearer.These oxygen sensors, the discovery of which was recentlyacknowledged by the 2019 Nobel prize award to three HIF-biologists, are discussed in a review by Young et al. and thespecific impact of altitude hypoxia on the pulmonary circulationis highlighted.While hypoxia has a defining role in PH associatedwith hypoxia and lung disease, the relevance of hypoxia at earlystages of the pathogenesis of other forms of PH is less clear.One important mediator of vascular remodeling with apotentially ubiquitous role across all forms of PH is neutrophilelastase. Neutrophils are considered the dominant source ofelastase in vivo but as noted by Taylor et al., they are a relativelyunderstudied cell in PH. Nonetheless, an excess of neutrophils(or high neutrophil to lymphocyte ratio) is reportedly correlatedwith poor outcomes in patients with PH (9) and inhibition ofneutrophil elastase reversed disease in mouse models (10). Theeffect of elastase on turnover of the vascular extracellular matrix,and specifically changes resulting in stiffening of the large andsmall pulmonary vessels, is the subject of the review by Sunand Chan. Recent work from this group has shown that changesin arterial stiffness precede proliferative remodeling and thatmechanosensitive pathways play important roles in regulatingvascular cell expansion (11).The complexity of pro-proliferative signaling in thepulmonary vasculature is further illustrated by the role ofTRAIL, reviewed by Braithwaite et al.. Cleavage of TRAIL,a transmembrane protein, results in a soluble cytokine thatcan signal via a number of cell surface receptors but canalso bind to decoy receptors. TRAIL canonically inducesapoptosis in cancer cells and in virus-infected epithelial cellsbut paradoxically promotes vascular smooth muscle cellproliferation. These contrasting effects are mediated by atleast two distinct signaling pathways and but exactly how celland context-specific effects of TRAIL are mediated requiresfurther study. Notably, the importance of TRAIL in infection,fibrosis and cancer might complicate therapeutic targeting ofthis pathway. However, other mediators known to interactwith TRAIL, such as osteoprotegerin, have shown therapeuticpromise (12).Mechanistic insights are increasingly being generated byomics studies (13, 14) and this burgeoning field is reviewedby Hemnes. Blood-based or genetic signatures to enhancethe granularity of patient classification or simply to facilitatediagnosis would have great utility, although relatively smallpatient numbers limit power and validation of predictivesignatures. Furthermore, identifying whether omics arecapable of detecting changes that precede pulmonary vascularremodeling will be challenging. Nonetheless, omics approachescould not only be used to stratify or diagnose PH but could alsoprovide more personalized treatment approaches. Followinginteresting work on patients with positive vasodilator responses(15), Hemnes suggests using omics data to identify signaturesdefining a good response with other treatments. The conceptof enriching clinical studies using specific omics signaturesand then refining those signatures based on clinical response isproposed. Such strategies might increase the efficiency of laterphase clinical trials.While the majority of topic articles focus on the pulmonarycirculation, Charalampopoulos et al. provide a comprehensiveoverview of PH due to left heart disease. Echocardiographicfeatures that favor left heart disease over PAH are highlighted andthe authors discuss studies reporting use of fluid challenges orexercise during right heart catheterization to identify occult leftheart disease. The question of whether pulmonary vasodilatorshave any role in these patients or in patients with combinedpre- and post-capillary pulmonary hypertension is the subjectof ongoing clinical trials (e.g., SERENADE, NCT02246634) butunfortunately for this large group of patients, there is as yet, noclear answer.The final review in the topic, by Middleton et al., notes thelack of specific guidelines for arrhythmia management in PAH.Indeed, there is a paucity of data on arrhythmia prevalenceand on how frequently arrhythmia contributes to death inPAH patients. Deterioration in the context of atrial arrhythmiais a common clinical scenario that is potentially reversible.Therefore, exciting advances in monitoring technology,including wearable or implantable monitors, are an importantavenue for future research. Indeed, our group are examining theutility of invasive pulmonary artery pressure and implantablerhythm monitors.The broad and systematic approaches covered by themanuscripts included in this Research Topic highlight many ofthe current challenges to improve patient outcome and well-being in PH. Earlier diagnosis of patients with PH remains amajor challenge. Despite advances in treatment and increasingawareness of the disease over the last 2–3 decades, many patientsFrontiers in Medicine | www.frontiersin.org 2 April 2020 | Volume 7 | Article 125Thompson et al. Pulmonary Hypertension; Mechanisms and Managementarrive at specialist centers after a significant diagnostic delay (16).While not reviewed in this topic, recent work from our centerhas sought to improve this issue by highlighting the potentialuse of artificial intelligence to interrogate routine healthcare datain order to identify patients at high risk of idiopathic PAHat an earlier stage (5). Furthermore, the topic only alludes tothe use of novel tools to phenotype these high-risk patients.Multi-omic profiling and imaging of cardiac and lung structureand function (17, 18) including the use of emerging techniquessuch as hyperpolarised gases (19) or 4-dimensional magneticresonance imaging (20) will likely hold the key to developingmore sensitive and specific assessment tools. Such tools shouldgenerate new insights into molecular targets that alter vascularremodeling and could provide better clinical trial endpoints forassessment of treatment efficacy. The development of biomarkersand imaging tools using patients with earlier disease should bea priority for improving the treatment of PH in the precisionmedicine era.AUTHOR CONTRIBUTIONSAT and AL drafted the editorial with input from MW, JW,and DK.FUNDINGAT is supported by a British Heart Foundation IntermediateClinical Fellowship (FS/18/13/33281). AL is supported by BritishHeart Foundation Senior Basic Science Research Fellowship(FS/13/48/30453).ACKNOWLEDGMENTSThe authors gratefully acknowledge topic contributors and thesponsorship of the topic by Actelion, a Janssen PharmaceuticalCompany. The sponsor played no role in the writing ofthis editorial.REFERENCES1. Heath D. Travellers on a Hidden River. J Med Biogr. (1998) 6:105–113.doi: 10.1177/0967772098006002082. Heath D, Whitaker W. Hypertensive pulmonary vascular disease. Circulation.(1956) 14:323–43. doi: 10.1161/circ.14.3.3233. Quadery SR, Swift AJ, Billings CG, Thompson AAR, Elliot CA,Hurdman J, et al. The impact of patient choice on survival in chronicthromboembolic pulmonary hypertension. Eur Respir J. (2018) 52:1800589.doi: 10.1183/13993003.00589-20184. National Audit of Pulmonary Project Board. National Audit of PulmonaryHypertension, 10th Annual Report - NHS Digital. (2019). Available onlineat: https://digital.nhs.uk/data-and-information/publications/statistical/national-pulmonary-hypertension-audit/2019 (accessed November 24,2019).5. Bergemann R, Allsopp J, Jenner H, Drage E, Samyshkin Y, SchmittC, et al. High levels of healthcare utilization prior to diagnosis inidiopathic pulmonary arterial hypertension support the feasibility of anearly diagnosis algorithm: the SPHInX project. Pulm Circ. (2018) 8:1–9.doi: 10.1177/20458940187986136. Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, et al. ASPIREregistry: Assessing the Spectrum of Pulmonary hypertension Identified at a.Eur Respir J. (2012) 39:945–55. doi: 10.1183/09031936.000784117. Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A,Elliot CA, et al. idiopathic and systemic sclerosis-associated pulmonaryarterial hypertension: a comparison of demographic, hemodynamic,and MRI characteristics and outcomes. Chest. (2017) 152:92–102.doi: 10.1016/j.chest.2017.02.0108. Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, KhannaD, et al. Evidence-based detection of pulmonary arterial hypertension insystemic sclerosis: the DETECT study. Ann Rheum Dis. (2014) 73:1340–9.doi: 10.1136/annrheumdis-2013-2033019. Harbaum L, Baaske KM, Simon M, Oqueka T, Sinning C, Glatzel A,et al. Exploratory analysis of the neutrophil to lymphocyte ratio in patientswith pulmonary arterial hypertension. BMC Pulm Med. (2017) 17:72.doi: 10.1186/s12890-017-0407-510. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Completereversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor.Nat Med. (2000) 6:698–702. doi: 10.1038/7628211. Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q,et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysisto drive pulmonary hypertension. J Clin Invest. (2016) 126:3313–35.doi: 10.1172/JCI8638712. Arnold ND, Pickworth JA, West LE, Dawson S, Carvalho JA, Casbolt H,et al. 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The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Medicine | www.frontiersin.org 3 April 2020 | Volume 7 | Article 125

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Editorial : pulmonary hypertension : mechanisms and management, history and future

Editorial : pulmonary hypertension : mechanisms and management, history and future

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