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The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH), the current approach to patient phenotyping integrates clinical, haemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iterations of the PH clinical classification are likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools and clinical trial design, and improve treatment selection in clinical practice., Competing Interests: Conflict of interest: J. Weatherald reports grants from Janssen, Bayer, Merck and AstraZeneca; consulting fees and lecture honoraria from Janssen and Merck; payment for expert testimony from Sprigings Intellectual Property Law; travel support from Janssen; advisory board participation with Janssen, Acceleron and Université Laval; and a leadership role on the medical advisory committee for Pulmonary Hypertension Association of Canada, outside the submitted work. A.R. Hemnes reports grants from NIH; consulting fees from Gossamer Bio, United Therapeutics, Bayer, Janssen, Merch and Tenax Therapeutics; advisory board participation with NIH/NHLBI; leadership roles with the Nashville Ballet and Pulmonary Vascular Research Institute; and stock or stock options with Tenax Therapeutics, outside the submitted work. B.A. Maron reports grants from NIH/NHLBI; consulting fees from Actelion and Tenax Therapeutics; and the following patents: PCT/US2019/059890, #9605047 and PCT/US2020/066886, outside the submitted work. L.M. Mielniczuk reports consulting fees from Bayer, Merck and Janssen; lecture honoraria from Janssen and Merck; and leadership roles as Chair of Pulmonary Hypertension Association of Canada and Vice President of Canadian Heart Failure Society, outside the submitted work. C. Gerges reports support for the present manuscript from OrphaCare; outside the submitted work, C. Gerges reports lecture honoraria from AOPHealth, AstraZeneca, Janssen and Ferrer; and travel support from AOPHealth, AstraZeneca, Cordis, Janssen and MSD. L.C. Price reports grants from Ferrer; lecture honoraria from Janssen, Ferrer and MSD; travel support from Janssen, Ferrer Pharmaceuticals and Altavant; and advisory board participation with Janssen, outside the submitted work. M.M. Hoeper reports consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Gossamer Bio, Janssen, Keros and MSD; lecture honoraria from Acceleron, Actelion, AOP Health, Bayer, Ferrer, Janssen and MSD; and US patent application #63466014 (Methods of improving lung diffusion capacity in a patients with pulmonary arterial hypertension, application filed by MSD), outside the submitted work. M. Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics; lecture honoraria from Janssen and Merck; and advisory board participation with Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Abstract: With the declining use of the pulmonary artery catheter (PAC), transesophageal echocardiography (TEE) has become an appealing alternative to obtain pulmonary artery pressure non-invasively using the simplified Bernoulli equation. The validation of this method in the perioperative setting has been scarce with no clear recommendations about which view is the most accurate to estimate right ventricular systolic pressure (RVSP).Therefore, we performed a prospective, observer-blinded, diagnostic test accuracy study to assess the difference in systolic pulmonary artery pressure (sysPAP) measuring both, invasively sysPAP and estimated RVSP with TEE in 3 different views: the mid-esophageal (ME) 4Chamber, the ME right ventricular (RV) inflow-outflow and the ME modified bicaval view.To show a clinically significant difference of at least 10% in RVSP, we included 40 cardiac surgical patients divided into 3 subgroups: Patients with mild to moderate tricuspid regurgitation (TR) and mean PAP <25 mm Hg, patients with mild to moderate TR and mean PAP≥ 25 mm Hg, and patients with severe TR.For the whole cohort, bias of estimated RVSP compared to measured sysPAP was 5.27 mm Hg, precision was 7.96 mm Hg, limits of agreement were -10.66 to 21.19 mm Hg. The best agreement between the 2 methods was found in patients with severe TR and in the ME RV inflow-outflow and the modified bicaval view. Good Doppler signals were available in 35% and 46% in these views, and in 20% in the ME 4 chamber view.The estimation of the sysPAP by TEE cannot be considered reliable in the clinical perioperative setting. Only measurements that provide a full Doppler envelope show sufficient precision to provide accurate estimations., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pulmonary capillary haemangiomatosis (PCH) is a rare and incompletely understood histopathological finding characterised by abnormal capillary proliferation within the alveolar interstitium, which has long been noted to share many overlapping features with pulmonary veno-occlusive disease (PVOD). But are PCH and PVOD distinct entities that occur in isolation, or are they closely intertwined manifestations along a spectrum of the same disease? The classic clinical features of both PCH and PVOD include signs and symptoms related to pulmonary hypertension, hypoxaemia, markedly impaired diffusion capacity of the lung and abnormal chest imaging with ground glass opacities, septal lines and lymphadenopathy. In recent years, increasing evidence suggests that the clinical presentation, histopathological features, genetic substrate and pathobiological mechanisms of PCH and PVOD are overlapping and usually indistinguishable. The discovery of biallelic mutations in the eukaryotic translation initiation factor 2 α kinase 4 ( EIF2AK4 ) gene in heritable PCH and PVOD greatly advanced our understanding of the overlapping nature of these conditions. Furthermore, recognition of PCH and PVOD-like changes in other pulmonary vascular diseases and in conditions that cause chronic pulmonary venous hyper-perfusion or hypertension suggests that PCH/PVOD may develop as a reactive process to various insults or injuries to the pulmonary vasculature, rather than being primary angiogenic disorders., Competing Interests: Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, and grants from Alberta Lung Association Canadian Vascular Network, European Respiratory Society and Canadian Thoracic Society, outside the submitted work. Conflict of interest: P. Dorfmüller has nothing to disclose. Conflict of interest: F. Perros has nothing to disclose. Conflict of interest: M-R. Ghigna has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: M. Humbert reports personal fees and non-financial support from Acceleron, grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck and United Therapeutics, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK Pfizer, MSD and Chiesi, outside the submitted work., (Copyright ©ERS 2020.)

Purpose of Review: Pediatric pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. Herein we review the diagnosis and classification for pediatric PAH and detail the current therapeutic options available for use in the pediatric PAH population., Recent Findings: Classification and treatment of pediatric PAH is guided by adult criteria and treatment algorithms, yet the distribution of factors contributing to PAH in children differs significantly from that seen in adults. It is necessary to understand these differences in order to appropriately tailor therapy to the needs of the child or adolescent. An expanding array of targeted PAH drugs are now approved for use in adults, and many of these drugs are used "off-label" to treat children and adolescents with PAH. Use of these novel therapies has coincided with marked improvement in outcomes, suggesting significant benefit. However, because most of these drugs have not been studied in rigorous randomized, controlled trials in children, it is critical that physicians understand their mechanisms of action, potential benefits, and safety profiles. Pediatric PAH outcomes have improved substantially in the modern era, coinciding with the "off-label" use of targeted PAH drugs in children and adolescents. Ideally, care should be provided at centers with specialized expertise in the diagnosis and treatment of pediatric PAH by providers who understand the appropriate diagnostic algorithms, classification schemes, and treatment approaches.

Purpose of Review: Pulmonary arterial hypertension (PAH) leads to progressive increases in pulmonary vascular resistance (PVR), right heart failure, and death if left untreated. This review will summarize and discuss recent updates in the classification and management of patients with PAH., Recent Findings: PAH requires careful hemodynamic assessment and is defined by a mean pulmonary artery pressure > 20 mmHg with normal left-sided filling pressures and a PVR ≥ 3 Wood units. Most patients with PAH require targeted pharmacotherapy based on multiparametric risk stratification. Significant improvements in clinical outcome have been realized through the approval of 14 unique pharmacotherapeutic options. The latest clinical recommendations provide the updated hemodynamic definition and clinical classification as well as evidence-based treatment recommendations. An important change is the focus on initial upfront combination therapy for most patients with PAH. Structured follow-up and escalation of treatment for those not achieving low-risk status is paramount.

Which combination of clinical parameters improves the prediction of prognosis in patients with pulmonary arterial hypertension (PAH) remains unclear. We examined whether combined assessment of pulmonary vascular resistance and right ventricular function by echocardiography is useful for classifying risks in PAH. In 41 consecutive patients with PAH (mean age of 48.9 ± 17.3 years, 31 females), a 6-min walk test, pulmonary function test, and echocardiography were performed at baseline and during PAH-specific therapies. The study endpoint was defined as a composite of cardiovascular death and hospitalization for PAH and/or right ventricular failure. During a follow-up period of 9.2 ± 8.7 months, 18 patients reached the endpoint. Multivariate regression analysis showed that the ratio of tricuspid regurgitation pressure gradient to the time-velocity integral of the right ventricular outflow tract (TRPG/TVI) and tricuspid annular plane systolic excursion (TAPSE) during PAH-specific treatment were independent prognostic predictors of the endpoint. Using cutoff values indicated by receiver operating characteristic analysis, the patients were divided into four subsets. Multivariate analyses by Cox's proportional hazards model adjusted for age, sex and body mass index indicated that subset 4 (TRPG/TVI ≥ 3.89 and TAPSE ≤ 18.9 mm) had a significantly higher event risk than did subset 1 (TRPG/TVI < 3.89 and TAPSE > 18.9 mm): HR = 25.49, 95% CI 4.70-476.97, p < 0.0001. Combined assessment of TRPG/TVI and TAPSE during adequate PAH-specific therapies enables classification of risks for death and/or progressive right heart failure in PAH.

Accurately predicting and testing the types of Pulmonary arterial hypertension (PAH) of each patient using cost-effective microarray-based expression data and machine learning algorithms could greatly help either identifying the most targeting medicine or adopting other therapeutic measures that could correct/restore defective genetic signaling at the early stage. Furthermore, the prediction model construction processes can also help identifying highly informative genes controlling PAH, leading to enhanced understanding of the disease etiology and molecular pathways. In this study, we used several different gene filtering methods based on microarray expression data obtained from a high-quality patient PAH dataset. Following that, we proposed a novel feature selection and refinement algorithm in conjunction with well-known machine learning methods to identify a small set of highly informative genes. Results indicated that clusters of small-expression genes could be extremely informative at predicting and differentiating different forms of PAH. Additionally, our proposed novel feature refinement algorithm could lead to significant enhancement in model performance. To summarize, integrated with state-of-the-art machine learning and novel feature refining algorithms, the most accurate models could provide near-perfect classification accuracies using very few (close to ten) low-expression genes., Competing Interests: The authors have declared that no competing interests exist.

Background: The diagnosis of pulmonary arterial hypertension (PAH) is challenging, and there is significant overlap with the more heterogenous diagnosis of pulmonary hypertension (PH). Clinical and research efforts that rely on administrative data are limited by current coding systems that do not adequately reflect the clinical classification scheme. The aim of this systematic review is to investigate current algorithms to detect PAH using administrative data and to appraise the diagnostic accuracy of these algorithms against a reference standard., Methods: We conducted comprehensive searches of Medline, Embase, and Web of Science from their inception. We included English-language articles that applied an algorithm to an administrative or electronic health record database to identify PAH in adults., Results: Of 2,669 unique citations identified, 32 studies met all inclusion criteria. Only four of these studies validated their algorithm against a reference standard. Algorithms varied widely, ranging from single International Classification of Diseases (ICD) codes to combinations of visit, procedure, and pharmacy codes. ICD codes alone performed poorly, with positive predictive values ranging from 3.3% to 66.7%. The addition of PAH-specific therapy and diagnostic procedures to the algorithm improved the diagnostic accuracy., Conclusions: Algorithms to identify PAH in administrative databases vary widely, and few are validated. The sole use of ICD codes performs poorly, potentially leading to biased results. ICD codes should be revised to better discriminate between PH groups, and universally accepted algorithms need to be developed and validated to capture PAH in administrative data, better informing research and clinical efforts., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Paediatric pulmonary arterial hypertension (PAH) shares common features of adult disease, but is associated with several additional disorders and challenges that require unique approaches. This article discusses recent advances, ongoing challenges and distinct approaches for the care of children with PAH, as presented by the Paediatric Task Force of the 6th World Symposium on Pulmonary Hypertension. We provide updates of the current definition, epidemiology, classification, diagnostics and treatment of paediatric PAH, and identify critical knowledge gaps. Several features of paediatric PAH including the prominence of neonatal PAH, especially in pre-term infants with developmental lung diseases, and novel genetic causes of paediatric PAH are highlighted. The use of cardiac catheterisation as a diagnostic modality and haemodynamic definitions of PAH, including acute vasoreactivity, are addressed. Updates are provided on issues related to utility of the previous classification system to reflect paediatric-specific aetiologies and approaches to medical and interventional management of PAH, including the Potts shunt. Although a lack of clinical trial data for the use of PAH-targeted therapy persists, emerging data are improving the identification of appropriate targets for goal-oriented therapy in children. Such data will likely improve future clinical trial design to enhance outcomes in paediatric PAH., Competing Interests: Conflict of interest: E.B. Rosenzweig reports institutional grants from Actelion, GSK, Gilead, Bayer and United Therapeutics/Lung Biotech, outside the submitted work. Conflict of interest: S.H. Abman reports grants from Shire and United Therapeutics, outside the submitted work. Conflict of interest: I. Adatia reports personal fees (for data and safety monitoring board work for selexipag trial in children, and for clinical oversight committee work for macitentan trial in children) from Actelion, personal fees (for data and safety monitoring board work for citruline trial in children) from Asklepion, and personal fees (for clinical oversight committee work for tadalafil trial in children) from Eli Lilly, outside the submitted work. Conflict of interest: M. Beghetti reports grants and personal fees from Actelion, grants, personal fees and non-financial support from Bayer Healthcare, and personal fees from GSK, Eli Lilly, MSD and Pfizer, during the conduct of the study. Conflict of interest: D. Bonnet reports personal fees from Actelion Pharmaceuticals Novartis, Bayer Healthcare and Eli Lilly, outside the submitted work. Conflict of interest: S. Haworth has nothing to disclose. Conflict of interest: D.D. Ivy: the University of Colorado School of medicine contracts with Actelion, Bayer, Lilly and United Therapeutics for D.D. Ivy to be a consultant and perform research studies. Conflict of interest: R.M.F. Berger: University Medical Center Groningen contracts with Actelion and Lilly for consultancy and advisory board activities of R.M.F. Berger., (Copyright ©ERS 2019.)