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STUDY OBJECTIVES: We assessed the efficacy of bosentan in transitioning from prostacyclin infusions in patients with pulmonary arterial hypertension (PAH). METHODS: Twenty-two PAH patients were recruited from five PAH centers if they had been clinically stable while receiving therapy with IV epoprostenol or subcutaneous treprostinil for at least 3 months. Patients were observed in an open-label prospective trial while bosentan was added to therapy, and then epoprostenol or treprostinil were tapered after 2 months. RESULTS: Ten of the 22 patients were transitioned off prostacyclin infusion therapy after a mean (+/- SEM) duration of 6.1 +/- 1.2 months. Of those patients, seven patients have continued not receiving prostacyclin infusion therapy for a mean duration of 17.7 +/- 5.3 months, with no significant changes in pulmonary artery (PA) pressure estimated by echocardiography, World Health Organization (WHO)/New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), or Borg dyspnea score. The conditions of three patients deteriorated, necessitating the resumption of prostacyclin therapy, and two patients subsequently died. Twelve patients failed to transition or even lower the prostacylin infusion rate and had worsening of their WHO/NYHA functional class and estimated systolic PA pressures, and had a trend toward deterioration in their mean 6MWD (294 +/- 41 to 198 +/- 34 m, respectively; p = 0.2). Of these, two patients subsequently died. The baseline characteristics of those who transitioned successfully vs those who transitioned unsuccessfully were a lower prostacyclin infusion rate, and less severe elevations in the mean and estimated systolic PA pressures. CONCLUSION: Transitioning from therapy with prostacyclin to bosentan is possible in some PAH patients, mainly in those receiving lower prostacyclin doses and having less pulmonary hypertension at baseline. Careful patient selection and close interim monitoring is needed because the conditions of patients can deteriorate, and they may not respond to the resumption of therapy with prostacyclin. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This "cell biopsy" method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH., (© 2023. The Author(s).)

Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by an obliterative vasculopathy of the distal pulmonary circulation. Despite significant progress in our understanding of the pathophysiology, currently approved medical therapies for PAH act primarily as pulmonary vasodilators and fail to address the underlying processes that lead to the development and progression of the disease. Endothelial dysregulation in response to stress, injury or physiologic stimuli followed by perivascular infiltration of immune cells plays a prominent role in the pulmonary vascular remodeling of PAH. Over the last few decades, our understanding of endothelial cell dysregulation has evolved and brought to light a number of transcription factors that play important roles in vascular homeostasis and angiogenesis. In this review, we examine two such factors, SOX17 and one of its downstream targets, RUNX1 and the emerging data that implicate their roles in the pathogenesis of PAH. We review their discovery and discuss their function in angiogenesis and lung vascular development including their roles in endothelial to hematopoietic transition (EHT) and their ability to drive progenitor stem cells toward an endothelial or myeloid fate. We also summarize the data from studies that link mutations in Sox17 with an increased risk of developing PAH and studies that implicate Sox17 and Runx1 in the pathogenesis of PAH. Finally, we review the results of recent studies from our lab demonstrating the efficacy of preventing and reversing pulmonary hypertension in animal models of PAH by deleting RUNX1 expression in endothelial or myeloid cells or by the use of RUNX1 inhibitors. By investigating PAH through the lens of SOX17 and RUNX1 we hope to shed light on the role of these transcription factors in vascular homeostasis and endothelial dysregulation, their contribution to pulmonary vascular remodeling in PAH, and their potential as novel therapeutic targets for treating this devastating disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Simmons Beck, Liang and Klinger.)

Background: The burden of pulmonary hypertension (PH) among patients with chronic obstructive pulmonary disease (COPD) is not well understood. The present retrospective cohort study aimed to quantify the clinical and economic burden of PH in patients with COPD., Methods: Adults with COPD were retrospectively identified in the Optum® Clinformatics® Data Mart between July 1, 2016 and June 30, 2021. Those diagnosed with PH were assigned to the PH-COPD cohort and those without a diagnosis of PH were assigned to the COPD cohort. Outcomes, including the number of visits for exacerbations and all-cause and COPD-related healthcare resource utilization (HCRU) and costs per patient per month (PPPM), were compared between cohorts. Baseline and study outcomes were analyzed descriptively. For significance testing, continuous variables were analyzed using Student's t-tests and categorical variables were analyzed using Chi-square tests., Results: A total of 1627 patients with PH-COPD were matched 1:1 to COPD patients without PH. A greater percentage of PH-COPD patients experienced COPD exacerbations vs. the COPD cohort (p < 0.001) and the PH-COPD cohort had more total (p < 0.001) and severe exacerbation-related visits PPPM (p < 0.001). All-cause and COPD-related HCRU PPPM estimates were higher among the PH-COPD cohort vs. the COPD cohort (p < 0.01). Total all-cause (p < 0.001) and COPD-related costs (p < 0.001) were higher among PH-COPD patients than COPD patients., Conclusions: Patients with PH-COPD had higher rates of severe exacerbations, hospitalizations, and costs compared to COPD patients without PH, underscoring the need for targeted therapies to prevent and manage PH in patients with COPD., Competing Interests: Declaration of competing interest BW, KM, and PC are employees of United Therapeutics Corporation and own stocks/shares in the company., (Copyright © 2023. Published by Elsevier Ltd.)

Previous studies have shown that atrial natriuretic peptide (ANP) attenuates agonist-induced pulmonary edema and that this effect may be mediated in part by the ANP clearance receptor, natriuretic peptide receptor-C (NPR-C). Obesity has been associated with lower plasma ANP levels due to increased expression of NPR-C, and with decreased severity of acute lung injury (ALI). Therefore, we hypothesized that increased expression of NPR-C may attenuate ALI severity in obese populations. To test this, we examined ALI in Npr3 wild-type (WT) and knockout (KO) mice fed normal chow (NC) or high-fat diets (HFD). After 12 weeks, ALI was induced with intra-tracheal administration of Pseudomonas aeruginosa strain 103 (PA103) or saline. ALI severity was determined by lung wet-to-dry ratio (W/D) along with measurement of cell count, protein levels from bronchoalveolar lavage fluid (BALF), and quantitative polymerase chain reaction was performed on whole lung to measure cytokine/chemokine and Npr3 mRNA expression. ANP levels were measured from plasma. PA103 caused ALI as determined by significant increases in W/D, BALF protein concentration, and whole lung cytokine/chemokine expression. PA103 increased Npr3 expression in the lungs of wild-type (WT) mice regardless of diet. There was a nonsignificant trend toward increased Npr3 expression in the lungs of WT mice fed HFD versus NC. No differences in ALI were seen between Npr3 knockout (KO) mice and WT-fed NC, but Npr3 KO mice fed HFD had a significantly greater W/D and BALF protein concentration than WT mice fed HFD. These findings support the hypothesis that Npr3 may help protect against ALI in obesity., Competing Interests: The authors declare that there is no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin., Areas Covered: Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved., Expert Opinion: Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17 , which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development., Methods: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico - predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17 -signal 1 enhancer region ( SOX17 -4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia., Results: CRISPR inhibition of SOX17 -signal 2 and deletion of SOX17 -signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension., Conclusions: Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature., Competing Interests: Disclosures None.

Aims: Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. Previously, we found that transcription factor RUNX1-dependent haematopoietic transformation of endothelial progenitor cells may contribute to the pathogenesis of PAH. However, the therapeutic potential of RUNX1 inhibition to reverse established PAH remains unknown. In the current study, we aimed to determine whether RUNX1 inhibition was sufficient to reverse Sugen/hypoxia (SuHx)-induced pulmonary hypertension (PH) in rats. We also aimed to demonstrate possible mechanisms involved., Methods and Results: We administered a small molecule specific RUNX1 inhibitor Ro5-3335 before, during, and after the development of SuHx-PH in rats to investigate its therapeutic potential. We quantified lung macrophage recruitment and activation in vivo and in vitro in the presence or absence of the RUNX1 inhibitor. We generated conditional VE-cadherin-CreERT2; ZsGreen mice for labelling adult endothelium and lineage tracing in the SuHx-PH model. We also generated conditional Cdh5-CreERT2; Runx1(flox/flox) mice to delete Runx1 gene in adult endothelium and LysM-Cre; Runx1(flox/flox) mice to delete Runx1 gene in cells of myeloid lineage, and then subjected these mice to SuHx-PH induction. RUNX1 inhibition in vivo effectively prevented the development, blocked the progression, and reversed established SuHx-induced PH in rats. RUNX1 inhibition significantly dampened lung macrophage recruitment and activation. Furthermore, lineage tracing with the inducible VE-cadherin-CreERT2; ZsGreen mice demonstrated that a RUNX1-dependent endothelial to haematopoietic transformation occurred during the development of SuHx-PH. Finally, tissue-specific deletion of Runx1 gene either in adult endothelium or in cells of myeloid lineage prevented the mice from developing SuHx-PH, suggesting that RUNX1 is required for the development of PH., Conclusion: By blocking RUNX1-dependent endothelial to haematopoietic transformation and pulmonary macrophage recruitment and activation, targeting RUNX1 may be as a novel treatment modality for pulmonary arterial hypertension., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Atrial natriuretic peptide (ANP) protects against acute lung injury (ALI), but the receptor that mediates this effect is not known. Transgenic mice with 0 (knockout), 1 (heterozygote), or 2 (wild-type) functional copies of Npr3 , the gene that encodes for natriuretic peptide receptor-C (NPR-C), were treated with intravenous infusion of ANP or saline vehicle before oropharyngeal aspiration of Pseudomonas aeruginosa (PA103) or saline vehicle. Lung injury was assessed 4 h following aspiration by measurement of lung wet/dry (W/D) weight, whole lung leukocyte and cytokine levels, and protein, leukocyte, and cytokine concentration in bronchoalveolar lavage fluid (BALF). PA103 induced acute lung injury as evidenced by increases in lung W/D ratio and protein concentration in BALF. The severity of PA103-induced lung injury did not differ between NPR-C genotypes. Treatment with intravenous ANP infusion reduced PA103-induced increases in lung W/D and BALF protein concentration in all three NPRC genotypes. PA103 increased the percentage of leukocytes that were neutrophils and cytokine levels in whole lung and BALF in NPR-C wild-type and knockout mice. This effect was blunted by ANP in wild-type mice but not in the NPR-C knockout mice. NPR-C does not mediate the protective effect of ANP on endothelial cell permeability in settings of PA103-induced injury but may mediate the effect of ANP on inhibition of the recruitment of neutrophils to the lung and thereby attenuate the release of inflammatory cytokines.

Chitinase 3 like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggest CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including group 1 PAH and group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1-null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a target for the treatment of PAH and PH associated with fibrotic lung disease.

Rationale: There is a noticeable underrepresentation of minorities in clinical trials and registries in pulmonary arterial hypertension (PAH). Prior studies evaluating the association between Hispanic ethnicity and clinical outcomes in patients with PAH have not assessed the socioeconomic profile of Hispanic individuals or the significance of social determinants of health in clinical outcomes. Objectives: To determine the association between Hispanic ethnicity, social determinants of health, and clinical outcomes in PAH. Methods: This was a prospective cohort study of adult participants with PAH enrolled in the Pulmonary Hypertension Association Registry, a multicenter U.S.-based registry of patients treated at pulmonary hypertension care centers. Participants were classified as Hispanics and non-Hispanic White individuals, based on self-reported ethnicity. A comparison of baseline clinical and sociodemographic characteristics between groups was performed as well using absolute standardized differences (ASD). The primary outcome of the study was to assess transplant-free survival between Hispanics and non-Hispanic White individuals. A Cox proportional hazards model was used for the multivariable analysis after adjusting for age, sex, PAH etiology, annual income, education level, and health insurance. Results: A total of 683 individuals were included, 98 (14.3%) of Hispanic ethnicity. Hispanic patients had impaired access to health care (31.6% vs. 12.9% Medicaid/uninsured; ASD, 0.35), lower education level (72.6% vs. 94.0% high school graduates or higher; ASD, 0.60), and lower annual income (32.0% vs. 17.4% with income <20,000 U.S. dollars; ASD, 0.47), compared with non-Hispanic White individuals. Hispanic patients had a higher frequency of emergency room visits and a higher number of hospitalizations, despite having similar disease severity (incidence rate ratio, 1.452; 95% confidence interval [CI], 1.326-1.590; and 1.428; 95% CI, 1.292-1.577, respectively). Although the unadjusted analysis showed a lower transplant/death hazard ratio for Hispanics (hazard ratio, 0.47; 95% CI, 0.24-0.94; P  = 0.032), there was no association between Hispanic ethnicity and outcome in the multivariable model after adjusting for social determinants of health and other covariates (HR, 0.76; 95% CI, 0.35-1.62; P  = 0.474). Conclusions: Hispanic ethnicity was not associated with differences in survival after adjusting for social determinants of health and other factors. Social determinants of health are important to consider when assessing the association between ethnicity and outcomes in PAH.

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 ( strongly disagree ) to +5 ( strongly agree ) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable., Competing Interests: Franck F. Rahaghi reports consultation, research, and speakership honoraria from Bayer and Janssen, consultation and speakership from United Therapeutics, and consultation fees from Acceleron. Vijay P. Balasubramanian reports a research grant from United Therapeutics and serves on a speakers bureau for Bayer. Robert C. Bourge reports research grant support to my institution from United Therapeutics and Bayer, and service on a Scientific Advisory Board at United Therapeutics. Murali M. Chakinala reports grants or contracts from Actelion/Janssen, Bayer, Medtronic, NIH, Reata, Liquidia, Phase Bio, Complexa, United Therapeutics, Altavant, Trio Health Analytics, Reata, Acceleron, Arena, and Gossamer; consulting fees from Altavant, Vaderis Therapeutics, Aerovate, Reata, VWave, and Arena; honoraria from Bayer, Gilead, Simply Speaking, WebMD, and United Therapeutics; support for attending meetings and/or travel from Actelion/Janssen, United Therapeutics, Bayer, Acceleron, Reata, and Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Express Scripts, Phase Bio, Altavant, Gossamer, United Therapeutics, Bayer, Acceleron, and Liquidia; and leadership or a fiduciary role in the Pulmonary Hypertension Association and the Cure HHT Global Research and Medical Advisory Board. Michael S. Eggert reports research contracts with United Therapeutics (BREEZE and ADVANCE Outcomes), Acceleron, and Actelion. Jean M. Elwing reports grants from Actelion, Acceleron, Reata, United Therapeutics, Liquidia, Phase Bio, Complexa, Gossamer Bio, Bayer, Arena, Eiger, Akros, Bellerophon, and Lung LLC and consulting fees from United Therapeutics, Acceleron, Liquidia, Altavant, Bayer, Gossamer Bio, Actelion, Bayer. Jeremy Feldman reports consulting and giving talks for Bayer, United Therapeutics, and Jansen. Christopher King reports personal fees from Actelion, personal fees from Genentech, United Therapeutics, and Boehringer Ingelheim; has served on advisory boards for and is on the Speakers’ Bureau of Actelion, Boehringer‐Ingelheim Pharmaceuticals, and United Therapeutics. James R. Klinger reports that his institution receives research funding from United Technologies, service on a Steering Committee and a Clinical Outcomes Committee for Bayer, and a leadership role in the Pulmonary Hypertension Association. Stephen C. Mathai reports personal fees from United Therapeutics; participation on a data safety monitoring board or advisory board from United Therapeutics, Actelion, and Bayer, and leadership or a fiduciary role in the PCORI Rare Disease Advisory Panel and the World Symposium on Pulmonary Hypertension. John Wesley McConnell reports consulting fees from Actelion, Bayer, Gossamer, Altavant, and Liquidia; honoraria from Actelion, Bayer, Simply Speaking, Impact PH, and Reata, and participation on a data safety monitoring board or advisory board for Actelion, Liquidia, Gossamer, and Altavant. Harold I. Palevsky reports honoraria for serving on scientific advisory boards for Acceleron, Actelion/Janssen, PhaseBio and United Therapeutics, and serving on a DSMB for United Therapeutics. Ricardo Restrepo‐Jaramillo reports serving on speaker's bureau for United Therapeutics, Bayer, and Actelion. Zeenat Safdar reports serving on a speakers bureau, consultation and advisory boards for Actelion, United Therapeutics, Boehringer Ingelheim, Bayer, and Roche. Jeffrey S. Sager reports personal fees from Bayer pharmaceuticals, grants and personal fees from United Therapeutics, grants and personal fees from Janssen (J and J), and grants from Reata outside the submitted work. Namita Sood reports a speaking fee from Bayer. Roxana Sulica reports research grants from Bayer, United Therapeutics, Complexa, and Reata, and serves on advisory boards for Actelion, Bayer, United Therapeutics, and Reata. R. James White reports research grants from United Therapeutics, Reata, Bayer, Merck, and Janssen and consulting fees from Merck and Bayer. Nicholas S. Hill reports honoraria from Axon Research for this study; grants to his institution from Actelion, Bayer, Gilead, and United Therapeutics; consulting fees from United Therapeutics; and participation in Data Safety Monitoring Boards for United Therapeutics and Pfizer. All authors had access to the Delphi questionnaire analysis and data and participated in the review, revision, and approval of the content of the manuscript for submission. Charles D. Burger reports no disclosures or conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Rationale: Mesenchymal stem cell extracellular vesicles (MSC EVs) reverse pulmonary hypertension, but little information is available regarding what dose is effective and how often it needs to be given. This study examined the effects of dose reduction and use of longer dosing intervals and the effect of hypoxic stress of MSC prior to EV collection., Methods: Adult male rats with pulmonary hypertension induced by Sugen 5416 and three weeks of hypoxia (SuHx-pulmonary hypertension) were injected with MSC EV or phosphate buffered saline the day of removal from hypoxia using one of the following protocols: (1) Once daily for three days at doses of 0.2, 1, 5, 20, and 100 µg/kg, (2) Once weekly (100 µg/kg) for five weeks, (3) Once every other week (100 µg/kg) for 10 weeks, (4) Once daily (20 µg/kg) for three days using EV obtained from MSC exposed to 48 h of hypoxia (HxEV) or MSC kept in normoxic conditions (NxEV)., Main Results: MSC EV reversed increases in right ventricular systolic pressure (RVSP), right ventricular to left ventricle + septum weight (RV/LV+S), and muscularization index of pulmonary vessels ≤50 µm when given at doses of 20 or 100 μg/kg. RVSP, RV/LV+S, and muscularization index were significantly higher in SuHx-pulmonary hypertension rats treated once weekly with phosphate buffered saline for five weeks or every other week for 10 weeks than in normoxic controls, but not significantly increased in SuHx-pulmonary hypertension rats given MSC EV. Both NxEV and HxEV significantly reduced RVSP, RV/LV+S, and muscularization index, but no differences were seen between treatment groups., Conclusions: MSC EV are effective at reversing SuHx-pulmonary hypertension when given at lower doses and longer dosing intervals than previously reported. Hypoxic stress does not enhance the efficacy of MSC EV at reversing pulmonary hypertension. These findings support the feasibility of MSC EV as a long-term treatment for pulmonary hypertension., (© The Author(s) 2021.)

Pulmonary arterial hypertension (PAH) is a rare disease characterized by an obliterative vasculopathy of the distal pulmonary circulation that results in severe elevation in pulmonary pressure and pulmonary vascular resistance. PAH is a progressive and devastating disease that usually results in right heart failure and death. Currently available medications have only moderate effects and none are curative. Thus, there is a pressing need for new pharmacologic approaches to this disease. In order to meaningfully advance the treatment of PAH, new agents must target the underlying cause of disease induction and progression. This review discusses the extensive work that has been done in the areas of altered glucose metabolism, tyrosine kinase inhibitions, signaling pathways associated with disease causing gene mutations such as the bone morphogenic protein receptor 2, and inflammation and immunomodulation including the effects of mesenchymal stem cells and the extracellular vesicles they secrete. Epigenetic modifications including the roles of micro RNAs, DNA methylation, histone acetylation and transcription factors that modulate pulmonary vascular remodeling are also reviewed. A brief background of each area of interest is provided with emphasis on those components that have potential to be exploited for the treatment of PAH. Significant findings of cell-based and animal studies and, where available, the results of early clinical trials, are presented to illustrate the potential of these novel therapeutic targets. Current challenges to the development of small peptides and biologicals for the treatment of PAH and direction for future studies are also briefly discussed. © 2021 American Physiological Society. Compr Physiol 11:1-53, 2021., (Copyright © 2021 American Physiological Society. All rights reserved.)

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..)

Pulmonary arterial hypertension (PAH) remains life-limiting despite numerous approved vasodilator therapies. Right ventricular (RV) function determines outcome in PAH but no treatments directly target RV adaptation. PAH is more common in women, yet women have better RV function and survival as compared to men with PAH. Lower levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester are associated with more severe pulmonary vascular disease, worse RV function, and mortality independent of other sex hormones in men and women with PAH. DHEA has direct effects on nitric oxide (NO) and endothelin-1 (ET-1) synthesis and signaling, direct antihypertrophic effects on cardiomyocytes, and mitigates oxidative stress. Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) is an on-going randomized double-blind placebo-controlled crossover trial of DHEA in men ( n  = 13) and pre- and post-menopausal women ( n  = 13) with Group 1 PAH funded by the National Heart, Lung and Blood Institute. We will determine whether orally administered DHEA 50 mg daily for 18 weeks affects RV longitudinal strain measured by cardiac magnetic resonance imaging, markers of RV remodeling and oxidative stress, NO and ET-1 signaling, sex hormone levels, other PAH intermediate end points, side effects, and safety. The crossover design will elucidate sex-based phenotypes in PAH and whether active treatment with DHEA impacts NO and ET-1 biosynthesis. EDIPHY is the first clinical trial of an endogenous sex hormone in PAH. Herein we present the study's rationale and experimental design., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization., (© The Author(s) 2021.)

Introduction: While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States., Methods: Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score., Results: We analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of -6.0 points (range -5.0--7.6 points)., Conclusions: The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions., Competing Interests: Conflict of interest: M. Borgese has nothing to disclose. Conflict of interest: D. Badesch reports grants, personal fees and other (long-term stockholder in Johnson & Johnson) from Actelion/Janssen/Johnson & Johnson, grants and personal fees from Arena/United Therapeutics/Lung LLC, Acceleron, Complexa, Liquidia and Belleraphon, personal fees from Pfizer, grants from Altavant, outside the submitted work. Conflict of interest: T. Bull reports grants from Bayer, personal fees from Liquidia, outside the submitted work; and is a member of a clinical trial steering committee for Liquidia. Conflict of interest: M. Chakinala reports grants and consultancy fees from Actelion, Reata Pharmaceuticals, United Therapeutics, Phase Bio and Acceleron, grants from Medtronic, Eiger Bio Pharmaceuticals, GeNO LLC, GSK, Liquidia, Complexa, Altavant and Trio Health Analytics, consultancy and lecture fees from WedMD LLC (Medscape), consultancy fees from SteadyMed Therapeutics Inc. and Express Scripts Holding Company, grants, personal fees for lectures and consultancy fees from Bayer and Gilead Sciences, outside the submitted work. Conflict of interest: T. DeMarco serves as a consultant to Actelion, United Therapeutics, Arena and SCOPE/BIAL, and as PI on a multicenter trial sponsored by Acceleron. Conflict of interest: J. Feldman reports personal fees for consultancy and lectures from United Therapeutics and Actelion, personal fees for consultancy from Acceleron, Bayer and Altavant, outside the submitted work. Conflict of interest: H.J. Ford reports grants and personal for consultancy fees from United Therapeutics and Actelion/Jannsen, personal fees for consultancy from Bayer, grants from Liquidia, outside the submitted work. Conflict of interest: D. Grinnan reports grants from Johnson & Johnson, Bayer and United Therapeutics, outside the submitted work. Conflict of interest: J.R. Klinger has nothing to disclose. Conflict of interest: L. Bolivar has nothing to disclose. Conflict of interest: O.A. Shlobin has nothing to disclose. Conflict of interest: R.P. Frantz has nothing to disclose. Conflict of interest: J.S. Sager reports personal fees for consultancy, lectures and research from Actelion and United Therapeutics, personal fees for consultancy from Bayer, personal fees for research from Reata and PhaseBio, outside the submitted work. Conflict of interest: S.C. Mathai reports personal fees for consultancy from Actelion, Arena, Liquidia and United Therapeutics, outside the submitted work; and is a member of the Rare Disease Advisory Panel for the Patient Centered Outcomes Research Institute. Conflict of interest: S. Kawut reports grants from NIH, non-financial support from ATS, and grants from Actelion, United Therapeutics, Gilead, Lung Biotech, Bayer and Mallinkrodt to the Perelman School of Medicine for CME courses; reports grants and non-financial support from Cardiovascular Medical Research and Education Fund and non-financial support from Pulmonary Hypertension Association; and has served in an advisory capacity (for grant review and other purposes) for United Therapeutics, Akros Pharmaceuticals, GlaxoSmithKline and Complexa, Inc. without financial support or in-kind benefits. Conflict of interest: P.J. Leary has nothing to disclose. Conflict of interest: M.P. Gray has nothing to disclose. Conflict of interest: R.A. Popat has nothing to disclose. Conflict of interest: R.T. Zamanian reports grants from Actelion, Tenax, PHaware and United Therapeutics, personal fees for consultancy from Morphogen-IX and Vivus, outside the submitted work; and has a patent FK506 for PH issued., (Copyright ©ERS 2021.)

Rationale: Sex hormones play a role in pulmonary arterial hypertension (PAH), but the menstrual cycle has never been studied. Objectives: We conducted a prospective observational study of eight women with stable PAH and 20 healthy controls over one cycle. Methods: Participants completed four study visits 1 week apart starting on the first day of menstruation. Relationships between sex hormones, hormone metabolites, and extracellular vesicle microRNA (miRNA) expression and clinical markers were compared with generalized linear mixed modeling. Results: Women with PAH had higher but less variable estradiol (E2) levels ( P  < 0.001) that tracked with 6-minute walk distance ( P  < 0.001), N-terminal prohormone of brain natriuretic peptide ( P  = 0.03) levels, and tricuspid annular plane systolic excursion ( P  < 0.01); the direction of these associations depended on menstrual phase. Dehydroepiandrosterone sulfate (DHEA-S) levels were lower in women with PAH (all visits, P  < 0.001). In PAH, each 100-μg/dl increase in DHEA-S was associated with a 127-m increase in 6-minute walk distance ( P  < 0.001) and was moderated by the cardioprotective E2 metabolite 2-methoxyestrone ( P  < 0.001). As DHEA-S increased, N-terminal prohormone of brain natriuretic peptide levels decreased ( P  = 0.001). Expression of extracellular vesicle miRNAs-21, -29c, and -376a was higher in PAH, moderated by E2 and DHEA-S levels, and tracked with hormone-associated changes in clinical measures. Conclusions: Women with PAH have fluctuations in cardiopulmonary function during menstruation driven by E2 and DHEA-S. These hormones in turn influence transcription of extracellular vesicle miRNAs implicated in the pathobiology of pulmonary vascular disease and cancer.

Globally, non-communicable diseases are increasing in people living with HIV. Pulmonary hypertension is a rare non-communicable disease in people living with HIV with a reported prevalence of <1%. However, data on pulmonary hypertension in people living with HIV from Africa are scarce and are non-existent from Ethiopia. This study aimed to examine the prevalence and severity of echocardiographic pulmonary hypertension and risk factors associated with pulmonary hypertension in people living with HIV in Ethiopia. A total of 315 consecutive adult people living with HIV followed at the Tikur Anbessa Specialized Hospital HIV Referral Clinic were enrolled from June 2018 to February 2019. Those with established pulmonary hypertension of known causes were excluded. A structured questionnaire was used to collect data on demographics, respiratory symptoms, physical findings, physician-diagnosed lung disease, and possible risk factors. Pulmonary hypertension was defined by a tricuspid regurgitant velocity of ≥2.9 m/sec on transthoracic echocardiography. A tricuspid regurgitant velocity ≥3.5, which translates into a pulmonary arterial pressure/right ventricular systolic pressure of ≥50 mmHg, was considered moderate-to-severe pulmonary hypertension. The mean age of the participants was 44.5 ± 9.8 years and 229 (72.7%) were females. Pulmonary hypertension was diagnosed in 44 (14.0%) of participants, of whom 9 (20.5%) had moderate-to-severe disease. In those with pulmonary hypertension, 17 (38.6%) were symptomatic: exertional dyspnea, cough, and leg swelling were seen in 12 (27.3%), 9 (20.5%), and 4 (9.1%), respectively. There was no significant difference in those with pulmonary hypertension compared to those without the disease by gender, cigarette smoking, previous history of pulmonary tuberculosis treatment, physician-diagnosed chronic obstructive pulmonary disease or bronchial asthma, duration of anti-retroviral therapy therapy or anti-retroviral regimen type. Pulmonary hypertension looks to be a frequent complication in people living with HIV in Ethiopia and is often associated with significant cardiopulmonary symptoms. Further studies using right heart catheterization are needed to better determine the etiology and prevalence of pulmonary hypertension in people living with HIV in Ethiopia compared to other countries., Competing Interests: Conflict of interest: The authors whose names are listed above certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. This case was presented at the American Thoracic Society International Conference in Dallas, Texas, May 2019., (© The Author(s) 2020.)

Background: RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement., Methods: RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders., Results: Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status., Conclusions: NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response., Competing Interests: Declaration of Competing Interest RLB reports grants from Bellerophon, Bayer AG, Actelion, and EIGER. PAC reports grants and personal fees (University Research Fund) from Bayer AG, and personal fees from Actelion and GSK. JRK reports his institution received grant support for clinical trials in pulmonary hypertension from Actelion, Bayer AG, Lung Biotechnology, and United Therapeutics. DL reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutic, PhaseBio, and United Therapeutics. RN reports Advisory Board member fees from Actelion, Bayer AG, and Lung Biotechnology Corporation, personal fees from Actelion and GSK, and grants from Reata. GS reports grants, personal fees, and non-financial support from Actelion, Bayer AG, GSK, and Merck. HAG reports grants and personal fees from Actelion, Bayer AG, Ergonex, and Pfizer, and personal fees from Gilead, GSK, Merck, and Novartis. PJ reports being an investigator for Actelion and Bayer AG, and personal fees from AOP. SR reports grants and personal fees from Actelion, Bayer AG, Gilead, GSK, Novartis, Pfizer, United Therapeutics, Arena, Ferrer, Merck Sharp&Dohme, and Abbott, and research support from Actelion, Bayer AG, Novartis, Pfizer, and United Therapeutics. LS has nothing to disclose. TT reports personal fees (Advisory Board/CME) from Actelion and Gilead. AR reports honoraria from Bayer AG, research support from United Therapeutics, and consulting fees from St Jude. CM is an employee of Bayer AG. DB was an employee of Chrestos Concept GmBH & Co during writing of the manuscript. MMH reports consultancy fees from Actelion, Bayer AG, and Pfizer, and personal fees from Actelion, Bayer AG, Pfizer, and MSD., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a rare form of pulmonary hypertension characterized by a progressive obliterative vasculopathy of the distal pulmonary arterial circulation that usually leads to right ventricular failure and death. Over the last 25 years, more than a dozen drugs representing five drug classes have been developed and approved for the treatment of this devastating disease. Due to the small number of patients afflicted by PAH, most health care providers have little experience with its management. To address this gap in medical knowledge, treatment guidelines have been developed by professional organizations and expert committees. Over the last few years, these guidelines have been updated to address findings from recent clinical trials and ongoing experience with these drugs. This review provides an update on the most recently published treatment guidelines for pharmacologic treatment of PAH and incorporates them into a contemporary approach to the treatment of this disease.

Mesenchymal stem cell extracellular vesicles attenuate pulmonary hypertension, but their ability to reverse established disease in larger animal models and the duration and mechanism(s) of their effect are unknown. We sought to determine the efficacy and mechanism of mesenchymal stem cells' extracellular vesicles in attenuating pulmonary hypertension in rats with Sugen/hypoxia-induced pulmonary hypertension. Male rats were treated with mesenchymal stem cell extracellular vesicles or an equal volume of saline vehicle by tail vein injection before or after subcutaneous injection of Sugen 5416 and exposure to 3 weeks of hypoxia. Pulmonary hypertension was assessed by right ventricular systolic pressure, right ventricular weight to left ventricle + septum weight, and muscularization of peripheral pulmonary vessels. Immunohistochemistry was used to measure macrophage activation state and recruitment to lung. Mesenchymal stem cell extracellular vesicles injected before or after induction of pulmonary hypertension normalized right ventricular pressure and reduced right ventricular hypertrophy and muscularization of peripheral pulmonary vessels. The effect was consistent over a range of doses and dosing intervals and was associated with lower numbers of lung macrophages, a higher ratio of alternatively to classically activated macrophages (M2/M1 = 2.00 ± 0.14 vs. 1.09 ± 0.11; P  < 0.01), and increased numbers of peripheral blood vessels (11.8 ± 0.66 vs. 6.9 ± 0.57 vessels per field; P  < 0.001). Mesenchymal stem cell extracellular vesicles are effective at preventing and reversing pulmonary hypertension in Sugen/hypoxia pulmonary hypertension and may offer a new approach for the treatment of pulmonary arterial hypertension.

Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH) but there are no established methods to study pulmonary artery endothelial cells (PAECs) from living patients. We sought to culture PAECs from pulmonary artery catheter (PAC) balloons used during right-heart catheterisation (RHC) to characterise successful culture attempts and to describe PAEC behaviour.PAECs were grown in primary culture to confluence and endothelial cell phenotype was confirmed. Standard assays for apoptosis, migration and tube formation were performed between passages three to eight. We collected 49 PAC tips from 45 subjects with successful PAEC culture from 19 balloons (39%).There were no differences in subject demographic details or RHC procedural details in successful versus unsuccessful attempts. However, for subjects who met haemodynamic criteria for PAH, there was a higher but nonsignificant (p=0.10) proportion amongst successful attempts (10 out of 19, 53%) versus unsuccessful attempts (nine out of 30, 30%). A successful culture was more likely in subjects with a lower cardiac index (p=0.03) and higher pulmonary vascular resistance (p=0.04). PAECs from a subject with idiopathic PAH were apoptosis resistant compared to commercial PAECs (p=0.04) and had reduced migration compared to PAECs from a subject with portopulmonary hypertension with high cardiac output (p=0.01). PAECs from a subject with HIV-associated PAH formed fewer (p=0.01) and shorter (p=0.02) vessel networks compared to commercial PAECs.Sustained culture and characterisation of PAECs from RHC balloons is feasible, especially in PAH with high haemodynamic burden. This technique may provide insight into endothelial dysfunction during PAH pathogenesis., Competing Interests: Conflict of interest: C.E. Ventetuolo reports grants from National Institutes of Health (R01 HL141268 and P20GM103652), during the conduct of the study; institutional grants from United Therapeutics and Eiger; personal fees from Acceleron Pharma, outside the submitted work; and her spouse was a recent employee of CVS Health. Conflict of interest: J.M. Aliotta has nothing to disclose. Conflict of interest: J. Braza has nothing to disclose. Conflict of interest: H. Chichger has nothing to disclose. Conflict of interest: M. Dooner has nothing to disclose. Conflict of interest: D. McGuirl has nothing to disclose. Conflict of interest: C.J. Mullin has nothing to disclose. Conflict of interest: J. Newton has nothing to disclose. Conflict of interest: M. Pereira has nothing to disclose. Conflict of interest: A. Princiotto has nothing to disclose. Conflict of interest: P.J. Quesenberry has nothing to disclose. Conflict of interest: T. Walsh has nothing to disclose. Conflict of interest: M. Whittenhall has nothing to disclose. Conflict of interest: J.R. Klinger has nothing to disclose. Conflict of interest: E.O. Harrington has nothing to disclose., (Copyright ©ERS 2020.)

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling and ultimately death. Two rodent models of PH include treatment with monocrotaline or exposure to a vascular endothelial growth factor receptor inhibitor and hypoxia. Studies in these models indicated that damaged lung cells evolve extracellular vesicles which induce production of progenitors that travel back to the lung and induce PH. A study in patients with pulmonary myelofibrosis and PH indicated that 100 cGy lung irradiation could remit both diseases. Previous studies indicated that murine progenitors were radiosensitive at very low doses, suggesting that 100 cGy treatment of mice with induced PH might be an effective PH therapy. Our hypothesis is that the elimination of the PH-inducing marrow cells by low dose irradiation would remove the cellular influences creating PH. Here we show that low dose whole-body irradiation can both prevent and reverse established PH in both rodent models of PH., (© 2019 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.)

Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling ( e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field., Competing Interests: Conflict of interest: M. Humbert reports personal fees from Actelion and Merck, and grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: S. Bonnet has nothing to disclose. Conflict of interest: P. Dorfmüller reports personal fees from MSD, Bayer, Actelion and Roche, outside the submitted work. Conflict of interest: J.R. Klinger reports grants for animal study of extra cellular vesicles from United Therapeutics, outside the submitted work. Conflict of interest: M.R. Nicolls has nothing to disclose. Conflict of interest: A.J. Olschewski has nothing to disclose. Conflict of interest: S.S. Pullamsetti has nothing to disclose. Conflict of interest: R.T. Schermuly has nothing to disclose. Conflict of interest: K.R. Stenmark reports grants from ContraFect, personal fees for advisory board work from Pfizer, New York, personal fees for membership of a steering Committee Member (Entelligence Awards Program) from Actelion, and personal fees for scientific advisory board work from Janssen Research and Development, outside the submitted work. Conflict of interest: M. Rabinovitch reports use of FK506 for the treatment of PAH. The Board of Trustees of Leland Stanford Junior University, assignee. Patent PCT/US2012035793., (Copyright ©ERS 2019.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct type of pulmonary hypertensive disease, characterized by incomplete or abnormal resolution of acute pulmonary embolism such that residual emboli become organized and fibrotic. CTEPH can occur in patients without a prior history of venous thromboembolism, and is diagnosed based on precapillary pulmonary hypertension on right heart catheterization with evidence of chronic emboli on ventilation/perfusion scan, chest imaging, or pulmonary angiogram. Pulmonary endarterectomy (PEA) is often curative, and results in improved survival. In patients for whom PEA is not feasible, medical therapy has been effective in improving hemodynamics and functional capacity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL -1 ) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH., Competing Interests: Conflict of interest: S.M. Kawut reports grants (for research and CME) from Actelion, United Therapeutics, Gilead, Lung Biotech, Bayer and the Cardiovascular Medical Research and Education Fund, and personal fees (for travel) from the American Thoracic Society, outside the submitted work. Conflict of interest: J.R. Klinger reports grants from Actelion, United Therapeutics, Gilead, Eiger and Bayer, outside the submitted work. Conflict of interest: H.I. Palevsky reports personal fees from Actelion, Janssen, Bayer, GSK and United Therapeutics, outside the submitted work. Conflict of interest: I.R. Preston reports grants and personal fees from Actelion, grants from Bayer and Gilead, and personal fees from Arena, United Therapeutics and Pfizer, outside the submitted work. Conflict of interest: A. Smith reports grants from Actelion, Gilead and United Therapeutics, outside the submitted work. Conflict of interest: M. Whittenhall reports personal fees from Actelion, Bayer, Gilead and United Therapeutics, outside the submitted work. Conflict of interest: C.E. Ventetuolo reports personal fees from Bayer, Acceleron and United Therapeutics and grants from the CHEST Foundation (Actelion sponsored) and Eiger paid to her institution, outside the submitted work. Conflict of interest: C. Archer-Chicko reports personal fees from Actelion, outside the submitted work., (Copyright ©ERS 2018.)

: Previous studies have associated biomarkers indicative of acute inflammation with pulmonary embolism, which may amplify coagulation, inhibit fibrinolysis and increase risk of venous thromboembolism (VTE) recurrence. The aim of this study was to measure inflammatory and hemostatic biomarkers in acute submassive pulmonary embolism at diagnosis and 3-month follow-up and to test the impact of treatment with fibrinolysis. Secondary analysis of a multicenter, double-blinded, randomized controlled trial including patients with submassive pulmonary embolism. Blood samples were obtained within 24 h of diagnosis and prior to bolus-dose tenecteplase (TNK) or placebo; all patients received standard anticoagulation and blood was redrawn 3 months later. Plasma concentrations of inflammatory [Interleukin 6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO)] and hemostatic [plasminogen activator inhibitor-1 (PAI-1), fibrinogen, thrombin-activatable fibrinolysis inhibitor and D-dimer] biomarkers were quantified. The median values of the biomarkers of inflammation (IL-6, CRP, MPO) were all significantly decreased at 3-month follow-up, ranging from a 60 to 91% reduction over this time period. Concentrations of PAI-1 and fibrinogen did not change significantly. D-dimer concentration at 3-month follow-up was lower in patients treated with fibrinolysis vs. placebo and appeared to have a trend toward significance (placebo 310 vs. TNK 220 ng/ml, P = 0.051). Acute pulmonary embolism causes marked but transient inflammation, as demonstrated by the significant elevation in the inflammatory biomarkers at diagnosis, followed by their reduction in more than 80% of patients at 3-month follow-up.

Women have an increased risk of pulmonary hypertension (PH) but better survival compared to men. Few studies have explored sex-based differences in population-based cohorts with PH. We sought to determine whether sex was associated with hemodynamics and survival in US veterans with PH (mean pulmonary artery pressure [mPAP] ≥ 25 mm Hg) from the Veterans Affairs Clinical Assessment, Reporting, and Tracking database. The relationship between sex and hemodynamics was assessed with multivariable linear mixed modeling. Cox proportional hazards models were used to compare survival by sex for those with PH and precapillary PH (mPAP ≥ 25 mm Hg, pulmonary artery wedge pressure [PAWP] ≤ 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood units) respectively. The study population included 15,464 veterans with PH, 516 (3%) of whom were women; 1,942 patients (13%) had precapillary PH, of whom 120 (6%) were women. Among those with PH, women had higher PVR and pulmonary artery pulse pressure, and lower right atrial pressure and PAWP (all p <0.001) compared with men. There were no significant differences in hemodynamics according to sex in veterans with precapillary PH. Women with PH had 18% greater survival compared to men with PH (adjusted HR 0.82, 95% CI 0.69-0.97, p = 0.020). Similarly, women with precapillary PH were 29% more likely to survive as compared to men with PH (adjusted HR 0.71, 95% CI 0.52-0.98, p = 0.040). In conclusion, female veterans with PH have better survival than males despite higher pulmonary afterload.

Aims: The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (PH). We sought to determine the role of EHT in mouse models of PH, to characterize specific cell types involved in this process, and to identify potential therapeutic targets to prevent disease progression., Methods and Results: When transgenic mice with fluorescence protein ZsGreen-labelled ECs were treated with Sugen/hypoxia (Su/Hx) combination to induce PH, the percentage of ZsGreen+ haematopoietic cells in the peripheral blood, primarily of myeloid lineage, significantly increased. This occurrence coincided with the depletion of bone marrow (BM) ZsGreen+ c-kit+ CD45- endothelial progenitor cells (EPCs), which could be detected accumulating in the lung upon PH-induction. Quantitative RT-PCR based gene array analysis showed that key transcription factors driving haematopoiesis were expressed in these EPCs. When transplanted into lethally irradiated recipient mice, the BM-derived EPCs exhibited long-term engraftment and haematopoietic differentiation capability, indicating these EPCs are haemogenic in nature. Specific inhibition of the critical haematopoietic transcription factor Runx1 blocked the EHT process in vivo, prevented egress of the BM EPCs and ultimately attenuated PH progression in Su/Hx- as well as in monocrotaline-induced PH in mice. Thus, myeloid-skewed EHT promotes the development of PH and inhibition of this process prevents disease progression in mouse models of PH. Furthermore, high levels of Runx1 expression were found in circulating CD34+ CD133+ EPCs isolated from peripheral blood of patients with PH, supporting the clinical relevance of our proposed mechanism of EHT., Conclusion: EHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)