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Pulmonary hypertension (PH) due to interstitial lung disease (ILD), a commonly encountered complication of fibrotic ILDs, is associated with significant morbidity and mortality. Until recently, the studies of pulmonary vasodilator therapy in PH-ILD have been largely disappointing, with some even demonstrating the potential for harm. This paper is part of a series of Consensus Statements from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative for Group 3 Pulmonary Hypertension, with prior publications covering pathogenesis, prevalence, clinical features, phenotyping, clinical trials, and impact of PH-ILD. It offers a comprehensive review of and a holistic approach to treatment of PH-ILD, including the management of underlying interstitial lung diseases, importance of treating the comorbidities, emphasis on importance of exercise and palliation of dyspnea, and review of the most up-to-date guidelines for referral for potential lung transplant work up. It also summarizes the prior, ongoing, and possibly future studies in treatment of the vascular derangement of this morbid condition., Competing Interests: Dr. Oksana A. Shlobin has consulted for United Therapeutics, Bayer, Altavant, Aerovate, Jenssen&Jenssen and Merck, and is on the speaker bureau for UT, Bayer, and J&J. Mr. Eric Shen is an employee of United Therapeutics Corporation and owns stocks/shares in the company. Dr. Lucilla Piccari has received research funding from and served as a speaker for Janssen and Ferrer, advised Janssen, Ferrer, and United Therapeutics as well as received support for attending congresses from Janssen, MSD, and Ferrer, all of which not related to this manuscript. Dr. John A. Scandurra is an employee of Aria CV Inc. and owns stocks/shares in the company. Dr. Paul M. Hassoun serves on a scientific advisory board for Merck, an activity unrelated to the current work. Dr. Stephen J. Wort received honoraria from Janssen, MSD, Bayer, and Acceleron for advisory boards, received honoraria from Janssen for educational activity, received unrestricted research grants from Janssen and Bayer, and travel grants, conference registration and accommodation from Actelion and GSK. Dr. Sylvia M. Nikkho is an employee of Bayer AG. Dr. Steven D. Nathan a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Merck, and Daewoong., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m 2 . However, there is no clear definition denoting severity of sarcoidosis-associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut-off values where transplant-free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant-free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan-Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut-off values where transplant-free survival was decreased. Decreased transplant-free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant-free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut-offs with decreased transplant-free survival in the SAPH population. Neither cut-off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant-free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. J. W. has received honoraria for lectures and advisory boards from Janssen (previously known as Actelion), Bayer, MSD and GSK. He has received travel grants from Janssen and GSK. He has received research grants from Bayer and Janssen. RPB has grant support from Gilead, Bayer, Actelion, Genentech, aTyr, Novartis, and Bellephron for studies in sarcoidosis. O. A. S. consults for and is a speaker for Bayer, United Therapeutics, and Janssen & Janssen. She also consults for Altavant. L. C. P. declares personal fees from Janssen Pharmaceuticals, outside the submitted work. SB has received consultancy fees from aTy and Kinevant. S. D. N. is a consultant for Boehringer‐Ingelheim, Roche, United Therapeutics, Bellerophon, Third Pole, and Merck. He is on the speakers bureau for Boehringer‐Ingelheim and United Therapeutics. R. G. has received consultancy fees from Mallinckrodt. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. The remaining author declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes., Competing Interests: Dr. Lucilla Piccari has received research funding from and served as a speaker for Janssen and Ferrer, advised Janssen, Ferrer and United Therapeutics as well as received support for attending congresses from Janssen, MSD and Ferrer, all of which not related to this manuscript. Prof Katerina Antoniou has a consultant role for Roche, Boehringer‐Ingelheim, GSK, honoraria for lecturing for Roche, Boehringer‐Ingelheim, GSK, Astra‐Zeneca, Chiesi & Menarini. Dr. Paul M. Hassoun serves on a scientific advisory board for Merck, an activity unrelated to the current work. Dr. Sylvia M. Nikkho is an employee of Bayer AG. Dr. Rajan Saggar has a Consulting and Advisory Role for United Therapeutics, Third Pole, Novartis, Acceleron, Aerovate, and Janssen. Dr. Oksana A. Shlobin has consulted for UT, Bayer, Altavant, Aerovate, Jenssen&Jenssen and Merck, and is on the speaker bureau for UT, Bayer, and JJ. Dr. Steven D. Nathan is a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Merck and Daewoong. Dr. Stephen John Wort received honoraria from Janssen, MSD, Bayer and Acceleron for advisory boards; received honoraria from Janssen for educational activity, received unrestricted research grants from Janssen and Bayer, and travel grants, conference registration, and accommodation from Actelion and GSK. The remaining authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary hypertension (PH) has been linked to worse outcomes in chronic lung diseases. The presence of PH in the setting of underlying Interstitial Lung Disease (ILD) is strongly associated with decreased exercise and functional capacity, an increased risk of hospitalizations and death. Examining the scope of this issue and its impact on patients is the first step in trying to define a roadmap to facilitate and encourage future research in this area. The aim of our working group is to strengthen the communities understanding of PH due to lung diseases and to improve the care and quality of life of affected patients. This introductory statement provides a broad overview and lays the foundation for further in-depth papers on specific topics pertaining to PH-ILD., Competing Interests: Dr. Nikkho is an employee of Bayer AG; Dr. Richter received funding from the JLU‐CAREER program (German Research Foundation, DFG, 413584448) and from the Collaborative Research Center (SFB) 1213—Pulmonary Hypertension and Cor Pulmonale, grant number SFB1213/1, project B08 (German Research Foundation, Bonn, Germany); Eric Shen is an employee of United Therapeutics Corporation; Dr. Abman serves as a scientific advisor to Oak Hill Bio and NHLBI grants HL68702, HL145679 and UHL151458 not related to this manuscript; Dr. Antoniou has no conflict of interest.; Dr. Chung has no conflict of interest as it pertains to this paper; Peter Fernandes is an employee of Bellerophon Pharma; Dr. Hassoun serves on a scientific advisory board for Merck, an activity unrelated to the current work; Howard M. Lazarus is an employee of Altavant Sciences; Dr. Olschewski received funding from Actelion, Algorithm Sciences, AOP, Astra Zeneca, Bayer, Boehringer, Chiesi, GSK, Janssen, Menarini, MSD, Novartis, Ludwig Boltzmann Society, Ferrer, MedUpdate, and Mondial not related to this work; Dr. Piccari has received research funding from and served as a speaker for Janssen as well as received support for attending congresses from Janssen, MSD and Ferrer, not related to this manuscript; Dr. Psotka has no conflict of interest; Dr. Saggar has a Consulting and Advisory Role for United Therapeutics, Third Pole, Novartis, Acceleron, Aerovate, and Janssen; Dr. Shlobin has consulted for UT, Bayer, ALtavant, Aerovate, Jenssen & Jenssen, and Merck, and is on the speaker bureau for UT, Bayer, and J&J; Dr. Stockbridge has no conflict of interest; Dr. Vizza has no conflict of interest regarding this topic; Dr. Vitulo has no conflicts of interest to disclose; Dr. S. John Wort received honoraria from Janssen, MSD, Bayer and Acceleron for advisory boards; received honoraria from Janssen for educational activity, received unrestricted research grants from Janssen and Bayer, and travel grants, conference registration and accommodation from Actelion and GSK; Dr. Nathan is a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Merck and Daewoong., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Vascular endothelial cell dysfunction is reported in severe coronavirus disease 2019 disease, however, controversy exists regarding levels of angiotensin-converting enzyme 2 (ACE2) expression, a coreceptor for severe acute respiratory syndrome coronavirus 2, in these cells. We report ACE2 expression and positive regulation by both interleuki-6, hepcidin, and ferroportin knock-down in pulmonary artery endothelial cells with potential implications for viral infection., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm -5 , success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm -5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm -5 , success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study., (© The Author(s) 2021.)

Pulmonary arterial hypertension describes a group of diseases characterised by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between pulmonary arterial hypertension and controls using both human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells. Human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalisation, we examined differentially expressed genes and applied gene set enrichment analysis to the differentially expressed genes to identify putative activated pathways. Human pulmonary microvascular endothelial cells displayed 1008 significant ( p  ≤ 0.0001) differentially expressed genes in pulmonary arterial hypertension samples compared to controls. In human pulmonary artery smooth muscle cells, there were 229 significant ( p  ≤ 0.0001) differentially expressed genes between pulmonary arterial hypertension and controls. Pathway analysis revealed distinctive differences: human pulmonary microvascular endothelial cells display down-regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal- and cell-adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in pulmonary arterial hypertension pathogenesis. In contrast, pathways in human pulmonary artery smooth muscle cells were mainly up-regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell-cell and adherens junction interactions suggesting a more energy-driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in pulmonary arterial hypertension pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression., (© The Author(s) 2021.)

Acute respiratory distress syndrome in patients with Coronavirus disease 19 is associated with an unusually high incidence of pulmonary embolism and microthrombotic disease, with evidence for reduced fibrinolysis. We describe seven patients requiring invasive ventilation for COVID-19-associated acute respiratory distress syndrome with pulmonary thromboembolic disease, pulmonary hypertension ± severe right ventricular dysfunction on echocardiography, who were treated with alteplase as fibrinolytic therapy. All patients were non-smokers, six (86%) were male and median age was 56.7 (50-64) years. They had failed approaches including therapeutic anticoagulation, prone ventilation ( n  = 4), inhaled nitric oxide ( n  = 5) and nebulised epoprostenol ( n  = 2). The median duration of mechanical ventilation prior to thrombolysis was seven (5-11) days. Systemic alteplase was administered to six patients (50 mg or 90 mg bolus over 120 min) at 16 (10-22) days after symptom onset. All received therapeutic heparin pre- and post-thrombolysis, without intracranial haemorrhage or other major bleeding. Alteplase improved PaO 2 /FiO 2 ratio (from 97.0 (86.3-118.6) to 135.6 (100.7-171.4), p  = 0.03) and ventilatory ratio (from 2.76 (2.09-3.49) to 2.36 (1.82-3.05), p  = 0.011) at 24 h. Echocardiographic parameters at two (1-3) days ( n  = 6) showed right ventricular systolic pressure (RVSP) was 63 (50.3-75) then 57 (49-66) mmHg post-thrombolysis ( p  = 0.26), tricuspid annular planar systolic excursion (TAPSE) was unchanged (from 18.3 (11.9-24.5) to 20.5 (15.4-24.2) mm, p  = 0.56) and right ventricular fractional area change (from 15.4 (11.1-35.6) to 31.2 (16.4-33.1)%, p  = 0.09). At seven (1-13) days after thrombolysis, using dual energy computed tomography imaging ( n  = 3), average relative peripheral lung enhancement increased from 12.6 to 21.6% ( p  = 0.06). In conclusion, thrombolysis improved PaO 2 /FiO 2 ratio and ventilatory ratio at 24 h as rescue therapy in patients with right ventricular dysfunction due to COVID-19-associated ARDS despite maximum therapy, as part of a multimodal approach, and warrants further study., (© The Author(s) 2020.)

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients ( IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease ( IPAH no lung disease ). Patients with ' IPAH lung disease ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ' IPAH no lung disease '. We described the outcome of the cohort of patients with ' IPAH no lung disease ' in a previous paper. Here, we have compared incident ' IPAH lung disease ' patients with ' IPAH no lung disease ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with ' IPAH no lung disease ' ( n  = 355), ' IPAH lung disease ' patients ( n  = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ' IPAH lung disease ' and ' IPAH no lung disease '. However, survival of ' IPAH lung disease ' was lower than ' IPAH no lung disease ' (one year survival: 72% compared with 93%). This survival was significantly worse in ' IPAH lung disease ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. ' IPAH lung disease ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with ' IPAH no lung disease ' patients. This suggests that ' IPAH lung disease ' are a separate phenotype and should not be lumped with ' IPAH no lung disease ' in clinical trials of Group 1 pulmonary arterial hypertension., (© The Author(s) 2020.)

A 36-year-old woman presented with recurrent pulmonary emboli (PE) despite oral anticoagulation. She was a type I diabetic with severe gastroparesis requiring insertion of multiple long-term peripherally inserted central catheters (PICC) over a 10-year period. Imaging at presentation demonstrated a PICC-associated mobile mass in the right atrium and signs of pulmonary hypertension (PH). She was thrombolyzed and fully anticoagulated, and diabetic management without PICC strongly recommended. PH persisted, however, and she developed chronic thromboembolic pulmonary hypertension (CTEPH), for which successful pulmonary endarterectomy (PEA) surgery led to symptomatic and hemodynamic improvement. This was the first case of CTEPH reported related to long-term PICC use outside the setting of malignant disease, and a novel observation that the PEA specimen contained multiple plastic fragments. Long-term PICC placement increases the risk of CTEPH, a life-threatening, albeit treatable, complication.

Early diagnosis of pulmonary artery hypertension (PAH) is diagnostically challenging given the extent of pulmonary vascular remodeling required to bring about clinical signs and symptoms. Exercise testing can be invaluable in this setting, as stressing the cardiopulmonary system may unmask early disease. This report describes a young patient with a positive family history of PAH in whom contemporaneous invasive cardiopulmonary exercise testing and surgical lung biopsy reveal the novel association between exercise pulmonary hypertension (ePH) and early histological changes of PAH. Exercise PH currently carries no pathological correlates which means the hemodynamic effects of early pulmonary vascular remodeling remain unknown. Following the recent proceedings from the World Symposium in Pulmonary Hypertension 2018, which broaden the hemodynamic definition of PAH, this report suggests an important association between ePH and early pulmonary vascular remodeling supporting a role for exercise hemodynamic evaluation in patients at increased familial risk of PAH.

Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.

In a subgroup of patients with systemic sclerosis (SSc), vasospasm affecting the pulmonary circulation may contribute to worsening respiratory symptoms, including dyspnea. Noninvasive assessment of pulmonary blood flow (PBF), utilizing inert-gas rebreathing (IGR) and dual-energy computed-tomography pulmonary angiography (DE-CTPA), may be useful for identifying pulmonary vasospasm. Thirty-one participants (22 SSc patients and 9 healthy volunteers) underwent PBF assessment with IGR and DE-CTPA at baseline and after provocation with a cold-air inhalation challenge (CACh). Before the study investigations, participants were assigned to subgroups: group A included SSc patients who reported increased breathlessness after exposure to cold air (n = 11), group B included SSc patients without cold-air sensitivity (n = 11), and group C patients included the healthy volunteers. Median change in PBF from baseline was compared between groups A, B, and C after CACh. Compared with groups B and C, in group A there was a significant decline in median PBF from baseline at 10 minutes (-10%; range: -52.2% to 4.0%; P < 0.01), 20 minutes (-17.4%; -27.9% to 0.0%; P < 0.01), and 30 minutes (-8.5%; -34.4% to 2.0%; P < 0.01) after CACh. There was no significant difference in median PBF change between groups B or C at any time point and no change in pulmonary perfusion on DE-CTPA. Reduction in pulmonary blood flow following CACh suggests that pulmonary vasospasm may be present in a subgroup of patients with SSc and may contribute to worsening dyspnea on exposure to cold.