"Dissecting the Lung Transcriptome of Pulmonary Fibrosis-associated Pulmonary Hypertension".

Integrative multiomics can help elucidate the pathophysiology of pulmonary fibrosis (PF) associated pulmonary hypertension (PH) (PF-PH). Weighted gene co-expression network analysis (WGCNA) was performed on a transcriptomic dataset of explanted lung tissue from 116 patients with PF. Patients were stratified by pulmonary vascular resistance (PVR) and differential gene expression analysis was conducted. Gene modules were correlated with hemodynamics at the time of transplantation and tested for enrichment in the lung transcriptomics signature of an independent pulmonary arterial hypertension (PAH) cohort. We found 1,250 differentially expressed genes between high and low PVR groups. WGCNA identified that black and yellowgreen modules negatively correlated with PVR, while the tan and darkgrey modules positively correlated with PVR. Additionally, the tan module showed the strongest enrichment for an independent PAH gene signature, suggesting shared gene expression patterns between PAH and PF-PH. Pharmacotranscriptomic analysis using the Connectivity Map implicated the tan and darkgrey modules as potentially pathogenic in PF-PH, given their combined module signature demonstrated a high negative connectivity score for Treprostinil, a medication used in the treatment of PF-PH, and a high positive connectivity score for Bone morphogenetic protein loss of function. Pathway enrichment analysis revealed that inflammatory pathways and oxidative phosphorylation were downregulated, whereas epithelial mesenchymal transition was upregulated in modules associated with increased PVR. Our integrative systems biology approach to the lung transcriptome of PF with and without PH identified several PH-associated co-expression modules and gene targets with shared molecular features with PAH warranting further investigation to uncover potential new therapies for PF-PH.

Immature reticulocyte fraction: A novel biomarker of hemodynamic severity in pulmonary arterial hypertension.

Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease-related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p < 0.001), pulmonary vascular resistance (0.52, p = 0.001), and right atrial pressure (0.46, p = 0.005), and significant negative correlations with cardiac index (-0.43, p = 0.009), PA compliance (PAC) (-0.60, p < 0.001), stroke volume index (SVI) (-0.57, p < 0.001), and mixed venous oxygen saturation (-0.51, p = 0.003). IRF correlated with markers of iron deficiency (ID) and erythropoiesis. On multivariable linear regression, IRF was associated with elevated mPAP and reduced SVI and PAC independent of EPO levels, transferrin saturation, and soluble transferrin receptor levels. We identified IRF as a novel and potent biomarker of PAH hemodynamic severity, possibly related to its associations with erythropoiesis, ID, and tissue hypoxia.

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.

Modelling costs of interventional pulmonary embolism treatment: implications of US trends for a European healthcare system.

AIMS: Catheter-directed treatment (CDT) of acute pulmonary embolism (PE) is entering a growth phase in Europe following a steady increase in the USA in the past decade, but the potential economic impact on European healthcare systems remains unknown. METHODS AND RESULTS: We built two statistical models for the monthly trend of proportion of CDT among patients with severe (intermediate- or high-risk) PE in the USA. The conservative model was based on admission data from the National Inpatient Sample (NIS) 2016-20 and the model reflecting increasing access to advanced treatment from the PERT™ national quality assurance database registry 2018-21. By applying these models to the forecast of annual PE-related hospitalizations in Germany, we calculated the annual number of severe PE cases and the expected increase in CDT use for the period 2025-30. The NIS-based model yielded a slow increase, reaching 3.1% (95% confidence interval 3.0-3.2%) among all hospitalizations with PE in 2030; in the PERT-based model, increase would be steeper, reaching 8.7% (8.3-9.2%). Based on current reimbursement rates, we estimated an increase of annual costs for PE-related hospitalizations in Germany ranging from 15.3 to 49.8 million euros by 2030. This calculation does not account for potential cost savings, including those from reduced length of hospital stay. CONCLUSION: Our approach and results, which may be adapted to other European healthcare systems, provide a benchmark for healthcare costs expected to result from CDT. Data from ongoing trials on clinical benefits and cost savings are needed to determine cost-effectiveness and inform reimbursement decisions.