Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).We report on a prospective series of 56 consecutive patients who underwent 266 BPA interventions (median, five per patient) at two German institutions. All patients underwent a comprehensive diagnostic work-up including right heart catheterisation at baseline and 24 weeks after their last intervention.BPA resulted in improvements in WHO functional class, 6 min walk distance (mean change, +33 m), right ventricular function and haemodynamics, including a decline in mean pulmonary artery pressure by 18% and in pulmonary vascular resistance by 26%. Procedure-related adverse events occurred in 9.4% of the interventions. The most common complications were related to pulmonary vascular injury and consecutive pulmonary bleeding. Most of these events were asymptomatic and self-limiting, but one patient died from pulmonary bleeding, resulting in a mortality rate of 1.8%.BPA resulted in haemodynamic and clinical improvements but was also associated with a considerable number of complications, including one fatal pulmonary bleeding. As the effects of BPA on survival are unknown, randomised controlled outcome trials comparing BPA with approved medical therapies in patients with inoperable CTEPH are required to allow for appropriate risk–benefit assessments.

Symptomatic patients with residual pulmonary perfusion defects or vascular lesions but no pulmonary hypertension at rest are diagnosed with chronic thromboembolic disease (CTED). Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but data regarding the safety and efficacy of BPA in patients with CTED are lacking. We report a prospective series of ten consecutive patients with CTED who underwent 35 BPA interventions (median of four per patient) at two German institutions. All patients underwent a comprehensive diagnostic workup at baseline and 24 weeks after their last intervention. BPA was safe, with one pulmonary vascular injury and subsequent self‐limiting pulmonary bleeding as the only complication (2.9% of the interventions, 10% of the patients). After the procedures, World Health Organization functional class, 6‐min walking distance, pulmonary vascular resistance, and pulmonary arterial compliance improved, and NT‐proBNP concentrations declined in 9/10 patients. BPA may be a new treatment option for carefully selected patients with CTED. A larger, prospective, international registry is required to confirm these results.

COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9–20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients’ hospitalization time. The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.

Patients after lung transplantation are at risk for life-threatening infections. Recently, several publications on COVID-19 outcomes in this patient population appeared, but knowledge on optimal treatment, mortality, outcomes, and appropriate risk predictors is limited. A retrospective analysis was performed in a German high-volume lung transplant center between 19^th March 2020 and 18^th May 2021. Impact of COVID-19 on physical and psychological health, clinical outcomes, and mortality were analyzed including follow-up visits up to 12 weeks after infection in survivors. Predictive parameters on survival were assessed using univariate and multivariate proportional hazards regression models. Out of 1,046 patients in follow-up, 31 acquired COVID-19 during the pandemic. 12 of 31 (39%) died and 26 (84%) were hospitalized. In survivors a significant decline in exercise capacity (p = 0.034), TLC (p = 0.02), and DLCO (p = 0.007) was observed at follow-up after 3 months. Anxiety, depression, and self-assessed quality of life remained stable. Charlson comorbidity index predicted mortality (HR 1.5, 1.1–2.2; p = 0.023). In recipients with pre-existing CLAD, mortality and clinical outcomes were inferior. However, pre-existing CLAD did not predict mortality. COVID-19 remains a life-threatening disease for lung transplant recipients, particularly in case comorbidities. Further studies on long term outcomes and impact on pre-existing CLAD are needed.

Alterations in specific signalling pathways within the bone morphogenetic protein/transforming growth factor-β (BMP/TGF-β) family, involving several precisely regulated activator or inhibitor ligands, have been identified as pathogenic drivers of pulmonary arterial hypertension (PAH). These alterations, particularly affecting BMPRII and activin-dependent pathways, have led to innovative therapies, notably the development of sotatercept [1, 2]. Sotatercept, a fusion protein of the extracellular domain of human ACTRIIA and the Fc domain of human IgG1, has shown promising results in improving key clinical, functional, and haemodynamic parameters in PAH patients, as evidenced by positive results in the phase 2 PULSAR and phase 3 STELLAR trials [3, 4]. This progress was partly based on preclinical studies showing that reducing activin-induced Smad2/3 phosphorylation levels, by suppressing activin production in mice [5] or using soluble receptors in rats [6, 7], can attenuate pulmonary vascular remodelling. Despite these advancements, the precise mechanisms of action of these approaches in humans and rodents need to be better understood to enhance these valuable tools. Sotatercept raises several critical questions regarding its mechanism of action, and a deeper understanding could reveal the pathophysiological mechanisms of PAH, leading to more effective therapeutic approaches.

Iron deficiency is common in patients with pulmonary hypertension [1, 2]. The underlying pathomechanisms are complex and include impaired iron absorption, elevated hepcidin levels, augmented gastrointestinal loss and reduced availability from the reticuloendothelial system [1, 3, 4]. In patients with pulmonary hypertension, iron deficiency is associated with aggravated symptoms and an increased mortality risk [3, 5].