ERS Congress 2025: highlights from the Pulmonary Vascular Diseases Assembly

Extract

The 2025 European Respiratory Society (ERS) Congress provided a comprehensive overview of contemporary advances in pulmonary vascular diseases, reflecting a shift towards precision medicine across pulmonary hypertension (PH) phenotypes. This summary, written collaboratively by both early career members and experts in pulmonary vascular diseases, emphasises key themes including improved phenotyping beyond haemodynamics, integration of right ventricular (RV) biology into therapeutic decision-making, earlier initiation of disease-modifying strategies, and the development of structured care models to optimise outcomes. This article focuses on pulmonary arterial hypertension (PAH), PH associated with lung diseases, chronic thromboembolic pulmonary hypertension (CTEPH), and acute pulmonary embolism (PE), highlighting both shared and disease-specific insights.

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Introduction

The 2025 European Respiratory Society (ERS) Congress provided a comprehensive overview of contemporary advances in pulmonary vascular diseases, reflecting a shift towards precision medicine across pulmonary hypertension (PH) phenotypes. This summary, written collaboratively by both early career members and experts in pulmonary vascular diseases, emphasises key themes including improved phenotyping beyond haemodynamics, integration of right ventricular (RV) biology into therapeutic decision-making, earlier initiation of disease-modifying strategies, and the development of structured care models to optimise outcomes. This article focuses on pulmonary arterial hypertension (PAH), PH associated with lung diseases, chronic thromboembolic pulmonary hypertension (CTEPH), and acute pulmonary embolism (PE), highlighting both shared and disease-specific insights.

Prognostic factors in PH

Risk assessment remains the cornerstone of PAH management. Traditional stratification tools combine clinical variables, exercise capacity, biomarkers, and invasive haemodynamics. However, multiple presentations at the 2025 ERS Congress demonstrated that further refinement of risk classification may improve prognostic accuracy.

Cardiac magnetic resonance imaging (cMRI) continues to emerge as a potential tool for risk assessment. A study from the UK found that various cMRI measures were predictive of prognosis in the ASPIRE registry of patients with PH associated with lung diseases [1], independent of age and pulmonary vascular resistance. Importantly, integration of cMRI parameters with established risk models, including multiparametric scores such as REVEAL, led to substantial reclassification of patients across risk categories: 36% into a lower-risk and 11% into a higher-risk group [2]. As nearly half of patients were re-stratified when cMRI metrics were incorporated [2], these findings underscore the added prognostic value of advanced imaging beyond conventional clinical risk assessment.

Cardiopulmonary exercise testing received renewed attention as a window into pulmonary vascular reserve. The mean pulmonary arterial pressure to oxygen uptake slope correlated strongly with invasive haemodynamic measures and demonstrated high prognostic potential [3, 4]. These findings support the use of dynamic, exercise-based indices to detect early pulmonary vascular dysfunction and refine risk estimation in borderline or intermediate phenotypes.

Phenotyping extends beyond pulmonary vasculature and RV metrics. For example, in idiopathic PAH, the presence of respiratory comorbidities was shown to exert a strong influence on treatment response, possibly exceeding the prognostic weight of cardiac comorbidities [5]. These data challenge simplified “vascular-only” models of PAH and support systematic multidimensional evaluation. As another example, in CTEPH, body composition parameters measured on opportunistic chest computed tomography (CT), including skeletal muscle index and intermuscular adipose tissue, were independently associated with long-term outcomes. Patients with reduced muscle mass and increased adiposity demonstrated worse survival, highlighting systemic frailty and metabolic alterations as clinically relevant determinants [6].

Collectively, these findings emphasise that contemporary PH risk assessment must integrate haemodynamic, imaging, functional, and systemic parameters within a comprehensive framework.

Novel pathogenic pathways and RV biology

A dominant theme at the 2025 ERS Congress was the expansion of mechanistic understanding in pulmonary vascular disease and its role in the development of novel therapeutic agents.

The transforming growth factor-β superfamily continues to represent a central signalling axis in PAH. Sotatercept, a first-in-class activin receptor type IIA ligand trap, was originally developed to inhibit pro-proliferative activin/GDF (growth differentiation factor)-mediated SMAD2/3 signalling. Recent proteomics evidence from patients treated with sotatercept indicates that the drug also reduces circulating bone morphogenetic protein (BMP) ligands, particularly the vascular quiescence factors BMP9 and BMP10 associated with SMAD1/5/8 signalling [7]. In accordance with this evidence, the StratosPHere-1 study analysed a panel of circulating proteins linked to BMPR2 activity, a major vascular receptor for BMP ligands. The study reported that patients treated with sotatercept displayed decreased levels of these BMPR2-related circulating proteins driven by a depletion of BMP9 and BMP10 [8], which may explain the occurrence of bleeding events and telangiectasia observed in treated patients. Consequently, next-generation ligand traps are under development to selectively inhibit activin/GDF ligands while preserving BMP signalling. Preclinical data on compounds such as HS235 and ALG-801 demonstrated improvements in pulmonary haemodynamics, reduction in RV hypertrophy, and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, with favourable tolerability profiles in early-phase trials [9, 10].

Furthermore, preclinical studies exploring endothelial mitochondrial dysfunction demonstrated that luteolin, a natural flavonoid, alleviates hypoxia-induced PAH in experimental models. This effect was mediated through activation of the SIRT1–PGC1α–AMPK pathway, which improved mitochondrial energy metabolism, reduced oxidative stress, and attenuated vascular remodelling [11]. These results reinforce the paradigm of metabolic reprogramming as a central driver of PAH pathobiology. Additionally, RV dysfunction was highlighted as a principal determinant of clinical outcomes across PH subgroups. Integrin signalling (specifically integrin α5β1) was shown to be upregulated in the RV of PAH patients and experimental models. Inhibition of this pathway in human RV tissue slices demonstrated antifibrotic and antihypertrophic effects, highlighting integrin α5β1 as a potential RV-specific therapeutic target [12, 13]. These findings reflect a broader conceptual shift: effective PH treatment must address not only pulmonary vascular remodelling but also RV adaptation and maladaptation.

Finally, in the setting of CTEPH, genetic susceptibility as a contributing mechanism was highlighted. Specifically, whole-genome sequencing analyses identified cathepsin S (CTSS) as a gene associated with CTEPH and venous thromboembolic events [14]. Furthermore, independent population-based analyses identified specific fibrinogen variants associated with CTEPH but not with acute PE or deep vein thrombosis [15]. These observations suggest that chronic thromboembolic disease is not simply a mechanical consequence of unresolved emboli but may reflect distinct genetic and inflammatory predispositions.

Early disease modification: the HYPERION trial

Sotatercept has demonstrated remarkable efficacy in PAH, improving haemodynamics, morbidity, RV function, and mortality in patients receiving background therapy in the PULSAR, STELLAR and ZENITH trials [16–18]. However, prior large randomised controlled trials enrolled patients on stable therapy with a mean duration of 8 years from diagnosis. The phase 3 HYPERION trial assessed the use of sotatercept in patients with PAH diagnosed within the prior year who were functional class II–III [19], at intermediate or high risk, and receiving double or triple background therapy. This double-blind, randomised, placebo-controlled trial had clinical worsening as its primary endpoint, a composite of death, unplanned hospitalisation >24 h for PAH worsening, atrial septostomy, lung transplantation, or exercise deterioration due to PAH. The trial was stopped early due to positive results from previous studies. Among 320 patients (median follow-up 13.2 months), 80 primary events occurred in 76 patients: 17 (10.6%) in the sotatercept group versus 59 (36.9%) in placebo (hazard ratio 0.24; 95% CI 0.14–0.41; p<0.001). Among the prespecified sequentially tested secondary endpoints, multicomponent improvement and a low REVEAL Lite 2 risk score at 24 weeks favoured sotatercept, although the third secondary endpoint (change in simplified French risk score) was not statistically significant; therefore, subsequent analysis was not performed. Subsequent secondary endpoints that were not eligible for testing favoured sotatercept, including improvement in World Health Organization functional class, 6-min walk distance, and NT-proBNP levels.

PH associated with lung diseases

PH associated with chronic lung diseases (Group 3 PH) remains an area of substantial unmet need, characterised by diagnostic uncertainty, heterogeneous phenotypes, and limited therapeutic options.

When PH is suspected in patients with underlying lung disease, echocardiography should be performed and interpreted alongside clinical assessment, pulmonary function testing and thoracic CT imaging [20, 21]. However, echocardiography lacks sufficient accuracy in this context; therefore, right heart catheterisation (RHC) remains essential when diagnostic confirmation is expected to influence management. In these patients, RHC should be performed during clinical stability in experienced centres with complete haemodynamic assessment [20, 21], with emphasis on averaging pressures across respiratory cycles to account for large intrathoracic pressure swings that may distort end-expiratory measurements. Limited access to invasive testing and the absence of validated non-invasive diagnostic algorithms specific to lung disease continue to represent important barriers, underscoring the need for research in this field.

Therapeutic strategies remain controversial. Randomised trials and recent meta-registry data suggest that phosphodiesterase-5 inhibitors may be beneficial in select patients with PH associated with interstitial lung disease (ILD) [22, 23] and COPD [24], although many historical studies lacked mandatory RHC confirmation of PH. Endothelin receptor antagonists may have a role in select settings, but some therapies are clearly contraindicated; specifically, ambrisentan and riociguat should not be used in PH-ILD [25, 26]. In the INCREASE trial, inhaled treprostinil demonstrated benefit in patients with PH-ILD, particularly in patients with pulmonary vascular resistance >4 Wood units [27]; conversely, the PERFECT trial, evaluating inhaled treprostinil in patients with PH-COPD, was terminated early due to increased adverse events and lower survival [28]. Overall, treatment patterns vary substantially across centres, with phosphodiesterase-5 inhibitors remaining the most commonly used therapy in clinical practice.

Emerging mechanistic insights suggest that pulmonary vascular disease in ILD is not merely the consequence of parenchymal destruction but may represent an active biological process. This vascular-parenchymal crosstalk could explain why certain PH therapies such as inhaled treprostinil may attenuate forced vital capacity decline [29, 30]. Experimental work suggests that dysregulation of BMP signalling may contribute to pulmonary vascular remodelling in ILD. Restoration of aberrant BMP signalling with agents such as tacrolimus have shown preclinical promise for reversing pulmonary vascular remodelling and fibrogenesis [31]. Other novel therapies that warrant further exploration in PH-ILD include seralutinib and sotatercept, which together resulted in synergistic reductions in profibrotic markers in vitro [32].

A particularly thought-provoking, evidence-based discussion challenged the traditional concept of a distinct “lung phenotype” of PAH. Analyses comparing large registries indicate that patients with a lung phenotype of idiopathic PAH and those classified as Group 3 PH share similar characteristics, including age, sex, risk scores, response to therapy, and survival outcomes [33, 34]. Cluster analyses highlight a large subgroup of these patients: older male smokers with markedly reduced diffusing capacity of the lung for carbon monoxide (<45% predicted), relatively preserved lung volumes, and pronounced exercise-induced hypoxaemia. Responses to classical PAH-specific therapy are often limited [33, 34]. Emerging structural data demonstrate microvascular rarefaction, loss of the alveolar–capillary membrane, and microscopic combined pulmonary fibrosis and emphysema-like features, supporting substantial overlap with Group 3 PH rather than classical PAH [35, 36]. Overall, the clinical and physiological profile of these patients closely parallels that observed in PH associated with lung diseases. Taken together, these observations suggest that reclassification and management according to Group 3 PH principles, rather than conventional PAH algorithms, may be more appropriate in selected cases, reflecting an ongoing evolution in the conceptual framework of smoking-associated pulmonary vascular disease [37].

CTEPH

Balloon pulmonary angioplasty (BPA) is recommended in patients with CTEPH who are not eligible for surgery [20]. Results from a large collaborative Japanese–French research initiative evaluating 1013 patients with BPA demonstrated favourable long-term outcomes, with a 10-year survival rate of 79.5% [38]. Moreover, haemodynamic and functional improvements were sustained at a median follow-up of 56 months post-BPA. Post-procedural mean pulmonary arterial pressure below 30 mmHg and preserved 6-min walk distance were associated with improved long-term survival. Conversely, recent malignancy and reduced exercise capacity predicted poorer outcomes. These data confirm BPA as an effective long-term strategy and highlight the importance of haemodynamic optimisation and functional assessment in prognostication [39].

Innovations in pulmonary vascular imaging

Imaging continues to evolve as both a diagnostic and disease-characterisation tool in pulmonary vascular disorders, driven by the need for higher spatial resolution, functional assessment, and reduced procedural burden. Given the anatomical complexity of the lungs and pulmonary circulation, optimal chest imaging must allow precise visualisation of small-calibre vessels while distinguishing pathological from physiological vascular changes.

Dual energy CT pulmonary angiogram (DECTPA) combines anatomic and functional information in a single scan, improving diagnostic accuracy and supporting PE and CTEPH evaluation. For acute PE, DECTPA provides enhanced detection (up to 6% more) of peripheral acute PE, along with meaningful information regarding RV dysfunction, utilising perfusion blood volume deficit [40]. It has also been studied in the detection of CTEPH [41], which typically demonstrates patchy and/or triangular perfusion defects, and may help clinicians make informed decisions regarding therapeutic interventions such as BPA and pulmonary endarterectomy. Photon-counting CT is another novel modality for the diagnosis of PE that relies on counting individual photons and recording their energy, while reducing contrast and radiation doses. Compared to conventional CTPA or DECTPA, the photon-counting CT contrast dose is nearly half (28 mL versus 45 mL) along with significantly lower radiation exposure (5.9 mSv versus 10–12 mSv) [42].

cMRI is the gold-standard imaging technique to provide a comprehensive cardiopulmonary assessment with highly reproducible and accurate 3-D images. However, although cMRI may be useful to predict the presence of PH (with RV/left ventricular mass, degree and angle of interventricular septum deviation and diastolic pulmonary artery size) [43], RHC remains essential for a definitive diagnosis. cMRI is known to be effective for risk stratification of patients with PAH and to predict mortality and clinical worsening [2]. More recently, cMRI has been shown to reflect how a patient with PAH feels, functions, and survives. These outcomes were found to be associated with RV ejection fraction, RV end-diastolic and end-systolic volumes [44].

Nuclear imaging has also undergone significant evolution. Pulmonary scintigraphy has evolved from planar ventilation/perfusion (V̇/Q̇) imaging to V̇/Q̇ single-photon emission CT (SPECT), now validated as a reliable alternative to CTPA and planar V̇/Q̇ imaging for the diagnosis of PE and CTEPH [45]. Although its accessibility remains limited, this three-dimensional technique improves the characterisation of perfusion defects and enhances diagnostic accuracy, while avoiding contraindications related to contrast allergy or renal impairment. When combined with low-dose CT, it also provides anatomical correlation and alternative diagnoses useful in PH management. Its diagnosis performance has been recently supported by the SPECTACULAR study (NCT02983760), with results pending publication.

Looking to the future, V̇/Q̇ positron emission tomography-CT offers promising opportunities. By using positron-emitting isotopes, it provides superior image acquisition technology compared with SPECT V̇/Q̇ [46]. Molecular tracers, such as ⁶⁸Ga-FAPI, which target fibroblast activation protein, may enable non-invasive assessment of vascular remodelling in PAH, opening perspectives for early detection and therapy monitoring [47]. These advances hold promise for refining diagnostic precision in pulmonary vascular disease.

Finally, point-of-care ultrasound (PoCUS) continues to expand its role, particularly in the setting of acute PE. The main advantages of PoCUS in acute PE include real-time reassessment and the ability to easily evaluate response to treatment. It may also help to differentiate between acute versus chronic right heart failure, via multiple parameters including RV free wall thickness, tricuspid regurgitation pressure gradient, and right atrial size [48]. Triple PoCUS (i.e. including lung, heart and veins) increases the accuracy of clinical pretest probability estimation in patients with suspected PE and can be a valuable alternative if CTPA is unavailable [49].

PE

Acute PE management is increasingly complex, particularly in intermediate- and high-risk presentations requiring timely yet nuanced therapeutic decisions. Contemporary data demonstrate a clear volume–outcome relationship: centres managing more than 40 PE cases annually exhibit a 44% reduction in adjusted PE-related mortality compared with low-volume institutions [50], underscoring the importance of experience and structured care pathways. In this context, multidisciplinary PE Response Teams (PERTs) have emerged as an organisational innovation aimed at improving coordination and therapeutic decision-making.

Current European guidelines support the use of PERTs in appropriate settings, reflecting the growing consensus that rapid, expert-led evaluation may optimise outcomes in patients at risk of clinical deterioration [51]. Beyond facilitating early risk stratification, PERTs enable a standardised yet individualised treatment approach, particularly when advanced options such as catheter-directed therapies, systemic thrombolysis, or surgical embolectomy are considered [52]. They also provide a platform for research, education, and structured outpatient follow-up. Meta-analyses of retrospective observational studies suggest that PERT implementation is associated with lower in-hospital mortality, shorter length of stay, reduced 30-day readmission rates, and potentially lower healthcare costs [53, 54]. However, the current evidence base remains largely observational and subject to inherent limitations. It remains unclear whether improved outcomes derive primarily from multidisciplinary collaboration, early specialist involvement in high-risk cases, or the systematic application of predefined management algorithms. Moreover, the practical implementation of PERT models may pose challenges in smaller centres, including organisational complexity and potential delays related to multidisciplinary activation. Robust prospective and cluster-randomised evaluations are therefore warranted.

The therapeutic landscape is simultaneously evolving. Several ongoing randomised controlled trials are investigating invasive percutaneous strategies and modified thrombolytic regimens in intermediate-high risk PE, including studies evaluating mechanical thrombectomy systems and reduced-dose thrombolysis. These trials aim to clarify whether early interventional approaches can improve clinical deterioration, RV recovery, functional capacity, and longer-term outcomes compared with anticoagulation alone (table 1).

TABLE 1.

Ongoing randomised controlled trials investigating invasive percutaneous strategies or different approaches of thrombolysis for pulmonary embolism (PE) management

Trial	Population	Intervention and comparators	Primary outcomes	Expected completion date
PEERLESS II NCT06055920	Intermediate high risk (RV dysfunction plus two extra risk factors)	FlowTriever System (Inari Medical, Inc., Irvine, CA, USA) plus anticoagulation, compared to anticoagulation alone	Combined win ratio (clinical deterioration, bailout therapy, hospital readmission, change in dyspnoea)	June 2026
STORM PE NCT05684796	Intermediate high risk patients	Indigo Aspiration System (Penumbra, Inc., Alameda, CA, USA) plus anticoagulation compared to anticoagulation alone	Change in RV/LV ratio at 48 h on original therapy as assessed by CTPA	October 2026
HI PEITHO NCT04790370	Intermediate high risk plus two other risk features	EkoSonic Endovascular Device (Boston Scientific, Marlborough, MA, USA) plus anticoagulation as compared to anticoagulation alone	Composite of death, decompensation and recurrent PE	August 2026
PEITHO 3 NCT04430569	Intermediate high risk plus one additional marker of severity	Reduced thrombolysis plus anticoagulation compared to anticoagulation alone	Composite of all cause death, haemodynamic decompensation or PE recurrence within 30 days of randomisation	August 2028
PE-TRACT NCT05591118	Intermediate high risk	Catheter directed therapy (mechanical thrombectomy or catheter directed thrombolysis) and anticoagulation compared to anticoagulation alone	Peak oxygen consumption at 3 months, NYHA at 12 months	June 2027

RV: right ventricular; LV: left ventricular; CTPA: computed tomography pulmonary angiogram; NYHA: New York Heart Association classification.

Long-term management also requires careful balancing of recurrence prevention against bleeding risk. This issue is particularly relevant in cancer-associated venous thromboembolism, where anticoagulation strategies must be individualised. The recently developed B-CAT score has demonstrated good predictive accuracy for clinically relevant bleeding at 6 months in patients with cancer-associated venous thromboembolism, supporting more personalised decisions regarding anticoagulant dosing and treatment duration [55]. Together, these developments reflect a broader shift towards structured, risk-adapted, and increasingly individualised care in acute PE.

Conclusions

The 2025 ERS Congress highlighted a transformative period in pulmonary vascular medicine. Across the spectrum of PH and PE, advances in mechanistic understanding, diagnostic testing, and multidimensional risk stratification are reshaping clinical practice. At the same time, emerging therapies targeting novel pathogenic pathways illustrate a shift towards disease-modifying strategies aimed at remodelling the pulmonary vasculature and/or right ventricle. Increasing emphasis on early and aggressive intervention to prevent irreversible cardiopulmonary remodelling further reflects this evolving paradigm. Parallel developments in PH associated with lung diseases, CTEPH, and acute PE also emphasise more patient-centred and individualised approaches to care. Collectively, these advances highlight the growing role of multidimensional phenotyping and precision medicine in the management of this complex patient population.