# Evolving paradigms in pulmonary hypertension: Highlights of the 6th French Pulmonary Hypertension Network Meeting

Athénaïs Boucly, Antoine Beauvais, Thomas Lacoste-Palasset, Mitja Jevnikar, Marianne Riou, Sabina Solinas, Fabrice Antigny, Fabrice Bauer, Laurent Bertoletti, Damien Bonnet, et al.

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## To cite this version:

Athénaïs Boucly, Antoine Beauvais, Thomas Lacoste-Palasset, Mitja Jevnikar, Marianne Riou, et al. Evolving paradigms in pulmonary hypertension: Highlights of the 6th French Pulmonary Hypertension Network Meeting. Respiratory Medicine and Research, 2025, 88, pp.101215. 10.1016/j.resmer.2025.101215. hal-05468026

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# Evolving paradigms in pulmonary hypertension: Highlights of the 6th French Pulmonary Hypertension Network Meeting

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Athénàis Boucly<sup>a,b</sup>, Antoine Beauvais<sup>a,b</sup>, Thomas Lacoste-Palasset<sup>b</sup>, Mitja Jevnikar<sup>a,b</sup>, Marianne Riou<sup>c</sup>, Sabina Solinas<sup>a,b</sup>, Fabrice Antigny<sup>b</sup>, Fabrice Bauer<sup>d,b</sup>, Laurent Bertoletti<sup>e</sup>, Damien Bonnet<sup>f</sup>, Ari Chaouat<sup>g</sup>, Vincent Cottin<sup>h</sup>, Michele D'Alto<sup>i</sup>, Marion Delcroix<sup>j</sup>, Mélanie Gallant Dewavrin<sup>k</sup>, Christophe Guignabert<sup>b</sup>, Sébastien Hascoet<sup>l</sup>, David G Kiely<sup>m</sup>, Xavier Jaïs<sup>a</sup>, Etienne-Marie Jutant<sup>n</sup>, Nicolas Lamblin<sup>o</sup>, Olaf Mercier<sup>l</sup>, Pamela Moceri<sup>p</sup>, Elise Noel-Savina<sup>q</sup>, François Picard<sup>r</sup>, Richard Trembath<sup>s</sup>, Cécile Tromeur<sup>t</sup>, Jean Luc Vachieri<sup>u</sup>, Laurent Savale<sup>a,b</sup>, Marc Humbert<sup>a,b</sup>, Olivier Sitbon<sup>a,b,*</sup>, David Montani<sup>a,b</sup>, on behalf on the French PH Network

## ARTICLE INFO

Keywords:

Guidelines

Pulmonary hypertension

Definition

Classification

Hemodynamics

## ARTICLE INFO

<footnote><sup>a</sup> Université Paris—Saclay, Department of Respiratory and Intensive Care Medicine (FHU André Cournand, ERN-LUNG), Hôpital Bicêtre (AP-HP), Le Kremlin Bicêtre, France</footnote>

<footnote><sup>b</sup> INSERM UMR S 999, Hypertension Pulmonaire: Physiopathologie and Innovation Thérapeutique (HPPIT), Le Kremlin Bicêtre, France</footnote>

<footnote><sup>c</sup> Department of Physiology and Functional Exploration, Nouvel hôpital civil, University Hospital of Strasbourg, Strasbourg, France</footnote>

<footnote><sup>d</sup> Université Paris—Saclay, Department of Cardiology, Hôpital Bicêtre (AP-HP), Le Kremlin Bicêtre, France</footnote>

<footnote><sup>e</sup> Department of Vascular and Therapeutic Medicine, Université Jean Monnet Saint-Étienne, CHU Saint-Étienne, Mines Saint-Étienne, INSERM, SAINBIOSE U1059, CIC 1408, Saint-Étienne, France</footnote>

<footnote><sup>f</sup> Université de Paris-Cité, M3C-Necker, Hôpital universitaire Necker-Enfants malades, Assistance Publique-Hopitaux de Paris, Paris, France</footnote>

<footnote><sup>g</sup> Université de Lorraine, CHRU-Nancy, Pôle des spécialités médicales/département de pneumologie, Inserm UMR S 1116 (DCAC), Nancy, France</footnote>

<footnote><sup>h</sup> Department of Respiratory Medicine, Hôpital Louis Pradel, Hospices Civils de Lyon, UMR 754, ERN-LUNG, University of Lyon, Lyon, France</footnote>

<footnote><sup>i</sup> Department of Cardiology, PH Unit A.O.R.N. "V. Monaldi", Napoli, Italy</footnote>

<footnote><sup>j</sup> Department of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium</footnote>

<footnote><sup>k</sup> Association des malades, aidants et transplantés Hypertension Pulmonaire: HTaPFrance, France</footnote>

<footnote><sup>l</sup> Université Paris-Saclay, Faculté de Médecine, Hôpital Marie Lannelongue, Le Plessis Robinson, France</footnote>

<footnote><sup>m</sup> Sheffield Pulmonary Vascular Disease Unit, Sheffield, United Kingdom</footnote>

<footnote><sup>n</sup> Department of Respiratory Medicine, CHU de Poitiers, INSERM CIC 1402, IS-ALIVE Research Group, University of Poitiers, Poitiers, France</footnote>

<footnote><sup>o</sup> Urgences et Soins Intensifs de Cardiologie, CHU Lille, University of Lille, Inserm U1167, Lille, France</footnote>

<footnote><sup>p</sup> Department of Cardiology, Nice University Hospital, Côte d'Azur University, Nice, France</footnote>

<footnote><sup>q</sup> Department of Respiratory Medicine, Larrey Hospital, CHU Toulouse, Toulouse, France</footnote>

<footnote><sup>r</sup> Unité de Traitement de l'insuffisance cardiaque, Centre de Compétence de l'hypertension pulmonaire, Hôpital Cardiologique Haut-Lévèque, Centre Hospitalier Universitaire de Bordeaux, Université de Bordeaux, Bordeaux, France</footnote>

<footnote><sup>s</sup> Department of Medical and Molecular Genetics, King's College London, London, United Kingdom</footnote>

<footnote><sup>t</sup> Department of Respiratory Medicine, CHU Brest, Université de Brest, INSERM 1304, GETBO (groupe d'étude de thrombose et de bretagne occidentale), Brest, France</footnote>

<footnote><sup>u</sup> Department of Cardiology, Erasme Academic Hospital Brussels, Brussels, Belgium</footnote>

<footnote>*Corresponding author at: Department of Respiratory and Intensive Care Medicine, 78 rue du général Leclerc, 94270 Le Kremlin Bicêtre, France.</footnote>

<footnote>E-mail address: olivier.sitbon@aphp.fr (O. Sitbon).</footnote>

<footnote>With the endorsement of the World Symposium on Pulmonary Hypertension (WSPH) Association, French Speaking Respiratory Society (Société de Pneumologie de Langue Française, SPLF), European Reference Network (ERN Lung), and the French Rare Diseases Network RespiFil.</footnote>
The 6th 'Journées du Réseau Français de l'Hypertension Pulmonaire' (JRF-HTP), held in October 2024, provided a timely and in-depth review of the evolving landscape in pulmonary hypertension (PH). Closely aligned with the outcomes of the 7th World Symposium on PH (WSPH 2024), the meeting brought together clinicians, researchers, and patient advocates to exchange on the most recent scientific, clinical, and organizational advances in PH.

Structured across thematic sessions, the symposium addressed key areas such as patient involvement in care and research, advances in pathophysiological mechanisms and genetics, novel imaging modalities, refined diagnostic classifications, and treatment algorithms. Emphasis was placed on developments in non-invasive risk stratification, the application of artificial intelligence, and the integration of innovative endpoints in clinical trials. The program also addressed the challenges of managing PH in complex clinical contexts, including chronic lung disease, left heart disease, paediatric populations, and perioperative situations, emphasizing the importance of multidisciplinary care and individualized approaches.

This report summarizes the main highlights from the 6th JRF-HTP 2024, reflecting both French national perspectives and broader international consensus.

## Patient perspectives

The formal recognition of the importance of the patient's perspectives at the 6th WSPH (Nice, 2018) led to the inclusion of two patient advocates in the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of PH, supporting the simultaneous publication of a patient-friendly lay summary in 12 languages [1-3]. Patient representatives emphasized the 2022 guideline recommendation that PH centres should systematically inform patients about the existence and role of patient associations, acknowledging their valuable contributions to education, emotional support, and the fight against misinformation. Furthermore, the 2022 guidelines encourage PH centres to collaborate with patient associations on initiatives aimed at empowering patients and improving their experience. Key areas targeted include health literacy, acquisition of digital skills, promotion of healthy lifestyles, attention to mental health, and reinforcement of self-management abilities.

Accordingly, the 7th WSPH recommended that patient organizations meet specific minimum criteria to ensure effective collaboration [4]. Organizations should be legally registered, patient- or caregiver-focused, and operate on a not-for-profit basis. They are encouraged to operate transparently, establish a scientific committee, and prioritize activities aimed at raising awareness of PH. The symposium highlighted the substantial achievements of patient associations at both global and French levels, including World PH Day (May 5th), PH Awareness Month (November), and Chronic Thromboembolic Pulmonary Hypertension Awareness Day (November 8th). These efforts also included advocacy campaigns, co-authorship of scientific publications, participation in international conferences, interviews in national newspapers, and the publication of a manifesto advocating for improved diagnosis and treatment of PH from the patient's perspective.

Patient-reported outcome measures (PROMs) were a key focus, particularly with the inclusion of the EMPHASIS-10 score in the French PH national registry and their use as quality indicators in the UK. While PROMs such as the emPHasis-10 provide validated, patient-centred assessments of symptoms and quality of life, evidence for incremental prognostic or predictive value beyond standard clinical, functional, hemodynamic, and imaging markers remains limited and heterogeneous. There was an emphasis on the need for PROMs as endpoints in clinical trials and further research.

Patient advocates also called for the inclusion of patients as partners in research and scientific initiatives, greater collaboration with stakeholders, stronger advocacy for pharmaceutical legislation, and the reduction of healthcare inequalities. They stressed the continued need

for improved access to care, heightened public and professional awareness, and better psychological support for PH patients.

## Pathobiology and mechanisms of PH

Pulmonary vascular remodelling is a hallmark of all forms of PH, defined by progressive thickening, eventual occlusion of the distal pulmonary vasculature, and vascular rarefaction. Although a wide range of histologic lesions has been described, highlighting significant heterogeneity, no single lesion can be considered solely responsible for the increase in pulmonary vascular resistance (PVR). Rather, these lesions collectively contribute to the progressive narrowing and obliteration of the pulmonary vasculature [5]. This remodelling process is orchestrated by three interrelated pathological mechanisms: 1) Pulmonary endothelial dysfunction, 2) Accumulation of vascular smooth muscle cells combined with adventitial dysfunction, and 3) inflammation and autoimmunity [6]. These mechanisms are further influenced by a complex interplay of genetic predispositions and environmental factors.

One of the most studied genetic contributors is the BMPR2 gene, which encodes bone morphogenetic protein receptor type II (BMPR-II) —a transmembrane serine/threonine kinase receptor that belongs to the transforming growth factors beta (TGF-β) family. BMPR-II activates Smad (small mothers against decapentaplegic)1/5/8 proteins that regulate genes critical for vascular homeostasis. Loss-of-function mutations in BMPR2 are identified in approximately 75 % of individual with heritable PAH, positioning these mutations as central drivers in disease initiation. However, BMPR-II dysfunction alone is generally insufficient to trigger the full clinical manifestation of PH, suggesting the necessity of a “second hit”, which may involve additional genetic, epigenetic, or environmental factors, to precipitate disease development. Recent evidence highlights the TGF-β/activin signalling pathway as a major contributor to disease progression. Overactivation of this pathway, frequently observed in PAH patients, leads to excessive phosphorylation of Smad2/3. This leads to abnormal nuclear accumulation of Smad2/3, which disrupts the function of both endothelial cells and vascular smooth muscle cells, while also promoting the infiltration of inflammatory and immune cells into the perivascular space. These events contribute to the accumulation of resident vascular cells, sustained inflammation, and the vascular dysfunctions that characterize PAH [7,8]. Sotatercept, a recently approved treatment, is a biologic that targets this pathogenic mechanism by acting as a ligand trap for activin receptor type II receptor ligands. By sequestering excess circulating ligand, such as activins, GDFs, BMP-9, and BMP-10, sotatercept attenuated Smad2/3 signalling, thereby mitigating the pathological overactivation of the TGF-β/activin pathway [9].

New genes predisposing to PAH, including those encoding transcription factors and ion channels, have been identified, and their further characterization could reveal novel therapeutic targets. The *T-Box transcription factor 4 (TBX4)* gene encodes TBX4, a transcription factor implicated in the organogenesis of lower limbs and the bronchial tree [10]. The presence of a pathogenic *TBX4* loss-of f-function variant is classically associated with small patella syndrome, characterized by lower limb anomalies with marked phenotypic variability. In addition to these bone manifestations, patients with a *TBX4* mutation may develop PH through two distinct mechanisms occurring at different stages of life. In the neonatal period, PH may arise in the context of severe pulmonary developmental abnormalities, corresponding to group 3 PH In adulthood, patients may develop PAH, sometimes associated with milder pulmonary abnormalities, most notably tracheobronchial diverticula [11]. The *SRY box transcription factor 17 (SOX-17)* gene encodes a transcription factor necessary for pulmonary vascular angiogenesis and cardiac mesoderm specification [12,13]. Patients with *SOX-17* mutations are predominantly young females, with pulmonary vascular abnormalities on CT, and potential risk of haemoptysis due to dilated bronchial arteries, and 40 % have associated a congenital heart disease [14]. Multiple channelopathies have also been reported. *ATP binding cassette subfamily*
C member 8 (ABCC8) gene encodes the sulfonylurea receptor 1 (SUR1), a regulator subunit of the ATP-sensitive potassium channel Kir6.2. It regulates the membrane potential and glycemia through insulin production. In comparison with the control, SUR1 and Kir6.2 protein expressions were unchanged in lung and pulmonary vascular cells in PAH patients. SUR1 pharmacological stimulation was identified as a potential therapeutic target in animal models [15]. By contrast, cases of PAH induced by diazoxide, A SUR1 activator, have been recently reported in infants suffering from hyperinsulinemic hypoglycemia [16]. The potassium channel subfamily K member 3 (KCNK3) gene encodes a two-pore domain potassium channel with a crucial role in the pathophysiology of PAH at pulmonary vascular and right ventricular levels [17]. In addition, dasatinib exposure was demonstrated to induce KCNK3 dysfunction [18]. A decrease in KCNK3 expression/function leads to membrane depolarization and enhanced intracellular calcium signalling. It has also been shown to upregulate Orai1 expression, a store-operated calcium channel. Orai1 protein expression and function were found to be increased in human pulmonary arterial smooth muscle cells from PAH patients as well as experimental models of PAH. In addition, pharmacological inhibition of Orai1 was found to restore human pulmonary arterial smooth muscle cell dysfunction and reduce PH in animal models at pulmonary vascular and right ventricular levels [19]. This new target has interesting potential for PAH, as demonstrated.

## Genetic and genomic in pulmonary arterial hypertension (PAH)

Since the discovery in 2000 of the association between heterozygous mutation in the *BMPR2* gene and PAH, mutations in over 20 genes have now been identified [20]. The assessment of these multiple genes using objective variables was recently conducted, based on genetic and experimental evidence [20]. A gene was considered definitively associated with PAH if it achieved a score ≥12 out of 18, with replication over time [21]. In this study, 12 genes (*BMPR2*, *ACVRL1*, *ATP13A3*, *CAVI1*, *EIF2AK4*, *ENG*, *GDF2*, *KCNK3*, *KDR*, *SMAD9*, *SOX17* and *TBX4*) were classified as having definitive evidence of association with PAH.

Genetic factors are more frequently identified in paediatric-onset PAH (>40 %), compared with adult-onset PAH (20–25 %). A recent multinational study estimated that 15 % of paediatric-onset PAH involves *de novo* rare variants [22]. Genetic testing should be offered to all adults with group 1 PAH using NGS with a specific PAH gene panel, with genome sequencing considered as a second line approach. In children with PH from groups 1 and 3, particularly those with developmental lung disorders, genetic testing should include genome sequencing, ideally in combination with parental testing (trio analysis) in absence of identification of pathogenic variant in PAH predisposing genes. Genetic testing within a family should begin with a symptomatic individual [20]. Once a pathogenic variant is identified, genetic counselling and cascade testing should be proposed to first-degree relatives. This counselling should include explanation on the disease (symptoms, treatment options, prognosis), screening program for PAH, reproductive implications and available reproductive options. Genetic variants are classified into five ACMG classes: 1) benign and 2) likely benign, 3) variants of unknown significance, 4) likely pathogenic and 5) pathogenic. Only likely pathogenic or pathogenic variants may be used for genetic counselling and testing for relatives [20].

## Right ventricular (RV) dysfunction in PAH

An updated review of pathophysiological mechanisms in chronic right ventricular (RV) failure was published by Hemnes et al [23], providing novel insights into RV inflammation and fibrosis as drivers of reduced contractility and increased stiffness. Meanwhile, other teams have recently focused on the right atrium (RA), often referred to as the “forgotten heart chamber,” to explore the impact of its remodelling and coupling with the RV on prognosis. In PAH, RA hypertrophy and increased contractility are typically observed, in contrast to RV fibrosis

and capillary rarefaction. Therefore, the RA–RV coupling index, defined as the ratio of RA minimal volume to RV end-diastolic volume, may provide more accurate prognostic information than RA area alone [24]. Notably, differences in prognosis based on RA and RV function in PAH had already been described in 2017 [25].

In the setting chronic RV pressure overload, RV–pulmonary arterial (PA) uncoupling is considered the main cause of RV maladaptation and, ultimately, RV failure. But how can RV–arterial coupling be studied non-invasively? In 2019, Tello et al. proposed that RV myocardial strain (measuring the relative shortening of segments of the RV free wall) was closely associated with RV–PA coupling [26]. More recently, two teams suggested using RV ejection fraction measured by cardiac MRI to stratify risk, each proposing a 3-strata model but with different thresholds [27,28]. Consensus is still needed regarding MRI methodology and reference values.

In clinical practice, echocardiography remains a cornerstone tool for rapid, bedside prognostic assessment. A novel echocardiographic score, REVEAL-ECHO, has recently emerged [29], introducing a three-strata risk classification that can be combined with the classic REVEAL score to derive a four-strata risk estimate. For assessing RV–PA coupling, the most promising echocardiographic marker appears to be the TAPSE/sPAP ratio. Fauvel et al [30] reported a clearly worse prognosis in patients with a low TAPSE/sPAP ratio, especially when associated with impaired NYHA functional class and elevated NT-proBNP levels. Building on this, an Italian group recently described four distinct echocardiographic phenotypes of RV remodelling and dysfunction, based on RV dilatation, TAPSE/sPAP ratio, and tricuspid regurgitation [31,32].

Overall, a better understanding of PAH pathophysiology is driving the development of new risk assessment metrics and scores, but the most reliable ones have yet to be determined. Phase 2 or 3 trials are needed to validate the best non-invasive parameters, which could potentially be used as future clinical trial endpoints.

## Definition and classification of PAH

Since the publication of the latest guidelines [2,3], no further revisions have been deemed necessary to the haemodynamic definition of PAH. Additional data confirmed the impaired survival of patients with mean pulmonary arterial pressure (mPAP) between 21 and 25 mmHg and PVR between 2 and 3 Wood units [33]. The pulmonary arterial wedge pressure (PAWP) threshold of 15 mmHg has been maintained, primarily due to its widespread use in clinical trials. However, PAWP values between 12 and 18 mmHg should be interpreted with caution on an individual basis. In exercise-induced PH, a mPAP/cardiac output (CO) slope of >3 mmHg/L/min is prognostically relevant, though it does not aid in determining the underlying cause or mechanisms of PH. These updated haemodynamic thresholds have led to a notable increase in the reported prevalence of PH: a 23 % increase in group 1, a 60 % rise in combined post- and pre-capillary PH, a 10–30 % increase in group 3, and a 23.5 % increase in group 4 [34–40]. As a result, expert centres must adapt by accommodating a larger number of patients and enhancing their technical capacities. However, the overall impact on management and treatment strategies has yet to be fully assessed. Preliminary data suggest improved exercise capacity in group 4 patients with mild PH receiving interventional management [41]. Patients with so-called “limited” PH must be evaluated based on comorbidities and group classification, and dedicated clinical trials are required for this population.

The PH classification remains a topic of ongoing debate, as it clusters together conditions with markedly different prevalence and prognoses. Nevertheless, no sufficiently robust data are available to support a new classification framework. Furthermore, the existing PH classification is widely adopted and facilitates international communication. Therefore, the most recent World Symposium on Pulmonary Hypertension did not propose any structural revisions to the classification scheme.

Within group 1, the main update from the last symposium was the formal addition of the subgroup of long-term responders to calcium
channel blockers (CCBs). In the 2022 guidelines, the previous subgroup of idiopathic PAH with “acute responders at vasoreactivity testing” was considered heterogeneous, as a significant proportion of acute responders does not maintain a long-term response to CCBs [42]. Long-term CCBs responders represent a distinct clinical entity, characterized by a markedly better prognosis, unique pathophysiology, and a specific management. Regarding drugs-associated PAH, mitomycin C and carfilzomib are now definitively associated with pulmonary veno-occlusive disease and PAH, respectively, while bortezomib and bevacizumab have been newly identified as drugs with a possible association.

Among the other PH groups, the most significant changes occurred in group 3, where the categorization shifted from ventilatory pattern-based subgroups to those based on clinical diagnosis of respiratory diseases. In group 2, each valvular heart disease is now considered separately. Sarcoidosis remains in group 5, alongside Langerhans cell histiocytosis, neurofibromatosis type 1, and the reintroduction of the subgroup of complex congenital heart disease, which had been excluded since 2018.

The five-step diagnostic algorithm for PH has undergone only minor revisions (Fig. 1). The tricuspid regurgitation velocity threshold of 2.8 m/s was maintained. The principal addition was a “Fast-Track” pathway, designed to rapidly identify and refer patients with suspected PAH or CTEPH to expert centres. In addition, it is suggested that any patient with suspected PH associated with interstitial lung disease should also be referred. Finally, cardiac MRI is now included as an optional test in step 4 of the diagnostic algorithm.

## New technologies to improve early diagnosis and refine treatment response

Several emerging imaging technologies have been developed in recent years, offering promising avenues for non-invasive assessment in PAH [43]. These innovations now allow for quantification of pulmonary vessels, measurement of arterial wall thickness, and even photon-counting CT, a technique that enables enhanced resolution without contrast administration [44]. Cardiac MRI has evolved to include model “4D-flow” dynamics and differentiate phenotypes based on vortex flow metrics [45]. Gas transfer and haemodynamic impairment can also be evaluated using hyperpolarised ¹²⁹Xenon imaging, via MRI and spectroscopy,

to identify disease-specific patterns [46]. Lung perfusion may be assessed using thoracic MRI—measuring mean transit time, pulmonary blood volume, and flow—or through dual-energy CT and lung subtraction iodine mapping [47,48].

To fully harness these new tools, artificial intelligence (AI) could become a powerful ally. AI applied to MRI has demonstrated stronger correlations with haemodynamic and higher reproducibility than manual contouring, in analyses of over 5000 MRIs performed in 3782 patients [49]. Moreover, AI can learn diagnostic and risk stratification tasks simply by exposure to large patient datasets, control groups, and survival curves. Dwivedi et al. have already demonstrated that AI can accurately phenotype PH-ILD by quantifying fibrosis on CT [50]. Finally, AI could significantly enhance educational tools through interactive 3D modelling, for example in teaching anatomy or hemodynamics.

However, before AI applications can be fully integrated into clinical care, it is critical to validate these tools as endpoints in clinical trials. This last step is essential to demonstrate their accuracy, reliability, and potential for automated integration into clinical decision-making pathways.

## Risk stratification and treatment goals

According to the guidelines, treatment decisions must be based on risk assessment at the time of diagnosis and during follow-up, using a panel of data derived from clinical evaluation, exercise testing, biochemical markers, echocardiography, and hemodynamic assessments [2,3]. The primary treatment goal is to achieve a low-risk profile, currently defined as a predicted one-year mortality of less than 5% [2,3].

The use of a three-strata model is recommended at baseline for patients without cardiopulmonary comorbidities. This evaluation is essential to determine whether a patient is at high risk, in which case triple combination therapy including a parenteral prostacyclin is recommended [2,3]. In contrast, during follow-up, the use of a four-strata risk assessment based on three non-invasive variables is recommended: functional class (FC), six-minute walking distance (6MWD), and brain natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP) levels [2,3].

However, these variables have limitations, as they are influenced by age, comorbidities, and physical condition [51]:

- NYHA/WHO-FC is based on a physician's subjective and non-standardized assessment of daily life limitations.

- 6MWD is not always correlated with PAH severity; for example, a normal walking distance may underestimate disease severity in younger patients, while deconditioning and comorbidities may impair performance in patients with mild disease.

- BNP or NT-proBNP reflect overall cardiac strain but are affected by factors such as age, obesity, renal function, and left heart disease. Normal or near-normal levels do not exclude severe PH.

While these are important prognostic markers for PAH and all-cause mortality, they are not sufficient alone to guide individualized treatment without a comprehensive assessment of disease severity and right ventricular (RV) function [51]. Among additional tools that can support treatment decisions by reflecting PH and RV dysfunction severity, cardiopulmonary hemodynamics obtained via right heart catheterization can refine risk stratification at follow-up for patients at intermediate risk [52]. In this setting, stroke volume index (SVI > 37 mL·m⁻²) and/or mixed venous oxygen saturation (SvO₂ > 65%) have shown significant prognostic value [52]. Selected parameters from cardiac imaging (echocardiography or MRI) have not yet demonstrated added value over the four-strata score [51].

The ultimate therapeutic goal in PAH is partial or complete reversal of pulmonary vascular remodelling, leading to improved hemodynamics and right heart function—thereby achieving a low-risk mortality profile [51].

<figure><img src="image_6.png" /><figcaption>Fig. 1. Five steps diagnostic algorithm of pulmonary hypertension from the 7th World PH Symposium, Barcelona June 2024</figcaption></figure>

**Abbreviations:** ABG: arterial blood gases; CT: computed tomography; CTEPH: chronic thromboembolic pulmonary hypertension; CPET: cardiopulmonary exercise testing; cpcPH: combined post-capillary and pre-capillary PH; FC: functional class; ILD: interstitial lung disease; MRI: magnetic resonance imaging; PAH: pulmonary arterial hypertension; PFT: pulmonary function test; PH: pulmonary hypertension; RHC: right heart catheterisation; TRV: tricuspid regurgitation velocity; 6MWT: six-minute walk test.
## PAH treatment algorithm

Since the publication of the latest ESC-ERS guidelines in 2022 [2,3], the major advance in the management of PAH has been the possibility of targeting the bone morphogenetic protein/activin signalling pathway, which plays a central role in the pathophysiology of PAH [53].

In terms of overall management, no major updates in supportive care have been made compared to previous ESC/ERS guidelines [2,3]. Anti-coagulation is no longer recommended but may be considered on an individual basis [53]. All patients with PAH should be vaccinated, with particular attention to respiratory pathogens (influenza virus, *Streptococcus pneumoniae*, and SARS-CoV-2) [2,3,53]. Diuretics are essential in cases of fluid retention, and long-term oxygen therapy is indicated when arterial oxygen pressure is persistently below 60 mmHg [2,3,53].

The definition of an acute vasodilator response (a decrease in mPAP >10 mmHg to a value <40 mmHg without a fall in cardiac output) remains unchanged [2,3,54]. If follow-up assessment indicates that a patient is not at low risk, PAH therapy must be initiated or escalated accordingly [2,3,53]. A recent multicentre study on acute vasoresponders showed that patients meeting these criteria and demonstrating improved pulmonary arterial compliance were more likely to sustain a prolonged response [55].

A key change in the 2022 ESC-ERS guidelines treatment algorithm, compared to the 2018 version following the 6th WSPH, is the focus on differentiating between patients with and without comorbidities [2,3]. However, this distinction has been removed in the treatment algorithm proposed at the 7th WSPH, where the same approach is now recommended regardless of comorbidity status [53].

Initial therapy is based on a binary approach according to the risk status: dual oral combination therapy with an endothelin-receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE-5) inhibitor is indicated non-high-risk patients while patients at high-risk should be initiated with triple combination therapy including parenteral prostacyclin and two oral drugs. At follow-up, treatment escalation is indicated in patients who do not achieve a low-risk status. Patients who are at intermediate-low risk should be considered for add-on therapy with an activin-signalling inhibitor (sotatercept) or an oral prostacyclin pathway agent (PPA, selexipag, oral treprostinil), or with an inhaled PPA, or with transition from an oral PDE-5 inhibitor to a soluble guanylate cyclase activator (riociguat). Patients at intermediate-high risk at follow-up should receive a parenteral prostacyclin or be considered for add-on sotatercept, while those at highest risk should receive a parenteral prostacyclin, if not already receiving [53]. There is no sufficient data to support the use of sotatercept as first-line therapy.

Early identification of patients with distinct phenotypes is crucial, both to target appropriate therapies and to recognize those with comorbidities who may experience more adverse events or reduced treatment efficacy. A common scenario is the unmasking of group 2 PH, where patients meet precapillary PH criteria at rest but show postcapillary physiology during provocative manoeuvres (exercise or fluid challenge). In such cases, initiating monotherapy may be preferred to monitor tolerance and treatment response. Additionally, an alternative or non-group 1 diagnosis may only emerge after initiating treatment. If so, PAH therapy should generally be discontinued and focus shifted to the underlying condition.

Referral for lung transplantation should be considered for high-risk patients at diagnosis and for those at intermediate-high or high risk at follow-up [53,56]. Despite therapeutic advances, PAH remains a progressive disease, and acutely decompensated right heart failure is a major negative prognostic event. In such cases, circulatory support (such as extracorporeal life support) can serve as a bridge to recovery, transplantation, or further decision-making. Timely identification of patients not meeting therapeutic goals is essential to evaluate transplant eligibility [56]. PAH-specific transplant eligibility criteria differ from those for other lung diseases, complicating access within organ allocation systems. Emergency allocation programs are a national priority,

shown to reduce mortality on the transplant waiting list. As the RV typically recovers after transplantation, bilateral lung transplantation is the preferred option. The decision to list a patient should be multifactorial, incorporating risk assessment, severity of RV failure, comorbidities, expected waiting time, donor availability, and patient preferences. Bridging strategies should be discussed and planned in advance [56].

## Management of PH in special conditions

Despite major advances in the diagnosis and treatment of PH in recent years, patients and caregivers continue to face several challenging situations, including anaesthesia and perioperative management, pregnancy, medication adherence, palliative care, and the impact of climate change [57]. The 6th meeting of the French PH Network provided an opportunity to explore strategies to address and improve the management of these complex scenarios. In light of the 7th WSPH, several key issues and opportunities for improvement were identified and are summarized in Table 1.

## Clinical trial design and endpoints in PAH

With the growing number of available treatment options and increasingly stable PAH patient populations, the design of clinical trials in PAH must evolve [58]. Initially, trials were of relatively short duration (12 to 24 weeks), included small numbers of patients receiving no background therapy, and used the 6MWD as the most common primary endpoint. Over time, phase 3 randomized controlled trials have shifted toward larger, event-driven designs with morbidity/mortality composite endpoints, which require larger sample sizes and longer follow-up durations —posing challenges in a rare disease such as PAH. Current challenges for future outcome-driven PAH trials include 1/ increasing the sample size of enrolled PAH patients and 2/ demonstrating incremental benefit on traditional endpoints in relatively stable patients already receiving background therapy.

To address these issues, novel trial features have been proposed, such as adaptive trial designs and enrichment strategies. Adaptive trials, such as seamless phase 2/3 designs (e.g., the IMPAHCT study, NCT05036135 [59], allow modifications of design and statistical procedures based on interim analyses [60]. In such cases, data from phase 2 guide the phase 3 study, reducing both cost and trial duration, an especially attractive option in rare diseases like PAH [58]. Additional advantages include improved dose selection and the identification of relevant covariates across trial phases. However, these designs require a robust and validated phase 2 endpoint, such as PVR.

Enrichment strategies represent another promising approach, aiming to reduce trial size by selecting patients most likely to respond to the investigational drug and/or those at higher risk of reaching the trial endpoint [58]. For example, the ZENITH trial (NCT04896008) limited enrolment to high-risk PAH patients defined by WHO/NYHA class III or IV and a REVEAL Lite 2 score ≥ 9.

Beyond trial design, another key challenge is redefining clinically meaningful endpoints. Monitoring daily physical activity via actigraphy may offer advantages over 6MWD, but its clinical relevance remains unconfirmed [61]. Additionally, implantable hemodynamic monitors such as CardioMEMS™ HF systems allow for continuous pulmonary artery pressure (PAP) monitoring [62,63]. However, since these devices only measure PAP and not cardiac output, they may not fully reflect PAH severity. The use of risk scores as trial endpoints is gaining interest, as demonstrated by the REPLACE (NCT02891850), PULSAR (NCT03496207), and STELLAR (NCT04576988) studies [64–66]. However, these scores include biomarkers that may not always reflect direct clinical benefit, limiting their utility as primary outcomes. To optimize their use in future trials, multi-parametric improvement criteria must be carefully reviewed to ensure that all components are both clinically meaningful and relevant to patients.
<table><caption>**Table 1**
Summary of raised questions in the management of special conditions in PH.</caption><thead><tr><th>Special conditions in PH</th><th>Questions raised</th></tr></thead><tbody><tr><td>Anesthesia and perioperative care</td><td>1/ Importance of multidisciplinary consultation (PH specialist team, anesthesiologist, surgeon, critical care team) with a central role of PH expert centres [98]<br>2/ Perioperative risk depends on the type of surgery, level of severity and type of PH [98]: Need to validate complication prediction scores including clinical (2022 ESC/ERS four-strata risk-assessment tool), hemodynamic and surgical data (type of procedure, urgency, duration of procedure (more or less than 3 hours), site of procedure)<br>3/ Need to fine-tune anesthesia practice for PH patients<br>4/ Importance of educating patients and their referring physicians as soon as PH is diagnosed: value of an emergency medical card indicating the patient's pathology and treatments, and the contact details of the referring PH expert centre</td></tr><tr><td>Pregnancy</td><td>1/ Central role of PH expert centres with a multidisciplinary intervention by on-site teams (PH specialist team, obstetricians, transplant physicians, psychologists, anesthesiologist, critical care team) = need for a local network2/ Plan delivery during the 36-38th gestational week in a PH expert centre with available ECMO3/ Close monitoring of PH in the first year after pregnancy4/ "In pregnant women with mild PH and in those whose disease is well controlled with medical therapy, the maternal and foetal/neonatal mortality risks are low" [99]:<br>- Can we provide threshold hemodynamic values (normal or near-normal)?<br>- Data based on cases reported in the literature only [100-102]<br>- Which patients are most concerned? = Long-term responders to calcium channel blockers and CTEPH patients after balloon pulmonary angioplasty and/or pulmonary endarterectomy<br>- What about patients who will improve on sotatercept?<br>o No human data available<br>o Problem of the long half-life of sotatercept<br>o Pregnancy = exclusion criteria in clinical trials<br>o Possible adverse effects on fertility and fecundity (animal data)<br>o Contraindication to breast-feeding</td></tr><tr><td>Medication adherence</td><td>1/ Identify patients with risk factors for low medication adherence [103]: elderly patients with comorbidities and/or polymedication and/or increased treatment frequency and/or treatment-related side effects<br>2/ Need to develop medical adherence monitoring tools specific to PH<br>3/ Importance of therapeutic patient education programs, central role of PH specialized nurses<br>4/ Identify differences between countries<br>- Conditions for providing PH-specific therapies?</td></tr><tr><td>Palliative care</td><td>1/ Lack of engagement with palliative care in PH, despite numerous complex situations:<br>- High-risk PH patients, ineligible for lung transplantation<br>- Refractory right heart failure<br>- Side effects of PAH therapy<br>- Severe dyspnea<br>- Severe hypoxemia<br>- Social isolation<br>- Psychological impact/anxiety 2/ Identify the needs of each PH patient over time (as soon as the PH diagnosis is made)<br>- Use of the PROMs, EMPHASIS-10 or PAH-SYMPACT quality of life questionnaires<br>- Use of the 2022 ESC/ERS four-strata risk-assessment tool to "trigger" palliative care<br>- Use of the oncologist's question "Would I be surprised if my patient is still alive in 6 to 12 months?"<br>- Ensuring access to a multidisciplinary approach, including psychological support 3/ Avoid presenting palliative care as end-of-life care- Prefer the term "supportive care"?4/ Proposal for an observatory / inventory of palliative care in PH in each country5/ Importance of collaboration with experienced palliative care teams- Assistance with drafting of advance healthcare directives</td></tr><tr><td>Climate change</td><td>1/ Better advising PH patients on what to do in the event of heatwaves or pollution peaks: stay inside, measure their blood pressure and heart rate closely, adjust diuretic therapies if necessary2/ Interest in limiting carbon dioxide emissions in PH management [104]:<br>- Improve PH diagnosis: earlier diagnosis for earlier therapy and to reduce the need for hospitalization<br>- Interest in telemonitoring and eHealth in stable low-risk patients<br>- Extension of rehabilitation programs (low environmental impact)</td></tr></tbody></table>

Abbreviations: CTEPH: chronic thromboembolic pulmonary hypertension; ECMO: extracorporeal membrane oxygenation; PAH-SYMPACT: Pulmonary Arterial Hypertension - Symptoms and Impact Questionnaire; PH: pulmonary hypertension; PROMS: Patient-Reported Outcome Measures.

Finally, involving patient partners in the design, implementation, and dissemination of clinical trials is crucial. They can help identify the most appropriate Patient-Reported Outcome Measures (PROMs) and Patient-Reported Experience Measures (PREMs) [67]. However, one challenge remains: such measures may vary according to socioeconomic context and country of origin.

## Pulmonary hypertension associated with left heart disease

In left heart disease (LHD), post-capillary PH (PH-LHD) is associated with poorer clinical outcomes. Notably, PVR >2 WU has been shown to correlate with worse prognosis, supporting the current definition of group 2 PH [2,3,68]. However, the optimal prognostic marker in PH-LHD remains uncertain, and other parameters, such as pulmonary artery compliance, may hold additional prognostic value [68]. In group 2 PH, the accuracy of RHC is critical, especially for the measurement of PAWP, which must be interpreted in the clinical context of LHD, including right atrial pressure [69]. Therefore, in cases of diagnostic uncertainty, RHC

should be performed in an expert PH centre to use appropriate methodology for PAWP measurement, that may be associated with provocation tests (exercise or fluid challenge) when PAWP falls in the grey zone (i.e., 12-18 mmHg) [2,3,70]. Once post-capillary PH is confirmed, disaggregating PH-LHD is essential, as clinical presentation, pathophysiology, prognosis, and treatment differ across subtypes, from valvular heart disease to specific cardiomyopathies and overlapping phenotypes.

One of the most significant challenges is distinguishing PAH with cardiovascular comorbidities from PH due to heart failure with preserved ejection fraction (HFpEF), particularly as the contribution of each comorbidity varies [71].

Staging PH-LHD is critical, ranging from:

- Stage A: Loss of left atrial compliance,

- Stage B: Pulmonary venous congestion and decreased PA compliance,

- Stage C: Pulmonary venous and arterial remodelling,

- Stage D: Pulmonary arteriopathy and RV-PA uncoupling [69].
Early identification of patients in stage A is key to prevent progression to advanced PH, especially given the often-underestimated role of left atrial disease. Accurate staging is essential, as therapeutic management depends on the specific LHD context, and clinical trial inclusion should be considered for advanced-stage patients (C or D) [69].

In clinical trials dedicated for group 2 PH, phenotyping by RHC is fundamental. However, the optimal inclusion criteria to identify patients most likely to benefit from therapies targeting the pulmonary vasculature remain unclear (e.g., PVR >5 WU? PAWP thresholds?). In this context, pragmatic trial designs are likely the most suitable for this heterogeneous population.

## Pulmonary hypertension associated with chronic lung disease

PH is a common and serious complication of chronic lung disease (CLD), often associated with a poor prognosis. The heterogeneity of CLD pathogenesis complicates the design of studies and randomized controlled trials (RCTs). The 7th WSPH proposed a revised classification based on pathological patterns, including the most frequent cause of PH-CLD: chronic obstructive pulmonary disease (COPD) and/or emphysema, interstitial lung disease (ILD), and combined pulmonary fibrosis and emphysema (CPFE).

### PH associated with COPD

A recent meta-analysis of 38 studies estimated the prevalence of PH in COPD at approximately 39% [72]. However, severe PH (initially defined as mean mPAP >35 mmHg and/or cardiac index <2L/min/m²) is rare, occurring in only 1–5% of COPD cases [73]. In this subset, PAH therapies have shown some hemodynamic benefits, including reductions in mPAP (–3.68 mmHg, 95% CI –2.03 to –5.32) and PVR (–1.40 WU, 95% CI –1.97 to –0.82). However, no clinical trials demonstrated efficacy in prognosis, and some studies suggest that PAH drugs may deteriorate gas exchange in COPD patients [74]. The PERFECT study evaluating inhaled treprostinil for COPD-PH (patients with COPD, FEV1 <80% predicted, mPAP ≥30 mmHg, and PVR ≥4 WU) was terminated early due to safety concerns and possible increased mortality [75]. An individualized approach in PH expert centres is recommended for managing severe PH in COPD, pending results from ongoing trials: INSIGNA (inhaled MK-5475, a soluble guanylate cyclase stimulator; NCT05612035), and ERASE PH-COPD (tadalafil; NCT05844462).

### PH associated with ILD

ILD-PH carries a worse prognosis than PH in COPD. Historically, most RCTs in this population have produced negative results. Both riociguat (RISE-IIP) in idiopathic interstitial pneumonia PH and ambrisentan (ARTEMIS) in idiopathic pulmonary fibrosis were associated with increased mortality or disease progression and are contraindicated in these respective settings [76,77]. Trials with bosentan failed to show clinical efficacy [78].

The INCREASE trial, evaluating inhaled treprostinil, was the first to demonstrate positive results in ILD-PH, showing improvements in 6MWD and several secondary endpoints (Table 2) [79]. Of note, the potential benefits were not significantly observed in moderate PH with PVR < 4 WU [80]. Retrospective analyses suggest that PDE-5 inhibitors may improve survival, particularly in patients with preserved RV function [81].

### CPFE-PH

PH affects approximately 30–50% of patients with CPFE. In INCREASE trial, inhaled treprostinil failed to demonstrate a benefit in 6MWD in this specific subgroup, but a decrease in the number of worsening events was observed.

## Unresolved questions in chronic thromboembolic pulmonary hypertension

Chronic Thromboembolic PH (CTEPH) remains significantly underdiagnosed. Registry data suggest an observational incidence of approximately 4–5 cases per million per year, rising to 13 per million per year when systematic follow-up is performed after pulmonary embolism [82] Pulmonary endarterectomy (PEA) remains the treatment of choice for operable patients and has a major impact on long-term outcomes, with 3-year and 5-year survival rates of 94% and 83%, respectively [83,84]. In inoperable patients, the introduction of balloon pulmonary angioplasty (BPA) has led to improved prognosis, with recent data showing a 3-year survival of 92%, thus comparable to that achieved after PEA [83]. By contrast, in patients deemed ineligible for both PEA and BPA, survival remains substantially lower, around 71% at 3 years [83].

### Operable CTEPH with high PVR

Operable CTEPH patients with high PVR (>10 WU) are at increased risk of early postoperative mortality after PEA [85]. Although medical therapy prior to surgery can improve hemodynamics, there is a lack of controlled evidence supporting this strategy, and it may unnecessarily delay definitive surgical treatment. For patients with mixed anatomical lesions and severe PH, a multimodal approach (combining medical therapy, BPA for inoperable segments, and PEA for operable lesions) has shown promising results. However, this strategy should be implemented exclusively in highly specialized expert centres [86].

### Persistent PH after PEA

BPA is now a well-established treatment option for patients with persistent PH following PEA, although procedural complexity is increased due to post-surgical vascular changes. These patients should be managed exclusively in expert centres capable of performing such high-risk interventions.

<table><caption>**Table 2**
Randomised control trials in ILD-PH.</caption><thead><tr><td>Author</td><td>Number of patients</td><td>Drug</td><td>Main results</td></tr></thead><tbody><tr><td>Krowka et al, 2007 [105]</td><td>51</td><td>Inhaled iloprost</td><td>No difference in 6MWT, NYHA FC, dyspnoea score</td></tr><tr><td>Raghu et al, 2013 [77]*</td><td>492, incl. 48 with PH</td><td>Ambrisentan</td><td>Terminated early for a possible increased risk for disease progression and respiratory hospitalizations</td></tr><tr><td>Corte et al, 2014 [78]</td><td>60</td><td>Bosentan</td><td>No effect on hemodynamics, symptoms or functional capacity</td></tr><tr><td>Nathan et al, 2019 [76]</td><td>147</td><td>Riociguat</td><td>Terminated early for unfavourable risk/benefit profile</td></tr><tr><td>Waxman et al, 2021 [79]</td><td>326</td><td>Inhaled treprostinil</td><td>Improved 6MWD, NT-proBNP, clinical worsening</td></tr></tbody></table>

<footnote>* Although the Raghu et al. trial was not designed as an ILD-PH study, a minority of enrolled patients had PH, and subgroup analyses stratified by PH status yielded results consistent with the overall cohort.</footnote>
## Inoperable CTEPH

In non-operable patients, riociguat therapy prior to planned BPA is supported by a randomized controlled trial and has been shown to improve pre-BPA hemodynamics and reduce procedural complication [87]. The ongoing IMPACT-CTEPH trial (NCT04780932) is expected to provide further insights into whether initial dual oral therapy with riociguat and macitentan is superior to riociguat monotherapy in lowering PVR prior to BPA.

## Treatment goals

In the era of multimodal treatment, the therapeutic goals in CTEPH require clearer definition. Goals should be individualized, accounting for age, comorbidities, anatomical distribution of lesions, and patient preferences, with the central aim of achieving and maintaining a low-risk profile. NYHA functional class (FC) is strongly correlated with prognosis and mortality; achieving FC I or II is therefore a key therapeutic objective [83,88]. Moreover, a recent studie suggested that CTEPH patients with a mean PAP <30 mmHg and a PVR <3 WU have excellent long-term survival [89]. Thus, normalization or near-normalization of resting pulmonary hemodynamics should be considered a primary treatment target in both operable and inoperable CTEPH.

## Treatment de-escalation

Treatment de-escalation may be considered in selected patients who achieve treatment goals after BPA, based on experience from expert centres [90].

Given the potential adverse effects and cost of long-term medical therapy, a randomized, multicentre trial is warranted to test whether discontinuing medical therapy after successful BPA is associated with an acceptably low risk of clinical worsening compared to continuing medical therapy.

## Paediatric pulmonary hypertension

In children older than 3 months, the definition of PH is identical to that in adults, with a mPAP threshold >20 mmHg [2,3].

Group 1 PH and Group 3 PH are the most common causes in paediatric PH, accounting for approximately 45 % and 49 % of cases, respectively. Within Group 1, 30–50 % of paediatric cases are associated with congenital heart disease (CHD) [91]. The subclassifications of CHD-associated PAH are outlined in Table 3. A new group E was introduced for patients who do not fit into Groups A–D, such as those with transposition of the great arteries repaired during the neonatal period without significant shunting. At the 7th WSPH, a new group was proposed for complex CHD associated with pulmonary vascular disease, specifically targeting CHD patients who do not meet the criteria of any of the existing groups [92].

Patients with small coincidental defects (Group C), repaired CHD (Group D), and no initial shunt (Group E) may benefit from conventional PAH drugs, aligned with Group 1 PAH management.

<table><caption>**Table 3**
Classification of congenital heart disease (CHD)-associated PAH.</caption><thead><tr><td>Group</td><td>Conditions</td></tr></thead><tbody><tr><td>A</td><td>Eisenmenger syndrome</td></tr><tr><td>B</td><td>Left-to-right shunt: correctable / not correctable</td></tr><tr><td>C</td><td>Coincidental defects, including all (isolated) atrial septal defects in childhood</td></tr><tr><td>D</td><td>Corrected CHD</td></tr><tr><td>E</td><td>Without (prolonged) initial shunt, e.g. neonatal arterial switch operation for transposition of the great arteries</td></tr></tbody></table>

In case of severe PAH, unresponsive to medical therapy, alternative interventions may include: atrial septostomy, heart-lung transplantation, or "reverse" Potts shunt, which involves creating a shunt between the pulmonary artery and the descending aorta [93,94].

Although the Potts shunt technique is gaining recognition, several uncertainties persist—particularly regarding patient selection, appropriate indications, timing and procedural access. It is recommended that lung transplant evaluation should be initiated concurrently with Potts shunt consideration [95,96].

In children with left-to-right shunts (Group B), a key consideration is the correction of the shunt, based on indexed pulmonary vascular resistance (PVRI):

- Children with a PVRI <4 WU·m² are typically candidates for surgical correction.

- Children with a PVRI >8 WU·m² are generally considered inoperable.

- The "grey zone" (4–8 WU·m²) requires individualized assessment and a multimodal decision-making approach [2,3,97].

Medical optimization should precede any interventional or surgical treatment.

## Conclusion

The 6th 'Journées du Réseau Français de l'Hypertension Pulmonaire' offered a comprehensive and forward-looking overview of the current landscape and future directions of PH care. By bridging basic science, clinical innovation, and patient advocacy, the meeting highlighted recent advances in our understanding of PH pathophysiology, the refinement of risk stratification tools, and the adaptation of treatment algorithms in light of newly available therapies and technologies. The symposium emphasized the integration of patient perspectives into both care and research, underscoring the evolving role of PROMs, AI-based diagnostics, and individualized treatment strategies. The expansion of PH definitions and classification systems, along with the emergence of novel imaging and trial methodologies, calls for continued collaboration across disciplines and expertise.

As PH becomes increasingly recognized as a multifaceted and heterogeneous condition, multidisciplinary coordination, early referral to expert centres, and tailored approaches to management are more essential than ever. The 2024 French PH Symposium thus served not only as a reflection of global consensus but also as a catalyst for national engagement and innovation in the ongoing fight against PH.

## Declaration of interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Marianne Riou reports a relationship with MSD France that includes: board membership, speaking and lecture fees, and travel reimbursement. Marianne Riou reports a relationship with Ferrer International that includes: board membership. Marianne Riou reports a relationship with Boehringer Ingelheim that includes: board membership. Marianne Riou reports a relationship with Menarini Laboratories that includes: speaking and lecture fees.

TROMEUR Cécile reports a relationship with Merck Sharp & Dohme: board membership, consulting or advisory, and speaking and lecture fees. Tromeur Cécile reports a relationship with UK Ltd that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Tromeur Cécile reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. Tromeur Cécile reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. Tromeur Cécile reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees.
VACHIERY Jean Luc reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

SAVALE Laurent reports a relationship with Merck Sharp & Dohme UK Ltd that includes: board membership, funding grants, and speaking and lecture fees. SAVALE Laurent reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. SAVALE Laurent reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees.

HUMBERT Marc reports a relationship with 35 Pharma that includes: consulting or advisory fees. Humbert Marc reports a relationship with Aerovate that includes: board membership, consulting or advisory fees. Humbert Marc reports a relationship with AOP Pharma that includes: board membership, consulting or advisory fees, speaking and lecture fees, funding grants. Humbert Marc reports a relationship with Bayer that includes: speaking and lecture fees. Humbert Marc reports a relationship with Chiesi Pharmaceuticals Inc that includes: board membership, consulting or advisory fees. Humbert Marc reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory, and speaking and lecture fees. Humbert Marc reports a relationship with Janssen that includes: board membership, consulting or advisory, and speaking and lecture fees. Humbert Marc reports a relationship with Keros that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Humbert Marc reports a relationship with United Therapeutics that includes: board membership, consulting or advisory.

Olivier SITBON reports relationships with pharmaceutical companies including Aerovate, Altavant, AOP Orphan, Gossamer Bio, Ferrer, Janssen, Liquidia, Merck, Respira Therapeutics, Roivant and United Therapeutics. In addition to being investigator in clinical trials involving these companies, relationships include board membership, consulting or advisory, and speaking and lecture fees. In addition, Dr Sitbon's institution received funding grants from AOP Orphan, Gossamer Bio, Ferrer, Janssen and Merck.

MONTANI David reports a relationship with Grupo Ferrer Internacional SA that includes: board membership, consulting or advisory, and speaking and lecture fees. Montani David reports a relationship with Merck Sharp & Dohme UK Ltd that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Montani David reports a relationship with Boehringer Ingelheim Ltd that includes: board membership, consulting or advisory, and speaking and lecture fees. Montani David reports a relationship with Chiesi Pharmaceuticals Inc that includes: speaking and lecture fees. Montani David reports a relationship with GlaxoSmithKline Inc that includes: speaking and lecture fees. Montani David reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees.

If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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