Definition, Classification, and Diagnosis of Pulmonary Hypertension PDF

EUROPEAN RESPIRATORY JOURNAL TASK FORCE REPORT G. KOVACS...

EUROPEAN RESPIRATORY JOURNAL TASK FORCE REPORT G. KOVACS ET AL. Definition, classification and diagnosis of pulmonary hypertension Gabor Kovacs1,2, Sonja Bartolome3, Christopher P. Denton 4, Michael A. Gatzoulis5,6, Sue Gu7, Dinesh Khanna8, David Badesch7 and David Montani 9,10,11 1 Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. 2Ludwig Boltzmann Institute for Lung Vascular Research Graz, Graz, Austria. 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. 4Division of Medicine, University College London, London, UK. 5 Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, Guy’s and St Thomas’s NHS Foundation Trust, London, UK. 6National Heart and Lung Institute, Imperial College, London, UK. 7Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Anschutz Medical Campus Aurora, Aurora, CO, USA. 8Scleroderma Program, Division of Rheumatology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA. 9Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France. 10Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 11INSERM UMR_S999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. Corresponding author: Gabor Kovacs ([email protected]) Shareable abstract (@ERSpublications) In this article, we provide the definitions, the current clinical classification and the diagnostic algorithm for pulmonary hypertension, based on the 7th World Symposium on Pulmonary Hypertension. https://bit.ly/3W442cD Cite this article as: Kovacs G, Bartolome S, Denton CP, et al. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J 2024; 64: 2401324 [DOI: 10.1183/13993003.01324-2024]. Abstract Copyright ©The authors 2024. Pulmonary hypertension (PH) is a haemodynamic condition characterised by elevation of mean pulmonary arterial pressure (mPAP) >20 mmHg, assessed by right heart catheterisation. Pulmonary arterial wedge This version is distributed under the terms of the Creative pressure (PAWP) and pulmonary vascular resistance (PVR) distinguish pre-capillary PH (PAWP Commons Attribution ⩽15 mmHg, PVR >2 Wood Units (WU)), isolated post-capillary PH (PAWP >15 mmHg, PVR ⩽2 WU) Non-Commercial Licence 4.0. and combined post- and pre-capillary PH (PAWP >15 mmHg, PVR >2 WU). Exercise PH is a For commercial reproduction haemodynamic condition describing a normal mPAP at rest with an abnormal increase of mPAP during rights and permissions contact exercise, defined as a mPAP/cardiac output slope >3 mmHg/L/min between rest and exercise. The core [email protected] structure of the clinical classification of PH has been retained, including the five major groups. However, This article has an editorial some changes are presented herewith, such as the re-introduction of “long-term responders to calcium commentary: channel blockers” as a subgroup of idiopathic pulmonary arterial hypertension, the addition of subgroups https://doi.org/10.1183/ in group 2 PH and the differentiation of group 3 PH subgroups based on pulmonary diseases instead of 13993003.01222-2024 functional abnormalities. Mitomycin-C and carfilzomib have been added to the list of drugs with “definite Received: 9 July 2024 association” with PAH. For diagnosis of PH, we propose a stepwise approach with the main aim of Accepted: 9 July 2024 discerning those patients who need to be referred to a PH centre and who should undergo invasive haemodynamic assessment. In case of high probability of severe pulmonary vascular disease, especially if there are signs of right heart failure, a fast-track referral to a PH centre is recommended at any point during the clinical workup. Haemodynamic criteria of pulmonary hypertension Pulmonary hypertension (PH) is a haemodynamic condition that is characterised by the elevation of mean pulmonary arterial pressure (mPAP) above the upper limit of normal. Based on a large number of invasive haemodynamic measurements in healthy subjects in the supine position, the upper limit of normal mPAP is 20 mmHg [1–4]. Pre-capillary PH is defined by mPAP >20 mmHg and the elevation of pulmonary vascular resistance (PVR) above the upper limit of normal that is considered to be 2 Wood Units (WU) [1–3, 5] and by a pulmonary arterial wedge pressure (PAWP) ⩽15 mmHg. This form of PH is characteristic of https://doi.org/10.1183/13993003.01324-2024 Eur Respir J 2024; 64: 2401324 EUROPEAN RESPIRATORY JOURNAL 7TH WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | G. KOVACS ET AL. haemodynamic conditions and diseases with pulmonary arterial involvement and no significant left heart disease. Post-capillary PH is defined by mPAP >20 mmHg and PAWP >15 mmHg and is strongly suggestive of left heart disease. The value of the PVR further distinguishes between isolated post-capillary PH (ipcPH, PVR ⩽2 WU) and combined post- and pre-capillary PH (cpcPH, PVR >2 WU). Exercise PH is a haemodynamic condition describing a normal mPAP at rest with an abnormal increase of mPAP during exercise and is defined as a mPAP/cardiac output (CO) slope >3 mmHg/L/min between rest and exercise. These haemodynamic criteria (table 1) adhere to the recommendations of the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of PH [1, 2]. In this section, we provide specific comments on these criteria, address related topics and identify gaps in the evidence in order to make proposals for future collaborative research efforts. Invasive assessment of pulmonary haemodynamics Invasive haemodynamic measurements by right heart catheterisation (RHC) are required to assess mPAP, PAWP and cardiac output and to calculate PVR with sufficient accuracy for the diagnosis and haemodynamic stratification of PH (table 1). Noninvasive methods such as echocardiography or cardiac MRI lack precision or are not sufficiently validated to accurately assess pulmonary haemodynamics. Incorporating haemodynamics into the clinical context Although the above haemodynamic criteria represent the cornerstone of the diagnosis of different forms of PH and highlight the importance of invasive haemodynamic assessment, they should always be interpreted within the clinical context. The final diagnosis and classification should reflect the results of all investigations. Some haemodynamic parameters may be strongly influenced by acute conditions (e.g. cardiac decompensation) or general treatment measures (e.g. diuretic treatment), which may strongly influence the haemodynamic stratification of patients. Definition of early PH It has been previously shown that elevated mPAP and PVR values above the upper limits of normal are associated with poor survival [6–8]. A large recent nationwide study from the UK revealed that in patients with mildly elevated mPAP (21–24 mmHg) or PVR (2–3 WU), independent of comorbid lung and heart disease, survival was worse than among those with normal pressures (mPAP 3 WU during follow-up, suggesting the presence of an early stage of progressive pulmonary vascular disease in these patients. Similarly, patients with systemic sclerosis presenting with mPAP 21– 24 mmHg and PVR 2–3 WU frequently develop mPAP ⩾25 mmHg during follow-up. These observations suggest that the current haemodynamic criteria of PH and pre-capillary PH are clinically relevant and that patients with a risk condition for PH and mPAP 21–24 mmHg and/or PVR 2–3 WU may be at risk of haemodynamic progression. Therefore, this haemodynamic condition may be referred to as TABLE 1 Haemodynamic criteria of pulmonary hypertension (PH) Haemodynamic characteristics PH mPAP >20 mmHg Pre-capillary PH mPAP >20 mmHg PAWP ⩽15 mmHg PVR >2 WU Isolated post-capillary PH (ipcPH) mPAP >20 mmHg PAWP >15 mmHg PVR ⩽2 WU Combined post- and pre-capillary PH (cpcPH) mPAP >20 mmHg PAWP >15 mmHg PVR >2 WU Exercise PH mPAP/CO slope >3 mmHg/L/min between rest and exercise mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; WU: Wood Units; CO: cardiac output. https://doi.org/10.1183/13993003.01324-2024 2 EUROPEAN RESPIRATORY JOURNAL 7TH WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | G. KOVACS ET AL. “early PH”. Conversely, many patients with mildly elevated mPAP and/or PVR may be haemodynamically and clinically stable. Further studies are needed to understand the long-term sequelae of this condition and to identify the patients at risk of progression. Impact of recent changes in the haemodynamic definition of PH on the number of patients with post-capillary PH The 2022 ESC/ERS PH guidelines lowered the threshold of PVR to distinguish cpcPH and ipcPH compared to previous recommendations, leading to a shift of patients from the ipcPH to the cpcPH subgroup. However, the current haemodynamic criteria for these forms of post-capillary PH are based on the upper limit of normal PVR and little is known about their clinical relevance. Further studies may reveal alternative haemodynamic thresholds among patients with post-capillary PH with prognostic and potentially therapeutic relevance. Distinguishing pre- and post-capillary PH The optimal threshold of PAWP for distinguishing pre- and post-capillary PH has been a topic of longstanding discussion. Importantly, PAWP should always be considered within the clinical context for appropriate classification of PH and for optimal decision-making regarding the management of patients. In addition, the value of PAWP may be influenced by the applied methodology and there are sources of potential imprecision. Based on the largest currently available systematic literature review, the upper limit of normal PAWP is 13 mmHg. However, based on the definition of pre-capillary PH, almost all therapeutic studies for pulmonary arterial hypertension (PAH) have included patients with PAWP up to 15 mmHg [1, 2] and demonstrated clinical efficacy of treatment, including patients with PAWP 13–15 mmHg. Notably, in patients with elevated mPAP, PAWP values 15 mmHg were associated with increased mortality. In those with PAWP 15 mmHg, this was mainly due to left heart disease. Taking into account all of these considerations, we propose maintaining the definition of post-capillary PH as PAWP >15 mmHg. However, when presented with an individual patient, especially when PAWP is 12–18 mmHg, we suggest that instead of focusing on a single haemodynamic parameter, the entire presentation of the patient including clinical history, cardiovascular risk factors, the history of episodes of pulmonary oedema, echocardiographic findings and perhaps PAWP response to provocation should be taken into consideration for the appropriate classification of patients. Different haemodynamic criteria for diagnosis and treatment of pre-capillary PH All currently available drugs for the treatment of PAH, chronic thromboembolic PH (CTEPH) or PH associated with lung diseases were approved based on clinical trials using previous haemodynamic definitions of PH and pre-capillary PH, characterised by mPAP ⩾25 mmHg, PAWP ⩽15 mmHg and PVR >3 WU. Therefore, these drugs should be administered exclusively to patients meeting these definitions. We are aware of the disparity between the current criteria for PH (and pre-capillary PH) and for the indication for targeted therapy. Presently, the treatment of patients with early PH, or mPAP 21–24 mmHg and PVR 2–3 WU, using PH drugs lacks justification due to the absence of sufficient data from clinical trials. We strongly advocate for more clinical trials to investigate the effects of PH drugs in patients with mildly elevated mPAP and/or PVR. Unclassified PH Patients exhibiting elevated mPAP but normal PVR (⩽2 WU) and PAWP ⩽15 mmHg do not meet the criteria for either pre-capillary or post-capillary PH and are considered to have “unclassified PH” [1, 2]. Many of these subjects are characterised by elevated pulmonary blood flow. While PH therapy is not indicated for these patients, the exploration of potential underlying conditions (congenital heart disease, liver disease, hyperthyroidism, alcoholism, etc.) is recommended. Exercise PH It has been shown in retrospective single-centre studies that the mPAP/CO slope is a robust predictor of prognosis in patients with exercise dyspnoea or at risk for PH. The normal value of the mPAP/CO slope is strongly age-dependent, but a slope >3 mmHg/L/min is abnormal even among the most elderly subjects and is independently associated with poor survival. A recent large multicentre study confirmed the mPAP/CO slope as an independent predictor of prognosis beyond the predictive value of resting haemodynamics alone. Patients with a mPAP/CO slope >3 mmHg/L/min had a significantly worse prognosis than those with a mPAP/CO slope ⩽3 mmHg/L/min. These results support the current haemodynamic criteria of exercise PH. Of note, mPAP increase during exercise was also associated with survival, but in a time-dependent manner. Initially, a smaller mPAP https://doi.org/10.1183/13993003.01324-2024 3 EUROPEAN RESPIRATORY JOURNAL 7TH WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | G. KOVACS ET AL. increase during exercise was associated with worse survival, while later a larger mPAP increase was associated with poor prognosis. This time-dependency and the dependency of mPAP on the level of exercise make this parameter less attractive when defining exercise PH. The mPAP at peak exercise was not an independent predictor of prognosis. Both the PAWP/CO slope with a threshold >2 mmHg/L/min and a PAWP threshold (e.g. 25 mmHg) during exercise have been suggested to distinguish between pre- and post-capillary causes of exercise PH. Further studies are needed to decide which of them is more helpful for this clinical question [18, 20–22]. Clinical classification of PH The general purpose of the clinical classification of PH is to categorise clinical conditions associated with PH according to similar pathophysiological mechanisms, clinical presentation, haemodynamic characteristics and therapeutic management [1, 2, 4]. The 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018 and the 2022 ESC/ERS guidelines [1, 2, 4] offered a comprehensive, simplified version of the classification for both children and adults, divided into five subgroups (table 2). We suggest retaining the core structure of the clinical classification of PH; however, some clarifications and adjustments might be needed. Here, we provide specific comments and underline potentially relevant areas of ambiguity and gaps in the evidence that warrant further research. Common and rare forms of PH The term “PH” defines a haemodynamic state rather than a disease entity. In aggregate, PH is a relatively common condition, with a global prevalence of ∼1% [1, 2]. The current classification of PH classifies the rare pulmonary vascular diseases into groups 1 and 4 (PAH and CTEPH), and PH as a complication of more common conditions such as left heart disease and lung disease and/or hypoxia into groups 2 and 3. A recent systematic review of the global disease burden found the mean reported prevalence of PAH confirmed by RHC to be 3.7 cases per 100 000. Group 2 and 3 PH are the most prevalent forms of PH, accounting for 90–95% of PH cases worldwide. Within groups 2 and 3 PH, most patients suffer from mild to moderate PH with limited pulmonary vascular involvement. An alternative classification might focus solely on pulmonary vascular diseases. Nevertheless, severe PH and significant pulmonary vascular involvement disproportionate to the severity of the underlying condition are occasionally observed, affecting ∼1–10% of patients with left heart or lung diseases. Thus, it seems challenging to exclude these conditions from pulmonary vascular diseases completely. The situation is even more complex in group 5 PH, which includes PH with unclear and/or multifactorial mechanisms, with sometimes severe and specific vascular involvement, such as sarcoidosis. Therefore, we propose to keep the architecture of the current clinical classification. In addition, the currently proposed clinical classification aims to disseminate information to nonspecialists, thereby highlighting the importance of listing all possible causes that should be considered in evaluating PH. Notably, in the 2022 ESC/ERS guidelines, the term “PH due to” for PH groups 2, 3 and 4 has been changed to “PH associated with”. We support this change in that it underscores the fact that the presence of an associated condition (such as left heart disease, chronic respiratory disease, or chronic thromboembolic disease) may not be sufficient to cause PH, but instead constitutes a risk factor associated with complex pathophysiological mechanisms. PAH with comorbidities In current clinical registries, the number of PAH patients with cardiopulmonary comorbidities may be as high as 60–85%, and even in pivotal PAH trials, ∼50% of subjects had cardiopulmonary comorbidities [25–27]. Registry data reveal that the age at PAH diagnosis is often >60 years, increasing the likelihood of concurrent cardiopulmonary comorbidities that are common in the general population at this age. We acknowledge that patients with PAH may suffer from cardiopulmonary comorbidities. At the same time, the presence of severe cardiac and pulmonary comorbidities is a strong indicator for classification as PH associated with left heart or lung diseases (groups 2 and 3 PH). However, when there is severe pre-capillary involvement and only mild or moderate cardiopulmonary comorbidity, distinguishing between PAH with comorbidities and group 2/3 PH is sometimes difficult and represents a gap in current knowledge. In cases involving cardiac comorbidities, the differentiation between pre- and post-capillary PH (i.e. PAWP ⩽15 mmHg versus >15 mmHg) is often used to determine whether a patient falls into group 1 or group 2 PH. Notably, a PAWP 25 mm IVC and RA IVC diameter >21 mm with decreased inspiratory collapse RA area (end-systole) >18 cm2 PA: pulmonary artery; IVC: inferior vena cava; RA: right atrium; RV: right ventricle; LV: left ventricle; LVEI: left ventricular eccentricity index; TAPSE: tricuspid annular plane systolic excursion; sPAP: systolic pulmonary arterial pressure; RVOT AT: right ventricular outflow tract acceleration time; AR: aortic root. https://doi.org/10.1183/13993003.01324-2024 12 EUROPEAN RESPIRATORY JOURNAL 7TH WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | G. KOVACS ET AL. In step 3, respiratory investigations are suggested as well. This includes arterial blood gas analysis, PFT with DLCO, imaging ( preferably chest computed tomography (CT)), and polygraphy or overnight oximetry if there is suspicion of hypoventilation syndromes. Patients with PAH usually have normal or slightly reduced partial pressure of oxygen. More severe reductions should raise suspicion for significant airflow obstruction, parenchymal lung disease, right-to-left shunt, PVOD or hepatic disease. Partial pressure of arterial carbon dioxide is typically normal or decreased in PAH due to alveolar hyperventilation, and PFT is usually normal or shows only mild abnormalities [71, 72]. More severe abnormalities suggest the presence of significant airway or parenchymal lung disease. A low DLCO (2 mmHg/L/min between rest and exercise and an increase of the absolute value of PAWP>25 mmHg are considered markers of post-capillary exercise PH. Besides exercise, volume challenge represents a method that may uncover left heart disease in patients with pre-capillary PH and PAWP 13–15 mmHg. In these subjects, rapid infusion of 500 mL saline may lead to a significant increase of PAWP, and values >18 mmHg may be suggestive of left heart disease. Based on the available data, fluid loading appears clinically safe; however, all studies were conducted in highly experienced centres. Further studies should provide information on the optimal management of patients with pre-capillary PH and a positive fluid loading test. Screening for PH in patients at risk Early detection and diagnosis of PH is an important goal and can be facilitated through appropriate screening of asymptomatic “high-risk” groups that have a high probability developing PH. These include bone morphogenetic protein receptor type 2 (BMPR2) mutation carriers, first-degree relatives of patients with HPAH, patients undergoing assessment for liver transplantation or transjugular portosystemic shunt and patients with SSc spectrum disorders [1, 2]. In general, annual echocardiography, ECG and NT-proBNP (or BNP) are considered valuable tools for screening in these patients. The DETECT screening tool can be applied to appropriate patients with SSc spectrum disorders who meet the key inclusion and exclusion criteria [33, 96–98]. Patients with other CTDs, portal hypertension or HIV infection have lower risk for the development of PH, thus screening of asymptomatic patients is not recommended, and triggered investigation is more appropriate, although frequency of PH may vary across different ethnic and geographic regions. If these patients develop signs or symptoms suggestive of PAH, the diagnostic algorithm for PH should be implemented (figure 1). https://doi.org/10.1183/13993003.01324-2024 15 EUROPEAN RESPIRATORY JOURNAL 7TH WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | G. KOVACS ET AL. Patients with PAH and suspected or confirmed associated CHD should be cared for in conjunction with a CHD centre. The updated classification of PAH-CHD is included elsewhere. Role of genetic testing in the diagnosis of PAH Although a possible genetic origin of PAH was described in the 1950s , a new era was opened when pathogenic germline mutations in the BMPR2 gene were found to be responsible for familial PAH cases in the late 1990s [101, 102]. Since then, several additional genes have been associated with PAH. An international expert panel recently classified 12 genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17 and TBX4) as having definitive evidence, while three further genes were classified as having moderate evidence (ABCC8, GGCX and TET2) and six genes as having limited evidence supporting a PAH gene–disease relationship. Based on the evidence on the potential genetic background of PAH, HPAH was introduced as a distinct subcategory of group 1 PH in the ERS/ESC PH guidelines in 2009 , comprising ∼3% of all PAH patients. According to the most recent ESC/ERS PH guidelines, all patients with idiopathic PAH, a family history of PAH (suspected HPAH), anorexigen-associated PAH and PAH associated with CHD should be informed about the possibility of a genetic condition [1, 2]. We suggest that genetic counselling and testing be offered to these patients [42, 104]. Genetic testing may reveal potential misclassifications, facilitating appropriate management. In addition, considering that HPAH patients frequently present with a more compromised haemodynamic profile and increased risk of clinical worsening, genetic testing may significantly influence therapeutic strategies. Genetic counselling and testing should also be offered for patients with suspected PVOD/pulmonary capillary haemangiomatosis. Biallelic pathogenic variants in the eukaryotic translation initiation factor 2α kinase 4 gene (EIF2AK4) support this diagnosis, allowing appropriate management and early referral for lung transplantation for eligible patients [1, 2, 42]. If a pathogenic variant is identified in a patient, genetic counselling for family members should be encouraged. There is insufficient evidence to recommend genetic testing for pulmonary hypertension patients in groups 2–5. Conclusion In conclusion, PH is characterised by the elevation of mPAP >20 mmHg. From the haemodynamic point of view, pre- and post-capillary forms of PH may be distinguished. Patients with exercise PH are characterised by a normal mPAP at rest, but an abnormal increase of mPAP during exercise. The clinical relevance of current haemodynamic criteria of PH has been supported by recent studies. They represent the cornerstone for diagnosis of different forms of PH, but they should always be interpreted within the individual patient’s clinical context. The core structure of the clinical classification of PH has been retained, including the five major groups. However, some changes have been implemented based on current developments. These include the re-introduction of “long-term responders to CCBs” as a subgroup of idiopathic PAH, the update of subgroups within group 2 and 3 PH and the addition of mitomycin-C and carfilzomib to the list of drugs with “definite association” with PAH. For diagnosis of PH, we propose a stepwise approach, starting with simple, noninvasive tools, and with the main aim of discerning those patients who need to be referred to a PH centre and should undergo invasive haemodynamic assessment. Conflict of interest: G. Kovacs reports grants from Janssen, Boehringer Ingelheim and European Respiratory Society, consultancy fees from MSD, Boehringer Ingelheim, AOP Orphan, Chiesi, Ferrer, Bayer, Janssen, GSK, Liquidia and AstraZeneca, payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD, Boehringer Ingelheim, AOP Orphan, Chiesi, Ferrer, Bayer, Janssen, GSK, Liquidia and AstraZeneca, support for attending meetings from MSD, Janssen, Boehringer Ingelheim and AOP Orphan, and participation on a data safety monitoring board or advisory board with MSD, Boehringer Ingelheim, Ferrer and Liquidia. S. Bartolome reports grants from United Therapeutics and Gossamer Bio, and consultancy fees from Merck and Janssen. C.P. Denton reports grants from Abbvie, Arxx, Servier, Horizon and GlaxoSmithKline, consultancy fees from Janssen, GlaxoSmithKline, Bayer, Sanofi, Boehringer Ingelheim, Roche, CSL Behring, Corbus, Acceleron, Horizon, Arxx, Lilly, Novartis and Certa, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, GlaxoSmithKline and Boehringer Ingelheim. M.A. Gatzoulis https://doi.org/10.1183/13993003.01324-2024 16 EUROPEAN RESPIRATORY JOURNAL 7TH WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | G. KOVACS ET AL. has no potential conflicts of interest to disclose. S. Gu reports grants from American Thoracic Society Early Career Investigator Award in Pulmonary Vascular Disease and Team PHenomenal Hope Global Impact Research Award. D. Khanna reports grants from NIH R01, DoD, Boehringer Ingelheim and Merck, consultancy fees from Abbvie, Amgen, Argenx, Boehringer Ingelheim, BMS, Cabaletta, Certa, Merck and Zura Bio, and participation on a data safety monitoring board or advisory board with Abbvie. D. Badesch reports grants from Acceleron/Merck, Arena/United Therapeutics, Altavant, Ikaria and AI Therapeutics, consultancy fees from Acceleron/Merck, a leadership role with PHA SLC, and stock (or stock options) with Johnson and Johnson. D. Montani reports grants from Acceleron, Janssen and Merck MSD, consultancy fees from Acceleron, Merck MSD, Janssen and Ferrer, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD. References 1 Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. 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