Pulmonary hypertension

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Omar Elshafei, MD[2], José Eduardo Riceto Loyola Junior, M.D.[3], Ralph Matar, Lisa Prior, Ann Slater, R.N., Rim Halaby, Mohamed Moubarak, M.D. [4]

Synonyms and keywords: Hypertensive pulmonary vascular disease; pulmonary arterial hypertension; PAH; hypertensive pulmonary vascular disease; Ayerza syndrome; Ayerza's syndrome; Ayerza-Arrilaga syndrome

Overview

Pulmonary hypertension (PH) is a hemodynamic and pathophysiological condition defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest, measured by right heart catheterization (RHC). The threshold was lowered from the historical value of ≥25 mmHg after studies of healthy subjects showed that resting mPAP rarely exceeds 20 mmHg, and in 2022 the pulmonary vascular resistance (PVR) threshold for pre-capillary PH was lowered to >2 Wood units (WU). Pre-capillary PH (pulmonary arterial wedge pressure [PAWP] ≤15 mmHg and PVR >2 WU) reflects disease of the pulmonary arterial bed, whereas post-capillary PH (PAWP >15 mmHg) is strongly suggestive of left heart disease.

PH is classified into five clinical groups: pulmonary arterial hypertension (PAH, group 1); PH associated with left heart disease (group 2); PH associated with lung diseases and/or hypoxia (group 3); PH associated with pulmonary artery obstructions, mainly chronic thromboembolic pulmonary hypertension (CTEPH, group 4); and PH with unclear and/or multifactorial mechanisms (group 5). PH affects about 1% of the world's population and up to 10% of people older than 65 years. Groups 2 and 3 account for most cases, whereas PAH and CTEPH are rare diseases that require care in specialized centers.

In most forms of PH, increased right ventricular (RV) afterload is the common final pathway, and adaptation of the right ventricle is perhaps the most important determinant of survival. In PAH, remodeling of the small pulmonary arteries is driven by endothelial dysfunction, smooth muscle cell proliferation, inflammation and an imbalance between vasodilator and vasoconstrictor pathways (nitric oxide, prostacyclin and endothelin) and between growth-inhibiting and growth-promoting signaling of the transforming growth factor beta superfamily. Heritable forms are most often caused by mutations in BMPR2.

Symptoms are nonspecific (exertional dyspnea, fatigue, bendopnea and exertional syncope, followed by signs of right heart failure), so the diagnosis is often delayed by years. Echocardiography estimates the probability of PH, ventilation/perfusion (V/Q) scanning excludes or suggests chronic thromboembolic disease, and RHC at an expert center confirms the diagnosis, defines the hemodynamic phenotype and includes acute vasoreactivity testing in idiopathic, heritable and drug-associated PAH. Asymptomatic high-risk groups, such as patients with systemic sclerosis, carriers of BMPR2 mutations and first-degree relatives of patients with heritable PAH, are candidates for systematic screening.

Treatment depends on the clinical group. In PAH, acute vasoresponders receive high-dose calcium channel blockers; most other patients start dual oral therapy with an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor, while high-risk patients receive initial triple therapy that includes a parenteral prostacyclin pathway agent. Therapy is escalated according to multiparametric risk assessment at follow-up, and the activin signaling inhibitor sotatercept is added for patients who remain at intermediate or high risk, so that maximal medical therapy now targets four pathways. CTEPH is managed with lifelong anticoagulation and pulmonary endarterectomy, balloon pulmonary angioplasty and/or medical therapy with riociguat. In groups 2 and 3, treatment is directed at the underlying heart or lung disease, and PAH drugs are generally not recommended; inhaled treprostinil for PH associated with interstitial lung disease is the main exception. Lung transplantation remains an option for eligible patients who do not respond adequately to maximal therapy. Survival has improved substantially since the untreated cohorts of the 1980s, but the median survival of PAH from diagnosis remains below 10 years.

Historical Perspective

• In October 1960, a World Health Organization (WHO) expert committee on chronic cor pulmonale met in Geneva, Switzerland. Its report described the hemodynamics of the pulmonary circulation and stated that PH is usually considered to be present when the mean pulmonary artery pressure exceeds 25 mmHg at rest.
• During the following decade, a sudden increase in cases in Switzerland, Germany and Austria was linked to the anorectic agent aminorex fumarate. The lungs of affected patients showed changes identical to those of so-called primary pulmonary hypertension, and the outbreak led the WHO to convene a meeting on primary pulmonary hypertension in Geneva from 15 to 17 October 1973. From this first World Symposium on Pulmonary Hypertension (WSPH) onward, PH was arbitrarily defined as an mPAP ≥25 mmHg at rest.
• The 1973 report prompted the National Institutes of Health (NIH) national prospective registry of primary pulmonary hypertension in the 1980s. In 194 untreated patients, median survival was 2.8 years (95% CI 1.9 to 3.7), and survival was 68%, 48% and 34% at 1, 3 and 5 years.
• In 1996, a 12-week randomized trial of continuous intravenous epoprostenol in 81 patients with severe primary pulmonary hypertension showed improved exercise capacity, quality of life and hemodynamics; all 8 deaths occurred in the group receiving conventional therapy alone (P = 0.003).
• The 1998 World Symposium in Evian, France, introduced the term pulmonary arterial hypertension and grouped the causes of PH into categories that share mechanisms and management. Calcium channel blockers and prostacyclins were proposed for treatment, and atrial septostomy and lung and heart-lung transplantation were in development.
• In 2000, heterozygous germline mutations in BMPR2, which encodes bone morphogenetic protein receptor type 2, were shown to cause familial primary pulmonary hypertension.
• Later symposia in Venice (2003), Dana Point (2008) and Nice (2013 and 2018) refined the classification, published evidence-based treatment algorithms and established sequential and then initial combination therapy for PAH and balloon pulmonary angioplasty for inoperable CTEPH.
• In 2018, the 6th WSPH proposed lowering the mPAP threshold to >20 mmHg, two standard deviations above the mean resting mPAP of 14.0 ± 3.3 mmHg found in a systematic review of 1,187 healthy subjects. The 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines adopted this threshold, lowered the PVR threshold to >2 WU and reintroduced the definition of exercise PH.
• In 2024, sotatercept, the first PAH therapy acting on a new pathway in nearly two decades, received approval from the U.S. Food and Drug Administration (FDA). The 7th WSPH, held in Barcelona, Spain, from 29 June to 1 July 2024 with 1,700 attendees, concluded that maximal medical therapy for PAH is now four-drug therapy.
• In September 2026, an ERS clinical practice guideline update, developed with the GRADE approach, recommended add-on sotatercept, on the basis of high-certainty evidence, for patients with PAH already receiving PAH drugs who are at intermediate-low, intermediate-high or high risk of death during follow-up.

Classification

PH is classified in two complementary ways: hemodynamically, according to RHC findings, and clinically, into five groups whose members share pathophysiological mechanisms, clinical presentation and management. The current definitions are those of the 2022 ESC/ERS guidelines, which the 7th WSPH endorsed in 2024.

Hemodynamic Definitions

Hemodynamic definitions of pulmonary hypertension (2022 ESC/ERS guidelines and 7th WSPH)

Definition	Hemodynamic criteria	Comments
Pulmonary hypertension	mPAP >20 mmHg at rest	Two standard deviations above the mean resting mPAP of healthy subjects
Pre-capillary PH	mPAP >20 mmHg PAWP ≤15 mmHg PVR >2 WU	Characteristic of conditions with pulmonary arterial involvement and no significant left heart disease
Isolated post-capillary PH (IpcPH)	mPAP >20 mmHg PAWP >15 mmHg PVR ≤2 WU	Strongly suggestive of left heart disease
Combined post- and pre-capillary PH (CpcPH)	mPAP >20 mmHg PAWP >15 mmHg PVR >2 WU	Left heart disease with an additional pre-capillary component
Exercise PH	mPAP/cardiac output (CO) slope >3 mmHg/L/min between rest and exercise	Normal resting mPAP; a PAWP/CO slope >2 mmHg/L/min and a PAWP >25 mmHg during exercise are markers of a post-capillary cause
Unclassified PH	mPAP >20 mmHg PAWP ≤15 mmHg PVR ≤2 WU	Often reflects increased pulmonary blood flow; PH therapy is not indicated, and congenital heart disease, liver disease, hyperthyroidism and alcoholism should be sought

• The largest systematic review places the upper limit of normal PAWP at 13 mmHg. The 7th WSPH kept the post-capillary threshold at >15 mmHg, because almost all PAH trials enrolled patients with PAWP up to 15 mmHg and showed efficacy also at 13 to 15 mmHg, and because a PAWP >15 mmHg in patients with an elevated mPAP was associated with increased mortality, mainly due to left heart disease; but it advised that, when PAWP is 12 to 18 mmHg, classification should rest on the whole presentation, including clinical history and cardiovascular risk factors, rather than on a single hemodynamic value.
• PVR is expressed in Wood units; 3 WU corresponds to 240 dyn·s·cm^-5.
• All drugs approved for PAH, CTEPH and PH associated with lung disease were tested in patients who met the earlier definition of pre-capillary PH (mPAP ≥25 mmHg, PAWP ≤15 mmHg and PVR >3 WU), so they should be used only in patients who meet those criteria. Treating early PH (mPAP 21 to 24 mmHg and PVR 2 to 3 WU) with PH drugs is not justified by current trial data.

Clinical Classification

Clinical classification of pulmonary hypertension (7th WSPH, 2024)

Group	Subgroups
Group 1: Pulmonary arterial hypertension (PAH)	1.1 Idiopathic PAH     1.1.1 Long-term responders to calcium channel blockersa 1.2 Heritable PAH 1.3 PAH associated with drugs and toxins 1.4 PAH associated with:     1.4.1 Connective tissue disease     1.4.2 HIV infection     1.4.3 Portal hypertension     1.4.4 Congenital heart disease     1.4.5 Schistosomiasis 1.5 PAH with features of venous/capillary involvement (pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis, PVOD/PCH) 1.6 Persistent pulmonary hypertension of the newborn
Group 2: PH associated with left heart disease	2.1 Heart failure:     2.1.1 With preserved ejection fraction     2.1.2 With reduced or mildly reduced ejection fraction     2.1.3 Cardiomyopathies with specific etiologies (hypertrophic, amyloid, Fabry disease and Chagas disease) 2.2 Valvular heart disease:     2.2.1 Aortic valve disease     2.2.2 Mitral valve disease     2.2.3 Mixed valvular disease 2.3 Congenital or acquired cardiovascular conditions leading to post-capillary PH
Group 3: PH associated with lung diseases and/or hypoxia	3.1 Chronic obstructive pulmonary disease (COPD) and/or emphysema 3.2 Interstitial lung disease 3.3 Combined pulmonary fibrosis and emphysema 3.4 Other parenchymal lung diseases (other than those in group 5) 3.5 Nonparenchymal restrictive diseases:     3.5.1 Hypoventilation syndromes     3.5.2 Pneumonectomy 3.6 Hypoxia without lung disease (high altitude) 3.7 Developmental lung diseases
Group 4: PH associated with pulmonary artery obstructions	4.1 Chronic thromboembolic pulmonary hypertension 4.2 Other pulmonary artery obstructions: sarcomas (high- or intermediate-grade or angiosarcoma), other malignant tumors (renal carcinoma, uterine carcinoma, germ-cell tumors of the testis), nonmalignant tumors (uterine leiomyoma), arteritis without connective tissue disease, congenital pulmonary arterial stenoses and hydatidosis
Group 5: PH with unclear and/or multifactorial mechanisms	5.1 Hematological disorders: inherited and acquired chronic hemolytic anemia and chronic myeloproliferative disorders 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis and neurofibromatosis type 1 5.3 Metabolic disorders: glycogen storage diseases and Gaucher disease 5.4 Chronic renal failure with or without hemodialysis 5.5 Pulmonary tumor thrombotic microangiopathy 5.6 Fibrosing mediastinitis 5.7 Complex congenital heart disease

^a Patients with heritable PAH or PAH associated with drugs and toxins might also be long-term responders to calcium channel blockers.

• The 2024 update kept the five-group structure but re-introduced "long-term responders to calcium channel blockers" as a subgroup of idiopathic PAH (a subgroup created as group 1.5 in 2018 and replaced in 2022 by acute responders and nonresponders at vasoreactivity testing), updated the subgroups of groups 2 and 3, added mitomycin C and carfilzomib to the drugs with a definite association with PAH and added bevacizumab and bortezomib as possible associations.
• Since 2022, groups 2 to 4 are described as PH "associated with" rather than "due to" the underlying condition, because the associated condition may not be sufficient on its own to cause PH and is better regarded as a risk factor acting through complex mechanisms.
• In current registries, as many as 60% to 85% of patients with PAH have cardiopulmonary comorbidities (about 50% in pivotal PAH trials), and age at diagnosis is often >60 years. Severe cardiac or pulmonary comorbidity favors classification in group 2 or 3, but the 7th WSPH did not create a separate PAH subgroup for comorbidities and recommends multimodal assessment (history, echocardiography, magnetic resonance imaging, pulmonary function tests and high-resolution CT) rather than reliance on any single measurement.
• When several conditions predisposing to PH coexist, such as COPD with left heart disease and chronic thromboembolic disease, or systemic sclerosis with PAH, interstitial lung disease and PVOD, the patient is classified by the presumed predominant cause of PH.

Drugs and Toxins Associated with PAH

Drugs and toxins associated with PAH (7th WSPH, 2024)

Definite association	Possible association
Aminorex Benfluorex Carfilzomib Dasatinib Dexfenfluramine Fenfluramine Methamphetamines Mitomycin Cb Toxic rapeseed oil	Alkylating agents Amphetamines Bevacizumab Bortezomib Bosutinib Cocaine Diazoxide Direct-acting antiviral agents against hepatitis C virus (sofosbuvir) Indigo naturalis (Chinese herb Qing-Dai) Interferon-α and -β Leflunomide L-tryptophan Phenylpropanolamine Ponatinib Solvents (trichloroethylene) St John's wort

^b Associated with PAH with features of venous/capillary (PVOD/PCH) involvement.

Functional Classification

World Health Organization functional classification of patients with pulmonary hypertension

Class	Description
I	No limitation of physical activity; ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope
II	Slight limitation of physical activity; comfortable at rest; ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope
III	Marked limitation of physical activity; comfortable at rest; less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope
IV	Inability to carry out any physical activity without symptoms; signs of right heart failure; dyspnea and/or fatigue may be present even at rest, and discomfort is increased by any physical activity

Pathophysiology

Normal Pulmonary Hemodynamics

• The pulmonary circulation is normally a low-pressure, low-resistance system. In a systematic review of RHC data from 1,187 healthy subjects in 47 studies, resting mPAP was 14.0 ± 3.3 mmHg, independent of sex and ethnicity, and rarely exceeded 20 mmHg. During mild exercise, mPAP rose to 19.4 ± 4.8 mmHg in subjects younger than 50 years and to 29.4 ± 8.4 mmHg in those aged 50 years or older.
• Pulmonary arterial pressure depends on pulmonary blood flow (cardiac output), PVR and downstream left atrial pressure, estimated by the PAWP. PVR is calculated as (mPAP - PAWP)/cardiac output, so PH can arise from increased resistance of the pulmonary vascular bed (pre-capillary PH), from increased left-sided filling pressures (post-capillary PH) or, with a normal PVR and PAWP, mainly from increased pulmonary blood flow (unclassified PH).

Pulmonary Vascular Remodeling

• Remodeling of the pulmonary vasculature is a hallmark shared by all forms of PH and mainly affects the distal pulmonary circulation: the arterioles in PAH, and the small to medium-sized veins and capillaries in PVOD, PCH and PH associated with left heart disease. These changes increase PVR and, in turn, the load on the right ventricle.
• In idiopathic PAH, four lesions are consistently observed: plexiform lesions, obliterative lesions, intimal-medial hypertrophy and adventitial remodeling. Plexiform lesions are a hallmark of PAH and are frequent in idiopathic and heritable PAH; some form connections with bronchial arteries and vasa vasorum that may relieve suprasystemic pressure but cause desaturation through shunting. Loss of small vessels (vascular rarefaction) also contributes to the rise in PVR.
• A key feature is the accumulation of vascular and immune cells within and around the vessel walls. High shear stress, chronic hypoxia, genetic predisposition and dysregulation of the transforming growth factor beta (TGF-β) family contribute, and patients with PAH already have established, potentially irreversible vascular lesions at diagnosis.

Cellular and Molecular Mechanisms

• Endothelial dysfunction and vasoactive mediators: remodeling is driven in part by changes in the secretion of vasoconstrictors and vasodilators by pulmonary endothelial cells. Most approved PAH therapies target three dysfunctional pathways: endothelin-1 (blocked by ERAs), nitric oxide-cyclic GMP (enhanced by PDE5 inhibitors and soluble guanylate cyclase stimulators) and prostacyclin-cyclic AMP (stimulated by prostacyclin pathway agents), whose modulation produces vasodilation and inhibits vascular cell growth.
• BMP and activin signaling: loss of bone morphogenetic protein receptor type II (BMPR-II) expression, together with an overabundance of the activin and TGF-β receptors ALK2, ALK4, ALK5, ACTRIIA and ACTRIIB, shifts signaling toward phosphorylated Smad2/3. Serum and lung levels of activin A, activin B, follistatin and follistatin-like 3 are increased in PAH, and elevated activin A and follistatin-like 3 predict death or lung transplantation. Sotatercept, a soluble ACTRIIA-IgG Fc construct that traps activins and related growth factors, rebalances this signaling.
• Growth factors and proliferation: receptor tyrosine kinases for epidermal, vascular endothelial, platelet-derived and fibroblast growth factors are upregulated and overactivated in vascular wall cells, and cells with features intermediate between smooth muscle cells and adventitial fibroblasts interact abnormally with immune cells.
• Inflammation and immunity: neutrophils, T cells and dendritic cells have been implicated in vascular pathology, and the proportion of regulatory T cells is reduced.
• Metabolism, ion channels and epigenetics: metabolic reprogramming (for example, an enlarged acetyl-CoA pool that drives histone acetylation and cell proliferation), the potassium channel KCNK3 (TASK-1), which sets the membrane potential of pulmonary arterial smooth muscle cells, and epigenetic changes in histone acetylation and methylation and DNA methylation all contribute to remodeling. In experimental models, accumulation of DNA damage and cellular senescence distinguished remodeled lungs that failed to reverse.
• Sex and sex hormones: female-to-male ratios range from 2.3:1 in idiopathic PAH to 9:1 in connective tissue disease-associated PAH, yet men have a worse prognosis, mainly because of differences in RV adaptation. Estrogens appear to have a dual role, promoting remodeling locally while protecting the right ventricle systemically; lowering estradiol with anastrozole did not improve 6MWD at 6 months in PHANTOM, a randomized, placebo-controlled phase 2 trial in 84 postmenopausal women and men with PAH (placebo-corrected effect -7.9 m; 95% CI -32.7 to 16.9).

Genetics

• Since heterozygous germline mutations in BMPR2 were linked to familial PAH in 2000, rare variants in more than 20 genes have been associated with PAH; nevertheless, genetic testing explains only about 25% of cases of idiopathic PAH.
• An international panel using the ClinGen framework classified 12 genes as having definitive evidence (ACVRL1, ATP13A3, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17 and TBX4), 3 as moderate (ABCC8, GGCX and TET2), 6 as limited and 5 as disputed; disputed genes should not be included in testing panels. ACVRL1 and ENG cause PAH associated with hereditary hemorrhagic telangiectasia.
• Most PAH genes are inherited in an autosomal dominant fashion with incomplete penetrance. The penetrance of BMPR2 mutations is about three times higher in women (42%) than in men (14%), and in the prospective DELPHI-2 study of 55 asymptomatic BMPR2 mutation carriers, the incidence of PAH was 2.3% per year (0.99% in men and 3.5% in women).
• Biallelic (autosomal recessive) mutations in EIF2AK4 cause heritable PVOD; they segregated with disease in all 13 families studied and were found in 5 of 20 sporadic cases.
• Whole-genome sequencing of 1,038 patients identified ATP13A3, AQP1 and SOX17 as PAH genes and validated GDF2, which encodes BMP-9. GDF2 variants occur in 0.8% to 1.2% of patients of European descent and in 6.7% of patients of Asian descent, and they reduce circulating BMP-9. Rare loss-of-function SOX17 variants may account for up to 3% of PAH associated with congenital heart defects, and genome-wide association identified common risk loci at SOX17 and HLA-DPA1/DPB1.
• Children with PAH carry a higher burden of germline rare variants than adults; about 15% of pediatric-onset cases are attributable to de novo variants (variants not inherited from either parent).

Pathophysiology in Other Clinical Groups

• Group 2 (left heart disease): elevated left-sided filling pressures are transmitted backward into the pulmonary circulation (post-capillary PH). In some patients, remodeling of the pulmonary veins, venules and arteries adds a pre-capillary component (CpcPH), identified by a PVR >2 WU; in PH associated with HFpEF, pulmonary veins and venules may become muscularized to the point of arterialization. Low pulmonary arterial compliance is associated with adverse outcomes even when PVR is <2 WU.
• Group 3 (lung disease and/or hypoxia): chronic hypoxia, vascular remodeling and loss of small vessels contribute. COPD-associated PH shows medial hypertrophy and new muscularization of small arterioles, and in idiopathic pulmonary fibrosis, interstitial fibrosis and pulmonary arterial remodeling often coexist; patients with severe PH show more microvascular remodeling than those with moderate or no PH. Plexiform lesions are generally absent in PH associated with lung disease.
• Group 4 (CTEPH): PVR rises because of unresolved, organized fibrothrombotic material in the pulmonary arteries and a secondary microvasculopathy. Microvasculopathy is suspected when the extent of mechanical obstruction does not match the hemodynamic severity; it is the target of PH drugs, whereas the obstruction is the target of pulmonary endarterectomy and balloon pulmonary angioplasty. Remodeling of pre- and post-capillary microvessels reflects increased shear stress and pressure rather than embolism.
• Group 5: mechanisms are multiple. In sarcoidosis, for example, hypoxemia, interstitial fibrosis, vascular remodeling resembling PAH and PVOD and compression of vessels by granulomas may all contribute.

Right Ventricular Adaptation and Failure

• The right ventricle and its response to increased afterload are perhaps the most important determinant of survival in PH of many causes. RV hypertrophy initially reduces wall stress and preserves coupling between RV contractility and arterial load. When contractility can no longer increase sufficiently, RV-pulmonary arterial uncoupling raises the RV end-systolic volume and then lowers the RV ejection fraction; RV end-diastolic dilatation may maintain stroke volume for a time, at the cost of higher wall stress, and progressive RV dilatation impairs left ventricular filling through ventricular interdependence.
• A combination of high RV volume with low RV mass, a pattern more frequent in older patients, is associated with worse outcomes and less adaptive remodeling during PAH therapy.
• Chronic right heart failure, with systemic venous congestion and, in advanced stages, low cardiac output, is the principal cause of death in PAH.

Causes

PH is a hemodynamic state rather than a single disease, and its causes are organized by the five clinical groups (see Classification).

Common Causes

• Left heart disease: heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, cardiomyopathies (hypertrophic, amyloid, Fabry disease and Chagas disease) and aortic or mitral valve disease.
• Lung disease and/or hypoxia: COPD and emphysema, interstitial lung disease, combined pulmonary fibrosis and emphysema, hypoventilation syndromes and chronic exposure to high altitude.
• Together, groups 2 and 3 account for 90% to 95% of PH worldwide.

Causes of Pulmonary Arterial Hypertension

• Idiopathic PAH: no identifiable cause or family history; genetic testing finds a causal variant in about 25% of patients classified as idiopathic.
• Heritable PAH: mutations in BMPR2 and other genes with definitive evidence (ACVRL1, ATP13A3, CAV1, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17 and TBX4); biallelic EIF2AK4 mutations cause heritable PVOD/PCH.
• Drugs and toxins: appetite suppressants (aminorex, fenfluramine, dexfenfluramine and benfluorex), methamphetamines, dasatinib, carfilzomib, mitomycin C (with PVOD/PCH features) and toxic rapeseed oil have a definite association. Stimulant-associated PAH is the most common form of drug- or toxin-associated PAH in the current era.
• Connective tissue disease: the most frequently associated conditions are systemic sclerosis (the best studied), mixed or overlap connective tissue disease and systemic lupus erythematosus.
• HIV infection: HIV is itself a risk factor for PAH, and a low CD4+ cell count and a high viral load predicted PH in veterans with HIV.
• Portal hypertension (portopulmonary hypertension): PAH in the setting of portal hypertension, with or without cirrhosis and across all Child-Pugh classes.
• Congenital heart disease: four subtypes have been recognized (Eisenmenger syndrome, PAH with persistent systemic-to-pulmonary shunts, PAH with small or coincidental defects and PAH after defect repair), and the 7th WSPH pediatric task force proposed a fifth group (E) for patients with congenital heart disease who never had a left-to-right shunt or had one for less than 1 to 2 weeks after birth, such as children with transposition of the great arteries repaired by a neonatal arterial switch operation.
• Schistosomiasis: usually in the setting of severe hepatosplenic schistosomiasis; one of the most common causes of PAH worldwide.

Causes of Chronic Thromboembolic and Other Obstructive PH (Group 4)

• CTEPH is caused by unresolved, organized fibrothrombotic material obstructing the pulmonary arteries, together with a secondary microvasculopathy.
• Other pulmonary artery obstructions include pulmonary artery sarcoma and other tumors, arteritis without connective tissue disease, congenital pulmonary artery stenoses and hydatid cysts.

Causes of PH with Unclear and/or Multifactorial Mechanisms (Group 5)

• Chronic hemolytic anemias (including sickle cell disease) and myeloproliferative disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1, glycogen storage diseases, Gaucher disease, chronic kidney failure with or without hemodialysis, pulmonary tumor thrombotic microangiopathy, fibrosing mediastinitis and complex congenital heart disease.

Causes of Unclassified PH

• An elevated mPAP with normal PVR (≤2 WU) and PAWP (≤15 mmHg) usually reflects high pulmonary blood flow; congenital heart disease, liver disease, hyperthyroidism and alcoholism should be sought.

Differentiating Pulmonary hypertension from other Diseases

The symptoms of PH (exertional dyspnea, fatigue, syncope and edema) overlap with those of left heart disease, chronic lung disease, chronic thromboembolic disease and deconditioning. Two questions guide the differential diagnosis: whether PH is present, which only RHC can confirm, and to which clinical group it belongs, because treatment differs fundamentally between groups. Classification should be based on multimodal assessment (history, echocardiography, pulmonary function tests including DLCO, chest CT, V/Q scanning and, when needed, provocative hemodynamic testing) rather than on any single parameter.

Differentiating PAH from PH Associated with Left Heart or Lung Disease

Features that help distinguish PAH from PH associated with left heart disease (group 2) and lung disease (group 3)

Feature	PAH (group 1)	PH associated with left heart disease (group 2)	PH associated with lung disease (group 3)
Clinical context	Risk factors for PAH (connective tissue disease, HIV, portal hypertension, congenital heart disease, drugs and toxins, family history); classical idiopathic PAH affects younger patients without cardiopulmonary comorbidities	Older age, obesity, systemic hypertension, diabetes, atrial fibrillation, coronary artery disease, sleep apnea, valvular or myocardial disease	Smoking history, COPD, emphysema, interstitial lung disease, hypoventilation, residence at high altitude
Echocardiography	Signs of RV pressure overload without the left heart abnormalities typical of group 2	Left atrial enlargement, grade 2 or higher diastolic dysfunction, reduced LV ejection fraction or left-sided valve disease	RV changes; signs of PH may be disproportionate to lung function in the pulmonary vascular phenotype
Lung function and CT	Normal or mildly abnormal pulmonary function tests and gas exchange	Often coexists with lung disease: in one deeply phenotyped cohort, 57% of patients with group 2 PH also had features of group 3	Significant airflow obstruction, restriction or parenchymal disease (fibrosis, emphysema) on high-resolution CT; DLCO often markedly reduced
Hemodynamics	PAWP ≤15 mmHg and PVR >2 WU	PAWP >15 mmHg (IpcPH if PVR ≤2 WU, CpcPH if PVR >2 WU); a PAWP of 12 to 15 mmHg with a PVR of 3 to 5 WU, or a PAWP >18 mmHg after fluid challenge, suggests occult left heart disease	Mostly pre-capillary, but post-capillary PH occurs in 5% to 20% of patients with interstitial lung disease; in COPD, severe PH is defined by a PVR >5 WU, whereas in interstitial lung disease severity is better viewed as a continuum
Response to PAH therapy	Established benefit	No proven benefit; possible harm, including fluid retention and pulmonary edema	Benefit shown only for inhaled treprostinil in interstitial lung disease; harm with riociguat in idiopathic interstitial pneumonia, ambrisentan in idiopathic pulmonary fibrosis and inhaled treprostinil in COPD

• Left heart disease: establishing the pre-test probability of left heart disease is the first step. Scores such as H₂FPEF and HFA-PEFF help estimate the likelihood of HFpEF but have not been validated to discriminate PAH from PH associated with left heart disease, so invasive hemodynamic evaluation is still required in most cases. The H₂FPEF score combines obesity, atrial fibrillation, age >60 years, treatment with two or more antihypertensives, an echocardiographic E/e' ratio >9 and an echocardiographic pulmonary artery systolic pressure >35 mmHg into a weighted score of 0 to 9; the odds of HFpEF doubled with each point (OR 1.98; 95% CI 1.74 to 2.30), with an area under the curve of 0.841 in the derivation and 0.886 in the validation cohort.
• The PAWP "grey zone" is probably 12 to 15 mmHg and may extend to 18 mmHg. Diuretics lower left atrial pressure and may mask left heart disease, and a fluid challenge (500 mL of saline or 7 mL/kg over 5 to 10 minutes, with a PAWP >18 mmHg considered positive) or exercise testing may unmask it.
• Lung disease: in former or current smokers with a DLCO <45% of predicted, high-resolution CT should be performed, and significant abnormalities of lung function or parenchymal disease favor classification in group 3. Patients classified as idiopathic PAH who have a DLCO <45% of predicted and a smoking history (the "lung phenotype") are older and more often male, respond less to PAH therapy and resemble patients with group 3 PH more than those with classical idiopathic PAH.
• A "pulmonary vascular phenotype" of COPD is characterized by severe PH, only moderate airflow limitation, no hypercapnia, a severely reduced diffusing capacity and a circulatory limitation to exercise or progressive RV failure; such patients should be referred to a PH center.

Differentiating PAH from Other Forms of Pre-capillary PH

Conditions to distinguish from PAH in patients with pre-capillary PH

Condition	Distinguishing features	Key investigations
Chronic thromboembolic pulmonary hypertension	History of venous thromboembolism (particularly recurrent or unprovoked), antiphospholipid syndrome, splenectomy or ventriculoatrial shunts	Mismatched perfusion defects on V/Q scan (sensitivity 96% to 97.4%, compared with 51% for CTPA); CTPA shows webs, bands, occlusions or mosaic perfusion; confirmation by RHC and pulmonary angiography
Pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis	More often men and smokers; lower PaO2, DLCO/VA and oxygen saturation nadir during the 6-minute walk test; exposure to mitomycin C; biallelic EIF2AK4 mutations	Septal lines, centrilobular ground-glass opacities and mediastinal lymphadenopathy on CT; pulmonary edema after the start of PAH therapy (43.8% in one series)
Pulmonary artery sarcoma and other obstructions	Mimic proximal chronic thromboembolic obstruction; arteritis, congenital stenoses and hydatid disease are other causes	CTPA, perfusion imaging and specialist review at an expert center
Sarcoidosis, pulmonary Langerhans cell histiocytosis and other group 5 conditions	Systemic disease; multifactorial mechanisms including parenchymal disease, vascular involvement and extrinsic compression	Chest CT, pulmonary function tests, disease-specific workup; referral to a PH center for phenotyping
High-flow states (unclassified PH)	Elevated mPAP with normal PVR (≤2 WU) and PAWP (≤15 mmHg)	Search for congenital shunts, liver disease, hyperthyroidism and alcoholism; measurement of cardiac output and oxygen saturations at RHC

Acute Pulmonary Embolism and Chronic Thromboembolic Disease

• Signs of pre-existing CTEPH on a CTPA performed for suspected acute pulmonary embolism include an enlarged pulmonary artery with intravascular webs or bands, mosaic perfusion and hypertrophy of the bronchial arteries and the right ventricle. Acute pulmonary embolism and its follow-up are addressed by the 2019 ESC and 2026 AHA/ACC guidelines.

Epidemiology and Demographics

Prevalence and Incidence

• PH is common in aggregate: its prevalence is estimated at about 1% of the global population, rising to up to 10% in people older than 65 years. Left heart disease and lung disease are the leading causes in almost all parts of the world, and about 80% of affected patients live in developing countries, where PH is often associated with congenital heart disease, schistosomiasis, HIV infection and rheumatic heart disease.
• Groups 2 and 3 account for 90% to 95% of PH cases worldwide. Most of these patients have mild to moderate PH, but severe PH with pulmonary vascular involvement disproportionate to the underlying condition affects about 1% to 10% of patients with left heart or lung disease.
• In an echocardiography-based study in Armadale, Australia, the minimum prevalence of PH (estimated pulmonary artery systolic pressure >40 mmHg) was 326 per 100,000 inhabitants, including 250 per 100,000 attributable to left heart disease and 15 per 100,000 with PAH.
• In a population-based cohort of 50,529 patients with groups 1 to 4 PH in Ontario, Canada, the annual adult incidence rose from 24.1 to 28.7 per 100,000 between 2003 and 2012, and prevalence rose from 99.8 to 127.3 per 100,000 between 1993 and 2012. Group 2 PH was the most common form (34.2% alone and 29.3% combined with group 3).
• PAH is rare. In a systematic review of the global disease burden, the mean reported prevalence of RHC-confirmed PAH was 3.7 cases per 100,000. The Global Burden of Disease Study 2021 estimated 192,000 (95% uncertainty interval [UI] 155,000 to 236,000) prevalent PAH cases worldwide, an age-standardized prevalence of 2.28 per 100,000 (95% UI 1.85 to 2.80) and 22,000 deaths attributable to PAH in 2021; age-standardized years of life lost improved by 38.2% compared with 1990.
• The French national registry (674 patients) estimated a PAH prevalence of 15.0 cases per million adults and an incidence of 2.4 cases per million adults per year; the authors considered these low estimates.
• CTEPH develops in a minority of patients after acute pulmonary embolism: a meta-analysis found an incidence of 0.56% in all comers, 3.2% in survivors and 2.8% in survivors without major comorbidities, and the prospective FOCUS study found a 2-year incidence of 2.3%.

PH in Left Heart and Lung Disease

• Rheumatic heart disease is the most common risk factor for PH associated with left heart disease worldwide. At least moderately elevated pulmonary pressures are present in 53% of patients with aortic stenosis, and in a cohort of 132 patients with cardiac amyloidosis, 76% had an mPAP >20 mmHg, mostly with CpcPH.
• In COPD, PH was present in 39.2% of patients in a meta-analysis of 38 studies; its prevalence is about 5% in GOLD stages 1 and 2, whereas up to 90% of patients with severe COPD have an mPAP >20 mmHg, mostly between 20 and 35 mmHg.
• Among 8,991 patients with idiopathic pulmonary fibrosis listed for lung transplantation in the United States, PH was present in 73.6% by the 2018 definition and in 47.6% by the previous definition. PH occurs in 30% to 50% of patients with combined pulmonary fibrosis and emphysema and in 3% to 5% of patients with sarcoidosis.

Distribution of PAH Subtypes

• In the French registry, PAH was idiopathic in 39.2% of patients, familial in 3.9%, associated with anorexigens in 9.5%, connective tissue disease in 15.3%, congenital heart disease in 11.3%, portal hypertension in 10.4% and HIV infection in 6.2%; 75% of patients were in New York Heart Association class III or IV at diagnosis.
• HIV-associated PAH has become less frequent in well-resourced countries, representing about 7% of newly diagnosed PAH cases in the French registry in 2008 and less than 3% in 2021.
• Portopulmonary hypertension accounts for about 5% to 15% of patients with PAH in the United States, France and Japan, and PAH develops in 2% to 6% of patients with portal hypertension.
• PAH develops in 8% to 12% of patients with systemic sclerosis, and connective tissue disease-associated PAH is the second-largest subgroup in PAH trials after idiopathic PAH (30% to 40% of participants).
• Schistosomiasis-associated PAH is one of the most common causes of PAH worldwide.

Age

• In the U.S. REVEAL registry, the 2,525 adults who met the traditional hemodynamic definition (of 2,967 patients enrolled) had a mean age of 53 ± 14 years.
• The age at diagnosis has increased: in contemporary registries it is often >60 years, which increases the likelihood of coexisting cardiopulmonary disease. In the European COMPERA registry, incident idiopathic PAH (587 patients) was diagnosed at a median age of 71 years.

Gender

• PAH predominantly affects women: 79.5% of these REVEAL patients were women, and 62% of prevalent PAH cases worldwide in the Global Burden of Disease Study 2021 were female.
• The female predominance is less pronounced in older patients: in COMPERA, the female-to-male ratio of idiopathic PAH was 2.3:1 in patients aged 18 to 65 years and 1.2:1 in patients older than 65 years.

Developed and Developing Countries

• In developing countries, PH is more often associated with congenital heart disease, schistosomiasis, HIV infection and rheumatic heart disease, and these forms predominantly affect people younger than 65 years.

Risk Factors

Pulmonary Arterial Hypertension

• Female sex: PAH is more common in women, with female-to-male ratios from 2.3:1 in idiopathic PAH to 9:1 in connective tissue disease-associated PAH.
• Genetic predisposition and family history: BMPR2 mutation carriers have a penetrance of about 42% in women and 14% in men, and asymptomatic carriers developed PAH at a rate of 2.3% per year in DELPHI-2.
• Drug and toxin exposure: appetite suppressants, methamphetamine and other stimulants, and certain anticancer agents (see Classification). In California hospital data, hospitalized (meth)amphetamine users had a 2.6-fold higher risk of a PAH diagnosis. The lowest estimate of the incidence of PH among dasatinib-exposed patients in France was 0.45%.
• Systemic sclerosis: 8% to 12% of patients develop PAH.
• Portal hypertension: PAH develops in 2% to 6% of patients with portal hypertension.
• HIV infection, particularly with a low CD4+ count and high viral load.
• Congenital heart disease with systemic-to-pulmonary shunts and schistosomiasis in endemic regions.

Chronic Thromboembolic Pulmonary Hypertension

• Characteristics of the pulmonary embolism: recurrent venous thromboembolism (OR 3.2; 95% CI 1.7 to 5.9) and unprovoked pulmonary embolism (OR 4.1; 95% CI 2.1 to 8.2) were associated with a higher risk of CTEPH.
• Thrombotic risk factors: antiphospholipid syndrome, present in about 10% of patients with CTEPH, and increased factor VIII. CTEPH occurs in 3.8% of patients with antiphospholipid syndrome.
• Medical conditions: splenectomy, chronic inflammatory disorders, ventriculoatrial shunts, infections and cancer; non-O blood groups are also associated with CTEPH.

PH Associated with Left Heart and Lung Disease

• Older age, systemic hypertension, diabetes, obesity, sleep apnea, atrial fibrillation and coronary artery disease increase the likelihood of left heart disease as the cause of PH.
• Smoking and chronic lung disease are risk factors for group 3 PH; a DLCO <45% of predicted with a history of smoking identifies a "lung phenotype" with a poor prognosis even when PH is classified as idiopathic PAH.
• Residence at high altitude causes hypoxic PH (group 3.6).

Screening

Screening of asymptomatic people is recommended only in groups with a high probability of developing PAH. In these groups, annual echocardiography, ECG and NT-proBNP (or BNP) are considered valuable screening tools.

Screening for pulmonary hypertension in high-risk groups

Population	Recommendation
Systemic sclerosis spectrum disorders	Systematic screening; annual echocardiography, ECG and NT-proBNP; the DETECT algorithm can be applied to patients who meet its inclusion and exclusion criteria
BMPR2 mutation carriers	Systematic screening with annual echocardiography, ECG and NT-proBNP
First-degree relatives of patients with heritable PAH	Systematic screening with annual echocardiography, ECG and NT-proBNP
Patients assessed for liver transplantation or a transjugular intrahepatic portosystemic shunt	Screening for portopulmonary hypertension
Other connective tissue diseases, portal hypertension and HIV infection	Lower risk; screening of asymptomatic patients is not recommended, but PH should be investigated promptly when symptoms appear

Systemic Sclerosis

• The DETECT study (466 patients with systemic sclerosis at increased risk, PAH confirmed by RHC in 19%) developed a two-step algorithm that missed 4% of PAH cases, compared with 29% using the echocardiography-based ESC/ERS criteria of the time.
• Earlier recommendations advised screening all patients with systemic sclerosis and scleroderma spectrum disorders with pulmonary function tests including DLCO, transthoracic echocardiography and NT-proBNP, with annual echocardiography and pulmonary function tests.
• Screening detects milder disease: in two French incident cohorts of 16 patients each, systemic sclerosis-associated PAH found by a detection program was less advanced at diagnosis than PAH diagnosed during routine care, and 8-year survival was 64% vs 17% (an observational comparison).

Genetic Testing and Relatives

• Genetic testing should be offered to adults with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease, PVOD/PCH and drug- or toxin-associated PAH, using a panel of genes with definitive or moderate evidence. Testing of a family should ideally begin with the affected patient; negative results in an unaffected relative are otherwise uninformative.
• Testing of asymptomatic relatives should be performed by a genetic counselor or medical geneticist and should include discussion of surveillance, treatment, prognosis and reproductive options; relatives may choose not to know their genetic status.
• In DELPHI-2, yearly screening of 55 asymptomatic BMPR2 mutation carriers detected PAH at a rate of 2.3% per year; all cases remained at low risk on oral therapy.

Portopulmonary Hypertension

• Patients with liver disease being evaluated for liver transplantation or a transjugular intrahepatic portosystemic shunt should be screened for portopulmonary hypertension, because the severity of PH determines eligibility for liver transplantation.

After Acute Pulmonary Embolism

• Systematic follow-up after acute pulmonary embolism may allow earlier diagnosis of CTEPH, and a V/Q scan is the first-line test in patients with persistent dyspnea or functional limitation and an echocardiographic high probability of PH.
• In the FOCUS cohort (1,017 patients), the 2-year cumulative incidence of post-PE impairment was 16.0%, and this finding identified 15 of the 16 patients who were diagnosed with CTEPH.
• Signs of pre-existing CTEPH may already be visible on the CT pulmonary angiogram performed for suspected acute PE: an enlarged pulmonary artery with intravascular bands or webs, mosaic perfusion and hypertrophy of the bronchial arteries and the right ventricle.
• In patients with antiphospholipid syndrome, active assessment for CTEPH may be considered.

Sickle Cell Disease

• In adults with sickle cell disease, a tricuspid regurgitant jet velocity ≥2.5 m/s, an NT-proBNP ≥160 pg/mL or RHC-confirmed PH identifies patients at increased risk of death.

Emerging Tools

• Artificial intelligence applied to the ECG and to echocardiography is being evaluated for earlier detection of PH.

Natural History, Complications and Prognosis

Natural History

• PH is usually progressive. A sustained rise in RV afterload leads to RV hypertrophy and dilatation, and when RV contractility can no longer match the afterload (RV-pulmonary arterial uncoupling), cardiac output falls and right heart failure develops. RV failure is the principal cause of death in PAH.
• Untreated idiopathic ("primary") PAH carried a median survival of 2.8 years (95% CI 1.9 to 3.7) in the NIH registry of the 1980s, with survival of 68%, 48% and 34% at 1, 3 and 5 years.
• In groups 2 and 3, the presence of PH, and particularly of an elevated PVR, is associated with more severe disease and higher mortality.

Complications

• Right heart failure with cardiogenic shock, hospitalization for clinical worsening and death; PAH-related hospitalization is a major component of clinical worsening events in contemporary trials.
• Supraventricular arrhythmias, which can trigger acute decompensation of right heart failure (see Acute Decompensated Right Heart Failure).
• Perioperative RV decompensation and cardiogenic shock, arrhythmias, cardiac arrest, need for prolonged mechanical support or extracorporeal membrane oxygenation, and death. In a prospective survey of 114 patients with PH undergoing major surgery, perioperative mortality was 3.5% overall, 15% for emergency procedures and 2% for nonemergency procedures.
• Maternal death and fetal or neonatal loss in pregnancy (see Special Populations).
• Life-threatening pulmonary edema after the start of PAH therapy in patients with PVOD/PCH; pulmonary edema developed in 43.8% of patients with histologically confirmed PVOD who received PAH therapy.
• Treatment-related complications, such as central venous catheter-related sepsis with continuous intravenous epoprostenol, life-threatening deterioration after abrupt interruption of parenteral prostacyclin therapy, and bleeding events and telangiectasias with sotatercept.

Prognosis

Survival in the Treatment Era

• In 2,635 patients in the U.S. REVEAL registry, survival from the diagnostic RHC was 85%, 68%, 57% and 49% at 1, 3, 5 and 7 years. In idiopathic or familial PAH, survival was 91%, 74%, 65% and 59%, compared with 68%, 47%, 36% and 32% predicted by the NIH registry equation.
• In incident patients with idiopathic, familial or anorexigen-associated PAH in France, survival was 85.7%, 69.6% and 54.9% at 1, 2 and 3 years; female sex, a longer 6-minute walk distance (6MWD) and a higher cardiac output were associated with better survival.
• In the U.S. Pulmonary Hypertension Association Registry (935 patients enrolled from 2015 to 2020), mortality was 8%, 16% and 21% at 1, 2 and 3 years, and initial combination therapy in treatment-naive patients was associated with better 1-year survival (adjusted HR 0.43; 95% CI 0.19 to 0.95).
• In 1,655 patients with PAH in the European COMPERA registry (2009 to 2020), Kaplan-Meier survival was 91.1%, 70.7% and 55.2% at 1, 3 and 5 years after diagnosis. Although survival from diagnosis is improving, the median survival of PAH remains below 10 years.

Prognosis by Clinical Group and Subtype

• In 1,344 treatment-naive patients diagnosed by catheterization at a UK referral center (ASPIRE), 3-year survival was 68% in PAH, 73% in PH associated with left heart disease, 44% in PH associated with lung disease, 71% in CTEPH and 59% in miscellaneous PH. Within PH associated with lung disease, 3-year survival was 90% for sleep disorders or alveolar hypoventilation, 41% for COPD and 16% for interstitial lung disease. Within PAH, survival in Eisenmenger syndrome was better than in idiopathic PAH, which was better than in systemic sclerosis-associated PAH.
• Systemic sclerosis-associated PAH has the worst outcome of the connective tissue disease subgroups, although median survival has improved and approaches 8 years.
• Idiopathic PAH is heterogeneous. Patients with a "lung phenotype" (diffusing capacity of the lung for carbon monoxide [DLCO] <45% of predicted and a history of smoking) had 5-year survival of 31% in COMPERA and 21% in ASPIRE, compared with 84% and 80% in classical idiopathic PAH. In a cluster analysis of COMPERA, 5-year survival was 84.6% in young, predominantly female patients without comorbidities, 59.2% in elderly women with comorbidities and 42.2% in elderly, predominantly male smokers with a low DLCO.
• Methamphetamine-associated PAH carried more than twice the risk of clinical worsening or death of idiopathic PAH (HR 2.04; 95% CI 1.28 to 3.25).
• In HIV-associated PAH in the modern treatment era, survival was 88% at 1 year and 72% at 3 years; a cardiac index >2.8 L/min/m² and a CD4+ count >200 cells/µL predicted survival.
• In schistosomiasis-associated PAH, survival at 1, 2 and 3 years was 95.1%, 95.1% and 85.9%, even though none of the patients received PAH-specific therapy.
• In PAH associated with congenital heart disease, 20-year survival was 87% in Eisenmenger syndrome and 86% in patients with systemic-to-pulmonary shunts, but 36% in patients with PAH after defect correction.
• In CTEPH, 3-year survival in an international registry was 89% in operated and 70% in not-operated patients; with contemporary multimodal therapy, 3-year survival exceeds 90%.
• In PH associated with interstitial lung disease, survival in COMPERA was 73.3%, 51.2% and 34.1% at 1, 2 and 3 years, and in an international registry, severe PH (PVR >5 WU) was associated with survival of 29% at 3 years and 18% at 5 years. In COPD, PVR is the strongest independent hemodynamic predictor of mortality.
• In HFpEF, the risk of death increases approximately two-fold with an mPAP >30 mmHg and 1.5-fold with a PVR >3.0 WU. In mitral stenosis, PVR fails to normalize in about 40% of patients with symptomatic severe disease after successful intervention.

Prognostic Relevance of Mild and Exercise PH

• In 21,727 U.S. veterans who underwent RHC, mortality rose from an mPAP of 19 mmHg; compared with an mPAP ≤18 mmHg, the adjusted HR for death was 1.23 (95% CI 1.12 to 1.36) for an mPAP of 19 to 24 mmHg and 2.16 (95% CI 1.96 to 2.38) for an mPAP ≥25 mmHg.
• In 40,082 veterans, mortality rose from a PVR of about 2.2 WU, and in patients with mPAP ≥19 mmHg and PAWP ≤15 mmHg, a PVR ≥2.2 WU was associated with an adjusted HR for death of 1.71 (95% CI 1.59 to 1.84).
• In 2,929 patients referred to UK PH centers, a mildly elevated mPAP (21 to 24 mmHg; HR 1.36, 95% CI 1.14 to 1.61) or PVR (>2 to ≤3 WU; HR 1.28, 95% CI 1.10 to 1.49) was associated with lower survival, independent of comorbid heart and lung disease. In contrast, in 1,097 patients with mild PH in an international registry, neither mPAP nor PVR predicted mortality, whereas arterial elastance, pulmonary artery compliance, stroke volume index and heart rate did.
• Exercise PH is prognostically relevant: an mPAP/CO slope >3 mmHg/L/min was associated with cardiovascular hospitalization or death in 714 patients with exertional dyspnea (HR 2.03; 95% CI 1.48 to 2.78) and with mortality in 764 patients with a resting mPAP <25 mmHg (HR 2.04; 95% CI 1.16 to 3.58).
• In post-capillary PH associated with heart failure, lowering the PVR threshold from 3 to 2 WU increased the prevalence of CpcPH by 60%, and CpcPH was associated with worse survival than IpcPH, with an optimal prognostic threshold of about 2.2 WU. An earlier cohort of 2,817 patients found similar adjusted mortality for CpcPH and IpcPH when CpcPH was defined by the diastolic pressure gradient (HR 1.14; 95% CI 0.96 to 1.35).

Risk Stratification in PAH

No single variable gives sufficient prognostic information, so risk is assessed with multiparametric tools. WHO functional class, 6MWD and brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) are the most consistent predictors and form the core of every validated tool. The ESC/ERS approach uses a three-strata model at diagnosis and a simplified four-strata model at follow-up; REVEAL 2.0 and REVEAL Lite 2 can be used interchangeably with the European tools.

Three-strata risk assessment at diagnosis (2022 ESC/ERS guidelines)

Determinant	Low risk	Intermediate risk	High risk
Estimated 1-year mortality	<5%	5% to 20%	>20%
Clinical signs of right heart failure	Absent	Absent	Present
Progression of symptoms	No	Slow	Rapid
Syncope	No	Occasional	Repeated
WHO functional class	I, II	III	IV
6MWD	>440 m	165 to 440 m	<165 m
Cardiopulmonary exercise testing	Peak VO2 >15 mL/min/kg (>65% predicted) VE/VCO2 slope <36	Peak VO2 11 to 15 mL/min/kg (35% to 65% predicted) VE/VCO2 slope 36 to 44	Peak VO2 <11 mL/min/kg (<35% predicted) VE/VCO2 slope >44
Biomarkers	BNP <50 ng/L NT-proBNP <300 ng/L	BNP 50 to 800 ng/L NT-proBNP 300 to 1,100 ng/L	BNP >800 ng/L NT-proBNP >1,100 ng/L
Echocardiography	Right atrial area <18 cm2 TAPSE/sPAP >0.32 mm/mmHg No pericardial effusion	Right atrial area 18 to 26 cm2 TAPSE/sPAP 0.19 to 0.32 mm/mmHg Minimal pericardial effusion	Right atrial area >26 cm2 TAPSE/sPAP <0.19 mm/mmHg Moderate or large pericardial effusion
Cardiac magnetic resonance imaging	RV ejection fraction >54% Stroke volume index >40 mL/m2 RV end-systolic volume index <42 mL/m2	RV ejection fraction 37% to 54% Stroke volume index 26 to 40 mL/m2 RV end-systolic volume index 42 to 54 mL/m2	RV ejection fraction <37% Stroke volume index <26 mL/m2 RV end-systolic volume index >54 mL/m2
Hemodynamics	Right atrial pressure <8 mmHg Cardiac index ≥2.5 L/min/m2 Stroke volume index >38 mL/m2 SvO2 >65%	Right atrial pressure 8 to 14 mmHg Cardiac index 2.0 to 2.4 L/min/m2 Stroke volume index 31 to 38 mL/m2 SvO2 60% to 65%	Right atrial pressure >14 mmHg Cardiac index <2.0 L/min/m2 Stroke volume index <31 mL/m2 SvO2 <60%

TAPSE: tricuspid annular plane systolic excursion; sPAP: systolic pulmonary arterial pressure; VO₂: oxygen uptake; VE/VCO₂: ventilatory equivalent for carbon dioxide; SvO₂: mixed venous oxygen saturation.

Four-strata risk assessment at follow-up (COMPERA 2.0, adopted by the 2022 ESC/ERS guidelines)

Determinant	Low risk (1 point)	Intermediate-low risk (2 points)	Intermediate-high risk (3 points)	High risk (4 points)
WHO functional class	I or II	(not used)	III	IV
6MWD	>440 m	320 to 440 m	165 to 319 m	<165 m
BNP	<50 ng/L	50 to 199 ng/L	200 to 800 ng/L	>800 ng/L
NT-proBNP	<300 ng/L	300 to 649 ng/L	650 to 1,100 ng/L	>1,100 ng/L
Observed 1-year mortality	0% to 3%	2% to 7%	9% to 19%	>20%

Each variable is graded 1 to 4, and the mean grade, rounded to the nearest integer, defines the stratum (NT-proBNP is used when both natriuretic peptides are available).

• In COMPERA 2.0, survival at 1, 3 and 5 years after diagnosis was 100%, 89.0% and 82.9% for patients at low risk at baseline, 97.9%, 85.6% and 78.6% at intermediate-low risk, 90.9%, 62.2% and 50.3% at intermediate-high risk and 78.1%, 46.5% and 28.2% at high risk. At first follow-up, 49.2% of patients changed stratum with the four-strata model, compared with 31.1% with the three-strata model, and these changes predicted long-term mortality.
• In 2,879 incident patients in the French registry, the four-strata model discriminated better than the three-strata model during follow-up, and 53% of patients changed risk category (39% with three strata).
• At first follow-up, adding stroke volume index >37 mL/m² and/or SvO₂ >65% refined risk in patients at intermediate-low or intermediate-high risk, but hemodynamics added no prognostic information in patients at low or high risk.
• REVEAL 2.0 combines modifiable and nonmodifiable variables (c-statistic 0.76), and each 1-point improvement in the REVEAL 2.0 score at follow-up was associated with a 26% reduction in the relative risk of death. REVEAL Lite 2 uses six noninvasive variables (functional class, systolic blood pressure, heart rate, 6MWD, BNP or NT-proBNP and renal insufficiency) and groups patients by estimated 1-year mortality: <5% (score 1 to 5), 5% to 10% (score 6 to 7) and >10% (score 8 to 14).
• Patients who meet all three noninvasive low-risk criteria on treatment (WHO functional class I or II, 6MWD >440 m and BNP <50 ng/L or NT-proBNP <300 ng/L) have a 5-year survival >90%, whereas meeting at least two of the three criteria is associated with a 5-year survival of about 80%.
• Risk tools have limitations: functional class is subjective, 6MWD is affected by age, comorbidities and motivation, and natriuretic peptides are affected by age, obesity, heart rhythm, kidney function and left heart disease. Model performance may be less robust in systemic sclerosis-associated PAH, and in older patients with comorbidities the tools still predict survival but, lacking disease specificity, may be less suitable for guiding PAH therapy.

Diagnosis

Diagnostic Study of Choice | History & Symptoms | Physical Examination | Laboratory Findings | Electrocardiography | Chest x-ray | CT | MRI | Echocardiography or Ultrasound | Right heart catheterization | Other Diagnostic Studies

Diagnostic Approach

The diagnostic workup aims to identify the patients who need referral to a PH center for invasive hemodynamic assessment, and the time between diagnostic steps should be kept short. The 7th WSPH describes five steps: clinical assessment (step 1), basic tests (step 2), echocardiography and respiratory investigations (step 3), ventilation/perfusion imaging and detailed laboratory testing (step 4) and RHC at a PH center (step 5). When PAH or CTEPH is highly probable, especially with signs of right heart failure, fast-track referral to a PH center is recommended at any point of the workup. Patients with interstitial lung disease and suspected PH, and patients with lung or left heart disease and suspected severe PH, should also be referred.

Suspected pulmonary hypertension Exertional dyspnea, fatigue, exertional syncope or signs of right heart failure

Steps 1 and 2 History including risk factors, physical examination, ECG, chest radiograph, SpO2, blood counts, electrolytes, kidney and liver function, BNP or NT-proBNP

Step 3 Transthoracic echocardiography (probability of PH and left heart assessment); arterial blood gases, pulmonary function tests with DLCO and chest CT

Low probability Peak TRV ≤2.8 m/s without other echocardiographic signs of PH

Intermediate probability Peak TRV 2.9 to 3.4 m/s without other signs, or ≤2.8 m/s with other signs of PH

High probability Peak TRV >3.4 m/s, or 2.9 to 3.4 m/s with other echocardiographic signs of PH; fast-track referral to a PH center if PAH or CTEPH is likely, especially with right heart failure

Consider an alternative diagnosis; reassess if symptoms persist or if risk factors for PAH or CTEPH are present

Evaluate for left heart disease and lung disease

Do left heart or lung disease explain the findings, without risk factors for PAH or CTEPH?

Yes Treat the underlying condition; refer patients with interstitial lung disease and suspected PH, and patients with suspected severe PH when the result would change management

No Continue the diagnostic workup

Step 4 V/Q scan; iron status, TSH, hepatitis and HIV serology, antinuclear, anticentromere and anti-Ro antibodies, urine drug screen; 6MWT and abdominal ultrasound; CPET and cardiac MRI in selected patients

Step 5 Referral to a PH center for right heart catheterization, with vasoreactivity testing, exercise testing or fluid challenge when indicated, to confirm PH, define the hemodynamic phenotype and assign the clinical group

Diagnostic Study of Choice

• Right heart catheterization is the diagnostic study of choice. It establishes the diagnosis, distinguishes pre-capillary from post-capillary PH, contributes to clinical classification and risk stratification and should be performed at a PH center by an experienced team.
• Transthoracic echocardiography is the key noninvasive test: it assigns the probability of PH and identifies left heart disease, but it cannot confirm or exclude PH on its own.
• Ventilation/perfusion scanning is the screening test of choice for chronic thromboembolic disease, because a negative scan excludes significant thromboembolic disease.

History and Symptoms

• The most frequent symptoms are dyspnea on exertion, fatigue and rapid exhaustion. Bendopnea (dyspnea when bending forward), weight gain from fluid retention and syncope during exertion may also occur.
• The history should look for conditions associated with PH: connective tissue disease, portal hypertension, HIV infection, congenital heart disease, previous venous thromboembolism, left heart disease, lung disease and illicit drug use. Drugs and toxins with a definite or possible association with PAH are also relevant (see Classification), and patients with a family history of PAH should be informed about the possibility of a genetic condition and offered genetic counseling and testing (see Other Diagnostic Studies).
• Because symptoms are nonspecific, diagnosis is often delayed. In REVEAL, the mean interval from symptom onset to diagnostic catheterization was 2.8 years, and 21.1% of patients had symptoms for more than 2 years before PAH was recognized. Delay was more likely with symptom onset before the age of 36 years (OR 3.07; 95% CI 2.03 to 4.66), obstructive airway disease (OR 1.93; 95% CI 1.5 to 2.47) and sleep apnea (OR 1.72; 95% CI 1.33 to 2.22).

Physical Examination

• Examination may reveal an accentuated second heart sound and, in more advanced disease, a systolic murmur of tricuspid regurgitation or a diastolic murmur of pulmonary regurgitation (Graham Steell murmur).
• Peripheral edema, distended and pulsating jugular veins, a hepatic heave and ascites indicate severe right heart failure.

Laboratory Findings

• Basic tests at the first evaluation include a complete blood count, serum electrolytes, kidney and liver function tests and BNP or NT-proBNP.
• Natriuretic peptides are not specific for PH, but they reflect right heart overload or dysfunction and carry prognostic information. In a meta-analysis of 16 studies including 6,999 patients, pooled unadjusted hazard ratios from the nine studies that used cut-off values showed that an elevated NT-proBNP (HR 2.75; 95% CI 1.86 to 4.07) and an elevated BNP (HR 3.87; 95% CI 2.69 to 5.57) predicted death or lung transplantation.
• Detailed laboratory testing in step 4 includes iron status, thyroid-stimulating hormone, hepatitis virus serology, HIV serology and basic immunology (antinuclear, anticentromere and anti-Ro antibodies). Screening for antiphospholipid syndrome is recommended when CTEPH is suspected, and a urine drug screen is recommended in all patients with idiopathic PAH or a history of substance use.
• Arterial blood gases usually show a normal or slightly reduced partial pressure of oxygen and a normal or reduced partial pressure of carbon dioxide (alveolar hyperventilation) in PAH. More severe hypoxemia suggests airflow obstruction, parenchymal lung disease, a right-to-left shunt, PVOD or liver disease.

Electrocardiogram

• In adults with dyspnea, right axis deviation on the ECG has a high positive predictive value for PH. The ECG may also show arrhythmias and signs of left heart disease.
• In the absence of severe dyspnea, a normal ECG together with a normal BNP or NT-proBNP and normal gas exchange makes PH unlikely.
• Artificial intelligence applied to the 12-lead ECG is under evaluation for early detection: a convolutional neural network identified patients likely to have PH with an area under the curve of 0.92 at the derivation institution and 0.88 at an external center, and of at least 0.79 and 0.73 up to 5 years before diagnosis.

Chest X-ray

• A chest radiograph is part of the basic workup. It may show enlargement of the pulmonary arterial trunk and pulmonary arteries and a characteristic configuration of the cardiac silhouette on the lateral view. Chest CT provides more information on PH and on underlying lung disease and is the preferred imaging modality.

CT

• Signs of PH on chest CT include an enlarged pulmonary artery diameter, an increased pulmonary artery-to-aorta diameter ratio and enlarged right heart chambers.
• Centrilobular ground-glass opacities, septal lines and mediastinal lymphadenopathy raise suspicion of PVOD. In a comparison of 24 histologically confirmed cases of PVOD with 24 cases of PAH, these findings were more frequent in PVOD, which was also associated with a lower partial pressure of oxygen and DLCO.
• In chronic lung disease, a pulmonary artery-to-aorta ratio >1 is associated with PH and mortality, and in interstitial lung disease a main pulmonary artery diameter ≥29 mm correlates strongly with PH regardless of the severity of the lung disease.
• High-resolution CT should be performed when the DLCO is low (<40% of predicted), because a low DLCO is frequently associated with parenchymal lung disease or PVOD, and CT may reveal combined pulmonary fibrosis and emphysema that is missed or underestimated by pulmonary function tests.
• CT pulmonary angiography (CTPA) detects direct and indirect signs of chronic thromboembolic pulmonary disease, including filling defects, webs and bands. A normal CTPA does not exclude CTEPH: in one referral cohort, CTPA had a sensitivity of 51% compared with 96% to 97.4% for V/Q scintigraphy.

MRI

• Cardiac magnetic resonance imaging is the gold standard for noninvasive assessment of RV volumes and function. It correlates closely with invasive pulmonary pressures in single-center studies, but it is not yet validated for the hemodynamic diagnosis of PH and is limited by cost and availability.
• In a meta-analysis of 22 studies including 1,938 patients with PAH, RV ejection fraction and RV volume indices measured by MRI predicted both clinical worsening and mortality, and left ventricular stroke volume and end-diastolic volume indices predicted mortality. MRI parameters are part of the ESC/ERS risk assessment.

Echocardiography or Ultrasound

• Echocardiography estimates the systolic pulmonary arterial pressure from the peak tricuspid regurgitation velocity (TRV) after excluding pulmonary stenosis, and assesses additional signs of PH, the left heart and the valves. The thresholds for echocardiographic probability did not change with the new hemodynamic definition.

Echocardiographic probability of pulmonary hypertension

Peak TRV	Additional echocardiographic signs of PH	Probability of PH
≤2.8 m/s	Absent	Low
≤2.8 m/s	Present	Intermediate
2.9 to 3.4 m/s	Absent	Intermediate
2.9 to 3.4 m/s	Present	High
>3.4 m/s	Not required	High

Additional echocardiographic signs suggestive of pulmonary hypertension

Ventricles	Pulmonary artery	Inferior vena cava and right atrium
RV/left ventricle basal diameter or area ratio >1.0 Flattening of the interventricular septum (left ventricular eccentricity index >1.1 in systole and/or diastole) TAPSE/sPAP ratio <0.55 mm/mmHg	RV outflow tract acceleration time <105 ms and/or mid-systolic notching Early diastolic pulmonary regurgitation velocity >2.2 m/s Pulmonary artery diameter larger than the aortic root diameter Pulmonary artery diameter >25 mm	Inferior vena cava diameter >21 mm with decreased inspiratory collapse Right atrial area (end-systole) >18 cm2

• Doppler estimates of pulmonary pressure are imprecise: in 65 patients studied within 1 hour of RHC, the echocardiographic systolic pressure differed by more than 10 mmHg from the invasive value in 48%, and underestimation more often misclassified the severity of PH. The final decision on RHC therefore rests on all clinical information; RHC is usually indicated when the probability is high, or intermediate in patients with risk factors for PAH or CTEPH.
• The ratio of tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) is a noninvasive index of RV-pulmonary arterial coupling. A cut-off of 0.31 mm/mmHg discriminated RV-arterial uncoupling (sensitivity 87.5%, specificity 75.9%) against pressure-volume loop measurements, and the ratio is used in risk stratification.
• Echocardiography identifies heart failure with reduced or preserved ejection fraction, valvular heart disease and cardiomyopathies, which may present like PAH or CTEPH; further exploration of PH in these patients is suggested only if severe CpcPH is suspected. In patients who develop new or more severe hypoxemia after starting PAH therapy, echocardiography with an agitated saline (bubble) study and high-resolution CT should be considered; if no other cause is found, previously unrecognized PVOD/PCH should be considered.
• Abdominal ultrasound is part of step 4 of the workup and is used to look for liver disease and portal hypertension.

Right Heart Catheterization

• Indications: RHC is performed when it is expected to provide clinically meaningful information or change management, most often when the echocardiographic probability is high, or intermediate in patients with risk factors for PAH or CTEPH. In patients with severe comorbidities, RHC may be omitted when it would not change management.
• Measurements: the baseline study should include mean, systolic and diastolic pulmonary arterial pressure, PAWP, right atrial pressure, heart rate and cardiac output, with calculation of PVR. Blood gases should be measured at least in a systemic artery, the pulmonary artery and the superior or inferior vena cava to calculate the arteriovenous oxygen difference and to detect systemic-to-pulmonary shunts.
• Methodology: the zero reference level is the mid-thoracic level (left atrial level) in the supine position. Pressures may be read at end-expiration without breath-holding or averaged over three to four respiratory cycles; averaging is more reliable in patients with large respiratory swings, such as those with obesity or COPD, and during exercise. The direct Fick method is the gold standard for cardiac output, thermodilution is a reliable alternative in patients without a shunt, and the indirect Fick method is not suggested.
• Acute vasoreactivity testing is recommended at the diagnostic RHC in idiopathic, heritable and drug-associated PAH to identify candidates for long-term calcium channel blocker therapy. Inhaled nitric oxide is the recommended agent; inhaled iloprost or intravenous epoprostenol are alternatives. A positive response is a fall in mPAP of ≥10 mmHg to an absolute value of ≤40 mmHg (2022 ESC/ERS guidelines; <40 mmHg in the 7th WSPH documents) with an unchanged or increased cardiac output. About 12% of patients with idiopathic or drug-associated PAH and fewer than 5% with heritable PAH respond, and fewer than two-thirds of acute responders have a sustained response after 1 year or more of calcium channel blocker therapy. In a French series of 557 patients (using an earlier definition of response), 12.6% were acute responders but only 6.8% were long-term responders. In other forms of PAH and in other PH groups, acute testing can be misleading, and true long-term responders are rare.
• Exercise RHC, with cycle ergometry as the preferred method, is performed in experienced centers in selected patients, mainly those with normal or moderately increased resting mPAP and/or a PAWP of 13 to 15 mmHg, to detect early pulmonary vascular or left heart disease.
• Fluid challenge: in patients with pre-capillary PH and a PAWP of 13 to 15 mmHg, rapid infusion of 500 mL of saline may unmask left heart disease; a PAWP >18 mmHg after loading suggests left heart disease.
• Safety: in 7,218 procedures performed in experienced centers, serious adverse events occurred in 1.1% (mostly venous access complications, arrhythmias and hypotensive episodes), and procedure-related mortality was 0.055%.

Other Diagnostic Studies

• Ventilation/perfusion lung scan: a negative V/Q scan excludes significant thromboembolic disease, while perfusion defects with normal ventilation are highly suggestive of it. Patchy abnormalities may be seen in PAH, and matched defects are common in parenchymal lung disease. V/Q scintigraphy had a sensitivity of 96% to 97.4% and a specificity of 90% to 95% for CTEPH.
• Pulmonary function tests are usually normal or mildly abnormal in PAH. Marked abnormalities suggest airway or parenchymal lung disease, and a DLCO <40% of predicted suggests parenchymal lung disease or PVOD.
• Polygraphy or overnight oximetry is suggested in step 3 when a hypoventilation syndrome is suspected.
• Cardiopulmonary exercise testing (CPET): a reduced peak oxygen uptake and an increased ventilatory equivalent for carbon dioxide with a low end-tidal carbon dioxide tension suggest PH. CPET can help detect CTEPH even when the echocardiographic probability of PH is low, and it is suggested in selected patients when echocardiography and other tests do not settle the need for RHC.
• Six-minute walk test: the 6MWD is used for risk assessment and follow-up; values >440 m and <165 m mark low and high risk.
• Genetic testing and counseling are suggested for patients with idiopathic, familial, anorexigen-associated or congenital heart disease-associated PAH and for patients with suspected PVOD/PCH, in whom biallelic EIF2AK4 mutations support the diagnosis and prompt early referral for lung transplantation. There is insufficient evidence to recommend genetic testing in groups 2 to 5.

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Initial Management

• Treatment is determined by the clinical group and the hemodynamic phenotype established at RHC. PAH-targeted drugs were approved on the basis of trials in patients with mPAP ≥25 mmHg, PAWP ≤15 mmHg and PVR >3 WU, and they should be prescribed only to patients who meet these criteria.
• Patients with PAH or CTEPH, and patients with suspected severe PH associated with left heart or lung disease, should be managed at or in collaboration with a PH center; patients with interstitial lung disease and suspected PH should also be referred.
• In groups 2 and 3, the first step is optimal treatment of the underlying heart or lung disease.
• In PAH, the initial strategy is chosen after vasoreactivity testing and baseline risk assessment: high-dose calcium channel blockers for acute vasoresponders, initial ERA plus PDE5 inhibitor therapy for patients not at high risk, initial triple therapy including a parenteral prostacyclin pathway agent for high-risk patients and, for patients with significant cardiopulmonary comorbidities, initial monotherapy, usually with a PDE5 inhibitor (see the treatment algorithm under Medical Therapy).
• Before therapy is prescribed, clinicians and patients should discuss the disease, the benefits, routes of administration, adverse effects and interactions of each treatment, comorbidities and patient preferences, in a process of shared decision-making.

General and Supportive Measures in PAH

Recommended supportive measures for patients with PAH (7th WSPH)

Measure	Details
Supervised exercise training	Supervised training in patients receiving PAH therapy (see Long-Term Management)
Psychological support	Recommended for patients with PAH (see Long-Term Management)
Immunization	Against SARS-CoV-2, influenza and Streptococcus pneumoniae; vaccination against respiratory syncytial virus is recommended in patients older than 60 years and can be considered in all patients with PAH
Diuretics	In patients with fluid retention
Long-term oxygen therapy	When arterial oxygen pressure is consistently <8 kPa (60 mmHg); the ESC/ERS guidelines advise oxygen when PaO2 is <8 kPa (alternatively, SaO2 <92%) on at least two occasions
Iron	Correction of iron status in patients with iron deficiency anemia
Pregnancy	Advise against pregnancy for most patients and give clear contraceptive advice; highly effective birth control should be offered to women of childbearing potential
Pre-transplant counseling	Weight optimization, avoidance of tobacco and illicit drugs and treatment of comorbidities, so that later barriers to transplantation are addressed

• Anticoagulation is not generally recommended in idiopathic, heritable or drug-associated PAH but may be considered on an individual basis, and routine anticoagulation is not recommended in connective tissue disease-associated PAH (see Medical Therapy).

Acute Decompensated Right Heart Failure

Acute decompensation of right heart failure is a major negative prognostic event. Its management rests mainly on physiological principles and expert opinion, and patients whose treatment can still be optimized, and who have no limitation on rescue therapies, should preferably be referred to centers that offer PH expertise, extracorporeal life support (ECLS) and urgent transplantation. A normal blood pressure does not exclude severe right heart failure, because reflex vasoconstriction can maintain it.

• Identify and treat triggers: supraventricular arrhythmias (avoid beta-blockers and calcium channel blockers; consider digoxin for rate control, amiodarone or electrical cardioversion, or ablation), infection (including central line infection in patients receiving epoprostenol: consider rapid empirical antibiotic treatment after cultures are taken, and remove an infected line), hypoxemia, pulmonary embolism, anemia and nonadherence to therapy.
• Volume management: intravenous loop diuretics are the cornerstone of treatment, given as a continuous infusion at a dose higher than the usual oral dose in patients already taking diuretics; a thiazide may be added if the response is inadequate. Renal replacement therapy is reserved for selected patients with refractory congestion without severe hemodynamic instability.
• Systemic pressure and inotropes: a mean arterial pressure of 70 to 75 mmHg is targeted with norepinephrine and/or vasopressin, the vasopressors of choice. Dobutamine is the inotrope of choice for low cardiac output, started at 2.5 µg/kg/min and not exceeding 5 to 7.5 µg/kg/min; milrinone and levosimendan lower systemic vascular resistance and should be used with caution, and epinephrine should not be used.
• Oxygenation and ventilation: noninvasive (high-flow) oxygen is used to keep oxygen saturation >90%, while mechanical ventilation, hypercapnia and hyperinflation should be avoided.
• RV afterload: PAH-specific drugs are not emergency medications: their systemic hypotensive effects can be harmful in unstable patients, so they should not be started before hemodynamic stability is achieved and the cause of PH is clearly identified. When right heart failure is the first presentation of PAH, combination therapy including a prostacyclin can markedly reduce RV afterload; RHC is mandatory if PH has not previously been diagnosed. Inhaled nitric oxide with dobutamine may serve as a transitional measure.
• Mechanical support: peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO), which can be inserted in an awake patient under local anesthesia, is the most frequently used support for the failing right ventricle; its only well-established indication is refractory right heart failure in a patient already listed for lung transplantation. It may serve as a bridge to decision in selected patients, as a bridge to urgent endarterectomy in exceptional cases of decompensated CTEPH, or as a bridge to recovery when a reversible trigger is present in a patient not yet receiving PAH therapy. An RV assist device should not be inserted when there is no realistic prospect of transplantation or recovery, and veno-venous ECMO does not support the failing right ventricle.
• Procedures to avoid in unstable patients: urgent atrial septostomy and creation of a Potts shunt are not recommended; atrial septostomy should be performed only electively.
• When transplantation and mechanical support are not options, team-based palliative care, including psychological and spiritual support, should be provided.

Medical Therapy

Pulmonary Arterial Hypertension (Group 1)

PAH therapies act on four pathways: endothelin receptor antagonists (ERAs) block endothelin-1 receptors; phosphodiesterase-5 inhibitors (PDE5i) and the soluble guanylate cyclase stimulator riociguat increase signaling through the nitric oxide-cyclic GMP pathway; prostacyclin pathway agents (PPAs) act on the prostacyclin (IP) receptor and raise cyclic AMP; and sotatercept, a biologic agent that acts as a ligand trap for activins and related growth factors, rebalances growth-promoting and growth-inhibiting signaling of the transforming growth factor beta superfamily. Combination therapy produces larger improvements than monotherapy, and most patients are candidates for oral or oral plus parenteral combination therapy from the time of diagnosis, with early reassessment and escalation when indicated. The treatment algorithm below applies mainly to idiopathic, heritable, drug-associated and connective tissue disease-associated PAH, which made up most trial populations.

PAH confirmed by right heart catheterization at a PH center Algorithm intended for idiopathic, heritable, drug-associated and connective tissue disease-associated PAH with mPAP ≥25 mmHg and PVR >3 WU; general and supportive measures for all patients

Positive acute vasoreactivity test Idiopathic, heritable or drug-associated PAH

Nonvasoreactive Phenotypically clear-cut PAH without significant cardiopulmonary comorbidity

Cardiopulmonary comorbidities Risk factors or features of left heart or lung disease

High-dose calcium channel blocker; reassess at 3 to 4 months, aiming for low risk and near-normal hemodynamics; otherwise treat as nonvasoreactive

Not high risk Initial ERA plus PDE5 inhibitor (tadalafil with macitentan or ambrisentan preferred)

High risk ERA plus PDE5 inhibitor plus parenteral prostacyclin; discuss lung transplant referral

Initial monotherapy, usually a PDE5 inhibitor, with close monitoring and individualized escalation

Reassess at 3 to 4 months Four-strata risk (WHO functional class, 6MWD, BNP or NT-proBNP), with imaging and right heart catheterization as needed

Low risk Continue therapy; individualized escalation may be considered

Intermediate-low risk Add-on sotatercept, or consider adding selexipag, oral treprostinil or an inhaled prostacyclin, or switching the PDE5 inhibitor to riociguat

Intermediate-high or high risk Intermediate-high: parenteral prostacyclin or add-on sotatercept. High: parenteral prostacyclin if not already receiving one, plus add-on sotatercept (maximal four-pathway therapy). Refer for lung transplant evaluation

Drugs approved for pulmonary arterial hypertension

Class	Agents and usual doses	Key randomized evidence	Common adverse effects and precautions
PDE5 inhibitors	Sildenafil 20 mg three times daily (uptitration to 80 mg three times daily can be considered); tadalafil 40 mg once daily	SUPER-1: placebo-corrected 6MWD +45, +46 and +50 m with 20, 40 and 80 mg three times daily, without a significant effect on clinical worsening; PHIRST: tadalafil 40 mg +33 m (95% CI 15 to 50) and a 68% relative risk reduction in clinical worsening	Headache, flushing, dyspepsia, epistaxis; rare loss of vision or hearing; avoid with nitrates and riociguat
Soluble guanylate cyclase stimulator	Riociguat, individually adjusted up to 2.5 mg three times daily	PATENT-1: 6MWD +36 m (95% CI 20 to 52) in treatment-naive and pretreated patients, with improved PVR, NT-proBNP, functional class and time to clinical worsening	Headache, dyspepsia, dizziness, hypotension; avoid in pregnancy; avoid with nitrates and PDE5 inhibitors
Endothelin receptor antagonists	Bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice daily (125 or 250 mg twice daily in BREATHE-1); ambrisentan 5 or 10 mg once daily; macitentan 10 mg once daily	BREATHE-1: bosentan 6MWD +44 m (95% CI 21 to 67); ARIES-1 and -2: ambrisentan +31 to +59 m by dose; SERAPHIN: macitentan 10 mg reduced morbidity or mortality events (31.4% vs 46.4% with placebo; HR 0.55, 97.5% CI 0.39 to 0.76)	Peripheral edema, nasal congestion, anemia; teratogenic (highly reliable contraception and monthly pregnancy testing); monitor hemoglobin and liver function (monthly for bosentan)
Prostacyclin receptor agonist	Selexipag, individualized doses up to 1,600 µg twice daily	GRIPHON: death or PAH complication 27.0% vs 41.6% with placebo (HR 0.60, 99% CI 0.46 to 0.78), driven by disease progression and hospitalization; no difference in mortality	Prostanoid-type effects (headache, diarrhea, nausea, jaw pain, flushing); discontinuation for adverse events 14.3% vs 7.1% with placebo in GRIPHON
Oral and inhaled prostacyclin analogues	Oral treprostinil three times daily; inhaled treprostinil (four sessions daily); inhaled iloprost (six to nine inhalations daily)	FREEDOM-EV: oral treprostinil added to monotherapy reduced clinical worsening (26% vs 36%; HR 0.74, 95% CI 0.56 to 0.97); TRIUMPH: inhaled treprostinil added to oral monotherapy, 6MWD +20.0 m (95% CI 8.0 to 32.8)	Prostanoid-type effects; cough with inhaled agents
Parenteral prostacyclin analogues	Continuous intravenous epoprostenol; intravenous or subcutaneous treprostinil; started at 1 to 2 ng/kg/min and uptitrated over weeks to months, typically to an initial target of 15 to 20 ng/kg/min for epoprostenol and ≥40 ng/kg/min for treprostinil, with further uptitration if needed (practice varies between centers)	Epoprostenol improved 6MWD and hemodynamics in severe primary PH, with 8 deaths, all in the conventional-therapy group, over 12 weeks	Prostanoid-type effects; catheter-related infections; infusion-site pain with subcutaneous treprostinil; abrupt interruption can be life-threatening
Activin signaling inhibitor	Sotatercept 0.3 mg/kg subcutaneously, then 0.7 mg/kg every 3 weeks	STELLAR: 6MWD +40.8 m (95% CI 27.5 to 54.1) on stable background therapy; ZENITH: fewer deaths, lung transplantations or hospitalizations for worsening PAH (HR 0.24; 95% CI 0.13 to 0.43); HYPERION: fewer clinical worsening events (HR 0.24; 95% CI 0.14 to 0.41)	Epistaxis, telangiectasia, bleeding events, increased hemoglobin, thrombocytopenia; avoid in pregnancy; possible reduction of fertility based on animal studies; monitor hemoglobin and platelets before each of the first five doses and periodically

Calcium Channel Blockers

• High-dose calcium channel blockers are indicated only for patients with idiopathic, heritable or drug-associated PAH who have a positive acute vasoreactivity test. They are started at low doses and uptitrated according to the overall response, including hemodynamics; high doses may be required. The goals are a low-risk profile and near-normal hemodynamics, assessed by comprehensive reassessment at 3 to 4 months. Former responders who lose their response are managed with the standard PAH algorithm.
• In a cohort of 557 patients with idiopathic PAH, all but one of the long-term responders were alive in New York Heart Association class I or II after 7.0 ± 4.1 years, whereas 5-year survival was 48% in patients in whom calcium channel blockers failed.

Initial Therapy

• Patients not at high risk: initial combination of an ERA and a PDE5 inhibitor is recommended. Both drugs can be started on the same day or sequentially within 1 to 2 weeks to assess tolerability, and tadalafil combined with macitentan or ambrisentan is preferred over combinations that contain bosentan or sildenafil because the evidence of efficacy is stronger.
  • In AMBITION (500 treatment-naive patients in WHO functional class II or III), initial ambrisentan plus tadalafil reduced clinical failure events compared with pooled monotherapy (18% vs 31%; HR 0.50, 95% CI 0.35 to 0.72), at the cost of more peripheral edema, headache, nasal congestion and anemia.
  • A single-tablet combination of macitentan and tadalafil reduced PVR by 29% compared with macitentan alone and by 28% compared with tadalafil alone (A DUE).
  • In a Cochrane review, a PDE5 inhibitor plus an ERA reduced clinical worsening compared with an ERA alone (RR 0.53, 95% CI 0.41 to 0.68; high-certainty evidence), with little or no difference in mortality (low-certainty evidence). An earlier meta-analysis of 17 trials found less clinical worsening with combination therapy than with monotherapy (17% vs 28%; RR 0.65, 95% CI 0.58 to 0.72).
• Patients at high risk should receive a parenteral PPA (intravenous epoprostenol or intravenous or subcutaneous treprostinil) together with an ERA and a PDE5 inhibitor, because observational studies suggest better outcomes, including survival, with initial triple combination therapy. A discussion of lung transplantation and potential referral should be considered at diagnosis in these patients, depending on patient, center and regional criteria. Some patients who are not high risk but have high-risk features may also be considered for initial parenteral therapy.
• Initial triple oral therapy is not recommended: in TRITON (247 newly diagnosed patients), adding selexipag to initial macitentan and tadalafil did not further reduce PVR at 26 weeks (54% vs 52% reduction; ratio 0.96, 95% CI 0.86 to 1.07). Inhaled prostacyclins and riociguat may be components of initial therapy, but the evidence is weaker than for ERA plus PDE5 inhibitor combinations.
• Patients with cardiopulmonary comorbidities who have risk factors for left heart disease (hypertension, diabetes, obesity, sleep apnea, atrial fibrillation or coronary artery disease) or lung disease have more adverse events with PAH therapy and possibly smaller responses. If PAH is judged to be present, initial monotherapy may be preferred, usually starting with a PDE5 inhibitor because adverse events and discontinuations may be more frequent with ERAs in this setting, followed by close follow-up; if a non-group 1 diagnosis becomes evident, PAH drugs should generally be stopped.
• Mildly elevated pressures: there are no approved therapies for patients with an mPAP of 21 to 24 mmHg, because current PAH drugs were studied in patients with an mPAP ≥25 mmHg and a PVR >3 WU. Clinical trial enrollment is recommended, if available, and all patients should be closely monitored for progression. The 7th WSPH definitions task force considers treatment with PH drugs unjustified in patients with an mPAP of 21 to 24 mmHg and a PVR of 2 to 3 WU (see Initial Management); if a decision to treat is nevertheless made, initial monotherapy is recommended over combination therapy.

Follow-up Assessment and Treatment Escalation

• The first reassessment is performed 3 to 4 months after treatment initiation in patients who are stable or improving; patients who clearly deteriorate should be considered for prompt treatment escalation. From the first follow-up onward, risk is assessed with the four-strata model.
• Low risk: most low-risk patients still have symptoms and reduced exercise capacity, and more than 20% had a clinical worsening event within 3 years in a combined analysis of AMBITION, GRIPHON and SERAPHIN. Management is individualized; additional goals that have been proposed include a PVR <5 WU, a large fall in PVR (>50% to 60%), a better stroke volume index and normal or near-normal RV size and function.
• Intermediate-low risk on oral combination therapy: options are add-on sotatercept, an oral PPA (selexipag or oral treprostinil), an inhaled PPA, or switching from a PDE5 inhibitor to riociguat. Sotatercept may be considered when symptom burden or exercise limitation is greater, whereas an oral PPA may be considered in patients at higher bleeding risk, such as those with hereditary hemorrhagic telangiectasia. In REPLACE (226 patients at intermediate risk on a PDE5 inhibitor), switching to riociguat increased the rate of clinical improvement (41% vs 20%; OR 2.78, 95% CI 1.53 to 5.06) and reduced clinical worsening (1% vs 9%), but the study was unblinded.
• Intermediate-high risk: a parenteral PPA should be added, or add-on sotatercept considered. High risk: a parenteral PPA should be started if the patient is not already receiving one. Maximal medical therapy is now four-drug therapy, because most patients in the sotatercept trials were receiving background triple therapy. Lung transplant evaluation is recommended in all patients with progression to, or persistence of, intermediate-high or high risk.
• The 2026 ERS guideline update recommends add-on sotatercept, on the basis of high-certainty evidence, for patients already receiving PAH drugs who are at intermediate-low, intermediate-high or high risk during follow-up; it makes no recommendation for low-risk patients. Patients receiving sotatercept should be treated in PH centers with regular follow-up. The update also suggests RHC during follow-up in patients at intermediate-low, intermediate-high or high risk when therapeutic consequences are expected.

Sotatercept

• In PULSAR (106 patients on background therapy), the least-squares mean difference in PVR at 24 weeks compared with placebo was -145.8 dyn·s·cm^-5 (95% CI -241.0 to -50.6) with 0.3 mg/kg and -239.5 dyn·s·cm^-5 (95% CI -329.3 to -149.7) with 0.7 mg/kg every 3 weeks.
• In STELLAR (323 patients in WHO functional class II or III on stable background therapy), sotatercept increased the 6MWD at 24 weeks by 40.8 m (95% CI 27.5 to 54.1) compared with placebo and improved 8 of 9 hierarchical secondary endpoints, including PVR, NT-proBNP, functional class and time to death or clinical worsening. The hazard ratio for death or clinical worsening was 0.16 (95% CI 0.08 to 0.35); 61% of patients were on triple background therapy and 40% on a parenteral PPA.
• In ZENITH (172 patients in WHO functional class III or IV at high risk, with a REVEAL Lite 2 score ≥9 despite maximally tolerated therapy), death, lung transplantation or PAH hospitalization of at least 24 hours occurred in 17.4% of patients receiving sotatercept and 54.7% receiving placebo (HR 0.24, 95% CI 0.13 to 0.43). Death occurred in 8.1% vs 15.1%, lung transplantation in 1.2% vs 7.0% and hospitalization in 9.3% vs 50.0%; the trial was stopped early for efficacy.
• In HYPERION (320 patients diagnosed less than 1 year earlier, at intermediate or high risk on double or triple therapy), clinical worsening occurred in 10.6% vs 36.9% of patients (HR 0.24, 95% CI 0.14 to 0.41) over a median follow-up of 13.2 months. The difference was driven mainly by deterioration in exercise testing (5.0% vs 28.8%) and unplanned hospitalization for worsening PAH (1.9% vs 8.8%); deaths occurred in 4.4% and 3.8%. Epistaxis (31.9%) and telangiectasia (26.2%) were the most common adverse events with sotatercept.
• In the open-label SOTERIA extension (426 patients), epistaxis occurred in 22.1%, telangiectasia in 16.9% and serious bleeding events in 5.2%.
• Unlike the other PAH drugs, sotatercept has no acute vasodilator effect. It improves right atrial pressure, mPAP and PVR but not cardiac index, and in seriously ill patients with a low cardiac index the far greater experience with parenteral PPAs means that they remain first line.
• The FDA label specifies a starting dose of 0.3 mg/kg and a target dose of 0.7 mg/kg given subcutaneously every 3 weeks, measurement of hemoglobin and platelet count before each of the first five doses, no initiation of treatment if the platelet count is <50,000/mm³, and effective contraception during treatment and for at least 4 months after the last dose. Serious bleeding occurred in 4% vs 1% of patients in STELLAR, 7% vs 5% in ZENITH and 4% vs 2% in HYPERION.
• Caution is advised in connective tissue disease with a tendency to gastrointestinal bleeding from vascular lesions.

Anticoagulation

• Randomized evidence is lacking, and observational data are conflicting. In COMPERA, anticoagulation was associated with better survival in idiopathic PAH (HR 0.79, 95% CI 0.66 to 0.94) but not in other forms of PAH. In 1,597 patients in the French registry, anticoagulation was not associated with survival (HR 0.997, 95% CI 0.84 to 1.18), and an updated meta-analysis found a pooled HR of 0.98 (95% CI 0.78 to 1.23).
• Anticoagulation is therefore not generally recommended in idiopathic, heritable or drug-associated PAH, although it may be considered individually; in connective tissue disease-associated PAH, registry data suggest no benefit and probable harm, and routine use is not recommended.

Treatments That Are Not Recommended

• Imatinib: in IMPRES (202 patients on at least two PAH therapies), imatinib increased the 6MWD by 32 m but did not improve time to clinical worsening or mortality; serious adverse events occurred in 44% vs 30%, and subdural hematoma developed in 8 patients receiving imatinib with anticoagulation.
• PDE5 inhibitors with riociguat, and either drug with nitrates, because of the risk of hypotension.
• Initial triple oral therapy with selexipag, a PDE5 inhibitor and an ERA (TRITON).
• PAH-targeted drugs in group 2 PH outside clinical trials, and in group 3 PH outside expert centers, because of harm or possible harm in several conditions (see below).

Meta-analyses of PAH Therapy

• A meta-analysis of 21 randomized trials (3,140 patients) found a 43% reduction in mortality with PAH therapy (RR 0.57, 95% CI 0.35 to 0.92).
• An individual participant data network meta-analysis of 20 phase 3 trials submitted to the FDA (6,811 patients) estimated the placebo-corrected improvement in 6MWD by pathway at 43.7 m for combined endothelin and nitric oxide pathway therapy, 29.4 m for nitric oxide pathway therapy, 25.3 m for endothelin pathway therapy, 19.1 m for oral or inhaled prostacyclin pathway therapy and 24.4 m for intravenous or subcutaneous prostacyclin therapy.

Investigational Therapies

• Ralinepag, an oral prostacyclin receptor agonist, reduced clinical worsening compared with placebo in the phase 3 ADVANCE OUTCOMES trial (18% vs 36%; HR 0.45, 95% CI 0.33 to 0.62; 687 patients analyzed, 80% on dual background therapy). Discontinuation for adverse events occurred in 19% vs 3% of patients, and 41 patients from sites in China were excluded from all analyses because of regulatory challenges and data-integrity concerns.

PH Associated with Left Heart Disease (Group 2)

• Treatment is directed at the underlying left heart disease: guideline-directed therapy for heart failure, optimization of volume status, management of comorbidities and valve intervention when indicated. The 7th WSPH task force concluded that recent trials reinforced its position that PAH-specific medications should not be used in PH associated with left heart disease outside clinical trials, because of a lack of benefit and possible harm. The only exception discussed is individualized symptom palliation in advanced (stage D) disease (see the staging table below). Patients with suspected severe CpcPH should be referred to a PH center for individualized decisions.

Randomized trials of pulmonary vasoactive drugs in PH associated with left heart disease

Trial	Population and intervention	Main result
SIOVAC	200 patients with mPAP ≥30 mmHg at least 1 year after successful valve surgery; sildenafil 40 mg three times daily vs placebo for 6 months	Worse composite clinical score with sildenafil (OR 0.39; 95% CI 0.22 to 0.67) and lower survival free of heart failure admission (0.76 vs 0.86; HR 2.0, 95% CI 1.0 to 4.0)
MELODY-1	63 patients with CpcPH due to left heart disease (diastolic pressure gradient ≥7 mmHg and PVR >3 WU); macitentan 10 mg vs placebo for 12 weeks	The composite of significant fluid retention or worsening NYHA class occurred in 7 patients receiving macitentan vs 4 receiving placebo (difference not significant), driven by fluid retention; no change in PVR
SERENADE	142 patients with HFpEF or heart failure with mildly reduced ejection fraction and pulmonary vascular disease; macitentan vs placebo	No effect on NT-proBNP (geometric mean ratio 1.02; 90% CI 0.88 to 1.19); fluid retention in 23% vs 14% and worsening heart failure in 28% vs 18% with macitentan vs placebo
PASSION	CpcPH with HFpEF; tadalafil vs placebo; stopped early after 125 of 372 planned patients because of drug-supply disruption	No difference in heart failure hospitalization or death (27% with tadalafil vs 32% with placebo; HR 1.02, 95% CI 0.52 to 2.01), with a possible signal of higher all-cause mortality with tadalafil (HR 5.10, 95% CI 1.10 to 23.69)
LEPHT	201 patients with PH due to systolic left ventricular dysfunction; riociguat vs placebo	No significant reduction in mPAP; cardiac index increased by 0.4 L/min/m2 with 2 mg
Sildenafil in HFpEF (Hoendermis)	52 patients with HFpEF and PH, mostly isolated post-capillary; sildenafil titrated to 60 mg three times daily vs placebo for 12 weeks	No benefit on mPAP (-2.4 mmHg with sildenafil vs -4.7 mmHg with placebo), PAWP, cardiac output or peak oxygen uptake
CADENCE (phase 2)	164 patients with CpcPH and HFpEF (median baseline PVR 5.2 WU); sotatercept vs placebo	Hodges-Lehmann shift in PVR compared with placebo of -1.02 WU (95% CI -1.81 to -0.23) with 0.3 mg/kg and -0.75 WU (95% CI -1.52 to 0.03) with 0.7 mg/kg; phase 3 testing planned; not an approved use

• Mitral stenosis: PAH medications should be avoided in moderate or severe mitral stenosis with PH, because of concern for precipitating pulmonary edema and lack of evidence of benefit. A noninvasive pulmonary artery systolic pressure >50 mmHg is a potential indication for intervention in asymptomatic patients with severe mitral stenosis.
• Aortic stenosis: PH alone is not sufficient reason to deny transcatheter aortic valve replacement, and PAH medications are not recommended before the procedure or as a test to discriminate the hemodynamic subtype.
• Cardiomyopathies: in obstructive hypertrophic cardiomyopathy, preoperative PAH drugs are not evidence-based and may be harmful; in cardiac amyloidosis, routine PAH pharmacotherapy is not indicated.
• Heart failure with reduced ejection fraction: PH marks more advanced disease and reduced survival, and an elevated PVR may preclude heart transplantation.
• Staging of PH associated with HFpEF: the 7th WSPH proposed four stages to identify patients for earlier referral to heart failure or PH centers.

Proposed stages of PH associated with HFpEF (7th WSPH)

Stage	Clinical features	Suggested management
A: At risk	Risk factors only (body mass index >30 kg/m2, systemic hypertension, glucose intolerance or diabetes, atrial fibrillation, possibly sleep apnea); no symptoms; normal exercise capacity, echocardiography and NT-proBNP	Treatment of comorbidities; risk factor and dietary modification
B: Structural heart disease	WHO functional class I to II; peak oxygen uptake >80% of predicted; mildly elevated TRV and left atrial volume, grade 1 to 2 diastolic dysfunction, normal RV; normal or mildly elevated NT-proBNP; mild PH	Optimized guideline-directed therapy; annual echocardiography; clinical trial enrollment
C: Symptomatic heart disease	WHO functional class II to III; peak oxygen uptake 50% to 80% of predicted; mildly to moderately elevated TRV and left atrial volume; mild to moderate RV dysfunction; NT-proBNP well above the upper limit of normal before diuresis, normal or elevated after diuresis	Follow-up twice yearly with functional testing and echocardiography; consider a pulmonary artery pressure monitoring device and referral to a PH center
D: Right heart predominant	WHO functional class IV; peak oxygen uptake <50% of predicted; severely elevated TRV, severe RV dysfunction; NT-proBNP very markedly elevated even after diuresis	Referral to a PH or heart failure center for individualized management; palliative PAH therapy may be considered in selected patients, with clear discontinuation criteria

PH Associated with Lung Disease and/or Hypoxia (Group 3)

• Optimal treatment of the underlying lung disease is the cornerstone, together with smoking cessation, vaccination, pulmonary rehabilitation, management of HFpEF and sleep-disordered breathing, and early palliative care when appropriate. The task force suggests treating hypoxemia at rest, on exertion and at night with oxygen. PH in chronic lung disease is an indication for referral for lung transplant evaluation in eligible patients.
• Interstitial lung disease: in INCREASE (326 patients with PH associated with interstitial lung disease, including combined pulmonary fibrosis and emphysema and connective tissue disease-associated disease, with mPAP ≥25 mmHg and PVR >3 WU), inhaled treprostinil increased the peak 6MWD at 16 weeks by 31.12 m (95% CI 16.85 to 45.39), lowered NT-proBNP (treatment ratio 0.58, 95% CI 0.47 to 0.72) and reduced clinical worsening (22.7% vs 33.1%; HR 0.61, 95% CI 0.40 to 0.92). Inhaled treprostinil was approved for this indication in the United States in 2021, and the 2022 ESC/ERS guidelines state that it may be considered in PH associated with interstitial lung disease. Patients with a PVR <4 WU had no gain in 6MWD.
• PDE5 inhibitors may be considered on an individual basis in PH associated with interstitial lung disease, especially in patients with severe hemodynamic impairment. In an international registry of 940 patients with PH associated with interstitial lung disease, PDE5 inhibitor treatment of severe PH (PVR >5 WU) was associated with better survival in PH associated with idiopathic interstitial pneumonia (HR 0.537; 0.370 to 0.781); these data are observational.
• Contraindicated drugs: riociguat in PH associated with idiopathic interstitial pneumonia (RISE-IIP, stopped early: serious adverse events 37% vs 23% and 8 vs 3 deaths) and ambrisentan in idiopathic pulmonary fibrosis (ARTEMIS-IPF, stopped early: disease progression 27.4% vs 17.2%; HR 1.74, 95% CI 1.14 to 2.66).
• COPD: inhaled treprostinil is not recommended for PH associated with COPD; in PERFECT (mPAP ≥30 mmHg and PVR ≥4 WU), the trial was stopped early because of an increased risk of serious adverse events and suggestive evidence of increased mortality. In a meta-analysis of 23 randomized and 23 nonrandomized studies, PDE5 inhibitors, but not ERAs, lowered the systolic pulmonary artery pressure in COPD (-5.9 mmHg, 95% CI -10.3 to -1.6) without consistent clinical benefit, and in a meta-analysis of 308 patients with severe COPD-associated PH, various PH drugs lowered mPAP and PVR without a significant change in 6MWD or natriuretic peptides.
• PH with mild COPD or mild interstitial lung disease: patients with mild COPD or interstitial lung disease (and/or a smoking history), a severely reduced DLCO and PH respond less well to therapy than patients with classic idiopathic PAH and should be referred to a PH center for phenotyping and management; if they are treated, initial monotherapy with close monitoring is recommended.
• Specific conditions: immunosuppression may improve inflammatory connective tissue disease-associated interstitial lung disease and its PH; sirolimus is recommended for the parenchymal disease of lymphangioleiomyomatosis; and patients with sarcoidosis-associated PH or pulmonary Langerhans cell histiocytosis with PH should be managed at PH centers.

Chronic Thromboembolic Pulmonary Hypertension (Group 4)

• All patients with chronic thromboembolic pulmonary disease, especially those with PH, should be referred to an expert center, where a multidisciplinary team (pulmonary endarterectomy surgeon, balloon pulmonary angioplasty specialist, PH expert and pulmonary vascular radiologist) decides on treatment. Operability is the first decision.
• Anticoagulation: lifelong therapeutic anticoagulation is recommended to prevent recurrent venous thromboembolism. Vitamin K antagonists are the established standard and are particularly recommended in patients with antiphospholipid syndrome. In a cohort of patients anticoagulated after pulmonary endarterectomy (794 receiving vitamin K antagonists and 206 receiving direct oral anticoagulants), recurrent venous thromboembolism was more frequent with direct oral anticoagulants (4.62% vs 0.76% per person-year), whereas major bleeding (0.68% vs 0.67% per person-year) and survival did not differ.
• Medical therapy targets the microvasculopathy in patients with inoperable CTEPH or with persistent or recurrent PH after pulmonary endarterectomy.
  • Riociguat (CHEST-1, 261 patients): 6MWD +46 m (95% CI 25 to 67) and PVR -246 dyn·s·cm^-5 (95% CI -303 to -190) compared with placebo at 16 weeks; it is approved for inoperable CTEPH and for persistent or recurrent PH after surgery.
  • Macitentan (MERIT-1, 80 patients with inoperable CTEPH): PVR at week 16 fell to 71.5% of baseline vs 87.6% with placebo (geometric means ratio 0.81, 95% CI 0.70 to 0.95). These are the figures of the 2024 republication; the original 2017 report was retracted.
  • Subcutaneous treprostinil (CTREPH, 105 patients with nonoperable CTEPH or persistent or recurrent PH after pulmonary endarterectomy): high-dose compared with low-dose therapy improved 6MWD at week 24 by 40.69 m (95% CI 15.86 to 65.53).
  • In patients who are candidates for balloon pulmonary angioplasty and have a PVR >4 WU, medical therapy should be considered before the intervention, although the quality of evidence is low; pretreatment with riociguat reduced serious adverse events related to angioplasty. The 7th WSPH algorithm proposes riociguat before angioplasty when the mPAP is ≥40 mmHg or the PVR is >4 WU.
• Multimodal therapy, the sequential combination of at least two of the three treatment modalities (surgery, angioplasty and medical therapy), is considered for persistent PH after pulmonary endarterectomy, for inoperable CTEPH and for selected high-risk patients with operable disease on one side and inoperable disease on the other. With contemporary multimodal care, 3-year survival exceeds 90% in both operated and nonoperated patients.
• Supplemental oxygen for exercise-induced desaturation (a fall of ≥4% in peripheral oxygen saturation to ≤92% during a 6-minute walk test) improved exercise capacity and quality of life in a randomized trial.

CTEPH Mismatched perfusion defects on V/Q scan, confirmed by RHC and pulmonary vascular imaging (CT pulmonary angiography and catheter-based pulmonary angiography)

Lifelong anticoagulation (vitamin K antagonist in antiphospholipid syndrome); assessment of operability by a multidisciplinary CTEPH team

Technically operable

Technically inoperable, or unfavorable risk-benefit ratio for surgery

Pulmonary endarterectomy (treatment of choice)

Medical therapy (riociguat; macitentan or subcutaneous treprostinil) and balloon pulmonary angioplasty; riociguat first if mPAP ≥40 mmHg or PVR >4 WU

Persistent or recurrent PH: medical therapy and/or balloon pulmonary angioplasty (multimodal therapy)

Structured follow-up, with imaging and RHC 3 to 6 months after pulmonary endarterectomy or balloon pulmonary angioplasty; aim for normal or near-normal resting hemodynamics

PH with Unclear and/or Multifactorial Mechanisms (Group 5)

• Group 5 comprises PH with unclear and/or multifactorial mechanisms, sometimes with severe and specific pulmonary vascular involvement, as in sarcoidosis; evidence for PAH-targeted therapy is limited.
• Sarcoidosis: the WASOG statement provides screening and RHC criteria, but no phenotype has been identified in which PH-specific therapy can be definitively recommended. In a 1-year double-blind, placebo-controlled trial of riociguat in only 16 patients, clinical worsening occurred in 5 of 8 patients receiving placebo and none of 8 receiving riociguat. In the RESAPH registry of sarcoidosis-associated PH, a PVR ≥5 WU, an mPAP ≥40 mmHg and a 6MWD <300 m were associated with lower transplant-free survival.
• Sickle cell disease: the ATS guideline strongly recommends hydroxyurea for patients at increased risk of death (tricuspid regurgitant velocity ≥2.5 m/s, NT-proBNP ≥160 pg/mL or RHC-confirmed PH) and strongly recommends against PAH-targeted therapy on the basis of an elevated tricuspid regurgitant velocity or NT-proBNP alone. In selected patients with RHC-confirmed PH, an elevated PVR and a normal PAWP, it suggests (weak recommendation) a prostacyclin agonist or an ERA and strongly recommends against PDE5 inhibitors.

Procedural / Surgical Therapy

Pulmonary Endarterectomy

• Pulmonary endarterectomy (PEA) is the guideline-recommended treatment of choice for technically operable CTEPH and the first consideration in every patient with CTEPH. At expert centers it normalizes pulmonary artery pressures in about 70% to 75% of patients, with an operative mortality of about 2%; survival exceeds 90% at 3 years and is 87% at 5 years and 78% at 10 years. Advanced age (>80 years), morbid obesity and repeat operations are not considered contraindications.
• At the University of California San Diego, in-hospital mortality fell from 5.2% in the first 1,000 to 2.2% in the most recent 500 of 1,500 patients operated between 1999 and 2010, and mean pulmonary artery pressure fell from 45.5 ± 11.6 to 26.0 ± 8.4 mmHg in the most recent group.
• Delaying surgery for a trial of PH drugs or balloon pulmonary angioplasty has no proven benefit in operable patients. Residual PH (defined at the time as mPAP ≥25 mmHg) has been reported in 17% to 51% of patients after PEA; an mPAP ≥38 mmHg with a PVR ≥5 WU 3 to 6 months after surgery was associated with worse survival.
• Expert PEA centers are expected to perform more than 50 operations per year with a mortality below 3% and to have ECMO support available.

Balloon Pulmonary Angioplasty

• Balloon pulmonary angioplasty (BPA) is recommended for symptomatic patients who are ineligible for PEA because of distal lesions and for those with persistent or recurrent PH after surgery; it may be considered for technically operable disease with a high proportion of distal lesions and an unfavorable risk-benefit ratio for surgery.
• Two randomized trials compared BPA with riociguat in inoperable CTEPH. In RACE (105 patients), PVR at week 26 fell to 39.9% of baseline with BPA vs 66.7% with riociguat (ratio 0.60, 95% CI 0.52 to 0.69), but treatment-related serious adverse events occurred in 42% vs 9%, mostly lung injury; complications were less frequent when BPA followed riociguat pretreatment. In MR BPA (61 patients), mPAP fell by 16.3 vs 7.0 mmHg at 12 months (difference -9.3 mmHg, 95% CI -12.7 to -5.9).
• In the International BPA Registry (484 patients at 18 centers), a median of 5 sessions reduced mPAP by 38% and PVR by 57%. Complications occurred in 11.3% of sessions and in 33.9% of patients, mostly hemoptysis, and no patient died within 30 days. In a Japanese nationwide registry of 1,202 patients, BPA-related mortality was 0.2% and 3-year survival was 94.7%.
• Lung injury, usually from wire perforation, occurs in about 10% of sessions and is more severe when mPAP is ≥40 mmHg. A final mPAP <30 mmHg has been proposed as the minimum hemodynamic goal of BPA, although this target has not been validated.

Lung and Heart-Lung Transplantation

• Bilateral lung transplantation or heart-lung transplantation is the only potentially life-prolonging option for patients with severe PH and RV failure refractory to medical therapy. Because the right ventricle almost always recovers sufficiently after lung transplantation, bilateral lung transplantation is preferred; heart-lung transplantation should be reserved for patients with post-tricuspid congenital cardiac defects or coexisting left heart disease.
• One-year survival after lung transplantation for PH now exceeds 90%, and in patients with PAH who survive the first year, the conditional median survival after bilateral lung transplantation is 10.0 years. Patients with PAH still have the highest waiting-list mortality and the lowest likelihood of transplantation.
• Indications for referral include high risk at diagnosis, intermediate-high or high risk during follow-up, failure to reach low risk on parenteral therapy, progression or a first acute decompensation despite optimal therapy, significant RV dysfunction, secondary liver or kidney dysfunction, a first episode of hemoptysis, systemic sclerosis or heritable PAH, and a diagnosis of PVOD or PCH. Ideally, patients are listed before admission to the intensive care unit or the onset of end-organ damage.
• Early referral allows modifiable barriers to be addressed, such as body mass index, deconditioning, smoking, vaccinations, social support and financial issues.

Atrial Septostomy and Potts Shunt

• Atrial septostomy has shown significant benefit in PAH, most notably where access to medications is limited, but familiarity with the procedure is uncommon worldwide. It should be performed only as an elective procedure, and urgent atrial septostomy is not recommended.
• Early data suggest a possible benefit of a Potts shunt in children, but the procedure carries high morbidity and mortality. It should be considered only in stable patients within systematic studies of safety and effectiveness, and not in unstable patients or as a bridge to transplantation. The pediatric task force, however, describes the Potts shunt as a palliative bridge to transplantation or as destination therapy in selected children (see Children). An ATS clinical practice guideline addresses the Potts shunt, atrial septostomy, ECMO and lung transplantation in children with progressive PH.

Other Procedures

• Liver transplantation may be considered in selected patients with portopulmonary hypertension; the International Liver Transplantation Society suggests hemodynamic targets before listing of an mPAP <35 mmHg with a PVR <5 WU, or an mPAP of 35 to 45 mmHg with a PVR <3 WU.
• Defect closure in congenital heart disease: in patients with PAH and systemic-to-pulmonary shunts, decisions on closure should follow a multiparametric assessment rather than hemodynamics alone, and closure after a period of targeted drug therapy has no proven long-term benefit, so caution is warranted.
• Valve intervention and other treatments of the underlying left heart disease are the main interventions in group 2 PH (see Medical Therapy).

Long-Term Management

Follow-up and Treatment Goals

• Patients with PAH need regular multiparametric reassessment, with the first reassessment 3 to 4 months after treatment initiation and regular reassessment thereafter, using WHO functional class, 6MWD and BNP or NT-proBNP and, when major treatment changes are considered, cardiac imaging and hemodynamics.
• The established treatment goal is to reach and maintain a low-risk profile. Treatment decisions should also integrate natriuretic peptides, RV imaging (for example, right atrial area <18 cm², TAPSE/sPAP >0.32 mm/mmHg and no pericardial effusion) and invasive hemodynamics, particularly during the first 3 to 6 months after treatment initiation.
• In patients receiving PAH drugs who are at intermediate-low, intermediate-high or high risk, RHC during follow-up is suggested when therapeutic consequences are expected.

Exercise Training and Rehabilitation

• In a European multicenter randomized trial (129 patients enrolled; 116 with PAH or CTEPH on disease-targeted therapy completed the study), standardized exercise training, started in hospital and continued at home, increased the 6MWD by 34.1 ± 8.3 m compared with usual care (95% CI 18 to 51) and improved peak oxygen uptake.
• In a Cochrane review, exercise-based rehabilitation increased the 6MWD by 48.52 m (95% CI 33.42 to 63.62; 11 studies, 418 participants; low-certainty evidence) without an increase in serious adverse events. The ATS conditionally recommends pulmonary rehabilitation for adults with PH.

General Measures

• Vaccination against influenza, SARS-CoV-2 and Streptococcus pneumoniae, and against respiratory syncytial virus in patients older than 60 years; diuretics for fluid retention; long-term oxygen for persistent hypoxemia; correction of iron status in iron deficiency anemia; and psychological support (see Initial Management).
• Women of childbearing potential should receive contraceptive counseling at diagnosis, and highly effective contraception is required with endothelin receptor antagonists, riociguat and sotatercept.
• Abrupt interruption of parenteral prostacyclin therapy can be life-threatening.
• Patients on sotatercept need monitoring of hemoglobin and platelet count and surveillance for bleeding and new telangiectasias.
• Transitions from parenteral to oral or inhaled prostacyclin pathway agents are sometimes attempted in patients with an excellent response (PVR <5 WU, normal cardiac index and low-risk findings), but data are limited and some patients deteriorate; they require close monitoring, often including RHC.

Medication Adherence

• More than 80% of patients with PAH take five or more medications (median nine), and reported adherence rates range from 48% to 76%. Adherence should be assessed regularly with nonintimidating methods, and fixed-dose combinations may help; the macitentan-tadalafil combination is the only one in clinical use.

Palliative Care

• Palliative care in PH is needs-based rather than reserved for the end of life. The 7th WSPH recommends early integration of palliative care, regular quality-of-life assessment with a PH-specific patient-reported outcome tool (such as emPHasis-10), automatic discussion or referral when risk status worsens, screening for depression, anxiety and insomnia, access to psychological support and documentation of advance care directives.
• Hospitalization, initiation of parenteral prostacyclin and referral for transplantation are suggested triggers for discussing palliative care.

Special Populations

Pregnancy

• The 2022 ESC/ERS guidelines recommend counseling women of childbearing potential at diagnosis about the risks and uncertainties of pregnancy, offering contraceptive advice and providing prompt counseling at an experienced PH center, including genetic counseling and shared decision-making, for women who consider or achieve pregnancy. The 2025 ESC guidelines on cardiovascular disease and pregnancy are the current European reference for pregnancy care in heart disease.
• The 7th WSPH task force concluded that most women with mild PH or PH well controlled on medical therapy may safely become pregnant and continue pregnancy with expert multidisciplinary care. The risk is particularly high in Eisenmenger syndrome and in severe, poorly controlled PH; these women should be discouraged from pregnancy, and if they become pregnant, termination should be discussed and, if chosen, performed at a PH center with psychological support. This position is more permissive than that of the 7th WSPH treatment task force, which maintains advice against pregnancy for most patients with PAH (see General and Supportive Measures in PAH), so counseling should be individualized, with shared decision-making.
• Outcomes: in series published from 2017 to 2023, maternal mortality ranged from 2% to 40% in more than 3,500 cases from developing countries and from 0 to 16% in 156 cases from developed countries. In a multinational registry of 26 pregnancies in women with PAH, 3 women (12%) died, and successful pregnancies occurred mainly in women with well-controlled PAH, 8 of whom were long-term responders to calcium channel blockers. In the ESC ROPAC registry (151 pregnancies in women with PH), maternal mortality was 3.3% up to 1 week after delivery and 43% (3 of 7) in idiopathic PAH, and heart failure occurred in 27%.
• Drug therapy: endothelin receptor antagonists, riociguat and selexipag are potentially teratogenic and are considered contraindicated in pregnancy; PDE5 inhibitors and prostacyclin analogues are considered safe and form the mainstay of treatment. Human data on sotatercept in pregnancy are lacking; it may impair fertility and remains detectable for at least 2 months after the last dose, and effective contraception is required during treatment and for at least 4 months after the last dose.
• Monitoring and delivery: clinical assessment, echocardiography and BNP or NT-proBNP are repeated at intervals of a few days to 2 to 3 months, and a rise in natriuretic peptides beyond normal variability is a warning sign. Most centers prefer a planned cesarean delivery at 36 to 38 weeks of gestation, usually under regional anesthesia. The risk of hemodynamic collapse is highest in the first 12 hours after delivery, and women with more than mild PH are monitored in an intermediate or intensive care unit for at least 24 to 72 hours. Breastfeeding is contraindicated when endothelin receptor antagonists are reintroduced after delivery.

Perioperative Care

• PH is an independent risk factor for in-hospital death, myocardial infarction and stroke after major noncardiac surgery. In a prospective series of 114 patients, major complications occurred in 6.1%, and perioperative mortality was 3.5% overall, 15% for emergency procedures and 2% for elective procedures; elevated right atrial pressure, a 6MWD <399 m, the need for vasopressors and emergency surgery predicted complications.
• Validated perioperative risk scores for PH are lacking. Assessment combines PH severity (validated PAH risk tools, comprehensive echocardiography of the right heart) with the risk of the procedure, and a multidisciplinary team including the PH specialist and a cardiac anesthesiologist is recommended.
• Targeted therapies should not be interrupted, and parenteral prostacyclin infusions must never be stopped. Both hypervolemia and hypovolemia should be avoided, systemic pressure is supported with norepinephrine and/or vasopressin, and high positive end-expiratory pressure should be avoided; inhaled nitric oxide or epoprostenol can help control pulmonary pressures. Regional and multimodal anesthesia may avoid intubation, and close postoperative monitoring is required because RV dysfunction may develop even in previously compensated patients.

Children

• Beyond the first months of life, PH in children is defined as in adults; the definition is generally applied after 3 months of age. Pre-capillary PH requires a PAWP ≤15 mmHg and an indexed PVR (PVRI) >3 WU·m², and indexed values are used until a body surface area of 1.5 m², with both PVR and PVRI reported during the transition to adulthood.
• In 30% to 50% of children with group 1 PAH, PAH is associated with congenital heart disease. Developmental lung diseases, most commonly bronchopulmonary dysplasia and congenital diaphragmatic hernia, belong to group 3, and PH in these conditions may regress with lung growth.
• Genetic variants contribute to about 42% of pediatric-onset PAH, compared with about 12.5% of adult-onset PAH, and genetic testing in children should include exome or genome sequencing, ideally with both biological parents.
• The pediatric treatment algorithm parallels the adult one: vasoreactivity testing in idiopathic, heritable and drug-associated PAH, with high-dose calcium channel blockers for responders; initial parenteral prostacyclin with rapid addition of a PDE5 inhibitor and/or an ERA for high-risk children, with early consultation for lung transplantation and interventional palliative procedures such as a Potts shunt; and upfront or sequential oral ERA plus PDE5 inhibitor combination for lower-risk children. Achieving and maintaining a low-risk profile is considered an adequate treatment response.
• In STARTS-1 (235 children), sildenafil did not significantly improve peak oxygen uptake when doses were combined (7.7 ± 4.0%; P = 0.056), and low doses were ineffective. In the long-term STARTS-2 extension, 3-year survival was 94%, 93% and 88% with low, medium and high doses, and mortality was higher with high than with low doses (HR 3.95, 95% CI 1.46 to 10.65).
• Atrial septostomy has been shown to prolong survival where continuous prostacyclin therapy and transplantation are unavailable. In a registry of 110 children with a Potts shunt, freedom from death or transplantation was 77% at 1 year and 58% at 5 years. Anticoagulation is generally not indicated in children without specific thromboembolic concerns. Pediatric care is also addressed by the AHA/ATS guideline, the European Pediatric Pulmonary Vascular Disease Network consensus and the ATS guideline on interventional strategies.

Older Patients and Patients with Comorbidities

• In COMPERA, patients older than 65 years with idiopathic PAH were less likely to reach treatment targets, received combination therapy less often and had lower survival than younger patients, even after adjustment for the survival of the general population.
• In GRIPHON, 51% of patients had at least one cardiovascular comorbidity (hypertension 33%, obesity 27%, diabetes 11% and coronary artery disease 10%). In subgroup analyses of GRIPHON and AMBITION, reductions in clinical worsening in patients with comorbidities were generally similar to the overall results, but adverse events were more frequent and improvements in symptoms and walk distance were smaller.

Connective Tissue Disease-Associated PAH

• The general PAH algorithm applies: in AMBITION, initial ERA plus PDE5 inhibitor therapy produced improvements in clinical worsening and 6MWD in connective tissue disease-associated PAH similar to those in idiopathic PAH. The 2023 EULAR recommendations support first-line combination therapy for newly diagnosed PAH associated with systemic sclerosis.
• Risk tools perform less well in systemic sclerosis, adverse events are more frequent, and a PVOD phenotype may be under-recognized. Sotatercept requires caution in patients prone to gastrointestinal bleeding from vascular lesions, and digital contractures may limit the use of parenteral therapy. In systemic lupus erythematosus and mixed connective tissue disease, optimal treatment of the underlying disease may substantially improve PH.

HIV-Associated PAH

• Patients with HIV-associated PAH are younger, more often male and have more severe hemodynamics than patients with idiopathic PAH, and the response to PAH therapy appears similar. Antiretroviral therapy and PAH therapy are both recommended. Protease inhibitors substantially increase sildenafil and tadalafil levels, and the manufacturers advise against PDE5 inhibitors with strong cytochrome P450 3A inhibitors.

Portopulmonary Hypertension

• Portopulmonary hypertension is PAH in the setting of portal hypertension (hepatic venous pressure gradient >5 mmHg or indirect signs), with or without cirrhosis. Volume overload and high cardiac output, which also occur in liver disease, must be distinguished from true PAH, and optimizing volume status and treating the liver disease are essential.
• In PORTICO (85 patients), macitentan reduced PVR by 35% compared with placebo at 12 weeks (ratio of geometric means 0.65, 95% CI 0.59 to 0.72) without hepatic safety concerns. Caution is needed in advanced liver disease because of impaired drug metabolism.
• In a large U.S. national cohort, cardiac index emerged as the critical hemodynamic variable for risk stratification, and liver transplantation gave the best long-term outcomes in selected patients; in observational studies, patients who received PAH therapy followed by liver transplantation had better survival than those treated with PAH therapy alone. The 2025 International Liver Transplantation Society guideline updates the hemodynamic criteria and the role of transplantation.

Congenital Heart Disease and Eisenmenger Syndrome

• Patients with PAH after repair of a congenital defect (more than 1 year earlier) are treated like patients with idiopathic PAH. Patients with Eisenmenger syndrome or persistent systemic-to-pulmonary shunts need a comprehensive evaluation at an experienced center, exclusion of post-capillary PH, assessment for iron deficiency, avoidance of routine phlebotomy, endocarditis prophylaxis when indicated and air filters on intravenous lines.
• In BREATHE-5 (54 patients with Eisenmenger syndrome), bosentan did not worsen oxygen saturation, reduced the PVR index by 472.0 dyn·s·cm^-5 and increased exercise capacity by 53.1 m compared with placebo. In MAESTRO, macitentan did not improve 6MWD (-4.7 m). Sequential, symptom-oriented therapy is generally recommended, and lung or heart-lung transplantation should be considered for persistent high-risk features.
• In adults, the proposed operability threshold is a baseline PVR <3 WU; the ESC/ERS guidelines add that, in an atrial septal defect with a baseline PVR >5 WU, a fall below 5 WU on PAH-targeted therapy allows closure, although the long-term benefit of this approach is unproven (see Other Procedures). Patients with Eisenmenger syndrome should not be considered for this approach.
• In a single-center cohort, 20-year survival was 87% in Eisenmenger syndrome but only 36% in PAH after defect correction. Management of adults with congenital heart disease is addressed by the 2025 ACC/AHA guideline, the 2020 ESC guideline and an AHA scientific statement on PH in congenital heart disease.

Drug- and Toxin-Associated PAH

• The causative drug should be stopped. Partial or complete reversal has been reported after discontinuation of dasatinib and interferon, so in patients with lower-risk features, observation for 3 to 4 months can be considered before starting PAH therapy. In 9 patients with dasatinib-associated PH, all but one improved within 4 months of stopping the drug, but none reached a normal mPAP.
• Stimulant-associated PAH rarely remits spontaneously and has a worse outcome than idiopathic PAH; patients should be treated according to the PAH algorithm and referred for treatment of substance use at diagnosis.

Schistosomiasis-Associated PAH

• PAH therapy (PDE5 inhibitors or ERAs, alone or combined) is associated with improved survival, and treatment of the parasitic infection is considered, although a hemodynamic benefit has not been established. In a Brazilian cohort, none of 54 patients responded to acute vasodilator testing.

Pulmonary Veno-occlusive Disease and Pulmonary Capillary Hemangiomatosis

• PVOD/PCH has a worse prognosis than PAH, and life-threatening pulmonary edema may follow the start of PAH therapy. There is no established medical therapy: a systematic review found only 14 case reports and 4 case series of 8 to 16 patients. PAH drugs should be used with great caution and only at expert centers, and lung transplantation is the preferred definitive treatment, with early referral.

Limited-Resource Settings

• Where PAH drugs are unavailable or unaffordable, diuretics and general supportive measures remain universally available, monotherapy is often the default and parenteral therapies are generally not available. Access to generic PAH medications and advocacy for equitable access are encouraged.

Case Studies

Case #1

External links

• Pulmonary Hypertension, National Heart, Lung, and Blood Institute (NHLBI)