Pulmonary hypertension: five groups and PAH-specific therapy

This page follows the 2022 ESC/ERS guideline from the haemodynamic definition, through the five groups and the diagnostic pathway, to risk-based PAH therapy and the group 2, 3 and 4 rows. The guideline was published simultaneously in the European Heart Journal (EHJ) and the European Respiratory Journal (ERJ); the recommendation rows below are quoted from the ERJ copy.^[1]

• Related topic: Pulmonary embolism: risk-stratified management.
• Related topic: Heart failure with preserved ejection fraction (HFpEF).
• Related topic: Cardiovascular disease in pregnancy.

Definitions: the haemodynamic language

The definitions of PH are haemodynamic, based on right heart catheterisation.^[1] ESC/ERS 2022 bases the definitions on haemodynamic assessment by RHC, but says the final diagnosis and classification should reflect the whole clinical context.^[1]

Haemodynamic definitions of pulmonary hypertension (ESC/ERS 2022, Table 5)

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Why 2 WU?^[1] ESC/ERS 2022 puts both the upper limit of normal PVR and the lowest prognostically relevant PVR threshold at about 2 WU.^[1] PVR depends on body surface area and age, and elderly healthy subjects have higher values.^[1]

The wedge cut-off is a compromise.^[1] The upper limit of normal PAWP is considered to be 12 mmHg, but the guideline keeps 15 mmHg as the threshold for pre-capillary PH and calls any PAWP threshold arbitrary.^[1] Phenotype, risk factors and echocardiographic findings, including left atrial volume, need to be considered when distinguishing pre- from post-capillary PH.^[1]

• PAH is pre-capillary PH in the absence of other causes of pre-capillary PH, such as CTEPH and PH associated with lung diseases (ESC/ERS 2022).^[1]
• Mixed pictures: all PH groups may comprise both pre- and post-capillary components, and the primary classification should be based on the presumed predominant cause of the pressure increase.^[1]
• Unclassified PH: mPAP above 20 mmHg with PVR of 2 WU or less and PAWP of 15 mmHg or less; these patients are frequently characterised by elevated pulmonary blood flow, the term 'unclassified PH' may be used, and they may present with congenital heart disease, liver disease, airway disease, lung disease or hyperthyroidism.^[1]
• Exercise PH has been re-introduced; an mPAP/CO slope above 3 mmHg/L/min is not physiological under 60 years and may rarely be present in healthy subjects over 60 years.^[1]
• An increased mPAP/CO slope does not allow for differentiation between pre- and post-capillary causes.^[1]

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The five groups

The five groups sort patients by mechanism, presentation, haemodynamics and treatment.^[1] ESC/ERS 2022 kept the basic structure of the 2015 ESC/ERS and 6th World Symposium (WSPH) classification.^[1]

Clinical classification of pulmonary hypertension (ESC/ERS 2022, Table 6)

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• Table 6 footnotes: patients with heritable PAH or PAH associated with drugs and toxins might be acute responders; HF with reduced ejection fraction means LVEF ≤40%, mildly reduced 41–49%.^[1]
• Other pulmonary artery obstructions include sarcomas (high or intermediate grade, or angiosarcoma), other malignant and non-malignant tumours, arteritis without connective tissue disease, congenital pulmonary arterial stenoses and hydatidosis.^[1]
• Group 5 examples: haematological disorders include inherited and acquired chronic haemolytic anaemia and chronic myeloproliferative disorders; systemic disorders include sarcoidosis, pulmonary Langerhans’s cell histiocytosis and neurofibromatosis type 1.^[1]

Three changes from 2015 are worth knowing.^[1] Non-responders and acute responders at vasoreactivity testing are now subgroups of idiopathic PAH (IPAH).^[1] PVOD/PCH and persistent PH of the newborn now sit inside group 1.^[1] In group 3, "hypoventilation syndromes" replaces "sleep-disordered breathing".^[1] Sole nocturnal obstructive sleep apnoea is generally not a cause of PH, but PH is frequent in hypoventilation syndromes causing daytime hypercapnia.^[1]

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Epidemiology and risk factors

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Start with the common causes. Globally, left heart disease (LHD) is the leading cause, and lung disease, especially chronic obstructive pulmonary disease (COPD), is the second most common cause.^[1] Prevalence is higher above 65 years, and developing PH is associated with worsening symptoms and increased mortality whatever the cause.^[1]

• PAH: heritable PAH affects twice as many females as males, but recent data from the USA and Europe suggest that PAH is now frequently diagnosed in patients aged 65 years or more, who often have cardiovascular comorbidities, with a more equal distribution between sexes.^[1]
• PAH subtypes: in most registries IPAH was the most common subtype (50–60% of all cases), followed by PAH associated with connective tissue disease (CTD), congenital heart disease (CHD) and portal hypertension.^[1]
• Group 2: post-capillary PH is a frequent complication mainly in heart failure with preserved ejection fraction (HFpEF), affecting at least 50% of these patients.^[1]
• Valve disease: PH can be found in 60–70% of patients with severe and symptomatic mitral valve disease and in up to 50% of those with symptomatic aortic stenosis.^[1]
• Group 3: mild PH is common in advanced parenchymal and interstitial lung disease.^[1]
• Group 5: the cause is often multifactorial and can be secondary to raised pre- and post-capillary pressure as well as direct effects on the pulmonary vasculature.^[1]

Drugs and toxins are classified by the strength of their association with PAH (Table 7).^[1]

Drugs and toxins associated with PAH (ESC/ERS 2022, Table 7)

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The 2024 Eur Respir J report on the definition, classification and diagnosis of PH has since added mitomycin-C and carfilzomib to the definite list; it is not a guideline and carries no class or level.^[8]

Pathophysiology

Whatever the group, symptoms of PH are mainly linked to right ventricular (RV) dysfunction.^[1] ESC/ERS 2022 says PH leads to RV pressure overload and dysfunction independent of the underlying aetiology.^[1] In PAH, symptoms are mainly related to progressive RV dysfunction as a consequence of progressive pulmonary vasculopathy.^[1]

ESC/ERS 2022 Figure 7 shows the current therapeutic targets of PAH (group 1): the endothelin, nitric oxide–cGMP and prostacyclin pathways.^[1] The 2026 ERS update adds sotatercept, which it calls an activin signalling inhibitor targeting a novel pathway.^[15]

^[1]

Left heart disease raises pulmonary pressure through several combined mechanisms.^[1] ESC/ERS 2022 lists them with its Figure 11.^[1]

• An initial passive rise in left ventricular filling pressures transmitted backwards into the pulmonary circulation.^[1]
• Pulmonary artery endothelial dysfunction, including vasoconstriction.^[1]
• Vascular remodelling, which may occur in venules and/or arterioles.^[1]
• RV dilatation and dysfunction with functional tricuspid regurgitation, and altered RV–pulmonary artery coupling.^[1]

In CTEPH the obstruction is not the whole story.^[1] ESC/ERS 2022 says PH there is not only a consequence of obstruction by organised fibrotic clots but can also be related to an associated microvasculopathy.^[1]

Clinical presentation

The story is breathlessness that creeps up.^[1] ESC/ERS 2022 names dyspnoea on progressively minor exertion as the cardinal symptom, typically associated with exercise early in the disease.^[1] Diagnosis is slow: the time from symptom onset to PH diagnosis remains over 2 years, with most patients presenting with advanced disease.^[1]

• Thoracic compression syndromes occur in a minority of patients with PAH and pronounced pulmonary artery dilation, and may occur at any disease stage, even with mild functional impairment (Figure 2 footnote).^[1]
• Who gets which group (Table 14): PAH has variable age, though young female patients may be predominantly affected; group 2 is mostly elderly with female predominance in HFpEF; group 3 is mostly elderly men, often smokers; group 4 has variable age, and CTEPH may occur without a history of venous thrombo-embolism.^[1]
• Table 14 adds that PAH may affect individuals of all ages and sexes, and diagnosis in males should not be delayed.^[1]

Differential diagnosis: which group is it?

Once PH is suspected, the work-up aims to establish the differential diagnosis and distinguish the causes of PH by the clinical classification.^[1] ESC/ERS 2022 Table 14 lines up the characteristic findings of groups 1 to 4.^[1]

Characteristic diagnostic features (ESC/ERS 2022, Table 14; selected rows)

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In older patients, cardiopulmonary comorbidities can make it challenging to distinguish PAH from group 2 and group 3 PH.^[1] PH with LHD is likely with known cardiac disease, multiple cardiovascular comorbidities or risk factors, atrial fibrillation at diagnosis, and imaging findings such as LV hypertrophy, increased left atrial size and reduced left atrial strain.^[1]

Phenotyping the likelihood of left heart disease (ESC/ERS 2022, Table 23; selected rows)

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• Validated HFpEF scores (HFA-PEFF, H2FPEF) may be helpful for detecting HFpEF as an underlying condition in PH (ESC/ERS 2022).^[1]
• For HFpEF itself, see Heart failure with preserved ejection fraction (HFpEF).

Bedside assessment: ECG, chest X-ray and lung function

Simple tests raise the suspicion but cannot settle it.^[1] In adults with suspected PH, such as unexplained exertional dyspnoea, right axis deviation has a high predictive value for PH.^[1] A normal ECG does not exclude PH, but a normal ECG with normal BNP/NT-proBNP is associated with a low likelihood of PH in patients referred for suspected PH or at risk of it, such as after acute PE.^[1]

Electrocardiogram abnormalities in patients with PH (ESC/ERS 2022, Table 8)

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• Chest X-ray: abnormal in most patients with PH, but a normal film does not exclude PH (ESC/ERS 2022).^[1]
• DLCO: a severely reduced DLCO (<45% predicted) with otherwise normal lung function can be found in SSc-associated PAH, PVOD, group 3 PH associated with emphysema, ILD or combined pulmonary fibrosis and emphysema, and some PAH phenotypes.^[1]
• Blood gases: PaCO2 is typically lower than normal in PAH because of alveolar hyperventilation.^[1]

Investigations

Echocardiography and the probability of PH

Echocardiography estimates the probability of PH.^[1][2] ESC/ERS 2022 says echocardiography alone is insufficient to confirm PH, which requires RHC.^[1] The guideline uses peak tricuspid regurgitation velocity (TRV), and not the estimated systolic pressure, as the key variable.^[1] A peak TRV above 2.8 m/s may suggest PH, but TRV alone cannot reliably determine whether PH is present.^[1]

Additional signs (Table 10) are used to define the echocardiographic probability of PH, which may then be low, intermediate or high.^[1] Signs from at least two of the three categories must be present to alter the level of probability.^[1]

Additional echocardiographic signs suggestive of PH (ESC/ERS 2022, Table 10)

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• TRV bands in Figure 5: peak TRV ≤2.8 m/s (or unmeasurable), 2.9–3.4 m/s and >3.4 m/s; the 2.8 m/s threshold was not changed with the new haemodynamic definition.^[1]
• Figure 5 footnote: RHC should be performed if useful information or a therapeutic consequence is anticipated, such as suspected PAH or CTEPH, and may not be indicated without risk factors or associated conditions for PAH or CTEPH, for example with mild PH and predominant LHD or lung disease.^[1]
• Left heart clues: ESC/ERS 2022 text says that, to separate group 2 from other forms of PH, left atrial size and signs of LV hypertrophy should always be measured.^[1]

Recommendation Table 2: echocardiography rows

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V/Q scan, CT and other tests

• V/Q scan: ventilation/perfusion or perfusion lung scan is recommended in unexplained PH to assess for CTEPH (ESC/ERS 2022, Class I, Level C).^[2]
• In the absence of parenchymal lung disease, a normal perfusion scan excludes CTEPH with a negative predictive value of 98% (ESC/ERS 2022).^[1]
• In most patients with PAH the V/Q scan is normal or shows a speckled pattern without the typical perfusion defects of PE or CTEPH; matched defects may be found in lung disease.^[1]
• CT pulmonary angiography (CTPA) is recommended in the work-up of suspected CTEPH (ESC/ERS 2022, Class I, Level C), but its accuracy for CTEPH is limited, with patient-level sensitivity and specificity of 76% and 96%.^[2][1]
• Chest CT should be considered in all patients with PH (ESC/ERS 2022, Class IIa, Level C); CT signs suggesting the presence of PH include an enlarged pulmonary artery, a pulmonary artery-to-aorta ratio above 0.9 and enlarged right heart chambers.^[2][1]
• Bloods: routine biochemistry, haematology, immunology, HIV testing and thyroid function tests are recommended in all patients with PAH to identify associated conditions (ESC/ERS 2022, Class I, Level C).^[2]
• Abdominal ultrasound is recommended for the screening of portal hypertension (ESC/ERS 2022, Class I, Level C).^[2]
• Lung function: pulmonary function tests with DLCO are recommended in the initial evaluation (ESC/ERS 2022, Class I, Level C).^[2]
• Digital subtraction angiography should be considered in the work-up of CTEPH (ESC/ERS 2022, Class IIa, Level C).^[2]
• Lung biopsy: open or thoracoscopic lung biopsy is not recommended in PAH (ESC/ERS 2022, Class III, Level C).^[2]
• CPET pattern in PAH: low end-tidal CO2, high ventilatory equivalent for CO2, low oxygen pulse and low peak oxygen uptake.^[1]

Right heart catheterisation

RHC is the gold standard for diagnosing and classifying PH.^[1] In PH centres, serious adverse events (1.1%) and procedure-related mortality (0.055%) are low.^[1] ESC/ERS 2022 text recommends the mid-thoracic level as the zero reference in the supine position, which is at the level of the left atrium in most patients.^[1] Its text says cardiac output should be assessed by direct Fick or thermodilution (mean of at least three measurements), and thermodilution should not be used with shunts.^[1]

Haemodynamic measures at RHC (ESC/ERS 2022, Table 11; selected rows)

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Recommendation Table 1: right heart catheterisation rows

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Vasoreactivity testing

The test identifies the small group of acute vasoresponders who may be candidates for high-dose CCBs.^[1] ESC/ERS 2022 states that pulmonary vasoreactivity testing is only recommended in idiopathic, heritable or drug-associated PAH (I/H/DPAH); the formal rows are below.^[1][2] Its text names inhaled nitric oxide or inhaled iloprost as the recommended test compounds; i.v. epoprostenol has similar evidence, but testing takes much longer and is less feasible.^[1] Intravenous adenosine is no longer recommended because of frequent side effects.^[1]

Recommendation Table 1: vasoreactivity rows

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Test compounds for vasoreactivity testing (ESC/ERS 2022, Table 12)

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In PH with LHD, vasoreactivity testing is restricted to evaluating heart transplant candidacy, and in congenital shunts it can be used to evaluate possible defect closure.^[1]

Exercise RHC and fluid challenge

• The main reason for exercise RHC is unexplained dyspnoea with normal resting haemodynamics, to detect early pulmonary vascular disease or left heart dysfunction (ESC/ERS 2022).^[1]
• A PAWP above 25 mmHg during supine exercise has been recommended for diagnosing HFpEF.^[1]
• Rapid infusion over 5–10 min of about 500 mL (7–10 mL/kg) of saline is generally accepted as enough to detect an abnormal rise in PAWP to 18 mmHg or more, suggestive of HFpEF, although validation and long-term evaluation are needed.^[1]

The diagnostic pathway and referral

ESC/ERS 2022 describes a multistep, pragmatic approach to diagnosis in unexplained dyspnoea or symptoms or signs raising suspicion of PH (Figure 6).^[1] The algorithm does not address screening of at-risk groups.^[1]

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Figure 6 of the guideline also notes that warning signs include rapid progression of symptoms, severely reduced exercise capacity, pre-syncope or syncope on mild exertion, and signs of right heart failure.^[1]

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Screening and early detection

ESC/ERS 2022 describes screening of asymptomatic high-risk groups, with a high prevalence of PAH or where the diagnosis significantly affects the proposed intervention.^[1] In systemic sclerosis (SSc), PAH prevalence is 5–19%, with an annual incidence of 0.7–1.5%.^[1] BMPR2 mutation carriers have a lifetime PAH risk of about 20%, with higher penetrance in women (42%) than men (14%).^[1]

Recommendation Table 3: screening rows (selected)

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After pulmonary embolism

CTEPH is the PE complication that this topic shares with Pulmonary embolism: risk-stratified management.^[1] ESC/ERS 2022 cites a meta-analysis reporting CTEPH incidence of 0.6% in all patients with acute PE, 3.2% in survivors and 2.8% in survivors without major comorbidities.^[1] In the prospective observational FOCUS study of follow-up after acute PE, the cumulative 2-year incidence was 2.3% for CTEPH and 16.0% for post-PE impairment, and both were associated with a higher risk of rehospitalisation and death.^[1]

• ESC/ERS 2022 notes that the guidelines current in 2022 did not recommend routine imaging follow-up of the pulmonary vascular tree after PE, but suggested checking the index PE scan for signs of CTEPH.^[1]
• Echocardiography is the preferred first-line test in suspected CTEPH.^[1]
• Up to 50% of patients have persistent perfusion defects after acute PE, but their clinical relevance is unclear.^[1]
• The optimal time to assess symptoms may be 3–6 months after acute PE, though earlier assessment may be needed in highly symptomatic or deteriorating patients.^[1]
• AHA/ACC 2026 PE guideline: with ongoing dyspnoea and/or functional impairment after 3 months or more of therapeutic anticoagulation after acute PE, a diagnostic evaluation for CTEPD is recommended (COR 1, LOE B-NR).^[4]
• AHA/ACC 2026: patients being evaluated for CTEPD should continue anticoagulation until the evaluation is complete, to prevent recurrent VTE and/or CTEPD progression, unless contraindicated by high bleeding risk (COR 1, LOE B-NR).^[4]
• AHA/ACC 2026: after PE with resolved symptoms and low suspicion for CTEPD, follow-up CTPA or lung perfusion scanning is not beneficial to assess thrombus resolution (COR 3: No Benefit, LOE B-NR).^[4]

PAH: severity and risk stratification

ESC/ERS 2022 supports a risk-based, goal-orientated treatment approach in PAH.^[1] ESC/ERS 2022 recommends achieving and maintaining a low-risk profile on optimised medical therapy as a treatment goal in PAH (Class I, Level B).^[2] Patients who achieve low-risk status have a much better long-term survival than those at intermediate or high risk.^[1]

Recommendation Table 4: risk assessment

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At diagnosis: the three-strata model

The 2015 ESC/ERS three-strata model originally used estimated 1-year mortality of <5%, 5–10% and >10%.^[1] Registry data have shown that observed 1-year mortality in the intermediate- and high-risk groups was sometimes higher than predicted (up to 20% and over 20%), so ESC/ERS 2022 updated these numbers in Table 16.^[1]

Comprehensive risk assessment in PAH, three-strata model (ESC/ERS 2022, Table 16; selected rows, estimated 1-year mortality in brackets)

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At follow-up: the four-strata model

The 2015 ESC/ERS three-strata tool classified 60–70% of patients as intermediate risk.^[1] The four-strata model gives better discrimination within that intermediate group.^[1] ESC/ERS 2022 cites two registry studies, together including more than 4000 patients with PAH, in which the four-strata tool performed at least as well as the three-strata model in predicting mortality.^[1] In those studies, observed 1-year mortality in the four strata was 0–3%, 2–7%, 9–19% and over 20%.^[1]

Simplified four-strata risk-assessment tool (ESC/ERS 2022, Table 18)

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• How to score: risk is calculated by dividing the sum of all grades by the number of variables and rounding to the next integer; WHO-FC I and II both score 1 point.^[1]
• Missing data: use at least the three variables; two may be used when variables are missing, especially a functional criterion (WHO-FC or 6MWD) with BNP or NT-proBNP.^[1]
• Three versus four strata: the three-strata model is kept for the initial assessment, which should be comprehensive and include echocardiographic and haemodynamic variables.^[1]
• What not to track: estimated sPAP at rest is not prognostic and is irrelevant to treatment decisions, and mPAP gives little prognostic information except in acute vasodilator responders.^[1]
• WHO-FC is one of the strongest predictors of survival, and worsening WHO-FC should trigger investigation of the cause of deterioration.^[1]
• Individual factors: ESC/ERS 2022 text says age, sex, disease type, comorbidities and kidney function should also be considered at any stage.^[1]
• Follow-up RHC (ERS 2026 update, abstract): to guide treatment strategy, the ERS task force suggests RHC during follow-up in PAH patients on PAH drugs at intermediate–low, intermediate–high or high risk of death, when therapeutic consequences are expected. It gives no recommendation at low risk because the certainty of evidence is very low.^[15]

WHO classification of functional status in PH (ESC/ERS 2022, Table 15)

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PAH treatment: general measures

Supportive care sits alongside the drugs.^[2] ESC/ERS 2022 Recommendation Table 5 sets out these rows.^[1]

Recommendation Table 5: general measures and special circumstances

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• Newer ESC row on rehabilitation: the 2026 ESC cardiac rehabilitation guideline says cardiac rehabilitation should be considered in PAH with RV dysfunction to improve physical functioning (6MWD, peak VO2, power) and health-related quality of life and to reduce pulmonary artery pressure and adverse events (Class IIa, Level B1).^[13]
• Anticoagulation in SSc-PAH: registry data and meta-analyses uniformly indicated that anticoagulation may be harmful (ESC/ERS 2022).^[1]
• Heart failure drugs: in PAH they may cause potentially dangerous drops in blood pressure, heart rate or both.^[1]
• Iron deficiency is defined as ferritin <100 µg/L, or ferritin 100–299 µg/L with transferrin saturation <20%.^[1]
• Surgery: in a prospective, multinational registry of 114 patients with PAH having non-cardiac, non-obstetric surgery, peri-operative mortality was 2% for elective and 15% for emergency procedures.^[1]
• Altitude: ESC/ERS 2022 text says patients should avoid altitudes above 1500 m without supplemental oxygen.^[1]

PAH treatment: the vasoreactive patient

Fewer than 10% of patients with idiopathic, heritable or drug-associated PAH are responders.^[1] An acute vasodilator response does not predict a favourable long-term CCB response in other forms of PAH.^[1] Nifedipine, diltiazem and amlodipine have predominantly been used, and the effective daily doses are relatively high and must be reached progressively.^[1] The most common adverse events are systemic hypotension and peripheral oedema.^[1]

Recommendation Table 7: vasoreactive IPAH, HPAH or DPAH

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• Timing: the recommendation row says reassessment after 3–4 months, including RHC; the narrative text of the same guideline says a complete reassessment after 3–6 months of therapy, including RHC, with repeat vasoreactivity testing.^[2][1]
• Why not try a CCB anyway? Patients without a vasoreactivity study or with a negative test should not start CCBs because of potentially severe side effects (e.g. severe hypotension, syncope and RV failure), unless prescribed at standard doses for other indications.^[1]

CCB dosing in adults (ESC/ERS 2022, Table 19)

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PAH treatment: non-vasoreactive patients

Two questions decide the first prescription: cardiopulmonary comorbidities, and risk.^[1] ESC/ERS 2022 stratifies treatment in idiopathic, heritable, drug-associated and CTD-associated PAH by the presence or absence of cardiopulmonary comorbidities and by risk.^[1]

Without cardiopulmonary comorbidities

Initial therapy in IPAH, HPAH or DPAH without cardiopulmonary comorbidities

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• Recommendation Table 8 footnote: initial triple therapy including i.v./s.c. prostacyclin analogues may also be considered at intermediate risk with severe haemodynamic impairment.^[1]
• The narrative gives examples of severe impairment: RAP ≥20 mmHg, cardiac index <2.0 L/min/m², SVI <31 mL/m² and/or PVR ≥12 WU.^[1]
• For high-risk patients the evidence for initial triple therapy is limited to case series, but the guideline reports consensus that it has the highest likelihood of success, citing French registry data.^[1]

AMBITION assessed initial dual therapy.^[5][1] It was an event-driven, double-blind trial in treatment-naive patients with WHO-FC II or III PAH, randomised 2:1:1 to ambrisentan 10 mg plus tadalafil 40 mg, or either drug with placebo, all once daily.^[5] The primary end point was the first clinical failure event: death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response.^[5]

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• The AMBITION authors concluded that, in treatment-naive PAH, initial combination therapy with ambrisentan and tadalafil gave a significantly lower risk of clinical-failure events than ambrisentan or tadalafil monotherapy.^[5]
• ESC/ERS 2022 reports AMBITION’s death rates at the end of the study as 10% with initial combination therapy and 14% with initial monotherapy (HR 0.67; 95% CI 0.42–1.08).^[1]
• ESC/ERS 2022 reports that TRITON (treatment-naive PAH; initial macitentan plus tadalafil, with or without selexipag) did not show a benefit of oral triple over oral double therapy at week 26.^[1]

Follow-up without cardiopulmonary comorbidities: escalating by four-strata risk

Sequential therapy in IPAH, HPAH or DPAH without cardiopulmonary comorbidities (selected rows)

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• For IPAH, HPAH or DPAH without cardiopulmonary comorbidities, ESC/ERS 2022 states the plan in its text: continue treatment once low-risk status is achieved; at intermediate–low risk on ERA/PDE5i, adding selexipag should be considered, and switching from PDE5i to riociguat may also be considered.^[1][2]
• Its text adds that at intermediate–high or high risk on oral therapies, adding i.v. epoprostenol or i.v./s.c. treprostinil and referral for LTx evaluation should be considered; if adding i.v./s.c. prostacyclin analogues is unfeasible, adding selexipag or switching from PDE5i to riociguat may be considered (no class given for this fallback).^[1][2]
• Riociguat with any PDE5i is contraindicated (Recommendation Table 10 footnote), and PDE5is and sGC stimulators must not be combined with each other or with nitrates, as this can result in systemic hypotension.^[2][1]
• Newer European row (ERS 2026 update, abstract): the ERS task force recommends add-on sotatercept in PAH patients who already receive PAH drugs and are at intermediate–low, intermediate–high or high risk of death during follow-up. The recommendation rests on high-certainty evidence from RCTs, and the task force gives no recommendation at low risk.^[15]

ESC/ERS 2022 reports the sequential-therapy trials this way.^[1]

• SERAPHIN (742 patients with PAH): in the subgroup on background PAH therapy, macitentan 10 mg daily reduced clinical worsening events versus placebo (HR 0.62; 95% CI 0.43–0.89).^[1]
• GRIPHON (1156 patients with PAH, treatment-naive or on an ERA, PDE5i or both): in the 376 on ERA/PDE5i combination, clinical worsening was lower with selexipag than placebo (HR 0.63; 95% CI 0.44–0.90).^[1]
• REPLACE (randomised, open-label; WHO-FC III on PDE5i-based therapy, 6MWD 165–440 m): clinical improvement at week 24 in 41% after switching to riociguat versus 20% who stayed on their PDE5i.^[1]
• Survival: ESC/ERS 2022 cites a 2016 meta-analysis in which combination therapy (initial and sequential) was associated with less clinical worsening (RR 0.65; 95% CI 0.58–0.72), but all-cause mortality was not improved (RR 0.86; 95% CI 0.72–1.03).^[1]

With cardiopulmonary comorbidities

Many patients now diagnosed with idiopathic PAH are older.^[1] In several contemporary registries the average age at diagnosis is about 60 years or older.^[1] ESC/ERS 2022 describes two phenotypes in elderly patients with IPAH.^[1]

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Recommendation Table 11: patients with cardiopulmonary comorbidities

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• Cardiopulmonary comorbidities are predominantly seen in elderly patients and include risk factors for HFpEF such as obesity, diabetes, coronary heart disease, a history of hypertension, and/or a low DLCO (Recommendation Table 8 footnote).^[1]
• These patients respond less well to PAH medication, discontinue it more often, are less likely to reach low risk, and have a higher mortality risk.^[1]

^{[2] [1] [15]}

PAH drug doses and practical points

PAH medication dosing in adults (ESC/ERS 2022, Table 19; selected rows)

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• Dosages in Table 19 are those commonly used in clinical practice, which does not exclude alternative dosages.^[1]
• Bosentan: dose-dependent rises in liver transaminases can occur in about 10% of patients (reversible after dose reduction or discontinuation), so liver function should be tested monthly; bosentan interacts with sildenafil, hormonal contraceptives and vitamin K antagonists.^[1]
• Macitentan: no liver toxicity has been shown, but haemoglobin fell to 8 g/dL or less in 4.3% of patients on 10 mg.^[1]
• Sildenafil: most side effects are mild to moderate and mainly related to vasodilation (headache, flushing and epistaxis).^[1]
• Epoprostenol has a half-life of 3–5 min and needs continuous i.v. infusion via a pump and a permanent tunnelled catheter; its efficacy was shown in three unblinded RCTs in IPAH (WHO-FC III and IV) and SSc-associated PAH, and ESC/ERS 2022 reports that epoprostenol improved symptoms, exercise capacity, haemodynamics and mortality, citing one of the IPAH trials.^[1]
• Selexipag is an oral, selective prostacyclin receptor agonist, chemically distinct from prostacyclin; ESC/ERS 2022 reports that in an event-driven phase 3 RCT of 1156 patients with PAH (GRIPHON), selexipag alone or on top of ERA and/or PDE5i therapy reduced the relative risk of composite morbidity/mortality events by 40%.^[1]

Advanced right heart failure and lung transplantation

When oral combination therapy is not enough, transplant planning starts.^[2] ESC/ERS 2022 recommends referral of potentially eligible candidates for LTx evaluation when the response to oral combination therapy is inadequate, indicated by intermediate–high or high risk or a REVEAL risk score above 7 (Class I, Level C).^[2]

Intensive care and lung transplantation

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Group 2: PH with left heart disease

Arguably, PH-LHD is the most prevalent form of PH: ESC/ERS 2022 puts it at 65–80% of cases.^[1] ESC/ERS 2022 defines PH with left heart disease (PH-LHD) as mPAP above 20 mmHg with PAWP above 15 mmHg.^[1] PVR then separates IpcPH (2 WU or less) from CpcPH (above 2 WU).^[1] The diastolic pressure gradient is no longer used to make that distinction because of conflicting prognostic data.^[1]

• How common: observational studies suggest PH in 40–72% of patients with HFrEF and 36–83% of those with HFpEF; about 20–30% of patients with HF and post-capillary PH have CpcPH when PVR defines the pre-capillary component.^[1]
• Severe pre-capillary component: a PVR above 5 WU may indicate it, which may prompt referral to a PH centre for specialised care.^[1]
• When to catheterise: with a high likelihood of LHD as the main cause, or established LHD with mild PH, invasive assessment is usually not indicated.^[1]
• Indications for RHC in LHD include suspected PAH or CTEPH; suspected CpcPH with a severe pre-capillary component, where further information will aid phenotyping and treatment decisions; and advanced HF with evaluation for heart transplantation.^[1]
• How to catheterise: in experienced centres, once LHD management is optimised and the patient is clinically stable, with all pressures read at end-expiration.^[1]
• Unmasking HFpEF: a PAWP above 18 mmHg on challenge with increased systemic venous return has been suggested to identify HFpEF as the cause despite a normal baseline PAWP; the therapeutic consequences remain to be determined.^[1]
• Unclear cases: severe PH with HFpEF and IPAH with cardiac comorbidities are hard to tell apart, and patients with an unclear diagnosis, particularly those with a predominant pre-capillary component (e.g. PVR above 5 WU), should be referred to a PH centre.^[1]

Treatment means treating the heart.^[1] The primary strategy is optimising treatment of the underlying cardiac disease, and diuretics remain the cornerstone with fluid retention.^[1] For HFpEF management, see Heart failure with preserved ejection fraction (HFpEF).

Recommendation Table 22: PH with left heart disease

^{[1] [2]}

• Why not PAH drugs? Recommendation Table 22 footnote: safety concerns have been identified with ERAs in heart failure (HFpEF and HFrEF, with or without PH) and with sildenafil in persistent PH after correction of valvular heart disease.^[2][1]
• Bosentan (in HFpEF-associated PH) and macitentan (in CpcPH with HF and ejection fraction above 35%) failed to show efficacy and led to more adverse events (fluid retention) than placebo (ESC/ERS 2022).^[1]
• ESC/ERS 2022 reports a randomised study of 231 patients with surgically corrected valve disease and persistent PH in which sildenafil was associated with a worse outcome than placebo; the study did not distinguish types of PH.^[1]
• Tricuspid repair: correcting tricuspid regurgitation in PAH, or in PH with non-valvular LHD and markedly raised PVR and/or RV dysfunction, must be considered with great caution, as this may be hazardous.^[1]
• The 7th World Symposium on PH (WSPH) PH-LHD task force (2024) reports that major randomised trials reinforced prior recommendations against PAH therapy in PH-LHD outside clinical trials and suggested possible harm.^[10]

Group 3: PH with lung disease and/or hypoxia

In lung disease, the key number is PVR.^[1] ESC/ERS 2022 separates non-severe PH (PVR 5 WU or less) from severe PH (PVR above 5 WU).^[1] Severe PH is uncommon, in 1–5% of COPD and under 10% of advanced interstitial lung disease (ILD).^[1] In the 2015 guideline, now history, severe PH meant mPAP above 35 mmHg, or mPAP of 25 mmHg or more with a cardiac index below 2.5 L/min/m².^[1]

• Prognosis: even non-severe PH in lung disease worsens symptoms and survival and is associated with more hospitalisation (ESC/ERS 2022).^[1]
• Phenotype clue: severe PH is largely independent of spirometry but usually comes with hypoxaemia, low PaCO2 and a markedly reduced DLCO.^[1]
• Sleep apnoea: PH is uncommon in obstructive sleep apnoea unless other conditions coexist, such as COPD or daytime hypoventilation.^[1]
• Echocardiography is less reliable: in advanced lung disease the TRV is unmeasurable in over 50% of patients in some studies.^[1]
• Timing: ideally, assess when the patient is clinically stable, as exacerbations can significantly raise pulmonary pressure.^[1]
• Treatment starts with optimising the lung disease, including supplementary oxygen and non-invasive ventilation where indicated, and pulmonary rehabilitation.^[1]

Recommendation Table 23: PH with lung disease and/or hypoxia

^{[1] [2]}

• INCREASE (phase 3 RCT, 326 patients with PH associated with ILD, inhaled treprostinil target 72 µg four times daily): ESC/ERS 2022 reports a placebo-corrected 6MWD improvement of 31 m at week 16, with improvements in NT-proBNP and clinical worsening.^[1]
• Harm signals: ambrisentan was associated with more clinical worsening in ILD with and without PH, and riociguat with more clinical worsening, including potential excess mortality, in PH with idiopathic interstitial pneumonia.^[1]
• Transplant: given the impact of even non-severe PH in lung disease, eligible patients should be referred for LTx evaluation.^[1]

Group 4: CTEPH and chronic thrombo-embolic pulmonary disease

CTEPH has its own set of treatments.^[1] ESC/ERS 2022 calls any patient whose symptoms can be attributed to post-thrombo-embolic fibrotic obstructions in the pulmonary arteries a case of chronic thrombo-embolic pulmonary disease (CTEPD), with or without PH.^[1] CTEPH remains the preferred term when PH is present.^[1]

• CTEPD definition: symptomatic patients with mismatched perfusion defects on V/Q scan and signs of chronic, organised, fibrotic clots on CTPA or DSA after at least 3 months of therapeutic anticoagulation.^[1]
• When to think of it after PE: if the diagnostic CTPA suggests CTEPH and/or echocardiographic sPAP is above 60 mmHg; when dyspnoea or functional limitation persists; and in asymptomatic patients with risk factors or a high CTEPH prediction score.^[1]
• Risk factors include permanent intravascular devices, inflammatory bowel disease, essential thrombocythaemia, polycythaemia vera, splenectomy, antiphospholipid syndrome, high-dose thyroid hormone replacement and malignancy.^[1]
• Imaging: V/Q scintigraphy remains the most effective tool to exclude CTEPD, while a negative CTPA, even of high quality, does not exclude it because distal disease can be missed.^[1]

Treatment matches the lesion.^[1] ESC/ERS 2022 combines PEA, balloon pulmonary angioplasty (BPA) and medical therapy to target proximal lesions, distal lesions and microvasculopathy respectively.^[1]

Recommendation Table 24: CTEPH and CTEPD without PH (selected rows)

^{[1] [2]}

• PEA is a complete bilateral endarterectomy down to segmental and subsegmental levels, in phases of deep hypothermic circulatory arrest.^[1]
• In CTEPH centres peri-operative mortality is below 2.5%; post-operative PH occurs in about 25%, and survival averages 90% at 3 years.^[1]
• Patients with operable proximal disease who decline surgery have a 5-year survival of 53%, compared with 83% after PEA (ESC/ERS 2022).^[1]
• BPA lowers PVR by 49–66% in selected patients with inoperable CTEPH or persistent/recurrent PH after PEA, but has serious and potentially fatal complications, including wire perforation and lung injury with haemoptysis and/or hypoxia.^[1]
• Because medical pre-treatment can reduce interventional complications, patients with PVR above 4 WU should be treated before BPA.^[1]
• Anticoagulation: a retrospective UK case series and a multicentre prospective registry (EXPERT) found similar bleeding with VKAs and NOACs in CTEPH, but more recurrent venous thrombo-embolism with NOACs; about 10% of the CTEPH population has antiphospholipid syndrome.^[1]
• Follow-up: regardless of the result of PEA or BPA, RHC 3–6 months after the intervention, allowing a multimodal approach to be considered; after successful treatment, yearly non-invasive follow-up with echocardiography and exercise capacity, because recurrent PH has been described.^[1]
• Centres: ideally more than 50 PEAs per year and more than 30 BPA patients or more than 100 BPA procedures per year.^[1]

CHEST-1 tested riociguat in inoperable CTEPH and in persistent or recurrent PH after PEA.^[6] In this phase 3, double-blind, placebo-controlled trial, 261 patients with inoperable CTEPH or persistent or recurrent PH after PEA were randomised to riociguat or placebo.^[6] By week 16, 6MWD had risen by a mean of 39 m with riociguat and fallen by 6 m with placebo (least-squares mean difference 46 m).^[6]

For acute PE care and follow-up after PE, see Pulmonary embolism: risk-stratified management. AHA/ACC 2026: for CTEPD with PH, referral to a centre with expertise in managing CTEPD is recommended to optimise evaluation and management (COR 1, LOE C-LD).^[4]

^{[2] [1]}

Group 5: unclear and/or multifactorial mechanisms

Group 5 is a collection of disorders rather than one disease.^[1] ESC/ERS 2022 says the cause is often multifactorial and can be secondary to raised pre- and post-capillary pressure and direct effects on the pulmonary vasculature.^[1] Table 6 lists haematological, systemic and metabolic disorders, chronic renal failure with or without haemodialysis, pulmonary tumour thrombotic microangiopathy and fibrosing mediastinitis.^[1]

Complications and pitfalls

• Calling PH on echocardiography: echocardiography alone cannot confirm PH; that requires RHC.^[1]
• Treating group 2 or 3 PH like PAH: drugs approved for PAH are not recommended in PH-LHD (ESC/ERS 2022, Class III, Level A), and PAH medication is not recommended in lung disease with non-severe PH (ESC/ERS 2022, Class III, Level C; this does not include inhaled treprostinil, which may be considered in PH associated with ILD irrespective of PH severity).^[2]
• Giving a CCB without a vasoreactivity test: CCBs are not recommended without a vasoreactivity study or in non-responders, unless prescribed for other indications (ESC/ERS 2022, Class III, Level C).^[2]
• Testing the wrong patient: vasoreactivity testing for CCB candidacy is not recommended outside idiopathic, heritable or drug-associated PAH (ESC/ERS 2022, Class III, Level C).^[2]
• Combining riociguat with a PDE5i: not recommended (ESC/ERS 2022, Class III, Level B); the combination is contraindicated.^[2]
• Heart failure drugs in PAH: ACEis, ARBs, ARNIs, SGLT-2is, beta-blockers and ivabradine are not recommended unless required by comorbidities (high blood pressure, coronary artery disease, left HF or arrhythmias) (ESC/ERS 2022, Class III, Level C).^[2]
• Missing CTEPH: a normal CTPA does not exclude CTEPD, and a ventilation/perfusion or perfusion lung scan is recommended in unexplained PH to assess for CTEPH (ESC/ERS 2022, Class I, Level C).^[1][2]
• Lung biopsy: open or thoracoscopic lung biopsy is not recommended in PAH (ESC/ERS 2022, Class III, Level C).^[2]

Prognosis and follow-up

Prognosis in PAH is read off the risk strata.^[1] In the two registry studies cited by ESC/ERS 2022, observed 1-year mortality in the four strata was 0–3%, 2–7%, 9–19% and over 20%.^[1] ESC/ERS 2022 reports a recent investigation in which 165 m and 440 m were the best absolute 6MWD thresholds for 1-year mortality and 1-year survival, respectively.^[1]

• Combination therapy and survival: in the 2016 meta-analysis cited by ESC/ERS 2022, combination therapy (initial and sequential) was associated with less clinical worsening, but all-cause mortality was not improved.^[1]
• CTEPH after PEA: an mPAP of 30 mmHg or more has been associated with starting medical therapy after PEA, and an mPAP of 38 mmHg or more with PVR of 5 WU or more with worse long-term survival.^[1]
• Australian and New Zealand data: in the PHSANZ registry (2044 patients with PAH diagnosed 2004–2017), the median diagnostic interval was 1.2 years, and a longer interval was associated with lower 5-year survival.^[11]

Special populations

Pregnancy

Pregnancy in PAH is covered by the 2025 ESC pregnancy guideline, the newest ESC source on pregnancy in PAH among the guidelines checked for this topic; see also Cardiovascular disease in pregnancy.^[3] It reports that maternal mortality has declined but remains high, at 11% to 25%.^[3] Women with PAH should be managed by a Pregnancy Heart Team with a PH expert.^[3]

PAH and pregnancy (ESC 2025 CVD and pregnancy guideline)

^[3]

• ESC 2025: PDE5 inhibitors and prostacyclin analogues can be used during pregnancy, and women with true vasodilator responsiveness who are well controlled on a CCB should continue it.^[3]
• History: the 2022 ESC/ERS row (Recommendation Table 6) said ERAs and riociguat are not recommended during pregnancy (Class III, Level B); ESC 2025 now lists ERAs, riociguat and selexipag (Class III, Level C).^[2][3][1]
• ESC/ERS 2022 also warns that bosentan can reduce the efficacy of hormonal contraceptives.^[1]

Older patients and comorbidity

Among elderly patients diagnosed with IPAH, ESC/ERS 2022 describes a left heart phenotype and a cardiopulmonary phenotype.^[1] In ESC/ERS 2022, initial monotherapy with a PDE5i or an ERA should be considered in IPAH, HPAH or DPAH with cardiopulmonary comorbidities (Class IIa, Level C).^[2] Compared with patients without cardiopulmonary comorbidities, those with them respond less well to PAH drugs and are less likely to reach low risk.^[1]

Children

• In children with idiopathic or heritable PAH, acute vasoreactivity testing is recommended to detect those who may benefit from CCB therapy (ESC/ERS 2022, Class I, Level C).^[2][1]
• It is recommended to define a positive response the same way in children and adults: a fall in mPAP of 10 mmHg or more to 40 mmHg or less, with an increased or unchanged cardiac output (ESC/ERS 2022, Class I, Level C).^[2]

Surgery and anaesthesia

Peri-operative risk is real.^[1] In a prospective, multinational registry of 114 patients with PAH, peri-operative mortality was 2% for elective and 15% for emergency non-cardiac, non-obstetric surgery.^[1] Multidisciplinary consultation at a PH centre to assess risk and benefit should be considered before interventions requiring anaesthesia (ESC/ERS 2022, Class IIa, Level C).^[2]

ESC 2022 non-cardiac surgery, published the same month as ESC/ERS 2022, gives rows for patients with PAH undergoing non-cardiac surgery (its Recommendation Table 26).^[16]

• Continuing chronic therapy for PAH in the peri-operative phase of non-cardiac surgery is recommended (Class I, Level C).^[16]
• Haemodynamic monitoring of patients with severe PAH is recommended to continue for at least 24 h in the post-operative period (Class I, Level C).^[16]
• If right heart failure progresses in the post-operative period in patients with PAH, optimising the diuretic dose and, if necessary, starting intravenous prostacyclin analogues under the guidance of a physician experienced in the management of PAH is recommended (Class I, Level C).^[16]
• Inodilator drugs (dobutamine, milrinone, levosimendan), which increase cardiac output and lower pulmonary vascular resistance, should be considered peri-operatively according to the haemodynamic status of the patient (Class IIa, Level C).^[16]

Evidence, guidelines and regional differences

Europe: the current guidelines

Among the guidelines checked for this topic, the 2022 ESC/ERS guideline is the newest joint ESC/ERS PH guideline. A 2023 corrigendum records changes to the references throughout the paper and to the references in the supplementary data file.^[14] Pregnancy rows now come from the 2025 ESC pregnancy guideline, and the 2026 ESC cardiac rehabilitation guideline adds a row on rehabilitation in PAH with RV dysfunction.^[3][13]

The 2026 ERS clinical practice guidelines update is the newer European source on PAH treatment.^[15] An ERS task force wrote it with the GRADE approach, addressing four PICO questions and one narrative question, with a focus on sotatercept and on RHC during follow-up.^[15] Only the abstract of the 2026 ERS update is held for this topic, so its rows here are quoted from that abstract.

The 2024 task-force reports

Three 2024 Eur Respir J task-force reports are cited here: on definition, classification and diagnosis; on the PAH treatment algorithm; and on PH with left heart disease.^[8][9][10] They are task-force reports, not guidelines, and carry no class or level.^[8][9][10] The definition task force keeps mPAP above 20 mmHg, the same PAWP and PVR thresholds, and the five groups.^[8]

• Classification changes proposed by the 2024 definition and classification report include: "long-term responders to calcium channel blockers" re-introduced as an IPAH subgroup, new group 2 subgroups, and group 3 subgroups based on lung disease type.^[8]
• Referral: with a high probability of severe pulmonary vascular disease, especially if there are signs of right heart failure, the task force recommends fast-track referral to a PH centre at any point during the clinical workup.^[8]
• Treatment: the treatment task force describes four pathways (endothelin-1, nitric oxide, prostacyclin and bone morphogenetic protein/activin signalling) and states that maximal medical therapy is now four-drug therapy.^[9]
• Group 2: the PH-LHD task force proposes individualising IpcPH versus CpcPH when PAWP lies in a diagnostic grey zone of 12–18 mmHg.^[10]

Sotatercept: the 2026 ERS recommendation and the trial evidence

The 2026 ERS update focuses on sotatercept, which it calls an activin signalling inhibitor targeting a novel pathway for the treatment of PAH, and on RHC during follow-up.^[15] STELLAR describes it as a fusion protein that traps activins and growth differentiation factors involved in PAH.^[7]

• ERS 2026 recommendation: add-on sotatercept in PAH patients who already receive PAH drugs and are at intermediate–low, intermediate–high or high risk of death during follow-up, based on high-certainty evidence from RCTs.^[15]
• Low risk: the ERS task force gives no recommendation because the certainty of evidence is low and few such patients were included in RCTs.^[15]
• Where: to monitor safety and efficacy, patients receiving sotatercept should be treated in PH centres, with regular follow-up and appropriate examinations.^[15]

^[7]

• STELLAR adverse events: epistaxis, dizziness, telangiectasia, increased haemoglobin levels, thrombocytopenia and increased blood pressure were more frequent with sotatercept than with placebo.^[7]

United States

No ACC/AHA pulmonary hypertension guideline was found in the census for this topic. The US rows used here come from the 2026 AHA/ACC acute PE guideline, which covers evaluation for CTEPD after PE and referral of CTEPD with PH to an expert centre.^[4]

Australia and New Zealand

No Australian or New Zealand PH guideline was found in the census for this topic. Australian and New Zealand data come from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry.^[12][11]

• Among patients diagnosed with CTEPH in the PHSANZ registry (January 2004 to March 2020): of 386 patients, 146 (37.8%) had PEA and 240 (62.2%) did not.^[12]
• Survival at 1, 3 and 5 years was 93%, 87% and 84% after PEA, compared with 86%, 73% and 62% without PEA (p < 0.001).^[12]
• The registry authors note that PEA was performed in only a minority of patients with CTEPH (37.8%), significantly less than overseas reports.^[12]

Guidelines checked

A row called the current one is so among the guidelines checked for this topic:

• Sources of the rows and statements used, besides the trial reports cited where they appear: ESC/ERS pulmonary hypertension (2022; EHJ and ERJ co-publications, with its 2023 corrigendum), the ERS update on PAH treatment (2026; abstract), ESC CVD and pregnancy (2025), ESC non-cardiac surgery (2022), ESC cardiac rehabilitation (2026), AHA/ACC acute pulmonary embolism (2026), three 2024 Eur Respir J reports (on the definition, classification and diagnosis of PH; the treatment algorithm for PAH; and PH associated with left heart disease, from the 7th World Symposium on Pulmonary Hypertension PH-LHD task force) and two PHSANZ registry reports (Respirology 2020 and 2021).^{[1][14][15][3][16][13][4][8][9][10][11][12]}
• Also swept for same-month or newer rows (the guidelines checked for this topic): ESC 2022 ventricular arrhythmias; ESC 2023 ACS, endocarditis and cardiomyopathies; ESC 2024 CCS, hypertension, peripheral and aortic disease, and AF; ESC/EAS 2025 lipids; ESC/EACTS 2025 valves; ESC 2025 myocarditis and pericarditis; ESC 2026 heart failure; ACC/AHA 2022 aortic disease, 2023 chronic coronary disease and AF, 2024 HCM, 2025 ACS and blood pressure, 2026 dyslipidaemia; ACC/AHA 2025 adult congenital heart disease; AHA/ACC/ADA/ASN 2026 cardiovascular-kidney-metabolic syndrome; the Fifth UDMI 2026.
• Not held as text for this topic: ESC 2022 cardio-oncology; ESC 2026 CKD (not held in its version of record); the AHA/ACC 2026 perioperative guideline (only its PubMed abstract is held). Checked, not used: the ACC/AHA 2025 adult congenital heart disease guideline, whose PH rows are written for adults with congenital heart disease (shunt lesions with PAH and Eisenmenger syndrome), a group whose treatment this topic does not give beyond the classification; and the AHA/ACC/ADA/ASN 2026 cardiovascular-kidney-metabolic guideline, which gives no PH row.
• Found in the census for this topic but not used, because they fall outside the ESC, ACC/AHA and ANZ guideline scope of this site: the JCS/JPCPHS 2025 Japanese guideline on PH and pulmonary embolism (title only on PubMed), other national guidelines, and society consensus and scientific statements.
• The JCS/JPCPHS 2025 Guideline on Pulmonary Hypertension and Pulmonary Embolism/Deep Vein Thrombosis (PMID 42386545) is not held as text in the evidence caches, so it was not checked for this topic.

Exam pearls

• PH: mPAP >20 mmHg. Pre-capillary: add PAWP ≤15 mmHg and PVR >2 WU. IpcPH: PAWP >15, PVR ≤2. CpcPH: PAWP >15, PVR >2 (ESC/ERS 2022, Table 5).^[1]
• Exercise PH: mPAP/CO slope >3 mmHg/L/min between rest and exercise.^[1]
• Echo threshold: peak TRV >2.8 m/s; signs from at least two of the three Table 10 categories (A/B/C) must be present to alter the level of echocardiographic probability.^[2][1]
• Positive vasoreactivity test: mPAP falls by ≥10 mmHg to ≤40 mmHg with an increased or unchanged CO; test only I/H/DPAH.^[2][1]
• Fewer than 10% of patients with I/H/DPAH are responders.^[1]
• Non-vasoreactive I/H/DPAH without cardiopulmonary comorbidities: at low or intermediate risk, initial combination therapy with a PDE5i and an ERA is recommended (ESC/ERS 2022, Class I, Level B; GRADE: low quality, conditional); at high risk, initial PDE5i, ERA and i.v./s.c. prostacyclin analogue therapy should be considered (ESC/ERS 2022, Class IIa, Level C), and initial triple-combination therapy including i.v./s.c. prostacyclin analogues may also be considered at intermediate risk with severe haemodynamic impairment (ESC/ERS 2022, Recommendation Table 8 footnote).^[2][1]
• Four-strata follow-up model: WHO-FC, 6MWD and BNP/NT-proBNP, with additional variables taken into account as necessary (ESC/ERS 2022, Class I, Level B).^[2]
• Group 3 severe PH: PVR >5 WU.^[1]
• CTEPH: lifelong, therapeutic doses of anticoagulation are recommended (ESC/ERS 2022, Class I, Level C); PEA is recommended as the treatment of choice when the fibrotic obstructions are accessible by surgery (ESC/ERS 2022, Class I, Level B).^[2]

References16ShowHide

1. [1]Humbert M, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J, 2022.PMID 36017548
2. [2]Humbert M, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J, 2023.PMID 36028254
3. [3]De Backer J, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J, 2025.PMID 40878294
4. [4]Creager MA, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2026.PMID 41712898
5. [5]Galiè N, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med, 2015.PMID 26308684
6. [6]Ghofrani HA, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med, 2013.PMID 23883377
7. [7]Hoeper MM, et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med, 2023.PMID 36877098
8. [8]Kovacs G, et al. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J, 2024.PMID 39209475
9. [9]Chin KM, et al. Treatment algorithm for pulmonary arterial hypertension. Eur Respir J, 2024.PMID 39209476
10. [10]Maron BA, et al. Pulmonary hypertension associated with left heart disease. Eur Respir J, 2024.PMID 39209478
11. [11]Khou V, et al. Diagnostic delay in pulmonary arterial hypertension: Insights from the Australian and New Zealand pulmonary hypertension registry. Respirology, 2020.PMID 31997504
12. [12]Kearney K, et al. Chronic thromboembolic pulmonary hypertension in Australia and New Zealand: An analysis of the PHSANZ registry. Respirology, 2021.PMID 34608706
13. [13]Bäck M, et al. 2026 ESC Guidelines on cardiac rehabilitation. Eur Heart J, 2026.PMID 42661418
14. [14]No authors listed Corrigendum to: 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur Heart J, 2023.PMID 36821743
15. [15]Kovacs G, et al. European Respiratory Society clinical practice guidelines update for the treatment of pulmonary arterial hypertension. Eur Respir J, 2026.PMID 42705705
16. [16]Halvorsen S, et al. 2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery. Eur Heart J, 2022.PMID 36017553