Pulmonary Hypertension

Definition

Pulmonary hypertension is a haemodynamic state defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest on right heart catheterisation — the 2022 ESC/ERS threshold, lowered from ≥25 mmHg. It affects approximately 1% of the global population, with left heart disease the leading cause worldwide. PH is not a single disease but the haemodynamic consequence of diverse aetiologies grouped into five clinical categories by pathophysiology and aetiology: Group 1 (PAH), Group 2 (PH-LHD), Group 3 (PH-lung disease/hypoxia), Group 4 (PH-pulmonary artery obstructions/CTEPH) and Group 5 (unclear/multifactorial). The classification is the foundation of management because PAH-specific therapy is appropriate only for Group 1 pre-capillary disease and is ineffective or contraindicated elsewhere. Irrespective of aetiology, PH is associated with worsening symptoms, right ventricular dysfunction and substantially increased mortality. (sources/PHT-ESC-2022, rating: very high)

Key Concepts

Haemodynamic Definitions

• Drug threshold caveat: every approved PAH drug was studied only in patients with mPAP ≥25 mmHg and PVR >3 WU. No efficacy data exist for the lower-threshold zone (mPAP 21–24 mmHg, PVR 2–3 WU). (sources/PHT-ESC-2022, rating: very high)
• PAWP uncertainty: the true physiological upper limit of normal is 13 mmHg (meta-analysis, n=940 healthy subjects; independent of BMI and age, slightly higher in women), but ESC uses PAWP >15 mmHg to define post-capillary PH. The resulting 13–15 mmHg grey zone may hide early left heart disease. (sources/rhc-hf-ehj-2025, rating: high)
• Zone of uncertainty (12–18 mmHg): interpret PAWP against the individual clinical probability of left heart disease; exercise RHC, fluid challenge or passive leg raise may be required. See concepts/RHC-Haemodynamic-Interpretation. (sources/rhc-hf-ehj-2025)

Classification and Epidemiology

• Cancer therapy-associated PAH (Group 1 drug/toxin): bleomycin causes PAH through endothelial apoptosis and reduced endothelial proliferation; cyclophosphamide is also associated; dasatinib causes PAH in 5% versus 0.4% with imatinib. See concepts/Cancer-Therapy-Related-CV-Toxicity. (sources/cardio-oncology-vascular-metabolic-aha-2019, rating: very high; sources/Cardio-Oncology-ESC-2022, rating: very high)
• Global prevalence: ~1%, higher over age 65; UK observed prevalence 125 cases/million, doubled over 10 years. (sources/PHT-ESC-2022, rating: very high)
• PAH: incidence ~6/million adults, prevalence 48–55/million. IPAH accounts for 50–60%; historically female-predominant, now increasingly older patients with equal sex distribution. (sources/PHT-ESC-2022)
• CTEPH: incidence 2–6/million, prevalence 26–38/million. Cumulative incidence after acute PE is 0.6% overall and 2.3% at 2 years in prospective data. (sources/PHT-ESC-2022)

Pathophysiology

• Pulmonary vascular resistance is the key haemodynamic driver in pre-capillary PH. Elevated PVR reflects remodelling — smooth muscle proliferation, endothelial dysfunction, in-situ thrombosis and adventitial fibrosis — which vasodilators alone cannot reverse in established disease. (sources/PHT-ESC-2022, rating: very high)
• Right ventricular adaptation: the RV initially maintains contractility through concentric hypertrophy. Failure occurs when it can no longer couple to the pulmonary circulation — RV–PA uncoupling leads to dilatation, tricuspid regurgitation and systemic venous congestion, and is the proximate cause of death in advanced PH. See concepts/RV-PA-Coupling. (sources/rv-failure-aha-2026, rating: very high)
• Vasoconstriction versus remodelling: early PAH has a partially reversible vasoconstrictor component (acute vasoreactivity testing identifies the ~10% eligible for calcium channel blockers); established PAH is dominated by fixed structural remodelling, with absent vasoreactivity in >90%. (sources/PHT-ESC-2022)
• Post-capillary mechanisms: elevated PAWP raises pulmonary venous pressure passively (IpcPH); compensatory pulmonary vasoconstriction in some patients produces CpcPH with elevated PVR. The primary strategy is to lower left atrial pressure with guideline-directed medical therapy, not pulmonary vasodilators. (sources/PHT-ESC-2022; sources/rvfailure-nejm-2023, rating: very high)
• Drivers of maladaptive RV remodelling: inflammation (TNF-α/IL-6/IL-1β/NLRP3 inflammasome), metabolic reprogramming (Warburg effect, fatty-acid oxidation to glycolysis shift) and extracellular matrix fibrosis (TGF-β/MMP/integrin pathways). (sources/rv-failure-aha-2026)

Diagnosis and Screening

• Right heart catheterisation is required to confirm PH and must precede PAH therapy. The three-step pathway is GP suspicion (ECG, BNP/NT-proBNP, oxygen saturation) → detection (echocardiography, pulmonary function tests, arterial blood gas) → confirmation (referral to a PH centre, RHC). (sources/PHT-ESC-2022, rating: very high)
• Echocardiography is the first-line non-invasive investigation (Class I/B) and assigns an echocardiographic probability of PH; the TRV threshold >2.8 m/s is retained. It cannot confirm PH — RHC is mandatory before starting PAH therapy. (sources/PHT-ESC-2022)
• V/Q scintigraphy is Class I in unexplained PH to screen for CTEPH; CT pulmonary angiography is Class I when CTEPH is suspected. (sources/PHT-ESC-2022)
• Warning signs requiring immediate hospitalisation: rapid progression to WHO-FC III/IV, signs of RV failure, syncope, low cardiac output or haemodynamic compromise. (sources/PHT-ESC-2022)
• Systemic sclerosis: annual PAH risk evaluation (Class I/B); the DETECT algorithm when disease duration >3 years, FVC ≥40% and DLCO <60% (Class I/B). PAH prevalence in SSc is 5–19%. (sources/PHT-ESC-2022)
• BMPR2 carriers: annual multimodal screening with ECG, NT-proBNP, DLCO, echocardiography and cardiopulmonary exercise testing; echocardiography alone is insufficient. Lifetime PAH risk is ~20% (42% in women, 14% in men). (sources/PHT-ESC-2022)
• After pulmonary embolism: evaluate for CTEPH/CTEPD when dyspnoea is persistent or new (Class I/C), and refer to a PH/CTEPH centre for mismatched perfusion defects persisting beyond 3 months (Class I/C). (sources/PHT-ESC-2022)

Genetics

• Additional reported genes with limited or disputed evidence: AQP1, ABCC8, KCNK3, SMAD9, SOX17, TBX4, ENG, ACVRL1 (HHT-associated) and GDF2. (sources/PHT-ESC-2022, rating: very high)
• Testing: the 2022 ESC guidelines recommend genetic counselling and testing in all PAH patients (Class I/C); BMPR2, CAV1, ATP13A3 and EIF2AK4 are the four genes with definitive ClinGen evidence. See concepts/ClinGen-Gene-Disease-Validity. (sources/PHT-ESC-2022; sources/clingen-summary-2026-05-09, rating: high)

PAH — General Measures and Drug Therapy

• Supervised exercise training: Class I/A (upgraded from IIa) — a large multicentre RCT showed a +34.1 m improvement in 6-minute walk distance in PAH/CTEPH patients on PAH drugs. (sources/PHT-ESC-2022, rating: very high)
• Iron deficiency: Class I/C — intravenous iron for anaemia; repletion without anaemia is Class IIb. (sources/PHT-ESC-2022)
• Anticoagulation: Class IIb, individualised only — not generally recommended, potentially harmful in SSc-PAH, with conflicting evidence in IPAH. (sources/PHT-ESC-2022)
• ACE inhibitors, ARBs, ARNIs, SGLT2 inhibitors and beta-blockers: Class III unless required by a comorbidity. (sources/PHT-ESC-2022)
• Pregnancy is strongly discouraged — maternal mortality 11–25%; ERAs and riociguat are contraindicated (Class III/B), whereas calcium channel blockers, PDE5 inhibitors and prostacyclins are considered safe. (sources/PHT-ESC-2022)
• Treatment target: the 3-strata low-risk profile — WHO-FC I/II, 6MWD >440 m, normal NT-proBNP, RAP <8 mmHg, CI ≥2.5 L/min/m², SVI ≥38 mL/m² and mixed venous oxygen saturation >65%. See concepts/PAH-Risk-Stratification. (sources/PHT-ESC-2022)
• Acute vasoreactivity testing: a positive response is now a fall in mPAP ≥10 mmHg to an absolute value ≤40 mmHg with maintained or increased cardiac output; ~10% of patients respond, and predictive value is confined to idiopathic, heritable and drug-induced PAH. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
• Vasoreactivity agents: inhaled nitric oxide and inhaled iloprost, and intravenous epoprostenol, are Class I. Adenosine is no longer recommended (AV block, bronchospasm, hypotension). (sources/hemodynamic-hf-pht-aha-2026)
• Calcium channel blockers: Class I/C only in vasoreactive IPAH/HPAH/DPAH (<10% qualify); an adequate response is WHO-FC I/II, mPAP <30 mmHg and PVR <4 WU at 3–6 months. Class III in non-responders. (sources/PHT-ESC-2022; sources/hemodynamic-hf-pht-aha-2026)
• Initial combination ERA + PDE5 inhibitor: Class I/B for low-to-intermediate-risk IPAH/HPAH/DPAH. Ambrisentan + tadalafil (AMBITION) and macitentan + tadalafil are Class I (the latter new in 2022); other ERA + PDE5i combinations are Class IIa. Bosentan + sildenafil is Class III (downgraded from IIb). (sources/PHT-ESC-2022)
• Escalation for intermediate-high or high risk: add parenteral prostacyclin or evaluate for lung transplantation. (sources/PHT-ESC-2022)
• Sotatercept is a first-in-class ACTRIIA-Fc activin-signalling inhibitor, FDA-approved as add-on therapy; it rebalances activin/BMP signalling to target remodelling rather than producing vasodilation. STELLAR increased 6MWD by 34.4 m with an 84% reduction in clinical worsening; ZENITH (WHO-FC III/IV, high risk) stopped early with a primary composite HR of 0.24 (17.4% vs 54.7%); HYPERION (early disease, WHO-FC II/III) showed HR 0.24 (10.6% vs 36.9%), NNT 5 at 12 months. Every trial required stable background therapy. See entities/Sotatercept. (sources/rv-failure-aha-2026, rating: very high; sources/sotatercept-zenith-nejm-2025, rating: very high; sources/sotatercept-hyperion-nejm-2025, rating: very high)
• CTEPH-specific therapy (PEA, BPA, riociguat) is covered in entities/CTEPH.
• Full detail: concepts/PAH-Treatment — initial and sequential drug therapy, drug classes, escalation and special populations.

Group 2 — PH-LHD

• RHC: Class I when the result will aid management of suspected PH-LHD, and before valve intervention for severe tricuspid regurgitation. (sources/PHT-ESC-2022, rating: very high)
• PDE5 inhibitors in HFpEF with IpcPH: Class III. SIOVAC showed worse outcomes with sildenafil after correction of left-sided valvular disease, yet 77% of US centres continue to use PAH-approved therapies in non-Group 1 PH. See entities/HFpEF. (sources/PHT-ESC-2022; sources/rvfailure-nejm-2023, rating: very high)
• Borderline PAWP (13–15 mmHg) with HFpEF features: exercise or fluid challenge may unmask post-capillary PH (Class IIb). (sources/PHT-ESC-2022)
• CpcPH with PVR >5 WU: individualised management with referral to a PH centre (Class I). (sources/PHT-ESC-2022)
• No approved therapy targets the pulmonary vascular component of Group 2 PH. PDE5 inhibitors are Class III in HFpEF with IpcPH and riociguat failed in HFpEF-associated PH.
• Pulmonary-artery denervation (PADN) is the first adequately powered RCT in Group 2 PH: 264 patients (44.7% IpcPH, 55.3% CpcPH) already on guideline-directed therapy, with 2-year clinical worsening reduced from 51.5% to 25.7% (HR 0.49, 95% CI 0.30–0.82, P=0.006), fewer recurrent events (HR 0.59) and no complications beyond access-site haematomas. It was open-label with no sham control, the individual hard endpoints were null, and the strongest signal was in IpcPH (HR 0.31) rather than the CpcPH phenotype the mechanism targets. A confirmatory sham-controlled trial (NCT07214376) is running. See concepts/Pulmonary-Artery-Denervation. (sources/padn-hf-ph-nejm-2026, rating: high)

Group 3 — PH-Lung Disease

• Optimise treatment of the underlying lung disease: Class I. (sources/PHT-ESC-2022, rating: very high)
• Inhaled treprostinil: Class IIb — may be considered in PH-ILD. (sources/PHT-ESC-2022)
• Ambrisentan: Class III — not recommended in PH-IPF. (sources/PHT-ESC-2022)
• Riociguat: Class III — not recommended in PH-IIP. (sources/PHT-ESC-2022)

CHD-PAH (ASD)

ASD-associated PAH is Group 1 pre-capillary disease. Because the shunt is still present, closure decisions depend on PVR: (sources/asd-ehj-2022, rating: high)

• Inhaled nitric oxide vasoreactivity testing is not recommended when deciding whether to close an ASD in PAH. (sources/asd-ehj-2022)
• LV impairment with ASD: invasive haemodynamic assessment is mandatory; balloon test occlusion helps choose complete versus fenestrated versus no closure (elevated PCWP after occlusion predicts worse HF risk). (sources/asd-ehj-2022)
• Eisenmenger syndrome (reversed or bidirectional shunt): closure is absolutely contraindicated; use proactive advanced PAH therapy with prostacyclins, preferring subcutaneous or inhaled over parenteral routes. (sources/asd-ehj-2022)
• Contemporary series report PH in <3% of closed ASD patients, reflecting earlier diagnosis and proactive closure. See concepts/Atrial-Septal-Defect. (sources/asd-ehj-2022)

Right Ventricular Failure, Transplantation and Perioperative Care

• RV–PA uncoupling is the haemodynamic hallmark of right heart failure in PH: Ees/Ea <≈0.7 indicates uncoupling, with optimal coupling at 1.5–2.0. Chronic pressure overload progresses from adaptive hypertrophy to dilatation, fibrosis and diastolic stiffness, then uncoupling and failure. (sources/rv-failure-aha-2026, rating: very high)
• RV afterload is multifactorial — PVR plus pulmonary artery compliance plus pulsatile load — so PVR alone does not characterise the haemodynamic burden. (sources/rv-failure-aha-2026)
• Non-invasive coupling surrogates: TAPSE/sPAP is widely used and prognostic; RV free wall strain/sPAP is superior for predicting PAH outcomes; change in RVEF tracks therapy. CMR is the gold standard for RV volumes and function, with LGE and T1/T2 mapping detecting fibrosis and 4D flow predicting PH versus RHC. (sources/rv-failure-aha-2026)
• BMPR2 carriers have more severe RV dysfunction independent of afterload and higher mortality or transplantation risk than non-carriers. See concepts/RV-PA-Coupling and concepts/Right-Ventricular-Failure. (sources/rv-failure-aha-2026)
• Transplant referral (any of): ESC/ERS intermediate or high risk or REVEAL >7 on appropriate therapy; progressive disease or recent hospitalisation; need for IV/SC prostacyclin; high-risk variants (PVOD, PCH, scleroderma-PAH); secondary liver or kidney dysfunction; recurrent haemoptysis. Listing requires high risk or REVEAL ≥10 on optimised therapy, usually including IV/SC prostacyclin, when expected 1-year medical mortality (>20%) exceeds post-transplant mortality (~10%). (sources/PHT-RVsupport-WSPH-2019, rating: high)
• No degree of RV dysfunction precludes bilateral lung transplantation — the RV recovers within weeks regardless of preoperative severity. Bilateral transplantation is the procedure of choice, with perioperative and prolonged postoperative ECMO as standard and 1-year survival >90%. See concepts/Lung-Transplantation-PAH. (sources/PHT-RVsupport-WSPH-2019)
• Acute RV failure in ICU: avoid intubation and fluid loading, use IV prostacyclin for afterload reduction, consider dobutamine or milrinone, and use vasopressin or norepinephrine for vasopressor support. See concepts/ECLS-in-PH. (sources/PHT-RVsupport-WSPH-2019)
• Perioperative care: continue all PAH-targeted therapy without interruption (COR 1), because abrupt withdrawal causes acute decompensation and death; manage severe PH undergoing elevated-risk noncardiac surgery at a specialist centre with a multidisciplinary team (COR 2a); use invasive haemodynamic monitoring and avoid fluid overload and agents that raise RV afterload (COR 2a); have inhaled nitric oxide or epoprostenol available for pulmonary hypertensive crises, with norepinephrine or vasopressin preferred to maintain RV perfusion pressure (COR 2a). PH confers 43% increased odds of postoperative death, MI or stroke, and Group 1 PAH carries 2.5× MACE and 5× cardiogenic shock risk. See concepts/Perioperative-Cardiovascular-Assessment. (sources/periop-aha-2024, rating: very high)

Contradictions / Open Questions

• The lower haemodynamic threshold is not backed by drug trial evidence: the 2022 definition labels mPAP 21–24 mmHg with PVR 2–3 WU as PH, but every approved PAH drug was studied only at mPAP ≥25 mmHg and PVR >3 WU. Clinicians can therefore make a diagnosis with no actionable treatment. (sources/PHT-ESC-2022, rating: very high)
• Exercise PH thresholds need prospective validation: the mPAP/CO slope >3 mmHg/L/min criterion is age-dependent, and its reproducibility across centres and prognostic value require confirmation before routine use. (sources/PHT-ESC-2022)
• Anticoagulation in IPAH remains unresolved: it was downgraded to Class IIb despite meta-analyses suggesting a survival benefit, there are no RCTs, it may be harmful in SSc-PAH, and the recommendation rests on expert opinion. (sources/PHT-ESC-2022)
• Physiological PAWP versus the classification threshold: the true upper limit of normal is 13 mmHg, but guidelines use 15 mmHg to define post-capillary PH; the 13–15 mmHg grey zone may under-recognise early left heart disease. (sources/rhc-hf-ehj-2025, rating: high)
• CTEPD without haemodynamic PH is a newly formalised entity with almost no evidence: prevalence is unknown, and BPA or PEA for symptomatic CTEPD without PH is Class IIa on very limited data. (sources/PHT-ESC-2022)
• The adaptive-to-maladaptive RV transition cannot be identified prospectively, and no validated serial multiparametric model integrates Ees/Ea surrogates or advanced RV imaging into follow-up; guidelines use imaging for diagnosis only. (sources/rv-failure-aha-2026, rating: very high)
• Sotatercept's benefit differs by disease stage and survival remains unproven: ZENITH showed HR 0.42 for all-cause death (8.1% vs 15.1%) that did not reach the prespecified alpha after early stopping, whereas HYPERION's benefit in early disease was functional with balanced deaths (4.4% vs 3.8%). (sources/sotatercept-zenith-nejm-2025, rating: very high; sources/sotatercept-hyperion-nejm-2025, rating: very high)
• Whether sotatercept can be used first-line is unanswered: STELLAR, ZENITH and HYPERION all required stable background therapy, so its role before ERA/PDE5i combination therapy is unknown. (sources/sotatercept-hyperion-nejm-2025)
• ClinGen disputes BMPR1A and BMPR1B in HPAH: the classification is "Disputing", so variants should not be reported as P/LP for HPAH without strong functional validation. (sources/clingen-summary-2026-05-09, rating: high)
• The positive Group 2 procedural trial has the field's classic failure mode: PADN-HF-PH was open-label without sham control and its individual hard endpoints were null, mirroring renal denervation before SYMPLICITY HTN-3. The effect was also larger in IpcPH (HR 0.31) — where PVR is ≤2 WU and a pulmonary-vascular mechanism is least plausible — than in CpcPH (HR 0.71), the target phenotype. The sham-controlled NCT07214376 will settle it. (sources/padn-hf-ph-nejm-2026, rating: high)

Connections

• Classification and phenotypes: entities/CTEPH · concepts/Atrial-Septal-Defect · entities/HFpEF · entities/Heart-Failure · concepts/Right-Ventricular-Failure
• Haemodynamics and diagnosis: concepts/RHC-Haemodynamic-Interpretation · concepts/RV-PA-Coupling · concepts/Pulmonary-Artery-Pulsatility-Index
• Therapy: concepts/PAH-Treatment · concepts/PAH-Risk-Stratification · entities/Sotatercept · concepts/Pulmonary-Artery-Denervation · concepts/Lung-Transplantation-PAH · concepts/ECLS-in-PH · concepts/Balloon-Pulmonary-Angioplasty
• Context and evidence: concepts/Perioperative-Cardiovascular-Assessment · concepts/Cancer-Therapy-Related-CV-Toxicity · concepts/ClinGen-Gene-Disease-Validity · concepts/Renal-Denervation

Sources

• sources/asd-ehj-2022
• sources/Cardio-Oncology-ESC-2022
• sources/cardio-oncology-vascular-metabolic-aha-2019
• sources/clingen-summary-2026-05-09
• sources/hemodynamic-hf-pht-aha-2026
• sources/padn-hf-ph-nejm-2026
• sources/periop-aha-2024
• sources/PHT-ESC-2022
• sources/PHT-RVsupport-WSPH-2019
• sources/rhc-hf-ehj-2025
• sources/rv-failure-aha-2026
• sources/rvfailure-nejm-2023
• sources/sotatercept-hyperion-nejm-2025
• sources/sotatercept-zenith-nejm-2025