Pulmonary Hypertension

Details

Pulmonary hypertension (PH) is a haemodynamic state defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest on right heart catheterization (RHC). It affects ~1% of the global population across all age groups, with left heart disease (LHD) being the leading cause globally. PH is classified into five clinical groups based on pathophysiology, haemodynamics, and aetiology: Group 1 (pulmonary arterial hypertension, PAH), Group 2 (PH due to LHD), Group 3 (PH due to lung disease/hypoxia), Group 4 (PH due to pulmonary artery obstructions, primarily CTEPH), and Group 5 (unclear/multifactorial). Irrespective of the underlying condition, developing PH is associated with worsening symptoms, RV dysfunction, and significantly increased mortality.

Key Facts

Haemodynamic Definitions

• PH: mPAP >20 mmHg at rest on RHC (2022 ESC/ERS; lowered from prior ≥25 mmHg threshold). (sources/PHT-ESC-2022, rating: very high)
• Pre-capillary PH: mPAP >20 mmHg + PAWP ≤15 mmHg + PVR >2 WU. (sources/PHT-ESC-2022, rating: very high)
• Isolated post-capillary PH (IpcPH): mPAP >20 mmHg + PAWP >15 mmHg + PVR ≤2 WU. (sources/PHT-ESC-2022, rating: very high)
• Combined post- and pre-capillary PH (CpcPH): mPAP >20 mmHg + PAWP >15 mmHg + PVR >2 WU. (sources/PHT-ESC-2022, rating: very high)
• Exercise PH (reintroduced 2022): mPAP/CO slope >3 mmHg/L/min between rest and exercise. Associated with impaired prognosis. Not physiological in subjects <60 years. (sources/PHT-ESC-2022, rating: very high)
• Unclassified PH: mPAP >20 mmHg + PVR ≤2 WU + PAWP ≤15 mmHg — often from elevated pulmonary blood flow (CHD, liver disease, hyperthyroidism). (sources/PHT-ESC-2022, rating: very high)
• Drug threshold caveat: All approved PAH drugs studied only in patients with mPAP ≥25 mmHg and PVR >3 WU; no efficacy data for the lower-threshold zone (mPAP 21–24 mmHg, PVR 2–3 WU). (sources/PHT-ESC-2022, rating: very high)

PAWP normal range and zone of uncertainty

• True physiological upper limit of normal PAWP: 13 mmHg (meta-analysis, n=940 healthy subjects; independent of BMI and age; women slightly higher than men). (sources/rhc-hf-ehj-2025, rating: high)
• ESC PH guideline post-capillary PH threshold: PAWP >15 mmHg — this creates a diagnostic grey zone (13–15 mmHg) where early LHD may be under-recognised.
• Zone of uncertainty (12–18 mmHg): PAWP in this range should be contextualised to individual clinical probability of left heart disease; provocative testing (exercise RHC, fluid challenge, passive leg raise) may be required. (sources/rhc-hf-ehj-2025, rating: high)
• See concepts/Right-Heart-Catheterization for full PAWP methodology and pitfalls.

Clinical Classification — 5 Groups

• Group 1 — PAH: Includes IPAH, HPAH, drug/toxin-associated PAH, PAH associated with CTD/HIV/portal hypertension/CHD/schistosomiasis, PVOD/PCH, and PPHN. Rare; prevalence 48–55/million adults. (sources/PHT-ESC-2022, rating: very high)
  • Cancer therapy-associated PAH (drug/toxin Group 1): Bleomycin (used in lymphomas and testicular cancer) causes PAH via endothelial apoptosis and ↓ EC proliferation; cyclophosphamide also associated with PAH; dasatinib (BCR-ABL TKI) causes PAH in 5% vs. 0.4% with imatinib. (sources/cardio-oncology-vascular-metabolic-aha-2019, rating: very high; sources/Cardio-Oncology-ESC-2022, rating: very high)
• Group 2 — PH-LHD: Most common globally; caused by HFrEF, HFmrEF, HFpEF, or valvular disease. Affects ≥50% of HFpEF patients. (sources/PHT-ESC-2022, rating: very high)
• Group 3 — PH-lung disease/hypoxia: Associated with COPD, ILD, hypoventilation syndromes; 1–5% of advanced COPD have mPAP >35–40 mmHg. (sources/PHT-ESC-2022, rating: very high)
• Group 4 — PH-PA obstructions: Primarily CTEPH; prevalence 26–38/million adults. CTEPD (without PH) newly formalised as a related entity. (sources/PHT-ESC-2022, rating: very high)
• Group 5 — Unclear/multifactorial: Haematological, systemic, metabolic disorders; sarcoidosis; neurofibromatosis; fibrosing mediastinitis. (sources/PHT-ESC-2022, rating: very high)

Epidemiology

• Global prevalence: ~1% of the global population; prevalence higher in individuals >65 years. UK observed prevalence: 125 cases/million (doubled over 10 years). (sources/PHT-ESC-2022, rating: very high)
• PAH (Group 1): Incidence ~6/million adults; prevalence 48–55/million adults. IPAH accounts for 50–60% of PAH; historically female-predominant but now increasingly older patients with equal sex distribution. (sources/PHT-ESC-2022, rating: very high)
• CTEPH (Group 4): Incidence 2–6/million adults; prevalence 26–38/million adults. Cumulative incidence post-acute PE: 0.6% (all patients), 2.3% at 2 years in prospective data. (sources/PHT-ESC-2022, rating: very high)

Diagnosis

• RHC: Required for PH confirmation; gold standard. Must be performed before initiating PAH therapy. (sources/PHT-ESC-2022, rating: very high)
• Echocardiography: First-line non-invasive investigation (Class I/B); assigns echocardiographic probability of PH. TRV threshold >2.8 m/s maintained. Echocardiography alone insufficient to confirm PH. (sources/PHT-ESC-2022, rating: very high)
• Diagnostic algorithm: Three-step: suspicion (GP: ECG + BNP/NT-proBNP + O₂ sat) → detection (echo + PFTs + ABG) → confirmation (PH centre + RHC). (sources/PHT-ESC-2022, rating: very high)
• V/Q scintigraphy: Recommended in unexplained PH to exclude CTEPH (Class I/C). (sources/PHT-ESC-2022, rating: very high)
• Warning signs for immediate hospitalization: Rapid WHO-FC III/IV progression, RV failure signs, syncope, low CO state, haemodynamic compromise. (sources/PHT-ESC-2022, rating: very high)

Screening

• SSc: Annual PAH risk evaluation recommended (Class I/B); DETECT algorithm when disease duration >3 years + FVC ≥40% + DLCO <60% (Class I/B). Prevalence of PAH in SSc: 5–19%. (sources/PHT-ESC-2022, rating: very high)
• BMPR2 carriers: Annual multimodal screening (ECG + NT-proBNP + DLCO + echo + CPET). Echocardiography alone insufficient. Lifetime PAH risk ~20%. (sources/PHT-ESC-2022, rating: very high)
• Post-PE: Evaluate for CTEPH/CTEPD in persistent/new dyspnoea after PE (Class I/C); refer to PH/CTEPH centre for mismatched perfusion defects persisting beyond 3 months (Class I/C). (sources/PHT-ESC-2022, rating: very high)

Genetics — Heritable PAH (HPAH)

• BMPR2 (AD): Definitive — the major genetic cause of HPAH; accounts for ~75–80% of familial PAH and ~20% of apparently idiopathic PAH. Lifetime penetrance ~20% (lower in women). (sources/clingen-summary-2026-05-09, rating: high; ClinGen classification date: 12/07/2020)
• CAV1 (AD): Definitive — caveolin-1; established genetic cause of HPAH. (sources/clingen-summary-2026-05-09, rating: high; ClinGen classification date: 07/30/2025)
• ATP13A3 (AD): Definitive — ATPase 13A3; established genetic cause of HPAH. (sources/clingen-summary-2026-05-09, rating: high; ClinGen classification date: 11/09/2021)
• EIF2AK4 (AR): Definitive — eukaryotic initiation factor 2 alpha kinase 4; established cause of pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH), a rare PAH subtype with poor prognosis and distinct pathology. Biallelic loss-of-function variants diagnostic. (sources/clingen-summary-2026-05-09, rating: high; ClinGen classification date: 12/02/2022)
• BMPR1A, BMPR1B (AD): Disputing — initial reports of these BMP receptor genes in HPAH have not been confirmed with sufficient evidence; ClinGen classification indicates evidence is insufficient to establish causality; variants in these genes should not be classified as P/LP for HPAH without functional evidence. (sources/clingen-summary-2026-05-09, rating: high)
• Genetic testing in PAH: 2022 ESC guidelines recommend genetic counselling and testing for BMPR2 and other HPAH genes in all PAH patients (Class I/C). ClinGen now validates which genes have sufficient evidence — BMPR2, CAV1, ATP13A3, and EIF2AK4 (for PVOD/PCH) are the four with definitive evidence. (sources/PHT-ESC-2022, rating: very high; sources/clingen-summary-2026-05-09, rating: high)

PAH General Measures

• Supervised exercise training: Class I/A (upgraded from IIa) — large multicentre RCT showed +34.1 m 6MWD improvement in PAH/CTEPH on PAH drugs. (sources/PHT-ESC-2022, rating: very high)
• Iron deficiency correction: Class I/C — iron deficiency common in PAH; i.v. iron for anaemia; repletion without anaemia is Class IIb. (sources/PHT-ESC-2022, rating: very high)
• Anticoagulation: IIb (individual basis only) — not generally recommended; potentially harmful in SSc-PAH; conflicting evidence for IPAH. (sources/PHT-ESC-2022, rating: very high)
• ACEi/ARB/ARNI/SGLT-2i/beta-blockers: Class III — not recommended in PAH unless required by comorbidities (systemic hypertension, CAD, left HF, arrhythmias). (sources/PHT-ESC-2022, rating: very high)
• Pregnancy: strongly discouraged — maternal mortality 11–25%; ERAs and riociguat contraindicated (Class III/B); CCBs/PDE5i/prostacyclins considered safe. (sources/PHT-ESC-2022, rating: very high)

PAH Drug Therapy

• Acute vasoreactivity testing (AVT) — updated positive response definition: mPAP decrease ≥10 mmHg to absolute value ≤40 mmHg with maintained or increased CO (replaces older 20% PVR reduction criterion); ~10% of PAH patients respond; predictive/prognostic value only in idiopathic/heritable/drug-induced PAH. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
• Preferred AVT agents: iNO and inhaled iloprost (Class I ESC 2022); IV epoprostenol (Class I ESC 2022); adenosine no longer recommended (ESC 2022) due to frequent adverse effects (AV block, bronchospasm, hypotension). (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
• Calcium channel blockers: Class I/C — only for vasoreactive patients with IPAH/HPAH/DPAH (<10% qualify). Adequate response: WHO-FC I/II + mPAP <30 mmHg + PVR <4 WU at 3–6 months. Class III in non-responders. Long-term CCB responders now assigned their own WSPH PH subclassification. (sources/PHT-ESC-2022, rating: very high) (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
• Initial combination ERA + PDE5i: Class I/B for low-to-intermediate-risk IPAH/HPAH/DPAH. Ambrisentan + tadalafil (AMBITION): Class I. Macitentan + tadalafil: Class I (new in 2022). Other ERA + PDE5i: Class IIa. (sources/PHT-ESC-2022, rating: very high)
• Bosentan + sildenafil: Class III (downgraded from IIb — no longer recommended). (sources/PHT-ESC-2022, rating: very high)
• Escalation for intermediate-high/high risk: Parenteral prostacyclin addition or lung transplantation evaluation. (sources/PHT-ESC-2022, rating: very high)
• See entities/CTEPH for CTEPH-specific therapy; see concepts/PAH-Risk-Stratification for treatment targets.

PH-LHD (Group 2)

• RHC: Class I — for suspected PH-LHD when results aid management; also for severe tricuspid regurgitation before valve intervention. (sources/PHT-ESC-2022, rating: very high)
• PDE5i in HFpEF + isolated post-capillary PH: Class III — not recommended (no benefit; GRADE: Low, Conditional against). (sources/PHT-ESC-2022, 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, rating: very high)
• CpcPH with PVR >5 WU: Individualized approach; referral to PH centre (Class I). (sources/PHT-ESC-2022, rating: very high)

PH-Lung Disease (Group 3)

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

RV Failure in PH — Mechanisms and Assessment

• RV–PA uncoupling is the haemodynamic hallmark of right heart failure in PH: Ees/Ea <≈0.7 = uncoupling threshold; optimal coupling 1.5–2.0. See concepts/RV-PA-Coupling. (sources/rv-failure-aha-2026, rating: very high)
• Progression: chronic pressure overload → RV hypertrophy (adaptive) → RV dilation, fibrosis, diastolic stiffness → RV–PA uncoupling (maladaptive) → right heart failure — primary cause of death in advanced PH. (sources/rv-failure-aha-2026, rating: very high)
• RV afterload is multifactorial: PVR + PA compliance + pulsatile load — PVR alone insufficient to characterise haemodynamic burden. (sources/rv-failure-aha-2026, rating: very high)
• Key drivers of maladaptive remodeling: inflammation (TNF-α/IL-6/IL-1β/NLRP3 inflammasome), metabolic reprogramming (Warburg effect, FAO → glycolysis), ECM fibrosis (TGF-β/MMP/integrin pathways). (sources/rv-failure-aha-2026, rating: very high)
• Noninvasive RV–PA coupling surrogates: TAPSE/sPAP (widely used; prognostic); RV free wall strain/sPAP (superior for PAH outcomes prediction); RVEF change with therapy. (sources/rv-failure-aha-2026, rating: very high)
• CMR: Gold standard for RV volumes/function; LGE and T1/T2 mapping detect fibrosis in maladaptive remodeling; 4D flow predicts PH vs RHC. (sources/rv-failure-aha-2026, rating: very high)
• BMPR2 mutation carriers: More severe RV dysfunction independent of afterload; higher mortality/transplantation risk vs non-carriers. (sources/rv-failure-aha-2026, rating: very high)

Sotatercept — RV-Targeted PAH Therapy

• Sotatercept (activin ligand trap / TGF-β superfamily signalling inhibitor): FDA-approved for advanced PAH. (sources/rv-failure-aha-2026, rating: very high)
• STELLAR trial (Phase 3): Improved PA pressures, PA compliance, PA–RV coupling, and RV function in PAH patients. (sources/rv-failure-aha-2026, rating: very high)
• SPECTRA trial (Phase 2b): Decreased RV mass; increased haemoglobin and peak VO₂ without changes in resting cardiac output; potential direct cardioprotective effect on cardiomyocytes. (sources/rv-failure-aha-2026, rating: very high)
• Long-term consequences of sotatercept's direct myocardial effects remain unclear and require further study. (sources/rv-failure-aha-2026, rating: very high)

Perioperative Management of PH

• Continue all PAH-targeted therapy perioperatively (COR 1): Abrupt discontinuation of ERA, PDE5i, or prostacyclins causes acute haemodynamic decompensation and death — these must be maintained without interruption including on the day of surgery. (sources/periop-aha-2024, rating: very high)
• Specialist centre referral (COR 2a): Severe PH patients undergoing elevated-risk NCS should be managed at centres with expertise in PAH — multidisciplinary team including PH cardiologist, anaesthesiologist, and intensivist. (sources/periop-aha-2024, rating: very high)
• Perioperative risk: PH confers 43% increased odds of postoperative death, MI, or stroke. Group 1 PAH patients specifically: 2.5× increased MACE risk and 5× increased cardiogenic shock risk vs patients without PH. (sources/periop-aha-2024, rating: very high)
• Invasive haemodynamic monitoring (COR 2a): Recommended for PH patients undergoing elevated-risk NCS to guide fluid management and vasopressor use; avoid fluid overload and avoid agents that increase RV afterload. (sources/periop-aha-2024, rating: very high)
• Inhaled pulmonary vasodilators (COR 2a): Inhaled NO or epoprostenol should be available for intraoperative or postoperative pulmonary hypertensive crises; vasopressors (norepinephrine, vasopressin) preferred over inotropes to manage hypotension and maintain RV perfusion pressure. (sources/periop-aha-2024, rating: very high)

Contradictions / Open Questions

• Lower haemodynamic threshold not yet backed by drug trial evidence: The 2022 definition extends PH diagnosis to mPAP 21–24 mmHg + PVR 2–3 WU, but all approved PAH drugs were studied only in patients with mPAP ≥25 mmHg and PVR >3 WU. No efficacy data exist for this lower-threshold zone — clinicians may face diagnostic labelling without actionable treatment options. (sources/PHT-ESC-2022, rating: very high)
• Exercise PH thresholds require further validation: mPAP/CO slope >3 mmHg/L/min is age-dependent; reproducibility across centres and prognostic implications in clinical practice require prospective validation before routine clinical use. (sources/PHT-ESC-2022, rating: very high)
• Anticoagulation in IPAH remains unresolved: Downgraded to Class IIb despite meta-analyses suggesting survival benefit; no RCT data; registry evidence conflicting; recommendation driven largely by expert opinion and concern about harm in SSc-PAH. (sources/PHT-ESC-2022, rating: very high)

Contradictions / Open Questions (updated)

• Normal PAWP vs PH classification threshold: True physiological PAWP upper limit is 13 mmHg (meta-analysis), but ESC guidelines use 15 mmHg as the post-capillary PH diagnostic threshold. The grey zone (13–15 mmHg) may lead to under-recognition of early LHD-related PH. (sources/rhc-hf-ehj-2025, rating: high)

Contradictions / Open Questions (updated)

• RV–PA uncoupling transition point remains elusive: The adaptive-to-maladaptive remodeling transition cannot be reliably identified prospectively; delayed diagnosis means most patients are already maladaptive at presentation; no validated serial monitoring algorithm integrates Ees/Ea surrogates into clinical practice. (sources/rv-failure-aha-2026, rating: very high)

• ESC/ERS guidelines lack comprehensive ongoing risk assessment incorporating advanced RV imaging: Current guidelines use imaging metrics for initial diagnosis only; no validated multiparametric model for serial RV monitoring in PH — identified as a major gap. (sources/rv-failure-aha-2026, rating: very high)

• ClinGen disputes BMPR1A and BMPR1B in HPAH (2026): These two BMP receptor subtype genes have been reported in PAH literature but ClinGen classification is "Disputing" — insufficient or contradicted evidence to establish gene-disease causality. Variants in BMPR1A and BMPR1B found on panel testing should not be labelled pathogenic/likely-pathogenic for HPAH without strong functional validation. This highlights the gap between published genetic associations and rigorously curated causal evidence. (sources/clingen-summary-2026-05-09, rating: high)

Connections

• Related to entities/CTEPH
• Related to concepts/PAH-Risk-Stratification
• Related to entities/Heart-Failure
• Related to concepts/HFpEF
• Related to concepts/Right-Heart-Catheterization
• Related to concepts/RV-PA-Coupling
• Related to sources/PHT-ESC-2022
• Related to sources/rhc-hf-ehj-2025
• Related to sources/rv-failure-aha-2026
• Related to concepts/Perioperative-Cardiovascular-Assessment
• Related to sources/periop-aha-2024
• Related to sources/cardio-oncology-vascular-metabolic-aha-2019
• Related to concepts/Cancer-Therapy-Related-CV-Toxicity
• Related to concepts/ClinGen-Gene-Disease-Validity
• Related to sources/clingen-summary-2026-05-09

Sources

• sources/Cardio-Oncology-ESC-2022
• sources/PHT-ESC-2022
• sources/cardio-oncology-vascular-metabolic-aha-2019
• sources/clingen-summary-2026-05-09
• sources/hemodynamic-hf-pht-aha-2026
• sources/periop-aha-2024
• sources/rhc-hf-ehj-2025
• sources/rv-failure-aha-2026