Pulmonary Hypertension: From the Kovacs et al., Eur Respir J 2024

Source: Kovacs G, Bartolome S, Denton CP, et al. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J 2024; 64: 2401324. (7th World Symposium on Pulmonary Hypertension)

1. DEFINITION

Haemodynamic Subtypes (Table 1 from the paper)

• PAWP (pulmonary arterial wedge pressure) distinguishes pre-capillary from post-capillary PH
• PVR (pulmonary vascular resistance) further stratifies post-capillary subtypes
• Gold standard for measurement: direct Fick method for cardiac output; thermodilution is an acceptable alternative

"Early PH"

Unclassified PH

Important note on treatment thresholds

2. ETIOLOGY / CLINICAL CLASSIFICATION (5 Groups)

Group 1: Pulmonary Arterial Hypertension (PAH)

Group 2: PH Associated with Left Heart Disease

• 2.1 Heart failure: with preserved EF (HFpEF), reduced/mildly reduced EF, specific cardiomyopathies (hypertrophic, amyloid, Fabry, Chagas)
• 2.2 Valvular heart disease: aortic, mitral, or mixed
• 2.3 Congenital/acquired cardiovascular conditions

Group 3: PH Associated with Lung Diseases and/or Hypoxia

• 3.1 COPD and/or emphysema
• 3.2 Interstitial lung disease
• 3.3 Combined pulmonary fibrosis and emphysema
• 3.4 Other parenchymal lung diseases
• 3.5 Nonparenchymal restrictive diseases (hypoventilation syndromes, pneumonectomy)
• 3.6 Hypoxia without lung disease (e.g., high altitude)
• 3.7 Developmental lung diseases

Group 4: PH Associated with Pulmonary Artery Obstructions

• 4.1 Chronic thromboembolic PH (CTEPH)
• 4.2 Other pulmonary artery obstructions (sarcomas, other malignancies, arteritis, congenital stenoses, hydatidosis)

Group 5: PH with Unclear/Multifactorial Mechanisms

• 5.1 Haematological disorders (haemolytic anaemia, myeloproliferative disorders)
• 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1
• 5.3 Metabolic disorders (glycogen storage diseases, Gaucher disease)
• 5.4 Chronic renal failure with/without haemodialysis
• 5.5 Pulmonary tumour thrombotic microangiopathy
• 5.6 Fibrosing mediastinitis
• 5.7 Complex congenital heart disease

3. PATHOGENESIS

Note: This paper focuses on definition, classification, and diagnosis. Detailed pathogenesis is not its scope. However, the following mechanistic points are mentioned:

• Pre-capillary PH (Groups 1, 3, 4) involves pulmonary arterial remodelling and elevated PVR
• Long-term CCB responders have PH driven primarily by vasoconstriction rather than arterial remodelling - a distinct pathophysiology
• Heritable PAH (HPAH): Caused by germline mutations, most commonly in BMPR2 (TGF-β receptor pathway). Other confirmed genes: ACVRL1, ENG, GDF2, KCNK3, SMAD9, CAV1, ATP13A3, SOX17, KDR, TBX4, EIF2AK4
  • HPAH patients present with more compromised haemodynamic profiles and higher risk of clinical worsening
• Drug-induced PAH (e.g., Mitomycin-C): causes pulmonary veno-occlusive disease via endothelial-to-mesenchymal transition (Smad3-dependent pathway)
• PVOD/PCH: Biallelic EIF2AK4 pathogenic variants are diagnostic
• HIV-associated PAH: Low CD4+ count and high viral load are risk factors; incidence declining with better HIV management
• Portopulmonary PH: Cardiac index is the critical haemodynamic variable for risk stratification; prognosis closely tied to liver disease severity
• SSc-associated PH: Multiple mechanisms - PAH (Group 1), ILD-associated PH (Group 3), diastolic dysfunction, PVOD, and thromboembolic PH

4. CLINICAL FEATURES

Symptoms

• Dyspnoea on exertion (most common)
• Fatigue and rapid exhaustion
• Bendopnoea (dyspnoea when bending forward)
• Weight gain due to fluid retention
• Syncope during physical exertion

Physical Examination Signs

• Accentuated second heart sound (P2)
• Systolic murmur of tricuspid regurgitation (in more advanced disease)
• Diastolic murmur from pulmonary valve insufficiency (Graham Steell murmur)
• Signs of right heart failure:
  • Peripheral oedema
  • Distended and pulsating jugular veins
  • Hepatic heave
  • Ascites

ECG Signs

• Right axis deviation - high positive predictive value for PH in adults with dyspnoea
• Can detect arrhythmias and signs of left heart disease
• Normal ECG + normal BNP/NT-proBNP + normal gas exchange = low likelihood of PH

5. DIAGNOSIS

Diagnostic Algorithm

• Assess WHO functional class (WHO-FC)
• Review risk conditions: CTD, portal hypertension, HIV, congenital heart disease, thromboembolic disease, illicit drug use, left heart and lung diseases
• Physical signs as above

• Chest radiograph
• ECG
• Oxygen saturation measurement
• Basic laboratory: blood count, electrolytes, renal/liver function, BNP or NT-proBNP
• Characteristic CXR: enlarged pulmonary arch and arteries, distinctive lateral cardiac silhouette

• RV/LV basal diameter ratio >1.0
• Flattening of interventricular septum (LVEI >1.1)
• TAPSE/sPAP ratio <0.55 mm/mmHg
• RVOT acceleration time <105 ms ± mid-systolic notch
• Early diastolic pulmonary regurgitation velocity >2.2 m/s
• PA diameter >25 mm; PA > aortic root
• IVC diameter >21 mm with decreased inspiratory collapse
• RA area (end-systole) >18 cm²
• Enlarged RA, RV, distended IVC
• Pericardial effusion
• D-shaped LV (LVEI >1)
• Reduced RV fractional area change <35%
• Decreased TAPSE <1.8 cm; Decreased S' <9.5 cm/s

• Arterial blood gas analysis
• Pulmonary function tests (PFT) with DLCO
• Chest CT (preferred over CXR): shows enlarged PA diameter, PA/aorta ratio, enlarged right heart chambers; parenchymal changes (ground-glass opacities, septal lines) suggest PVOD
• CT pulmonary angiography: detects filling defects/webs in CTEPH
• Polygraphy/overnight oximetry if hypoventilation suspected
• DLCO <40% predicted → perform HRCT (suggests parenchymal lung disease or PVOD)

• V/Q scan: negative result excludes significant thromboembolic disease; mismatched perfusion defects highly suggestive of CTEPH
• Detailed labs: iron status, TSH, hepatitis viruses, HIV, ANA, anticentromere antibodies, anti-Ro
• Antiphospholipid syndrome markers if CTEPH suspected
• Urine drug screening for all idiopathic PAH (methamphetamine)
• 6-minute walk test (6MWT)
• Abdominal ultrasound (portal hypertension)
• Optional: cardiopulmonary exercise testing (CPET), cardiac MRI

• Gold standard for final diagnosis
• Haemodynamic measurements: mean, systolic, diastolic PAP; PAWP; right atrial pressure; heart rate; cardiac output; PVR calculation
• Blood gases: arterial, pulmonary artery, large vein (to detect shunts)
• Vasoreactivity testing (for idiopathic PAH, heritable PAH, drug-associated PAH):
  • Agent: inhaled nitric oxide (recommended); inhaled iloprost or IV epoprostenol as alternatives
  • Positive response: decrease mPAP ≥10 mmHg to <40 mmHg with unchanged or increased cardiac output
  • Positive in ~12% of idiopathic PAH; <5% in heritable PAH
• Exercise haemodynamics: preferred by cycle ergometry; both step and ramp protocols acceptable
• Fluid loading: rapid infusion of 500 mL saline; PAWP >18 mmHg suggests latent left heart disease

Fast-Track Referral

Screening (High-Risk Groups)

• BMPR2 mutation carriers
• First-degree relatives of heritable PAH patients
• Patients assessed for liver transplant or TIPS
• Patients with systemic sclerosis spectrum disorders (use DETECT tool)

6. TREATMENT / DRUGS

Important limitation: This paper (Kovacs et al., 2024) is dedicated solely to definition, classification, and diagnosis. It does not provide treatment algorithms or drug dosages. The 7th WSPH companion paper on treatment is: Chin KM, Gaine SP, Gerges C, et al. "Treatment algorithm for pulmonary arterial hypertension." Eur Respir J 2024; 64: 2401325 (referenced as [41] in this paper).

• Long-term CCB responders (idiopathic/heritable/drug-associated PAH with positive vasoreactivity test and sustained response ≥1 year): treated with high-dose calcium channel blockers - this subgroup has been re-introduced into the classification (Group 1.1.1)
• Targeted PH drugs are NOT indicated for "early PH" (mPAP 21-24 mmHg, PVR 2-3 WU) - no sufficient clinical trial data
• No PH drugs are approved for Group 2 PH (left heart disease), though severe cpcPH warrants expert centre evaluation
• Drug thresholds for approved PAH therapy remain: mPAP ≥25 mmHg, PAWP ≤15 mmHg, PVR >3 WU
• Patients with PVOD/PCH and biallelic EIF2AK4 mutations: early referral for lung transplantation

Summary Table

This paper is from the 7th World Symposium on Pulmonary Hypertension (7th WSPH, 2023) and represents the most current international expert consensus as of 2024, aligned with 2022 ESC/ERS guidelines.