What is the recommended diagnostic work‑up and treatment strategy for a patient with suspected pulmonary hypertension, including classification, risk stratification, and first‑line therapy?

Pulmonary Hypertension: Diagnostic Work-up and Treatment Strategy

Definition and Hemodynamic Criteria

Pulmonary hypertension is definitively diagnosed by right heart catheterization demonstrating a mean pulmonary arterial pressure ≥25 mmHg at rest. 1 This invasive hemodynamic assessment is essential for accurate diagnosis and cannot be replaced by non-invasive testing alone. 2

• The normal mean PAP is 14 ± 3 mmHg with an upper limit of approximately 20 mmHg 1
• Patients with mean PAP between 21-24 mmHg require careful monitoring, particularly those at risk for developing PAH (connective tissue disease, family history of heritable PAH) 1
• Exercise-induced PH should not be used as a diagnostic entity due to lack of validated prognostic data 1

Clinical Classification System

The Dana Point classification divides PH into five distinct clinical groups based on pathophysiology, hemodynamics, and treatment approach: 1

Group 1 - Pulmonary Arterial Hypertension (PAH):

• Defined hemodynamically as mean PAP ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >3 Wood units 1
• Includes idiopathic PAH, heritable PAH (BMPR2, ALK1, endoglin mutations), drug/toxin-induced, and associated conditions (connective tissue disease, HIV, portal hypertension, congenital heart disease) 1
• Group 1' includes pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis 1

Group 2 - PH due to left heart disease:

• Post-capillary PH with PAWP >15 mmHg 1
• Includes systolic dysfunction, diastolic dysfunction, and valvular disease 1

Group 3 - PH due to lung diseases and/or hypoxemia:

• COPD, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation 1

Group 4 - Chronic thromboembolic pulmonary hypertension (CTEPH) 1

Group 5 - PH with unclear/multifactorial mechanisms:

• Hematological disorders, sarcoidosis, metabolic disorders, chronic renal failure on dialysis 1

Diagnostic Algorithm

Initial Screening and Non-Invasive Assessment

When PH is suspected clinically (dyspnea, fatigue, syncope, signs of right heart failure), transthoracic echocardiography is the primary screening tool. 2, 3

Step 1: Clinical evaluation and basic testing 1, 4

• WHO functional class assessment (critical prognostic indicator) 1, 4
• Physical examination focusing on loud P2, elevated JVP, peripheral edema, hepatomegaly 1
• Electrocardiography (right ventricular hypertrophy, right axis deviation) 2
• Chest radiography (enlarged pulmonary arteries, right heart enlargement) 2
• Pulmonary function tests with diffusing capacity 2
• Arterial blood gases 4

Step 2: Echocardiographic assessment 4, 2

• Tricuspid regurgitation velocity to estimate pulmonary artery systolic pressure 4
• Right ventricular size and function 4
• Right atrial enlargement 4
• Inferior vena cava diameter and collapsibility 4
• Pericardial effusion (sign of advanced disease) 4

Critical pitfall: Do not rely on a single echocardiographic parameter; multiple variables must be assessed together. 4

Step 3: Exclude common causes 2, 3

• Ventilation-perfusion scan is mandatory in all patients with suspected or confirmed PH without confirmed left heart or lung disease to exclude CTEPH 2
• CT pulmonary angiography if V/Q scan suggests CTEPH 2
• High-resolution chest CT for interstitial lung disease 2
• Overnight oximetry or polysomnography for sleep-disordered breathing 2
• Echocardiography to assess left ventricular function and valvular disease 2

Step 4: Serological and laboratory testing 4

• Brain natriuretic peptide (BNP) or NT-proBNP (indicates RV strain, correlates with severity) 4
• Complete blood count, liver function tests, thyroid function 4
• HIV serology, hepatitis serology 5
• Autoimmune serologies (ANA, anti-Scl-70, anti-centromere) for connective tissue disease 5

Definitive Diagnosis: Right Heart Catheterization

Right heart catheterization must be performed in all patients with suspected PAH or CTEPH to confirm diagnosis and guide treatment. 1, 2

Hemodynamic measurements required: 1

• Mean pulmonary arterial pressure
• Pulmonary artery wedge pressure (to distinguish pre-capillary from post-capillary PH)
• Cardiac output (thermodilution or Fick method)
• Pulmonary vascular resistance calculation
• Right atrial pressure

Critical pitfall: Optimize volume status before performing RHC, as volume overload affects hemodynamic accuracy. 4

Risk Stratification

All PAH patients must be risk-stratified using a comprehensive multiparametric approach to guide treatment intensity. 1

Three-Tier Risk Assessment Model 1

Low risk (estimated 1-year mortality <5%):

• WHO functional class I-II 1
• 6-minute walk distance >440 meters 1
• BNP <50 ng/L or NT-proBNP <300 ng/L 1
• No signs of right ventricular dysfunction on echocardiography 1
• Right atrial pressure <8 mmHg, cardiac index ≥2.5 L/min/m² 1

Intermediate risk (estimated 1-year mortality 5-10%):

• WHO functional class III 1
• 6-minute walk distance 165-440 meters 1
• Moderately impaired exercise capacity with signs of RV dysfunction but not RV failure 1

High risk (estimated 1-year mortality >10%):

• WHO functional class IV 1
• 6-minute walk distance <165 meters 1
• Progressive disease with severe RV dysfunction or RV failure 1
• Signs of secondary organ dysfunction 1

Critical pitfall: Worsening WHO functional class is one of the most alarming indicators and should trigger immediate reassessment—do not delay evaluation. 4

Follow-up Assessment

Regular follow-up assessments every 3-6 months are mandatory in stable PAH patients. 1 Each visit should include: 1

• WHO functional class 1
• 6-minute walk test 1
• BNP or NT-proBNP 1
• Echocardiography 1
• Consider repeat right heart catheterization at intervals 1

Treatment Strategy

Referral to Expert Centers

All patients with confirmed PAH or CTEPH must be referred to a specialist pulmonary hypertension center. 1, 2 Expert centers provide multidisciplinary care, access to advanced therapies, and participation in clinical trials. 1

Treatment Goals

The primary treatment goal is achieving and maintaining low-risk status, which translates to WHO functional class I-II and 6-minute walk distance >440 meters. 1

• Low-risk status is associated with good exercise capacity, quality of life, RV function, and low mortality risk 1
• Achievement/maintenance of intermediate-risk profile should be considered inadequate treatment response for most PAH patients 1
• Individual factors (age, comorbidities) may modify these targets, but younger healthy patients may require even higher thresholds 1

General Measures and Supportive Therapy 1

Pregnancy must be avoided in PAH patients (Class I recommendation). 1

Additional general measures: 1

• Immunization against influenza and pneumococcal infection (Class I) 1
• Psychosocial support (Class I) 1
• Supervised exercise training in physically deconditioned patients under medical therapy (Class IIa) 1
• In-flight oxygen for WHO functional class III-IV patients 1

Supportive therapy: 1

• Diuretics for fluid retention, hepatic congestion, peripheral edema 6
• Oral anticoagulation targeting INR 1.5-2.5 for PAH; INR 2-3 for CTEPH 6
• Supplemental oxygen for hypoxemia 1

PAH-Specific Therapy

Treatment strategy is determined by initial risk stratification at diagnosis. 1

Vasoreactivity Testing

Acute vasoreactivity testing with inhaled nitric oxide or intravenous epoprostenol should be performed in all patients with idiopathic, heritable, or drug-induced PAH. 1

• Positive response: decrease in mean PAP ≥10 mmHg to reach absolute mean PAP ≤40 mmHg with increased or unchanged cardiac output 1
• Only 10-15% of patients are vasoreactive 5
• Vasoreactive patients should receive high-dose calcium channel blockers (CCBs) as first-line therapy 1, 5
• CCB options: nifedipine (120-240 mg/day), diltiazem (240-720 mg/day), amlodipine (up to 20 mg/day) 5

First-Line Therapy for Non-Vasoreactive Patients

Current evidence supports initial combination therapy over monotherapy for most PAH patients. 5, 3

For low or intermediate-risk patients: 1

• Initial oral combination therapy targeting multiple pathways 1, 5
• Ambrisentan (endothelin receptor antagonist) plus tadalafil (phosphodiesterase-5 inhibitor) is a proven first-line combination with demonstrated mortality benefit 5

For high-risk patients: 1

• Initial triple combination therapy including intravenous prostacyclin analogues (epoprostenol or treprostinil) should be considered 1
• Add endothelin receptor antagonist and phosphodiesterase-5 inhibitor 1

PAH-Specific Drug Classes 5, 6

Three therapeutic pathways are targeted: 5, 6

1. Nitric oxide-cyclic GMP pathway:

   • Phosphodiesterase-5 inhibitors: sildenafil, tadalafil 5, 6
   • Soluble guanylate cyclase stimulator: riociguat 5, 6

2. Endothelin pathway:

   • Endothelin receptor antagonists: bosentan, ambrisentan 5, 6

3. Prostacyclin pathway:

   • Prostacyclin analogues: epoprostenol (intravenous), treprostinil (intravenous, subcutaneous, inhaled), iloprost (inhaled) 5, 6

With current combination therapy, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. 5

Treatment for Other PH Groups

Group 2 (PH due to left heart disease): Primary treatment is optimization of the underlying cardiac condition; PAH-specific therapies are not recommended. 2, 7

Group 3 (PH due to lung disease): Treatment focuses on the underlying lung disease and correction of hypoxemia; PAH-specific therapies are not recommended. 2, 7

Group 4 (CTEPH):

• Surgical pulmonary endarterectomy is the treatment of choice for eligible patients 2, 6
• Balloon pulmonary angioplasty for selected patients 1
• Riociguat is the only approved medical therapy for inoperable or persistent/recurrent CTEPH 2, 6

Group 5: Treatment targets the underlying condition; PAH therapeutics generally not recommended. 7

Escalation Strategy

If inadequate clinical response (failure to achieve/maintain low-risk status) on initial therapy: 1

• Sequential addition of drugs from different therapeutic classes 1
• Progress to triple therapy including intravenous prostacyclin if needed 1
• Patients with inadequate response to maximum medical therapy (triple therapy with intravenous prostacyclin) should be assessed for lung transplantation 1, 7

Critical pitfall: Do not assume clinical worsening is solely from PH progression—always exclude precipitating factors such as infection, arrhythmia, pulmonary embolism, medication non-adherence, or volume overload. 4