What is the recommended initial work‑up and treatment approach for a patient with suspected pulmonary hypertension, including classification into WHO groups and appropriate therapy?

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Pulmonary Hypertension: Diagnostic Work-Up and Treatment Approach

Begin with transthoracic Doppler echocardiography as your first-line screening test, then confirm every suspected case with right-heart catheterization before initiating any therapy—this hemodynamic confirmation is mandatory to establish the diagnosis, classify the WHO group, and guide treatment. 1, 2

Initial Screening and Clinical Suspicion

When to Screen

  • Screen patients presenting with unexplained dyspnea, exercise intolerance, syncope (occurs in ~40% of PH patients), fatigue, weakness, or chest pain 3, 4
  • Systematically screen high-risk populations even when asymptomatic:
    • Connective-tissue disease, especially scleroderma spectrum disorders (carries poor prognosis) 3
    • Portal hypertension (e.g., liver transplant candidates) 3
    • Congenital heart disease 3
    • Family history of PH or BMPR2 mutation 3
    • HIV infection 3
    • Prior venous thromboembolism 3
    • Exposure to appetite suppressants or chemotherapy (mitomycin-C, carmustine, etoposide, cyclophosphamide, bleomycin) 3

Physical Examination Findings

  • Accentuated pulmonary component of S2 at the apex (present in ~90% of idiopathic PAH) 3
  • Left parasternal lift (RV hypertrophy) 3
  • Right ventricular S4 gallop (~38% of patients) 3
  • Prominent jugular "a" waves 3
  • Advanced disease signs: pulmonary regurgitation murmur, peripheral edema, hepatomegaly, ascites 3

Diagnostic Algorithm

Step 1: Echocardiography-Based Risk Stratification

Perform transthoracic Doppler echocardiography first 1, 3

If Echocardiography Shows "PH Unlikely"

  • No symptoms → No further work-up needed 1, 3
  • Symptoms present + PAH risk factors → Schedule echocardiographic follow-up 1, 3
  • Symptoms present + no risk factors → Evaluate alternative causes of symptoms 1, 3

If Echocardiography Shows "PH Possible"

  • No symptoms + no risk factors → Echocardiographic follow-up 1, 3
  • Symptoms + risk factors → Consider right-heart catheterization 1, 3
  • Symptoms + no risk factors → Consider alternative diagnosis and echocardiographic follow-up; if symptoms at least moderate, consider RHC 1, 3

If Echocardiography Shows "PH Likely"

  • With symptoms (regardless of risk factors) → Right-heart catheterization is mandatory 1, 3
  • Without symptoms (regardless of risk factors) → Right-heart catheterization should be strongly considered 1, 3

Step 2: Exclude Left Heart Disease and Lung Disease

Before proceeding to RHC, evaluate for the most common causes (Groups 2 and 3): 1

  • Assess for left heart disease using:

    • Clinical history: age >65 years, metabolic syndrome features, persistent atrial fibrillation 5
    • Echocardiography: left atrial enlargement, LV systolic/diastolic dysfunction, valvular disease 1, 5

  • Assess for lung disease using:

    • Pulmonary function tests with DLCO 1, 3
    • Arterial blood gases 1
    • High-resolution CT chest 1

If left heart or lung disease is confirmed without severe PH/RV dysfunction → Treat the underlying disease 1

If severe PH/RV dysfunction is present despite left heart or lung disease → Refer to PH expert center 1

Step 3: Mandatory Right-Heart Catheterization

Right-heart catheterization is required in all patients with suspected PAH to confirm diagnosis, establish hemodynamic classification, assess prognosis, and guide therapy 1, 5, 2

Hemodynamic Definitions

  • Pulmonary hypertension: mean PAP ≥25 mmHg at rest (older definition) 1, 6 or ≥20 mmHg (newer threshold) 7
  • Precapillary PH (Groups 1,3,4,5): PAWP ≤15 mmHg AND PVR >3 Wood units 1, 5, 3
  • Postcapillary PH (Group 2): PAWP >15 mmHg 6

Variables to Record During RHC

  • Pulmonary artery systolic, diastolic, and mean pressures 5
  • Right atrial pressure 5
  • Pulmonary capillary wedge pressure 5
  • Right ventricular pressure 5
  • Cardiac output measured in triplicate (thermodilution or Fick method) 5

Step 4: Distinguish CTEPH from PAH

Perform ventilation/perfusion (V/Q) lung scan in all patients with unexplained PH—this is mandatory to exclude chronic thromboembolic PH 1, 5, 3

  • Multiple segmental perfusion defects → Suspect CTEPH (Group 4) 1

    • Proceed to contrast CT pulmonary angiography 1
    • Consider conventional pulmonary angiography for surgical planning 1

  • Normal or subsegmental "patchy" defects → Suspect PAH (Group 1) or Group 5 1

Critical pitfall: Do not rely on CT angiography alone to exclude CTEPH—V/Q scan is more sensitive 1

Step 5: Identify PAH-Associated Conditions

Obtain the following laboratory tests in all patients with confirmed PAH: 1, 3

  • Routine biochemistry, hematology, immunology 1
  • Thyroid function tests 1
  • HIV testing 1
  • Liver function tests 5
  • Abdominal ultrasound to screen for portal hypertension 1

WHO Clinical Classification (Five Groups)

Group 1 – Pulmonary Arterial Hypertension (PAH):

  • Idiopathic, heritable, drug-induced, or associated with connective-tissue disease, congenital heart disease, portal hypertension, HIV, schistosomiasis 3, 7

Group 2 – PH Due to Left Heart Disease:

  • Systolic/diastolic dysfunction, valvular disease 3, 7

Group 3 – PH Due to Lung Diseases/Hypoxemia:

  • COPD, interstitial lung disease, sleep-disordered breathing 3, 7

Group 4 – Chronic Thromboembolic PH (CTEPH) 3, 7

Group 5 – PH with Unclear/Multifactorial Mechanisms:

  • Sarcoidosis, hematologic or metabolic disorders 3, 7

Treatment Approach by WHO Group

Group 1 (PAH): Risk-Stratified Therapy

Vasoreactivity Testing (Idiopathic, Heritable, Drug-Induced PAH Only)

  • Perform acute vasoreactivity testing during RHC using IV epoprostenol, adenosine, or inhaled nitric oxide 1, 5
  • Positive response: decrease in mean PAP ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output 1, 2
  • Vasoreactivity testing is NOT recommended in PAH associated with connective-tissue disease, congenital heart disease, HIV, portopulmonary hypertension, or Groups 2–5 1, 5

High-Dose Calcium-Channel Blockers (CCBs) for Vasoreactive Patients (~10%)

  • CCBs are first-line for documented vasoreactive patients: long-acting nifedipine 120–240 mg daily, diltiazem 240–720 mg daily, or amlodipine up to 20 mg daily 5
  • Critical safety pitfall: Never start CCBs without documented positive vasoreactivity—risk of life-threatening hypotension and RV ischemia 5
  • Repeat RHC at 3–4 months; if patient is not WHO functional class I–II with marked hemodynamic improvement, add PAH-specific therapy 5

Initial Therapy for Non-Vasoreactive Patients

Low- or Intermediate-Risk Patients:

  • Start initial oral combination therapy with ambrisentan (endothelin-receptor antagonist) plus tadalafil (phosphodiesterase-5 inhibitor)—this delays clinical failure compared to monotherapy 5

High-Risk Patients:

  • Require initial combination therapy including intravenous prostacyclin analogue; IV epoprostenol is preferred because it reduces 3-month mortality 5

Sequential Escalation

  • If inadequate response to initial regimen, escalate to double or triple oral/intravenous combination therapy 5
  • Contraindication: Do not combine riociguat with a phosphodiesterase-5 inhibitor due to safety concerns 5

Advanced Therapies

  • Refer for lung transplantation when maximal combination therapy fails 5

Group 2 (Left Heart Disease)

PAH-specific drugs (endothelin-receptor antagonists, PDE-5 inhibitors, prostacyclins) are NOT recommended and may be harmful—focus on optimal treatment of the underlying cardiac condition and diuretics for volume control 5

Critical pitfall: Do not initiate PAH-specific drugs without confirming Group 1 PAH by RHC, as they can worsen outcomes in Group 2 PH 5

Group 3 (Lung Disease)

PAH-specific therapies are NOT recommended—treat the underlying lung pathology and provide long-term oxygen therapy when arterial oxygen tension is consistently <60 mmHg (8 kPa) to maintain saturations >90% 5, 6

Group 4 (CTEPH)

Surgical pulmonary endarterectomy performed in deep hypothermia with circulatory arrest is the treatment of choice and should be undertaken at experienced centers 5, 6

Operability assessment must be performed by a multidisciplinary expert team 5

Group 5 (Multifactorial)

Therapy is directed at the underlying disease; PAH-specific agents are not advised 5

Essential Supportive Care for All PAH Patients (Group 1)

  • Diuretics for signs of right-ventricular failure and fluid retention 5
  • Continuous long-term supplemental oxygen when arterial oxygen tension is consistently <60 mmHg or to maintain saturations >90% 5
  • Anticoagulation (target INR 1.5–2.5) should be considered in idiopathic, heritable, and anorexigen-induced PAH 5
  • Pregnancy is absolutely contraindicated—maternal mortality is 30–50% 5
  • Vaccination against influenza and pneumococcal disease 5
  • Avoid high altitude (>1,500–2,000 m) without supplemental oxygen 5
  • Supervised exercise rehabilitation when clinically appropriate 5

Monitoring and Treatment Goals

Follow-Up Schedule

Reassess stable patients every 3–6 months with: 5, 6

  • WHO functional class 5, 6
  • 6-minute walk distance (target >440 m; >500 m optimal) 5
  • BNP/NT-proBNP (target <50 ng/L) 5
  • Echocardiography 5, 6
  • Basic laboratory tests 5

Therapeutic Goal

The primary goal is to achieve and maintain a low-risk profile: 5

  • WHO functional class I–II 5
  • No signs of RV failure 5
  • No syncope 5
  • 6-minute walk >500 m 5
  • Normal BNP/NT-proBNP 5
  • No pericardial effusion 5
  • Right atrial pressure <8 mmHg 5
  • Cardiac index >2.5 L/min/m² 5

Critical Care and Advanced Interventions

  • ICU admission for hemodynamic instability: heart rate >110 bpm, systolic BP <90 mmHg, oliguria, rising lactate 5
  • Inotropic support for hypotensive patients 5
  • Balloon atrial septostomy as palliative or bridging procedure after failure of maximal medical therapy 5
  • Veno-arterial ECMO as bridge to lung transplantation in awake, end-stage PH patients 5

Critical Pitfalls to Avoid

  • Do not start PAH-specific drugs without RHC confirmation of Group 1 PAH—especially dangerous in Group 2 PH 5
  • Do not perform vasoreactivity testing in connective-tissue disease, congenital heart disease, HIV-associated PAH, portopulmonary hypertension, or Groups 2–5 1, 5
  • Do not start CCBs without documented positive vasoreactivity—risk of life-threatening hypotension 5
  • Do not omit V/Q scan—failure to perform it can miss treatable CTEPH 5, 3
  • Do not perform open or thoracoscopic lung biopsy in PAH patients 1
  • Do not rely solely on chest radiography—normal film does not exclude PH 3

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Diagnosis and differential assessment of pulmonary arterial hypertension.

Journal of the American College of Cardiology, 2004

3
Guideline

Pulmonary Hypertension – Evidence‑Based Diagnostic and Management Guidelines

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

5
Guideline

Pulmonary Hypertension Treatment Guidelines (Cited Evidence)

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Guideline

Pulmonary Hypertension Diagnosis and Management

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

7
Research

Pulmonary hypertension.

Nature reviews. Disease primers, 2024

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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