What is the appropriate diagnostic work‑up and management strategy for an adult presenting with unexplained dyspnea, exercise intolerance, syncope, or signs of right‑ventricular strain, especially if they have risk factors such as connective‑tissue disease, congenital heart disease, chronic lung disease, or a family history of pulmonary hypertension?

Pulmonary Hypertension: Diagnostic and Management Approach

Initial Diagnostic Strategy

Begin with transthoracic Doppler echocardiography as the primary screening tool in any adult presenting with unexplained dyspnea, exercise intolerance, syncope, or signs of right ventricular strain, particularly when risk factors such as connective tissue disease, congenital heart disease, chronic lung disease, or family history are present. 1, 2

Clinical Presentation Recognition

The presenting symptoms are nonspecific but follow recognizable patterns:

• Exertional dyspnea occurs in 60% at presentation and eventually affects virtually all patients 3
• Syncope or presyncope (especially with exertion) occurs in approximately 40% of patients and warrants urgent workup 1, 3
• Fatigue, weakness, and chest pain each affect approximately 40% during disease course 1, 3
• Progression from WHO Functional Class I to higher classes is an indication for immediate evaluation 2

Critical Risk Factor Assessment

Obtain a detailed history focusing on:

• Family history of pulmonary hypertension or BMPR2 mutations (warrants periodic screening even without symptoms) 1
• Connective tissue disease, particularly scleroderma spectrum disorders (carries poor prognosis and warrants screening) 1, 4
• Raynaud phenomenon, arthralgias, or swollen hands in the setting of dyspnea (raises suspicion for PAH related to connective tissue disease) 1, 4
• Portal hypertension (especially if undergoing liver transplant evaluation) 1, 2
• Congenital heart disease 1
• Drug and toxin exposure (appetite suppressants, chemotherapeutic agents including mitomycin-C, carmustine, etoposide, cyclophosphamide, bleomycin) 1
• HIV infection 1
• History of venous thromboembolism (though CTEPH can occur without recognized history) 1

Echocardiography-Guided Diagnostic Algorithm

The European Respiratory Society provides clear decision pathways based on echocardiographic findings 2:

When Echocardiography Shows "PH Unlikely"

• No symptoms present: No additional workup required 2
• Symptoms present WITH risk factors for PAH: Perform echocardiographic follow-up 2
• Symptoms present WITHOUT risk factors: Evaluate other causes for symptoms 2

When Echocardiography Shows "PH Possible"

• No symptoms and no risk factors: Echocardiographic follow-up 2
• Symptoms WITH risk factors: Consider right heart catheterization (RHC) 2
• Symptoms WITHOUT risk factors: Consider alternative diagnosis evaluation and echocardiographic follow-up; if symptoms are at least moderate, RHC may be considered 2

When Echocardiography Shows "PH Likely"

• With symptoms (regardless of risk factors): Proceed to right heart catheterization 2
• Without symptoms (regardless of risk factors): Consider right heart catheterization 2

Key echocardiographic parameters to assess: pericardial effusion presence, TAPSE (tricuspid annular plane systolic excursion), and right ventricular function 2

Comprehensive Diagnostic Workup

Mandatory Testing for All Suspected PH Patients

Right heart catheterization is required at baseline in all patients being evaluated for pulmonary arterial hypertension to confirm diagnosis (mean PAP ≥25 mmHg at rest), determine prognosis, and guide therapy 1, 2, 5

Ventilation/perfusion (V/Q) lung scan must be performed in all patients with unexplained PH to exclude chronic thromboembolic PH (CTEPH), which is a treatable cause that must not be missed 2

Additional Required Investigations

• Chest radiography: Often the first test performed; look for enlarged central pulmonary arteries (right interlobar artery >15 mm in women, >16 mm in men), rapid tapering (pruning), and right heart chamber enlargement 1

  • Critical caveat: CXR is insensitive for mild PH; normal CXR does not exclude PH 1

• Laboratory testing including routine biochemistry, hematology, thyroid function, and serological testing to identify associated conditions (liver disease, connective tissue disorders, HIV) 1, 2

• Pulmonary function tests and arterial blood gases to evaluate for lung disease 1

• Abdominal ultrasound for screening of portal hypertension 2

• High-resolution CT should be considered in all PH patients 2

• Contrast CT angiography for patients with suspected CTEPH 2

Physical Examination Findings

Look for these specific signs 1:

• Accentuated pulmonary component of second heart sound audible at apex (present in 90% of IPAH patients) 1
• Left parasternal lift from hypertrophied right ventricle 1
• Right ventricular S4 gallop (audible in 38%) 1
• Prominent jugular "a" wave suggesting high right ventricular filling pressure 1
• Signs of advanced disease: diastolic murmur of pulmonary regurgitation, leg swelling, abdominal distension, hepatomegaly, ascites 1, 3

Clinical Classification and Hemodynamic Definitions

Pulmonary hypertension is defined as mean PAP ≥25 mmHg at rest on right heart catheterization 1

The updated clinical classification includes five groups 1:

1. Group 1: Pulmonary Arterial Hypertension (PAH) - includes idiopathic, familial, drug-induced, and associated conditions (connective tissue disease, congenital heart disease, portal hypertension, HIV, schistosomiasis) 1
2. Group 2: PH due to left heart disease (systolic/diastolic dysfunction, valvular disease) 1
3. Group 3: PH due to lung diseases and/or hypoxemia (COPD, interstitial lung disease, sleep-disordered breathing) 1
4. Group 4: Chronic thromboembolic PH (CTEPH) 1
5. Group 5: PH with unclear/multifactorial mechanisms (sarcoidosis, hematologic disorders, metabolic disorders) 1

PAH specifically requires precapillary PH (pulmonary artery wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units) in the absence of other causes 1

Distinguishing PH Due to Left Heart Disease

Use a combination of diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) to define isolated versus combined post-capillary PH 2

Suspect left heart disease when 2:

• Age >65 years
• Features of metabolic syndrome
• History of heart disease or persistent atrial fibrillation
• Echocardiographic findings: left atrial enlargement, LV dysfunction

Disease Severity Assessment

Assess disease severity at diagnosis using WHO Functional Class, 6-minute walk test with Borg dyspnea score, and BNP/NT-proBNP levels 2

WHO Functional Classification 1, 3

• Class I: No limitation; ordinary activity does not cause symptoms 1, 3
• Class II: Slight limitation; comfortable at rest but ordinary activity causes dyspnea, fatigue, chest pain, or presyncope 3
• Class III: Marked limitation; comfortable at rest but less than ordinary activity causes symptoms (indicates more severe disease requiring prompt evaluation) 2, 3
• Class IV: Unable to perform any activity without symptoms; signs of right heart failure may be present at rest 3

Prognostic Indicators

Poor prognosis is associated with 1:

• Advanced functional class (III-IV)
• Poor exercise capacity on 6-minute walk test
• High right atrial pressure
• Significant right ventricular dysfunction
• Evidence of right ventricular failure
• Low cardiac index
• Elevated BNP
• Underlying scleroderma spectrum disease

Approximately 15% mortality occurs within 1 year even on modern therapy 1

Management Principles

Group-Specific Treatment Approach

The importance of accurate classification cannot be overstated: PAH-specific drugs targeting molecular pathways should only be used in Group 1 (PAH) and are contraindicated in other forms of PH, particularly Groups 2 and 3 6, 7

• Group 1 (PAH): Ten drugs from five substance classes are available, often used in combination; treatment strategy determined by risk stratification based on disease severity 7

• Group 4 (CTEPH): Surgical pulmonary endarterectomy is the preferred treatment; inoperable patients receive drugs and endovascular interventions 7

• Groups 2 and 3 (left heart and lung disease): Specific treatment for pulmonary hypertension generally only indicated if severe right-heart strain is present 7

Referral Recommendations

Refer urgently to a designated PH center if 8:

• Patient is syncopal
• Rapidly progressing symptoms
• Patient is in heart failure
• Pulmonary arterial hypertension or CTEPH suspected
• PH of uncertain cause

Diagnosis and treatment of severe forms of PH are complex and best carried out in close cooperation between the local physician and specialized centers 7

Critical Contraindications

Do NOT perform open or thoracoscopic lung biopsy in patients with PAH 2

Common Pitfalls to Avoid

• Do not rely on chest radiography alone: Normal CXR does not exclude PH, particularly mild disease 1
• Do not miss CTEPH: Always perform V/Q scan in unexplained PH, as this is a surgically treatable cause 2
• Do not use PAH-specific drugs in Groups 2 and 3 PH: These are contraindicated and potentially harmful 6, 7
• Do not delay evaluation of syncope: This symptom warrants urgent workup 2, 3
• Do not overlook connective tissue disease screening: Particularly important given poor prognosis in scleroderma-associated PAH 1, 4