How should I diagnose and initially manage an adult patient with unexplained dyspnea, fatigue, syncope and signs of right‑ventricular overload suggestive of pulmonary arterial hypertension?

Diagnosis and Initial Management of Suspected Pulmonary Arterial Hypertension

Begin with transthoracic Doppler echocardiography as your first-line screening test, but understand that right-heart catheterization is mandatory for definitive diagnosis—echocardiography alone cannot confirm pulmonary arterial hypertension. 1

Initial Clinical Assessment

Key Presenting Features to Identify

• Dyspnea on exertion is the most common presenting symptom, though it is nonspecific 2
• Syncope or presyncope occurs in approximately 40% of patients and warrants urgent evaluation 3
• Fatigue and weakness each affect roughly 40% of patients 3
• Chest pain (angina) may result from right ventricular ischemia or compression of the left main coronary artery by dilated pulmonary arteries 3, 4

Physical Examination Findings

• Accentuated pulmonary component of the second heart sound at the apex is present in ~90% of patients with idiopathic PAH 3
• Left parasternal lift reflecting right ventricular hypertrophy 3
• Right ventricular S4 gallop (heard in ≈38% of patients) 3
• Prominent jugular "a" waves indicating elevated right atrial pressure 3
• Signs of advanced disease: pulmonary regurgitation murmur, peripheral edema, hepatomegaly with pulsatile liver, ascites, abdominal distension, cool extremities 3, 4

Critical pitfall: The presence of digital clubbing should raise suspicion for pulmonary veno-occlusive disease, congenital heart disease, interstitial lung disease, or liver disease—not idiopathic PAH 4

Risk Factor Screening

Mandatory History Elements

• Family history of pulmonary hypertension or BMPR2 mutation (warrants periodic screening even if asymptomatic) 3
• Connective tissue disease, particularly scleroderma spectrum disorders (carries poor prognosis and requires systematic screening) 3
• Portal hypertension (e.g., in liver transplant candidates) 3
• Congenital heart disease 3
• Drug exposure: appetite suppressants or chemotherapy (mitomycin-C, carmustine, etoposide, cyclophosphamide, bleomycin) 3
• HIV infection 3
• Prior venous thromboembolism (raises suspicion for chronic thromboembolic PH) 3

Diagnostic Algorithm

Step 1: Transthoracic Echocardiography

Echocardiography provides risk stratification but cannot definitively diagnose PAH 1. The ESC/ERS guidelines stratify echocardiographic probability as "unlikely," "possible," or "likely" based on tricuspid regurgitation velocity and additional signs of right ventricular overload 3.

Key limitations to recognize:

• Tricuspid regurgitant jet velocity may be unobtainable in a substantial proportion of patients 1
• In chronic lung disease, hyperinflation and altered cardiac position markedly reduce the ability to measure TR jet velocities 1
• Qualitative signs (right atrial dilation, RV hypertrophy, septal flattening) have low predictive value without a measurable TR jet 1

Echocardiographic assessment should specifically evaluate:

• Tricuspid annular plane systolic excursion (TAPSE) 3
• Right atrial area 5
• Presence and size of pericardial effusion 5, 3
• Right ventricular function 3

Step 2: Comprehensive Non-Invasive Workup (Before Catheterization)

All patients with suspected PAH require the following tests 1, 3:

Imaging Studies

• Ventilation-perfusion (V/Q) scintigraphy: Preferred screening for chronic thromboembolic PH with >90% sensitivity and >94% specificity—must be performed in all patients with unexplained PH 1, 3
• High-resolution chest CT: Detects parenchymal lung disease that may be missed by normal pulmonary function tests 1
• Chest radiography: May show enlarged central pulmonary arteries (right interlobar artery >15 mm in women, >16 mm in men), peripheral vessel pruning, and right heart enlargement, but is insensitive for mild disease and a normal film does not exclude PH 3

Laboratory Tests

• NT-proBNP or BNP: Essential for risk stratification 5, 3
• Complete blood count, comprehensive metabolic panel 3
• Thyroid function tests 3
• Serologies for hepatitis B/C and HIV 1
• Autoimmune screening (ANA, and if positive, extended autoantibody panel): Up to 40% of idiopathic PAH patients have elevated autoantibodies 1
• Troponin, uric acid, iron status (at least annually or with clinical worsening) 5

Functional Assessment

• Full pulmonary function testing (including DLCO) and arterial blood gases: Identifies contribution of underlying lung disease 1, 3
• Six-minute walk test: Provides baseline functional capacity assessment 1, 3
• Cardiopulmonary exercise testing (if available): Peak VO₂ and VE/VCO₂ slope provide prognostic information 5

Additional Studies

• Abdominal ultrasound: Screens for portal hypertension 1, 3
• ECG: Right ventricular hypertrophy is present in 87% and right axis deviation in 79% of IPAH patients, though sensitivity (55%) and specificity (70%) are inadequate for screening 5

Step 3: Right-Heart Catheterization (Mandatory for Diagnosis)

Right-heart catheterization is the only method that definitively confirms pulmonary hypertension and is required in all patients being evaluated for PAH 1, 3, 2.

Hemodynamic Diagnostic Criteria

Pulmonary hypertension is defined as:

• Mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest (updated to ≥20 mmHg in 2022 guidelines) 1, 3, 2

Pulmonary arterial hypertension (Group 1) specifically requires:

• mPAP ≥25 mmHg (or ≥20 mmHg per 2022 update) 2
• Pulmonary artery wedge pressure (PAOP) ≤15 mmHg 1, 3, 2
• Pulmonary vascular resistance >3 Wood units 1, 3, 2

Essential Catheterization Measurements

• Systolic, diastolic, and mean pulmonary artery pressures 1
• Right atrial pressure 1
• Pulmonary artery wedge pressure 1
• Cardiac output (thermodilution or Fick method) 1
• Calculated pulmonary vascular resistance 1
• Mixed venous oxygen saturation (SvO₂) 5

Acute Vasoreactivity Testing

Perform acute vasoreactivity testing with inhaled nitric oxide when precapillary PH is confirmed to identify patients who may benefit from high-dose calcium channel blockers 1

Step 4: Clinical Classification

Once hemodynamic confirmation is obtained, classify the patient into one of five clinical groups 3, 2:

• Group 1 (PAH): Idiopathic, familial, drug-induced, or associated with connective tissue disease, congenital heart disease, portal hypertension, HIV, schistosomiasis 3
• Group 2: PH due to left heart disease (systolic/diastolic dysfunction, valvular disease)—most common form 3
• Group 3: PH due to lung diseases/hypoxemia (COPD, interstitial lung disease, sleep-disordered breathing) 3
• Group 4: Chronic thromboembolic PH 3
• Group 5: PH with unclear or multifactorial mechanisms (sarcoidosis, hematologic or metabolic disorders) 3

Critical distinction: If PAOP >15 mmHg, the patient has post-capillary PH (Group 2), and PAH-specific therapies are not recommended—optimize treatment of the underlying left heart disease instead 1, 3

Risk Stratification at Diagnosis

Classify the patient as low risk (<5% 1-year mortality), intermediate risk (5–10%), or high risk (>10%) using the comprehensive assessment below 5:

Parameter	Low Risk	Intermediate Risk	High Risk
Clinical signs of RHF	Absent	Absent	Present
Syncope	No	Occasional (with exertion)	Repeated (even with minimal activity)
WHO Functional Class	I, II	III	IV
6-Minute Walk Distance	>440 m	165–440 m	<165 m
NT-proBNP	<300 ng/L	300–1400 ng/L	>1400 ng/L
BNP	<50 ng/L	50–300 ng/L	>300 ng/L
Right atrial area	<18 cm²	18–26 cm²	>26 cm²
Pericardial effusion	None	None or minimal	Present
Cardiac index	≥2.5 L/min/m²	2.0–2.4 L/min/m²	<2.0 L/min/m²
Right atrial pressure	<8 mmHg	8–14 mmHg	>14 mmHg
SvO₂	>65%	60–65%	<60%

5

Important caveats: Most variables are based on expert opinion and have been validated primarily for idiopathic PAH—cut-off levels may not apply to other PAH forms 5. Consider rate of disease progression, presence of right heart failure or syncope, comorbidities, age, sex, and PAH subtype when interpreting risk 5.

Immediate Referral Indications

Refer urgently to a specialized pulmonary hypertension center if 3:

• Syncope, rapid symptom progression, or overt heart failure
• Suspected PAH (Group 1) or chronic thromboembolic PH (Group 4) after excluding left heart disease and lung disease
• Unexplained pulmonary hypertension of uncertain etiology
• Severe pulmonary hypertension and/or severe right ventricular dysfunction on echocardiography

Specialized centers provide 3:

• Multidisciplinary expertise (cardiology, pulmonology, nursing, radiology, psychological and social support)
• Definitive hemodynamic diagnosis and classification
• Determination of candidacy for PAH-specific therapy versus optimization of underlying disease treatment

Common Diagnostic Pitfalls to Avoid

1. Do not diagnose PAH based on echocardiography alone—this contravenes guideline definitions and risks inappropriate therapy 1
2. Do not assume obvious chronic thromboembolic changes on CTPA equate to pulmonary hypertension—organized thrombi may be present with normal pressures 1
3. Do not rely solely on chest radiography—a normal film cannot exclude PH, particularly in early disease 3
4. Always perform V/Q scanning in unexplained PH to avoid missing treatable chronic thromboembolic disease 1, 3
5. Do not initiate PAH-specific therapies for Group 2 (left heart disease) or Group 3 (lung disease) PH until robust long-term data are available 3

Initial Management Principles

For Confirmed Precapillary PAH (Group 1)

Current first-line therapy consists of combination drug therapy targeting multiple biological pathways 2:

• Nitric oxide-cyclic GMP pathway enhancers (sildenafil, tadalafil, riociguat) 2
• Prostacyclin pathway agonists (epoprostenol, treprostinil) 2
• Endothelin pathway antagonists (bosentan, ambrisentan) 2

Combination therapy (e.g., ambrisentan plus tadalafil) has demonstrated superior morbidity and mortality outcomes compared with monotherapy 2. With modern PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015 2.

Supportive Measures

• Diuretics: One of the most important treatments for right heart failure, addressing fluid retention, hepatic congestion, ascites, and peripheral edema 5
• Oral anticoagulation: Target INR 1.5–2.5 for PAH; 2–3 for chronic thromboembolic PH 5
• Long-term oxygen therapy: For patients with progressive hypoxemia 5
• Monitor for arrhythmias: ECGs should be obtained regularly to detect supraventricular arrhythmias (atrial flutter, atrial fibrillation), which occur frequently and compromise cardiac output 5, 4

For Post-Capillary PH (Group 2)

Optimize treatment of the underlying left heart disease—PAH-specific therapies are not recommended 1, 3

Prognosis

• Advanced WHO functional class (III–IV) predicts poorer survival 3
• Reduced 6-minute walk distance and elevated right atrial pressure are adverse prognostic markers 3
• Significant right ventricular dysfunction on imaging correlates with worse outcomes 3
• Approximately 15% of patients die within one year despite modern therapy 3
• Untreated PAH progresses to right heart failure and death 2