What are the differential diagnoses and recommended work‑up for a patient with a markedly enlarged main pulmonary artery, mild right‑ventricular dilation, and early‑stage pulmonary hypertension?

Differential Diagnosis: Severely Dilated Pulmonary Artery with Mild RV Dilation and Mild Pulmonary Hypertension

The combination of a markedly enlarged main pulmonary artery that is disproportionate to the degree of pulmonary hypertension and RV dilation should immediately raise suspicion for pulmonary artery aneurysm, post-stenotic dilation from pulmonary valve stenosis, chronic thromboembolic disease, or pulmonary veno-occlusive disease—not typical idiopathic pulmonary arterial hypertension, which would show more severe hemodynamic compromise for this degree of PA dilation. 1

Primary Differential Diagnoses

1. Pulmonary Valve Stenosis with Post-Stenotic Dilation

• This is the most likely diagnosis when PA dilation is severe but pulmonary hypertension is mild or absent. 1
• Isolated valvular pulmonary stenosis does NOT cause pulmonary arterial hypertension; if PAH is present, look for associated lesions such as atrial septal defect, peripheral pulmonary artery stenosis, or late VSD closure with pulmonary vascular disease. 1
• Post-stenotic dilation occurs downstream from the stenotic valve due to turbulent flow, creating marked PA enlargement without elevated distal pressures. 1
• Key diagnostic features: Peak RV systolic pressure <35 mmHg and systolic pulmonary valve gradient <10 mmHg are normal; gradients <30 mmHg show little progression and require only 5-year follow-up. 1
• Progressive RV dilation suggests an associated ASD or, postoperatively, restenosis or pulmonary regurgitation. 1

2. Pulmonary Artery Aneurysm

• Markedly enlarged pulmonary artery aneurysms can cause mechanical complications including compression of the left main coronary artery (causing angina), left recurrent laryngeal nerve (causing hoarseness), or large airways (causing wheeze). 1
• Life-threatening complication: Significant PA dilation may result in rupture or dissection, leading to cardiac tamponade. 1
• This diagnosis should be considered when PA diameter exceeds 40-50mm, particularly if symptoms suggest compression syndromes. 1

3. Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• CTEPH must be excluded in every patient with unexplained pulmonary hypertension and PA dilation. 1, 2
• Contrast CT angiography can identify complete obstruction, bands, webs, and intimal irregularities as accurately as digital subtraction angiography. 1
• Critical workup step: Ventilation-perfusion scan is MORE sensitive than CT for excluding CTEPH and has substantial therapeutic implications (surgical candidacy for pulmonary endarterectomy). 1, 2
• Patients with prior systemic-to-pulmonary artery shunts may have branch pulmonary artery stenosis at anastomosis sites. 1

4. Pulmonary Veno-Occlusive Disease (PVOD)

• PVOD presents with disproportionate PA dilation relative to hemodynamic severity and should be suspected when DLCO is severely reduced (<45% predicted). 1
• High-resolution CT findings: Diffuse central ground-glass opacification, thickening of interlobular septa, lymphadenopathy, pleural shadows, and effusions strongly support PVOD diagnosis. 1
• Clinical clue: Digital clubbing is NOT typical of idiopathic PAH and should raise suspicion for PVOD, cyanotic congenital heart disease, interstitial lung disease, or liver disease. 1, 3

5. Congenital Heart Disease with Shunt Lesions

• Atrial septal defect or other left-to-right shunts can cause PA dilation with initially mild pulmonary hypertension. 1, 4
• Progressive RV dilation in the setting of pulmonary stenosis strongly suggests an associated ASD. 1
• Cyanosis with RVOT lesions indicates either an associated ASD with elevated right atrial pressure causing right-to-left shunting through a patent foramen ovale, or an alternative source of cyanosis. 1

Essential Diagnostic Workup Algorithm

Immediate Studies (All Patients)

1. Transthoracic Doppler Echocardiography 5, 2

   • Assess RV size, function, and estimated PA systolic pressure
   • Evaluate for valvular abnormalities (pulmonary stenosis, tricuspid regurgitation, pulmonary regurgitation)
   • Screen for intracardiac shunts (ASD, VSD, PFO with bubble study)
   • Measure PA diameter (≥29mm suggests PH; PA:ascending aorta ratio ≥1.0 is highly specific) 1

2. Chest Radiograph 1, 2

   • Central pulmonary arterial dilatation with peripheral vascular "pruning" suggests PAH
   • RA and RV enlargement indicate more advanced disease
   • Distinguish arterial vs. venous PH by artery:vein ratios (increased in arterial, decreased in venous PH)

3. Electrocardiogram 1

   • Right axis deviation, RV hypertrophy, RV strain pattern (more sensitive than RV hypertrophy alone)
   • P pulmonale, right bundle branch block, QTc prolongation suggest severe disease
   • Caveat: Normal ECG does NOT exclude pulmonary hypertension

4. Pulmonary Function Tests with DLCO 1, 2

   • DLCO <45% predicted is associated with poor outcomes and suggests PVOD or PAH-scleroderma
   • Identify underlying airway or parenchymal lung disease (Group 3 PH)
   • Mild-to-moderate reduction in lung volumes is typical in PAH

Second-Tier Studies (Based on Initial Findings)

1. Ventilation-Perfusion (V/Q) Scan 1, 2

   • Mandatory to exclude CTEPH (more sensitive than CT angiography)
   • Perform BEFORE right heart catheterization if any suspicion of thromboembolic disease

2. Contrast-Enhanced CT Angiography of Pulmonary Arteries 1

   • Delineate complete obstruction, bands, webs, intimal irregularities in CTEPH
   • Identify pulmonary artery aneurysm and measure precise dimensions
   • High-resolution CT for PVOD features (ground-glass opacification, septal thickening)

3. Cardiac MRI 1

   • Accurate assessment of RV size, morphology, function, and mass
   • Evaluate for congenital heart disease if echocardiography is inconclusive
   • Late gadolinium enhancement, reduced PA distensibility, and retrograde flow have high predictive value for PH

Definitive Hemodynamic Assessment

1. Right Heart Catheterization 1, 6, 7
   • Required for definitive diagnosis: Mean PAP >20 mmHg defines PH; pre-capillary PH requires PAWP ≤15 mmHg and PVR >2 Wood Units
   • Measure gradients above, at, and below the pulmonic valve to confirm/exclude pulmonary stenosis
   • RV angiography defines contractile function, infundibular obstruction, and pulmonary valve mobility
   • Pulmonary angiography assesses degree of pulmonary regurgitation and stenotic lesions in branch/peripheral pulmonary arteries
   • Volume or exercise challenge may unmask left heart disease with preserved ejection fraction (HFpEF), though this requires further validation before routine use. 6

Specialized Testing (Selected Cases)

1. Blood Tests and Immunology 1

   • Connective tissue disease serologies (ANA, anti-Scl-70, anti-centromere) for scleroderma-associated PAH
   • HIV testing, liver function tests for portopulmonary hypertension
   • Thyroid function tests (thyroid disease is common in PAH)
   • NT-proBNP or BNP for prognostic stratification

2. Coronary Angiography or Stress Imaging 1

   • In older patients or those with coronary risk factors presenting with angina-type symptoms
   • Exclude left main coronary artery compression by enlarged PA aneurysm

Critical Clinical Pitfalls to Avoid

Pitfall 1: Assuming All PA Dilation Equals Severe PAH

• Severe PA dilation with only mild pulmonary hypertension is ATYPICAL for idiopathic PAH and should prompt investigation for pulmonary stenosis with post-stenotic dilation, PA aneurysm, or CTEPH. 1

Pitfall 2: Missing CTEPH

• CTEPH is potentially curable with pulmonary endarterectomy or balloon pulmonary angioplasty. 1
• V/Q scan is mandatory and more sensitive than CT; do not rely on CT alone. 1, 2

Pitfall 3: Attributing RV Dysfunction Solely to Pulmonary Stenosis

• Systemic venous congestion is uncommon in isolated PS; exclude cor pulmonale from intrinsic lung disease, left-sided heart disease, constrictive pericarditis, restrictive cardiomyopathy, severe TR from other causes (endocarditis, pacemaker lead, Ebstein's anomaly). 1

Pitfall 4: Overlooking Associated Lesions

• Progressive RV dilation despite mild stenosis strongly suggests ASD or significant pulmonary regurgitation. 1
• If PAH is present with isolated valvular PS, search for peripheral pulmonary artery stenosis, late VSD closure, or patent ductus repair with pulmonary vascular disease. 1

Pitfall 5: Misdiagnosing PVOD as Idiopathic PAH

• PVOD has dramatically different prognosis and treatment contraindications (pulmonary vasodilators may cause life-threatening pulmonary edema). 1
• High-resolution CT findings (ground-glass opacification, septal thickening) and severely reduced DLCO are key diagnostic clues. 1

Urgent Referral Indications

Immediate referral to a pulmonary hypertension center is indicated for: 5

• Syncope (especially exertional)
• Rapidly progressing symptoms
• Signs of right heart failure (elevated JVP, hepatomegaly, ascites, peripheral edema)
• Clinical or echocardiographic signs of severe PH and/or severe RV dysfunction
• Suspected mechanical complications (hoarseness, angina, hemoptysis suggesting PA compression or rupture) 1, 3