Cardiology > Pulmonary Arterial Hypertension (PAH)

Background 

Pulmonary arterial hypertension (PAH) is a chronic, progressive disorder characterized by elevated pulmonary arterial pressure (mean PAP ≥25 mmHg at rest by right heart catheterization) with a normal pulmonary capillary wedge pressure (≤15 mmHg), indicating pre-capillary pulmonary hypertension. It results from vascular remodeling of the small pulmonary arteries, leading to increased pulmonary vascular resistance (PVR), right ventricular overload, and eventual right heart failure.

Classification/Types 

• • I) WHO Group 1 PAH

• • Idiopathic PAH (IPAH) 

• • Heritable PAH (BMPR2 mutation, etc.) 

• • Drug- and toxin-induced (e.g., methamphetamine, fenfluramine) 

• • Associated with: 

• • Connective tissue diseases (especially systemic sclerosis) 

• • HIV infection 

• • Portal hypertension 

• • Congenital heart disease 

• • Schistosomiasis 

• • II) Subtypes (Pathologic/Functional)

• • Vasoreactive PAH (responsive to calcium channel blockers) 

  • Non-vasoreactive PAH (requires targeted therapy)

     

•  Pathophysiology 
• PAH involves endothelial dysfunction, smooth muscle proliferation, thrombosis in situ, and remodeling of small pulmonary arterioles. The imbalance between vasodilators (e.g., nitric oxide, prostacyclin) and vasoconstrictors (e.g., endothelin-1) results in progressive vasoconstriction and vascular remodeling. This leads to increased pulmonary artery pressures, elevated PVR, and right ventricular hypertrophy and failure.  

• Epidemiology 

  • Prevalence: ~15–50 cases/million in developed countries 

• • Age: Commonly diagnosed between 30–60 years 

• • Sex: More frequent in females (2:1 ratio) 

  • Associated with high mortality if untreated 

•    Etiology 

• • I) Idiopathic or Heritable Causes

• • BMPR2, ALK1, ENG mutations 

• • Sporadic (no family history) 

• • II) Associated Conditions

• • Connective tissue diseases (especially systemic sclerosis) 

• • Congenital systemic-to-pulmonary shunts 

• • HIV infection 

• • Portal hypertension 
• • Chronic hemolytic anemia 
  • Drug/toxin exposure (e.g., anorexigens, methamphetamines) 
•  

•    Clinical Presentation 

  I) History (Symptoms)

•  

• • Progressive exertional dyspnea 

• • Fatigue and weakness 

• • Non-productive cough 

• • Chest pain or tightness (especially on exertion) 

• • Syncope or near-syncope (suggests advanced disease) 

• • Palpitations 

• • Peripheral edema (late sign due to RV failure) 

    II) Physical Exam (Signs)

•  

• General Appearance 

  • Chronically ill appearance 

• • Signs of effort intolerance 

• • Cyanosis in advanced stages 

• Vital Signs 

  • Resting tachycardia 

• • Low-normal or decreased blood pressure 

• • Orthostatic hypotension may occur 

• • Hypoxemia on exertion or at rest 

• Respiratory System 

  • Clear lung fields early (unless concomitant lung disease) 

• • Late crackles may suggest superimposed interstitial disease 

• • Tachypnea 

• Cardiovascular System 

  • Loud, palpable P2 component of S2 (due to elevated pulmonary pressure) 

• • Right ventricular heave (from RV hypertrophy) 

• • Right-sided S3 or S4 

• • Tricuspid regurgitation murmur 

• • Jugular venous distension 

• • Hepatojugular reflux 

• • Peripheral edema, ascites in right heart failure 

• Neurological System 

  • Syncope or presyncope (especially on exertion) 

• • Confusion in severe hypoxemia or right heart failure 

• Skin/Extremities 

  • Digital clubbing (less common in isolated PAH, more common if associated with lung disease) 

  • Cyanosis (central or peripheral) 

  • Cool extremities in low-output states 

• Ocular 

  • No primary ocular findings, but hypoxia may manifest as papilledema in extreme cases  

•    Differential Diagnosis (DDx) 

  • Left heart disease (e.g., heart failure with preserved or reduced EF) 

• • Chronic thromboembolic pulmonary hypertension (CTEPH) 

• • Lung diseases/hypoxia (e.g., COPD, ILD) 

• • Pulmonary veno-occlusive disease 

• • Congenital heart disease with Eisenmenger syndrome 

• • Pericardial disease 

  • Anemia-related high-output states 

•  

•    Diagnostic Tests 

• • I) Initial Evaluation

• • Chest X-ray: Enlarged pulmonary arteries, right heart enlargement 

• • ECG: Right axis deviation, RV hypertrophy, right atrial enlargement 

• • CBC/CMP: Rule out anemia, assess liver/kidney function 

• • BNP or NT-proBNP: Marker of right ventricular strain 

• • ANA, HIV, LFTs: Identify associated conditions 

• • TTE (Transthoracic Echo): Elevated pulmonary artery systolic pressure (PASP), RV size and function, tricuspid regurgitation velocity 

• • 6-Minute Walk Test (6MWT): Functional status and desaturation monitoring 

• • II) Confirmatory Testing

• • Right Heart Catheterization (Gold Standard): 

• • Mean PAP ≥25 mmHg at rest 

• • Pulmonary capillary wedge pressure (PCWP) ≤15 mmHg 

• • Elevated PVR (>3 Wood units) 

• • Vasoreactivity Testing (in RHC): Inhaled nitric oxide, epoprostenol, or adenosine used to assess responsiveness 

• • Pulmonary Function Tests (PFTs): May show isolated ↓DLCO 

• • V/Q Scan: To exclude chronic thromboembolic disease (CTEPH) 

• • HRCT: Evaluate for associated parenchymal lung disease 

  • MRI of heart (if available): Detailed RV assessment 

•  

•    Treatment 

• • I) General Principles

• • Early diagnosis and management improve outcomes 

• • Identify and treat underlying conditions 

• • Treatment stratified by WHO functional class and risk status 

• • II) Pharmacologic Therapy

• Vasodilator Therapy (Targeted) 

  • Endothelin receptor antagonists: Bosentan, Ambrisentan 

• • Phosphodiesterase-5 inhibitors: Sildenafil, Tadalafil 

  • Prostacyclin analogs: Epoprostenol (IV), Treprostinil (SC/inhaled), Iloprost 

  • Soluble guanylate cyclase stimulators: Riociguat 

• Vasoreactive Patients 

  • High-dose calcium channel blockers (e.g., nifedipine, diltiazem) – Only if positive vasoreactivity test 

• Anticoagulation 

  • Consider in idiopathic PAH (controversial) 

  • Required in CTEPH (Group 4, not PAH) 

• Diuretics 

  • For symptom control of right heart failure (edema, ascites) 

• Oxygen Therapy 

  • If resting hypoxemia (SpO₂ <88%) 

• III) Supportive Measures 

  • Pulmonary rehabilitation 

• • Sodium/fluid restriction in RV failure 
• • Avoid pregnancy (high maternal/fetal mortality in PAH) 
  • Psychosocial support 
•  

•    Patient Education, Screening, and Prevention 

  • Educate about disease progression and medication adherence 

• • Avoid high altitudes, strenuous exertion, and volume overload 

• • Immunizations: Influenza, pneumococcal, COVID-19 

• • Genetic counseling in heritable PAH 

  • Routine screening for PAH in systemic sclerosis (e.g., annual echocardiography) 

•  

•    Consults/Referrals 

  • Pulmonology and cardiology (specialized PAH centers preferred) 
• • Rheumatology (if connective tissue disease suspected) 
• • Obstetrics (for counseling on contraception or pregnancy risks) 
  • Palliative care in advanced stages 
  • Transplant team if severe or refractory to therapy 
•  

•    Follow-Up 

• Short-Term 

  • Monitor functional class, symptoms, 6MWT 

• • Serial BNP/NT-proBNP levels 

• • TTE every 6–12 months

     

• Long-Term 

  • Periodic RHC if worsening or unclear clinical picture 

• • Evaluate for lung transplantation in advanced or refractory cases 

  • Monitor for drug-related side effects (e.g., liver function for endothelin receptor antagonists)  

• Prognosis 

  • Prognosis depends on etiology, functional class, and response to therapy 

• • Poor prognosis in: 

• • Systemic sclerosis-associated PAH 

• • Syncope, severe RV dysfunction 

• • Elevated BNP, rapid disease progression 

• • Median survival in untreated idiopathic PAH: ~2.8 years 

• • Targeted therapies and lung transplantation have significantly improved outcomes