What is the diagnosis and treatment approach for Pulmonary Arterial Hypertension (PAH)?

Pulmonary Arterial Hypertension: Comprehensive Overview

Definition and Classification

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease characterized by elevated pulmonary vascular resistance leading to right ventricular failure and death, defined hemodynamically as mean pulmonary artery pressure >20 mmHg, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance ≥3 Wood units. 1, 2

PAH represents one of five clinical groups of pulmonary hypertension, distinguished by its specific pathophysiology and treatment approach 1:

• Group 1 (PAH) includes idiopathic PAH (IPAH), familial PAH (FPAH), and PAH associated with connective tissue disease, congenital heart disease, portal hypertension, HIV infection, and drugs/toxins 1
• Group 2 encompasses pulmonary hypertension due to left heart disease 1
• Group 3 includes pulmonary hypertension associated with lung diseases and hypoxemia 1
• Group 4 represents chronic thromboembolic pulmonary hypertension 1
• Group 5 consists of pulmonary hypertension with unclear or multifactorial mechanisms 1

The prevalence of PAH is approximately 10.6 cases per 1 million adults in the United States, with untreated median survival historically around 2.8 years 1, 2.

Pathophysiology

The disease process involves complex interactions between genetic predisposition and environmental triggers 1. Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene have been identified in the majority of familial PAH cases, though only 10-20% of mutation carriers manifest disease, suggesting additional triggers are required. 1

The pathophysiological cascade involves 1:

• Endothelial dysfunction with imbalance between vasoconstrictor/vasodilator mediators 1
• Proliferative changes in smooth muscle cells, endothelial cells, and fibroblasts 1
• Thrombotic mechanisms with in situ thrombosis 1
• Inflammatory processes involving multiple cell types 1

These mechanisms result in progressive obstruction of distal pulmonary arteries through vasoconstriction, proliferation, thrombosis, and inflammation, ultimately increasing pulmonary vascular resistance and causing right ventricular overload 1.

Clinical Presentation and Diagnosis

Symptoms and Physical Examination

Clinical suspicion should arise in any patient with unexplained dyspnea on exertion, particularly when disproportionate to underlying heart or lung disease. 1 Additional symptoms include 1:

• Fatigue and weakness (common early symptoms) 1
• Chest pain (angina-like) 1
• Syncope or near-syncope (indicating severe disease) 1
• Abdominal distension (from right heart failure) 1

Physical examination findings include 1:

• Left parasternal lift (right ventricular heave) 1
• Accentuated pulmonary component of S2 1
• Pansystolic murmur of tricuspid regurgitation 1
• Diastolic murmur of pulmonary regurgitation 1
• Peripheral edema, jugular venous distension (signs of right heart failure) 3

Diagnostic Algorithm

The diagnostic approach follows a systematic four-stage process: clinical suspicion, detection of pulmonary hypertension, clinical class identification, and comprehensive PAH evaluation. 1

Stage 1: Initial Screening

• Electrocardiogram: Shows right ventricular hypertrophy in 87% and right axis deviation in 79% of IPAH patients, though sensitivity (55%) and specificity (70%) are inadequate for screening 1
• Chest radiograph: Abnormal in 90% of IPAH patients at diagnosis, showing central pulmonary arterial dilatation with peripheral "pruning," right atrial and ventricular enlargement 1
• Transthoracic echocardiography: Essential screening tool for detecting elevated pulmonary artery pressures and assessing right ventricular function 1

Stage 2: Confirmatory Testing

Right heart catheterization is mandatory to confirm PAH diagnosis, assess hemodynamic severity, and test vasoreactivity. 1, 4 Required measurements include 1:

• Pulmonary artery pressure (systolic, diastolic, mean) 1
• Right atrial pressure 1
• Pulmonary wedge pressure (must be ≤15 mmHg to confirm pre-capillary PAH) 1
• Cardiac output (measured in triplicate by thermodilution or Fick method) 1
• Pulmonary vascular resistance calculation 1

Vasoreactivity testing should be performed during right heart catheterization using short-acting vasodilators (inhaled nitric oxide, IV adenosine, or IV epoprostenol), with a positive response defined as a fall in mean pulmonary artery pressure ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output. 1, 4

Stage 3: Comprehensive Evaluation

• Pulmonary function tests: Typically show decreased DLCO (40-80% predicted) with mild-to-moderate reduction in lung volumes; normal or slightly decreased PaO2 with decreased PaCO2 1
• High-resolution CT chest: Identifies parenchymal lung disease, pulmonary veno-occlusive disease (ground-glass opacification, septal thickening), and chronic thromboembolic disease 1
• Ventilation-perfusion scan: Essential to exclude chronic thromboembolic pulmonary hypertension 1
• Blood tests: Complete blood count, comprehensive metabolic panel, thyroid function, HIV serology (mandatory), hepatitis serology, liver function tests, autoimmune screen (ANA, anti-centromere, anti-SCL70, RNP), thrombophilia screen (antiphospholipid antibodies, lupus anticoagulant, anticardiolipin antibodies) 1
• Six-minute walk test: Objective assessment of exercise capacity; distance <300m indicates worse prognosis 1, 4
• Cardiac MRI: Provides detailed evaluation of right ventricular size, morphology, function, and prognostic information 1

Functional Classification

The World Health Organization functional assessment classification stratifies patients into four classes based on symptom severity and activity limitation: 1

• Class I: No limitation of physical activity; ordinary activity does not cause symptoms 1
• Class II: Slight limitation of physical activity; comfortable at rest but ordinary activity causes symptoms 1
• Class III: Marked limitation of physical activity; comfortable at rest but less than ordinary activity causes symptoms 1
• Class IV: Inability to carry out any physical activity without symptoms; signs of right heart failure; symptoms may be present at rest 1

Treatment Approach

General Principles

All patients with PAH should be managed at specialized pulmonary hypertension centers with multidisciplinary expertise. 4, 5 Treatment strategy is determined by vasoreactivity status, WHO functional class, and risk stratification 4, 5.

Vasoreactive Patients (Approximately 10% of IPAH)

For patients demonstrating positive acute vasoreactivity, high-dose calcium channel blockers are recommended as first-line therapy. 1, 4, 5 Preferred agents include 4, 5:

• Long-acting nifedipine (120-240 mg daily) 4
• Diltiazem (240-720 mg daily) 4
• Amlodipine (up to 20 mg daily) 4

Verapamil should be avoided due to negative inotropic effects. 5 Patients must be closely monitored, and if they fail to improve to WHO functional class I or II within 3-6 months, additional PAH-specific therapy must be initiated 4, 5.

Non-Vasoreactive Patients: Treatment by Functional Class

WHO Functional Class II-III (Low to Intermediate Risk)

Initial oral combination therapy with ambrisentan (an endothelin receptor antagonist) and tadalafil (a phosphodiesterase-5 inhibitor) is recommended as first-line treatment, as this approach has proven superior to monotherapy in delaying clinical failure and improving outcomes. 4, 5, 2

Alternative monotherapy options if combination therapy is not tolerated include 4, 5:

• Endothelin receptor antagonists: Bosentan or ambrisentan 4, 5
• Phosphodiesterase-5 inhibitors: Sildenafil or tadalafil 4, 6
• Soluble guanylate cyclase stimulators: Riociguat 1, 2

WHO Functional Class IV (High Risk)

Continuous intravenous epoprostenol is strongly recommended as first-line therapy for WHO functional class IV patients, as it is the only treatment proven to reduce mortality and has reduced 3-month mortality rates in high-risk PAH patients. 4, 3, 5, 7 Epoprostenol is FDA-approved for PAH (WHO Group 1) to improve exercise capacity in patients with predominantly NYHA functional class III-IV symptoms 7.

Supportive Measures (All Patients)

Essential supportive therapies should be implemented alongside PAH-specific treatments: 4, 5

• Diuretics: Indicated for signs of right ventricular failure and fluid retention 4, 5
• Supplemental oxygen: Recommended when arterial oxygen saturation is consistently <90% or PaO2 <60 mmHg (8 kPa) 4, 5
• Oral anticoagulation: Should be considered for idiopathic PAH, heritable PAH, and anorexigen-associated PAH, targeting INR 1.5-2.5 4, 5
• Immunizations: Influenza and pneumococcal vaccines are recommended 5
• Supervised exercise rehabilitation: Should be considered for physically deconditioned patients on stable medical therapy 5
• Pregnancy avoidance: Pregnancy is contraindicated due to 30-50% maternal mortality risk 5

Treatment Escalation and Monitoring

Reassessment should occur every 3-6 months for stable patients, evaluating WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, and echocardiographic parameters. 4, 3 Treatment goals include achieving WHO functional class I or II and 6-minute walk distance >440m 5.

If treatment goals are not met on initial therapy, escalate to triple combination therapy targeting multiple pathways (endothelin receptor antagonist + phosphodiesterase-5 inhibitor + prostacyclin analogue). 4, 3 For patients unable to tolerate parenteral prostanoid therapy, inhaled prostanoid in combination with an ERA and PDE-5 inhibitor is advised 5.

Advanced Therapies

Lung transplantation should be considered early after inadequate clinical response on maximal medical therapy. 4, 5 Indicators for transplant evaluation include 4:

• WHO functional class III-IV despite maximal therapy 4
• Rapidly progressive disease 4
• Hemodynamic deterioration (right atrial pressure >15 mmHg or cardiac index <2.0 L/min/m²) 3
• Short 6-minute walk distance (<300m) 3
• Elevated and rising BNP/NT-proBNP levels 3
• Presence of pericardial effusion 3

Balloon atrial septostomy may be considered as a palliative or bridging procedure to transplantation in patients deteriorating despite maximal medical therapy. 4, 5

Management of Acute Exacerbations

Patients experiencing PAH exacerbation should be immediately referred to a specialized pulmonary hypertension center. 3 Immediate management includes 3:

• Assess for clinical evidence of right ventricular failure (peripheral edema, jugular venous distension, hypotension) 3
• Evaluate hemodynamic parameters including cardiac index, right atrial pressure, and mixed venous oxygen saturation 3
• Initiate intravenous epoprostenol for severe PAH exacerbation (WHO functional class IV) 3
• Continue background therapy including oral anticoagulants (if no contraindications), diuretics, supplemental oxygen to maintain saturation >90%, and digoxin for refractory right heart failure 3

For non-vasoreactive patients or those who failed calcium channel blocker therapy, initiate or optimize prostanoid therapy with IV epoprostenol 3. Consider combination therapy with endothelin receptor antagonists and/or PDE-5 inhibitors 3.

Special Populations

For PAH associated with connective tissue disease, the same treatment algorithm applies, though response patterns may differ from idiopathic PAH. 4, 5 Systemic sclerosis is the most important connective tissue disease to exclude, as it has high prevalence of PAH 1.

For Group 2 pulmonary hypertension (due to left heart disease), treatment should focus on optimizing the underlying cardiac condition; PAH-specific therapies are not recommended. 5 A pulmonary wedge pressure >15 mmHg excludes the diagnosis of pre-capillary PAH 1.

For Group 4 pulmonary hypertension (chronic thromboembolic), pulmonary endarterectomy is the treatment of choice when feasible. 5 Contrast CT angiography and traditional pulmonary angiography are required to identify surgically accessible disease 1.

Prognostic Indicators

Parameters indicating worse prognosis include: 3

• Clinical evidence of right ventricular failure 3
• Rapid progression of symptoms 3
• Syncope 3
• WHO functional class IV 3
• Short 6-minute walk distance (<300m) 3
• Elevated and rising BNP/NT-proBNP levels 3
• Presence of pericardial effusion on echocardiography 3
• Right atrial pressure >15 mmHg or cardiac index <2.0 L/min/m² 3

With contemporary PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. 2 Current treatment with combination drug therapy targeting multiple biological pathways has shown demonstrable improvement in morbidity and mortality compared with previous single-pathway targeted monotherapy 2.

Critical Pitfalls to Avoid

Do not use PAH-specific therapies in Group 2 pulmonary hypertension (left heart disease), as they are not recommended and may cause harm. 5 Adequate recording of pulmonary wedge pressure is required for differential diagnosis 1.

The combination of riociguat and PDE-5 inhibitors (such as sildenafil) is contraindicated due to risk of hypotension. 5

Do not delay referral to specialized centers, as early aggressive therapy with combination regimens improves outcomes 4, 5, 8.

Recognize that a normal ECG or chest radiograph does not exclude severe pulmonary hypertension. 1 Echocardiography and right heart catheterization remain essential for diagnosis 1.

For patients requiring surgery, coordinate care at a pulmonary hypertension center with careful monitoring of clinical status, oxygenation, and hemodynamics. 3