Pulmonary Arterial Hypertension: Etiology and Classification
Pulmonary arterial hypertension (PAH) is classified as WHO Group 1 pulmonary hypertension and encompasses idiopathic, heritable, drug/toxin-induced, and associated forms, with etiologies ranging from genetic mutations (particularly BMPR2) to connective tissue diseases, HIV, portal hypertension, and congenital heart disease. 1
Pathophysiology and Core Mechanism
PAH results from restricted flow through the pulmonary arterial circulation, causing increased pulmonary vascular resistance that ultimately leads to right heart failure. 2 The disease involves multiple pathogenic pathways at molecular and genetic levels affecting smooth muscle cells, endothelial cells, and adventitia. 2 Beyond the traditional vasoconstrictor/vasodilator imbalance, PAH fundamentally involves an imbalance favoring cellular proliferation over apoptosis, driving progressive vascular remodeling. 2
WHO Classification System
The current classification divides pulmonary hypertension into 5 major groups: 2
Group 1: Pulmonary Arterial Hypertension (PAH)
This is the primary category relevant to your question, subdivided into: 2
1.1 Idiopathic PAH (IPAH)
- Most common type in registries, more prevalent in women 2
- No identifiable cause after comprehensive evaluation 1
1.2 Heritable/Familial PAH (FPAH)
- BMPR2 gene mutations (bone morphogenetic protein receptor-2) 2
- ALK1 and endoglin mutations (with or without hereditary hemorrhagic telangiectasia) 2
- Inherited as autosomal dominant with incomplete penetrance and genetic anticipation 2
1.3 Drug and Toxin-Induced PAH
- Anorexigen-induced and other drug/toxin exposures 2
1.4 Associated PAH (APAH) includes: 2
- Connective tissue disorders (most common association)
- Congenital heart disease with systemic-to-pulmonary shunts
- Portal hypertension
- HIV infection
- Schistosomiasis
- Chronic hemolytic anemia (hemoglobinopathies, myeloproliferative disorders)
- Other: thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, splenectomy
1.4' Venous/Capillary Involvement:
1.5 Persistent Pulmonary Hypertension of the Newborn 2
Other WHO Groups (for context)
Group 2: PH due to left heart disease (systolic/diastolic dysfunction, valvular disease) 2
Group 3: PH associated with lung diseases and/or hypoxemia (COPD, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation, chronic high altitude exposure) 2
Group 4: Chronic thromboembolic PH (CTEPH) - proximal or distal thromboembolic obstruction 2
Group 5: PH with unclear/multifactorial mechanisms (sarcoidosis, hematological disorders, metabolic disorders, chronic renal failure on dialysis) 2
Hemodynamic Definition
PAH is definitively diagnosed by right heart catheterization demonstrating: 1, 3
- Mean pulmonary arterial pressure >20 mmHg at rest
- Pulmonary artery wedge pressure ≤15 mmHg (precapillary)
- Pulmonary vascular resistance ≥3 Wood units
Epidemiology
The prevalence of PAH is approximately 15 per million population based on French registry data, though US data suggests 10.6 cases per million adults. 2, 3 IPAH demonstrates female predominance and represents the most common PAH subtype in registries. 2
Critical Clinical Pitfall
Do not confuse PAH (Group 1) with the broader category of pulmonary hypertension. PAH specifically refers to precapillary PH in the absence of lung disease, left heart disease, or chronic thromboembolic disease. 1 Misclassification leads to inappropriate therapy, as PAH-specific medications are contraindicated or ineffective in Groups 2 and 3 PH. 2