What are the causes of Pulmonary Arterial Hypertension (PAH)?

Causes of Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is caused by multiple factors including genetic mutations, associated medical conditions, drug exposures, and molecular abnormalities that lead to vascular remodeling, increased pulmonary vascular resistance, and ultimately right heart failure. 1

Classification of PAH (WHO Group 1)

PAH is classified within the broader framework of pulmonary hypertension (defined as mean pulmonary arterial pressure ≥25 mmHg at rest) 2. The specific causes of PAH include:

Idiopathic PAH

• Occurs without identifiable causes with a prevalence of approximately 6 per million 3
• Female/male ratio of 1.7:1 with a mean age at diagnosis of 37 years, though cases are increasingly reported in patients over 70 years 3

Heritable/Familial PAH

• Accounts for 6-10% of PAH cases 3
• Associated with genetic mutations:
  • BMPR2 mutations in 50-90% of familial cases and up to 25% of idiopathic PAH cases 3, 1
  • Characterized by genetic anticipation and incomplete penetrance 3
  • ALK1 mutations in patients with hereditary hemorrhagic telangiectasia 1

Drug and Toxin-Induced PAH

• Associated with anorexigens (aminorex, fenfluramine, dexfenfluramine) 1
• Other substances including toxic rapeseed oil, amphetamines, L-tryptophan, and certain chemotherapeutic agents 1
• Fenfluramine-related PAH shows BMPR2 mutations in approximately 15% of cases 3

Associated PAH (APAH)

Connective Tissue Diseases

• Most common in limited cutaneous systemic sclerosis (formerly CREST syndrome) 3, 4
• Also occurs in systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis 3, 4
• Accounts for 75% of connective tissue disease-associated PAH cases 4
• Involves both vascular remodeling and inflammatory/autoimmune mechanisms 4

Congenital Heart Disease

• Results from uncorrected increased pulmonary blood flow with systemic-to-pulmonary shunts 3
• Most common with high-pressure shunts (ventricular septal defect, patent ductus arteriosus, truncus arteriosus) 3
• Can lead to Eisenmenger syndrome with shunt reversal 3, 1
• May develop years to decades after closure of congenital defects 1

HIV Infection

• Incidence approximately 0.5% in HIV-infected individuals (6-12 times that of general population) 3
• Independent of CD4 count but related to duration of HIV infection 3, 1
• Has not declined significantly despite antiretroviral therapy 3

Portal Hypertension

• Associated with portopulmonary hypertension 1
• Risk increases with severity of liver disease 3

Schistosomiasis

• Important cause in endemic regions 3

Chronic Hemolytic Anemia

• Including sickle cell disease, thalassemia, hereditary spherocytosis 3, 1

Persistent Pulmonary Hypertension of the Newborn

• Failure of normal circulatory transition at birth 3

Pathophysiological Mechanisms

The development of PAH involves several key pathological processes:

• Endothelial dysfunction: Imbalance between vasoconstrictors (endothelin-1) and vasodilators (nitric oxide, prostacyclin) 1
• Vascular remodeling: Intimal hyperplasia, medial hypertrophy, adventitial proliferation, and plexiform arteriopathy 1
• Thrombosis in situ: Procoagulant state with elevated fibrinopeptide A and plasminogen activator inhibitor-1 1
• Altered cellular phenotype: Decreased apoptosis/proliferation ratio in pulmonary artery smooth muscle cells 1
• Molecular abnormalities:
  • Serotonin abnormalities with elevated plasma levels 1
  • Potassium channel dysfunction (downregulation of Kv1.5) 1
  • Prostacyclin and thromboxane A2 imbalance 1

Clinical Implications

• PAH severity ranges from mild pressure elevation to profound systemic or suprasystemic levels 1
• Early detection is challenging due to non-specific symptoms (primarily dyspnea) 5
• Without treatment, PAH leads to right heart failure and premature death 1, 6
• Prognosis of connective tissue disease-associated PAH is worse than other forms 4

Important Distinctions

PAH (WHO Group 1) must be distinguished from other forms of pulmonary hypertension:

• Group 2: PH due to left heart disease (systolic/diastolic dysfunction, valvular disease) 3, 7
• Group 3: PH due to lung diseases and/or hypoxemia (COPD, interstitial lung disease, sleep disorders) 3, 7
• Group 4: Chronic thromboembolic PH 3, 7
• Group 5: PH with unclear or multifactorial mechanisms (hematological disorders, systemic disorders, metabolic disorders) 3, 7

Diagnostic Considerations

• Echocardiography is the investigation of choice for non-invasive screening 5, 8
• Right heart catheterization is mandatory for definitive diagnosis 5, 8
• Patients with septal or great artery shunts should undergo periodic screening with echocardiography 1
• Annual echocardiography is recommended for asymptomatic systemic sclerosis patients 4