Description

Pulmonary arterial hypertension (PAH) is characterized by abnormalities in the small pulmonary arteries (precapillary pulmonary hypertension [PH]) that produce increased pulmonary arterial pressure (PAP) and vascular resistance, eventually resulting in right-sided heart failure.

• Previously, PH was classified as primary PH (without cause, now idiopathic PAH [IPAH]) or secondary PH (with cause or associated condition); now, it is clear that some types of secondary PH closely match primary PH (IPAH) in their histology, natural history, and response to treatment. Therefore, WHO classifies PH into five groups based on mechanism, with PAH as group 1 in this classification.
• PAH is diagnosed by right-heart catheterization and defined by a mean PAP ≥20 mm Hg at rest and a pulmonary vascular resistance (PVR) of ≥3 Wood units when other groups of PH are ruled out; pulmonary capillary wedge pressure ≤15 mm Hg (excludes PH owing to left heart disease; i.e., group 2 PH) without:
  • Mild or absent chronic lung disease or other causes of hypoxemia (excludes PH owing to lung disease or hypoxemia; i.e., group 3 PH)
  • Venous thromboembolic disease (excludes chronic thromboembolic PH [CTEPH]; i.e., group 4 PH)
  • Systemic disorder (like sarcoidosis), hematologic disorders (like myeloproliferative disease), and metabolic disorders (like glycogen storage disease) (excludes group 5 PH)
• PAH is divided into following main categories:
  • Idiopathic: sporadic, with no family history or risk factors
  • Heritable: IPAH with mutations or familial cases with or without mutations
  • Drug or toxin induced: mostly associated with anorectics (e.g., fenfluramine), rapeseed oil, L-tryptophan, dasatinib (Bcr-Abl tyrosine kinase inhibitor), and illicit drugs such as methamphetamine, cocaine
  • Associated: connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), HIV infection, portal hypertension, congenital heart disease, schistosomiasis (chronic hemolytic anemia added to group 5 PH—unclear/multifactorial mechanisms)
  • Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) and persistent PH of the newborn (PPHN) are classified as separate categories due to more differences than similarities with PAH.
    • PVOD and/or PCH: rare cause of PH characterized by extensive diffuse occlusion of the pulmonary veins (unlike PAH which involves the small muscular pulmonary arterioles)

Epidemiology

• Age: can occur at any age; mean age 37 years
• Sex (IPAH): female > male (female:male ratio ranges from 1.7 to 4.8:1)

Incidence

• Overall PAH: 5 to 52 cases per million
• IPAH: low, ~2 to 6 per million
• Drug-induced PAH: 1/25,000 with >3 months of anorectic use
• HIV associated: 0.5/100
• Portal hypertension associated: 1 to 6/100
• Scleroderma associated: 6–60%

Prevalence
PAH: ~15 to 50 cases per million; IPAH: ~6 cases per million

Etiology and Pathophysiology

• Pulmonary: inflammation, vasoconstriction, endothelial dysfunction, and intimal proliferation causing remodeling of pulmonary arteries produced by increased cell proliferation and reduced rates of apoptosis lead to obstruction
• Cardiovascular: Right ventricular hypertrophy (RVH), eventually leading to right-sided heart failure and right ventricular (RV) ischemia due to reduced right coronary artery flow causes RV remodeling associated with PAH.
• IPAH: by definition, unknown. True IPAH is mostly sporadic or sometimes familial in nature.
• Pulmonary arteriolar hyperactivity and vasoconstriction, occult thromboembolism, or autoimmune (high frequency of antinuclear antibodies)

Genetics
75% of heritable PAH (HPAH) cases and 25% of IPAH cases have mutations in BMPR2 (autosomal dominant).

Risk Factors

Female sex, previous illicit anorectic drug use, recent pulmonary embolism, first-degree relatives of patient with familial PAH