Aetiology

The cause of IPAH is unknown. Its pathogenesis probably involves the interaction of genetic predisposition and risk factors that cause pulmonary vascular damage.[3]​ Mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor-beta (TGF-beta) superfamily, are responsible for familial cases of pulmonary arterial hypertension.[12] However, only 20% of BMPR2 mutation carriers will develop the disease over a lifetime.[13] BMPR2 mutations have been also found in 11% to 40% of cases of non-familial primary pulmonary hypertension. These mutations lead to changes in intracellular signalling pathways that result in proliferative and anti-apoptotic effects in the pulmonary vasculature. Other predisposing genetic factors include mutations and variants in the genes: ACVRL1 (encoding activin receptor-like kinase 1, a type 1 receptor for TGF-beta family proteins); ENG (encoding endoglin, a glycoprotein); SMAD9 (encoding a SMAD family protein, which transduces signals from TGF-beta family members); CAV1 (encoding caveolin 1 protein); and KCNK3 gene (encoding a potassium channel).[14] The exact environmental risk factors in IPAH remain unknown, but possibilities include infections, drugs such as appetite suppressants, and inflammatory insults.[15][16][17]

Pathophysiology

The main vascular changes are vasoconstriction, smooth-muscle cell and endothelial-cell proliferation, and thrombosis. These changes suggest the predominance of thrombogenic, mitogenic, pro-inflammatory, and vasoconstrictive factors, probably as a consequence of pulmonary endothelial-cell dysfunction or injury.[18] The levels of a prostacyclin metabolite, a potent vasodilator with antiproliferative and antiplatelet activity, are decreased in the urine of patients with pulmonary hypertension. However, the levels of thromboxane A2 metabolites (a vasoconstrictor and platelet agonist) are increased.[19] Furthermore, the expression of prostacyclin synthase is decreased in the pulmonary vascular tree of patients with severe pulmonary hypertension, particularly IPAH.[20]

Another potent vasoconstrictor and pro-proliferative mediator is endothelin-1. Its plasma levels are increased in pulmonary hypertension and correlate with the severity of IPAH.[21][22] There is also increased expression of endothelin-1 in vascular endothelial cells in patients with pulmonary hypertension.[23]

The third important mediator in IPAH is nitric oxide (NO), a potent vasodilator and inhibitor of platelet activation and smooth-muscle proliferation.[24]​ Levels of NO are lower in lungs of patients with IPAH compared with healthy controls.[25][26]​​ These low levels were initially thought to be due to decreased expression of endothelial NO synthase in the lung, but are more likely to be secondary to increased NO consumption or decreased NO synthesis due to decreased substrate availability.[27][28]

Alterations in serotonin, adrenomedullin, vasoactive intestinal peptide, vascular endothelial growth factor, platelet-derived growth factor, and potassium channels have been described as well.[18][29][30]

A procoagulant state and in situ pulmonary vascular thrombosis have been shown in IPAH and are reflected by elevated levels of fibrinopeptide A, D-dimer, von Willebrand's factor, and plasminogen activator inhibitor type-1.[31]

These changes cause pulmonary vascular narrowing with a consequent increase in pulmonary vascular resistance (PVR) that leads to right ventricular overload and eventually to right ventricular failure and death.

Classification

Updated clinical classification of pulmonary hypertension​ (PH)[2][3]

1. Pulmonary arterial hypertension (PAH)

  • 1.1 Idiopathic PAH

    • 1.1.1 Non-responders at vasoreactivity testing

    • 1.1.2 Acute responders at vasoreactivity testing

  • 1.2 Heritable PAH

  • 1.3 Drug- and toxin-induced PAH

  • 1.4 Associated with:

    • 1.4.1 Connective tissue disease

    • 1.4.2 HIV infection

    • 1.4.3 Portal hypertension

    • 1.4.4 Congenital heart diseases

    • 1.4.5 Schistosomiasis

  • 1.5 Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

  • 1.6 Persistent pulmonary hypertension of the newborn (PPHN)

2. Pulmonary hypertension due to left heart disease

  • 2.1 Heart failure

    • 2.1.1 With preserved ejection fraction

    • 2.1.2 With reduced or mildly reduced ejection fraction

  • 2.2 Valvular heart disease

  • 2.3 Congenital/acquired cardiovascular conditions leading to post-capillary pulmonary hypertension

3. Pulmonary hypertension due to lung diseases and/or hypoxia

  • 3.1 Obstructive pulmonary disease or emphysema

  • 3.2 Restrictive lung disease

  • 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

  • 3.4 Hypoventilation syndromes

  • 3.5 Hypoxia without lung disease

  • 3.6 Developmental lung disorders

4. PH due to pulmonary artery obstructions

  • 4.1 Chronic thromboembolic PH

  • 4.2 Other pulmonary artery obstruction

5. Pulmonary hypertension with unclear multifactorial mechanisms

  • 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy

  • 5.2 Systemic disorders: vasculitis, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis

  • 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

  • 5.4 Chronic renal failure with or without haemodialysis

  • 5.5 Pulmonary tumour thrombotic microangiopathy

  • 5.6 Fibrosing mediastinitis

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