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Key Points

  • Disease summary:

    • Pulmonary arterial hypertension (PAH) is a rare condition characterized by proliferative growth of the media and intima of the smallest pulmonary arteries.

    • Widespread obstruction of the smallest pulmonary arteries causes increased resistance to blood flow through the lungs and is usually lethal due to right ventricular failure. Mean survival untreated is less than 3 years.

    • PAH diagnosis is established by measuring increased pulmonary artery pressure (mean >25 mm Hg) at cardiac catheterization, along with exclusion of disorders which cause pulmonary hypertension (Table 120-1).

    • PAH may occur sporadically (idiopathic PAH [IPAH]) or in families (6%). Heritable PAH (HPAH) is the current terminology for familial or sporadic patients in whom a responsible genetic (eg, BMPR2) mutation is identified.

    • PAH occurs at all ages and disproportionately affects women, more than twice as commonly as men.

    • Nine therapies are now available for PAH, all in FDA approved in the past 15 years. But, most are expensive, labor intensive (require continuous IV infusion), and limited in overall effect.

    • Lung transplantation is possible for some patients with PAH, but has significant limitations.

  • Differential diagnosis:

    • Several conditions in addition to PAH are associated with pulmonary hypertension, as listed in Table 120-1. The commonest symptoms are nonspecific, and include dyspnea, chest pain, dizziness, or syncope.

  • Monogenic forms:

    • Mutations in bone morphogenetic protein receptor type 2 (BMPR2) are responsible for approximately 80% of familial PAH cases. More than 300 different BMPR2 mutations are described. Mutations in other transforming growth factor beta (TGF-β) pathway members known to cause hereditary hemorrhagic telangiectasia (HHT) (ALK-1 or endoglin) are rarely associated with PAH, with or without clinical evidence of HHT. Other members of the TGF-β family are also associated with familial PAH, such as via SMAD8 mutation.

    • Decreased penetrance (~20%) and variable age of onset (all ages) of PAH due to a BMPR2 mutation may conceal a true familial basis of disease because it can skip multiple generations. This confounds disease prediction in mutation carriers and limits the value of genetic counseling in this subset. A significant minority of patients (reports vary from 10% to 40%) otherwise believed to have IPAH actually carry a responsible BMPR2 mutation. Because the prevalence of sporadic PAH far exceeds familial PAH (~94% vs ~6%), the majority of BMPR2 mutations present in the overall population of PAH patients are actually possessed by patients thought to have sporadic disease and thus assigned the diagnosis of IPAH.

  • Family history:

    • Family history is positive in 6% of PAH patients. Skip generations due to reduced penetrance (20%) may conceal a familial basis, creating a false impression that familial disease is sporadic. Earlier age of onset in subsequent generations is apparent for many families but it remains unknown whether it has a biologic basis.

  • Twin studies:

    • Twin studies have not been reported for PAH.

  • Environmental factors implicated in the development of PAH:

    1. Drugs and toxins as causes of PAH:

      • Definite: aminorex, fenfluramine, dexfenfluramine, toxic rapeseed ...

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