Heritable pulmonary arterial hypertension

Heritable pulmonary arterial hypertension (HPAH), also known as familial pulmonary arterial hypertension (FPAH), is a rare and progressive vascular disorder characterized by abnormally elevated blood pressure in the pulmonary arteries — the blood vessels that carry blood from the heart to the lungs. This increased pressure forces the right side of the heart to work harder to pump blood through the lungs, eventually leading to right heart failure if untreated. The disease primarily affects the pulmonary vasculature and the heart, with pathological changes including thickening and narrowing of the small pulmonary arteries due to endothelial cell proliferation, smooth muscle hypertrophy, and in situ thrombosis. Key symptoms include progressive shortness of breath (dyspnea), especially during physical exertion, fatigue, chest pain, dizziness, syncope (fainting), and peripheral edema (swelling of the ankles and legs). As the disease advances, patients may experience cyanosis (bluish discoloration of the skin) and signs of right-sided heart failure. The most commonly implicated gene is BMPR2 (bone morphogenetic protein receptor type 2), with mutations identified in approximately 70-80% of familial cases. Other genes associated with HPAH include ALK1 (ACVRL1), ENG, SMAD9, CAV1, KCNK3, and EIF2AK4, among others. The disease demonstrates reduced penetrance, meaning not all individuals carrying a pathogenic variant will develop the condition. Current treatments aim to slow disease progression and improve quality of life, as there is no cure. Approved therapies target three main pathways: the endothelin pathway (e.g., bosentan, ambrisentan, macitentan), the nitric oxide pathway (e.g., sildenafil, tadalafil, riociguat), and the prostacyclin pathway (e.g., epoprostenol, treprostinil, selexipag). Combination therapy using drugs from multiple pathways is now standard of care. Calcium channel blockers may be effective in a small subset of vasoreactive patients. Lung transplantation remains an option for patients with advanced disease refractory to medical therapy. Genetic counseling is strongly recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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