Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disorder characterized by elevated pressure in the pulmonary arteries due to narrowing, remodeling, and obstruction of the small pulmonary vessels. This increase in pulmonary vascular resistance leads to right ventricular hypertrophy and eventual right heart failure. The pathogenesis of PAH involves complex interactions among endothelial dysfunction, smooth muscle proliferation, inflammation, thrombosis, and genetic predispositions. Key molecular pathways implicated include the endothelin, nitric oxide, and prostacyclin signaling cascades. Clinically, PAH manifests as exertional dyspnea, fatigue, chest pain, syncope, and signs of right heart dysfunction. Without timely intervention, the disease significantly impairs quality of life and is associated with high morbidity and mortality, particularly as right heart failure progresses.
Idiopathic PAH refers to cases where no identifiable cause can be found. It is diagnosed after excluding all known secondary causes of pulmonary hypertension. IPAH is characterized by vascular remodeling, plexiform lesions, and progressive increase in pulmonary vascular resistance. It often affects younger adults, with a female predominance, and can be rapidly progressive if untreated.
Heritable PAH includes cases with a family history or identifiable genetic mutations, most commonly in the BMPR2 gene. This form may present similarly to idiopathic PAH but is distinguished by its genetic basis and potential for earlier onset. Genetic counseling is recommended for affected families due to variable penetrance and expression.
This type results from exposure to certain drugs or toxins known to cause pulmonary vascular injury, such as appetite suppressants (e.g., fenfluramine), methamphetamines, or chemotherapy agents. Pathological changes mirror those seen in idiopathic PAH, and disease progression may continue even after discontinuation of the offending agent.
APAH encompasses PAH that develops in association with other medical conditions, including connective tissue diseases (notably systemic sclerosis), HIV infection, portal hypertension, congenital heart diseases, and schistosomiasis. The underlying conditions contribute to pulmonary vascular remodeling and increased risk of PAH development.
This rare subset of PAH is characterized by obstruction of pulmonary veins and/or proliferation of pulmonary capillaries. It often presents with severe hypoxemia and is associated with poor response to standard PAH therapies. Diagnosis is challenging and may require histopathological confirmation.
Pulmonary arterial hypertension is a rare disease with an estimated prevalence of 15–50 cases per million adults and an annual incidence of 2–7 cases per million. The disease is more common in females, with a female-to-male ratio of approximately 2:1, and typically presents between the ages of 30 and 60 years. Idiopathic and heritable forms account for a significant proportion of cases, while connective tissue disease-associated PAH is the most frequent form of associated PAH in developed countries. Survival rates have improved with modern therapies, but the median survival following diagnosis remains approximately 5–7 years, with worse outcomes in patients presenting with advanced functional impairment or right heart failure.
The diagnosis of pulmonary arterial hypertension requires a comprehensive approach combining clinical assessment, non-invasive testing, and invasive hemodynamic evaluation. Initial evaluation includes a detailed history and physical examination, electrocardiogram, chest radiography, pulmonary function tests, and echocardiography to estimate pulmonary pressures and assess right ventricular function. Definitive diagnosis is established by right heart catheterization, which demonstrates a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg at rest, a pulmonary arterial wedge pressure (PAWP) of 15 mmHg or less, and a pulmonary vascular resistance (PVR) greater than 2 Wood units. Additional diagnostic workup includes laboratory testing for connective tissue diseases, HIV, liver function, and screening for congenital heart disease. Vasoreactivity testing with inhaled agents may be performed during catheterization to identify candidates for calcium channel blocker therapy. Advanced imaging such as CT pulmonary angiography or ventilation-perfusion scanning is used to exclude other causes of pulmonary hypertension such as chronic thromboembolic disease. Genetic testing may be considered in cases suggestive of heritable PAH.
Sotatercept is an approved therapy for pulmonary arterial hypertension that acts as a fusion protein targeting the transforming growth factor-beta superfamily, aiming to restore the balance between pro-proliferative and anti-proliferative signaling in the pulmonary vasculature. The combination of macitentan and tadalafil provides dual pathway inhibition by blocking endothelin receptors and enhancing the nitric oxide–cGMP pathway through phosphodiesterase-5 inhibition, offering improved hemodynamic and functional outcomes. Selexipag is a selective prostacyclin receptor agonist that promotes vasodilation and inhibits smooth muscle proliferation, administered orally for long-term management of PAH. Treprostinil diethanolamine is a prostacyclin analog formulated for oral administration, exerting vasodilatory and antiproliferative effects to reduce pulmonary vascular resistance. Macitentan is an oral endothelin receptor antagonist that reduces the deleterious effects of endothelin-1, a potent vasoconstrictor implicated in PAH pathogenesis. Riociguat is a soluble guanylate cyclase stimulator that enhances the nitric oxide signaling pathway, leading to vasodilation and improved exercise capacity in PAH patients. Ambrisentan is a selective endothelin type A receptor antagonist that decreases pulmonary vascular resistance and is indicated for the treatment of PAH to improve exercise ability and delay clinical worsening. Tadalafil, a phosphodiesterase-5 inhibitor, increases cyclic GMP concentrations resulting in pulmonary vasodilation and improved functional capacity in affected individuals. Treprostinil sodium is a prostacyclin analog administered via various routes, including subcutaneous, intravenous, and inhaled, to provide symptomatic relief and slow disease progression. Bosentan is a dual endothelin receptor antagonist that improves exercise capacity and delays clinical worsening by blocking the effects of endothelin-1 on both type A and B receptors in the pulmonary vasculature.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| sotatercept (Prop INN; USAN); sotatercept-csrk | 1001080-50-7 | |||
| macitentan/tadalafil | ||||
 | selexipag (Prop INN; USAN) | 475086-01-2 | C26 H32 N4 O4 S | 496.622 |
 | treprostinil diethanolamine (Rec INNM); treprostinil diolamine (USAN) | 830354-48-8 | C23 H34 O5 . C4 H11 N O2 | 495.649 |
 | macitentan (Rec INN; USAN) | 441798-33-0 | C19 H20 Br2 N6 O4 S | 588.273 |
 | riociguat (Rec INN; USAN) | 625115-55-1 | C20 H19 F N8 O2 | 422.416 |
 | ambrisentan (Rec INN) | 177036-94-1 | C22 H22 N2 O4 | 378.421 |
 | tadalafil (Rec INN; USAN) | 171596-29-5 | C22 H19 N3 O4 | 389.404 |
 | treprostinil sodium (Rec INNM; USAN); uniprost | 289480-64-4 | C23 H33 O5 . Na | 412.495 |
 | bosentan (Rec INN; USAN; JAN) | 147536-97-8 | C27 H29 N5 O6 S | 551.614 |
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