Unraveling the mechanisms and therapeutic pathways in pulmonary arterial hypertension: A comprehensive review

Among the various forms of pulmonary hypertension, PAH is a critically important and well-studied subset of this serious cardiovascular disease. Defined by progressive vascular occlusion, increased pulmonary arterial pressures and remodel of the vasculature, PAH eventually results in right heart (RV) failure which poses a significant clinical challenge to clinicians managing a PAH-affected patient. Interestingly, PAH has been recognized as a disease with gender paradox—higher prevalence in women but better survival of female patients—a key feature of the disease that can be related to estrogen-mediated mechanisms. Despite the fact that current clinical effort to target vasodilation focused on small molecular agents (endothelin, NO/sGC/cGMP and prostacyclin pathways), broad spectrum vasodilators continue being developed. Further recent discoveries have also broadened our mechanistic understanding, bridging the gap between genetic determinants of PAH pathogenesis (e.g., mutations in BMPR2) and metabolic dysregulation, estrogen-related processes, and platelet-derived growth factor (PDGF) activity. These advances not only deepen our understanding of disease progression, but also reveal new potential therapeutic targets beyond the traditional three pathways. This review integrates key features of PAH, evaluates current and novel treatment modalities and structures a framework to apply in the dynamic era of therapeutics that targets beyond the three established signaling pathways within PAH, providing groundwork for guiding future investigative and clinical initiatives in PAH.