Transforming Pulmonary Arterial Hypertension: Key Milestones and Future Perspectives

Abstract

Pulmonary arterial hypertension (PAH) is a rare, progressive disease of the precapillary pulmonary arteries, characterized by fibroproliferative vascular remodeling, increased pulmonary vascular resistance, right ventricular failure, and premature death. Over the past four decades, substantial advances in understanding PAH pathobiology, epidemiology, diagnosis, and treatment have meaningfully improved patient outcomes. The pathobiology of PAH is multifaceted, involving endothelial dysfunction, smooth muscle cell hyperproliferation, inflammation, and dysregulation of key signaling pathways, including the prostacyclin, nitric oxide, endothelin 1, and bone morphogenetic/TGF-β (transforming growth factor β) axes. Dysregulation of the activin arm of the TGF-β pathway has emerged as a critical driver of vascular remodeling and is the target of sotatercept, the first antiremodeling therapy approved for PAH. Epidemiologically, PAH now more commonly affects older adults with cardiovascular and pulmonary comorbidities compared with historical cohorts. The global burden varies considerably, with methamphetamine-associated PAH rising in North America and schistosomiasis- and HIV-associated PAH prevalent in low- and middle-income countries, where underdiagnosis likely remains substantial. Diagnosis continues to be delayed, with advanced symptoms present at the time of diagnosis for most patients. Right heart catheterization remains essential for definitive diagnosis. Emerging tools, including artificial intelligence applied to electrocardiography, echocardiography, and electronic health records, hold promise for earlier case identification. Management and prognostication of PAH is based on regular risk stratification using validated multiparameter tools. The initial therapy choice is up-front combination therapy with 2 oral medications for most patients, with initial triple therapy that includes a parenteral prostacyclin used in high-risk patients. Add-on therapy with sotatercept is now an option for patients not achieving low risk, a strategy that led to improvements in hemodynamics, right heart function, and reduced the risk of adverse clinical outcomes in recent randomized trials. For patients who remain at higher risk despite maximal therapy, lung transplantation remains an important and life-saving option. Despite remarkable therapy progress, gaps persist in earlier detection, management of comorbid phenotypes, personalized therapy, and novel therapies targeting right ventricular failure. Ongoing clinical trials and translational research continue to advance the field toward the goal of normal survival and quality of life for patients with PAH.