Pulmonary Hypertension Associated With Left Heart Disease: Challenges, Emerging Strategies, and Future Directions

Pulmonary hypertension (PH) associated with left heart disease (LHD) is the most prevalent form of PH and is associated with substantial morbidity and mortality risk. Diagnosis is challenging because of overlapping phenotypes, imprecise echocardiographic estimates, and reliance on invasive hemodynamic assessment. Pulmonary arterial hypertension drugs have shown no benefit and may even be harmful in this population. There are no pharmacologic or interventional therapies approved specifically for PH-LHD to date, other than treatments directed at the underlying LHD. Multiple pharmacologic agents, such as sotatercept, relaxin analogues, and levosimendan, along with device-based strategies such as pulmonary artery denervation, transcatheter atrial shunts, and pericardiotomy, are under investigation. Progress in clinical trials has been hindered by patient recruitment, phenotypic heterogeneity, and a lack of standardized functional and hemodynamic outcomes. This review summarizes the current knowledge on PH-LHD, highlights emerging pharmacologic and invasive therapies, discusses barriers to trial design and regulatory approval, and proposes a framework to guide future investigations.