Pulmonary Hypertension in Left Heart Disease: From Pathophysiology to Emerging Therapies

Background: Pulmonary hypertension due to left heart disease (PH-LHD) is the most common form of pulmonary hypertension worldwide and represents a major determinant of morbidity and mortality in patients with heart failure and valvular heart disease. Its pathophysiology extends beyond passive transmission of elevated left-sided filling pressures, involving pulmonary vascular remodeling, endothelial dysfunction, inflammation, and progressive right ventricular–pulmonary arterial uncoupling. Methods: This review summarizes current concepts in the pathophysiology, classification, diagnosis, and management of PH-LHD, with particular emphasis on emerging therapeutic strategies. Contemporary hemodynamic definitions and the distinction between isolated post-capillary and combined post- and pre-capillary pulmonary hypertension are discussed, alongside the evolving role of echocardiography, right heart catheterization, exercise hemodynamics, and advanced phenotyping. Results: Chronic elevation of left atrial pressure promotes pulmonary venous and arterial remodeling, potentially producing a precapillary component that persists despite correction of the underlying cardiac disorder. Prognosis is strongly influenced by right ventricular function and the severity of pulmonary vascular disease. Current treatment remains centered on optimization of the underlying left heart disease, including guideline-directed heart failure therapy, management of volume status, and correction of significant valvular disease. In contrast, pulmonary arterial hypertension–specific therapies have generally failed to demonstrate consistent benefit and may cause harm in selected patients. Emerging approaches targeting pulmonary vascular remodeling, myocardial energetics, endothelial dysfunction, and novel molecular pathways are being investigated, while phenotype-guided interventions and advanced mechanical and structural therapies may provide new opportunities for selected patients. Conclusion: PH-LHD represents a heterogeneous cardiopulmonary syndrome in which pulmonary vascular remodeling and right ventricular dysfunction increasingly determine clinical outcomes. Improved hemodynamic phenotyping and identification of biologically distinct subgroups may enable more precise therapeutic strategies. Future clinical trials should prioritize well-defined PH-LHD phenotypes and evaluate targeted therapies capable of modifying pulmonary vascular disease without worsening pulmonary congestion.