UC Irvine

Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is a common and high-risk clinical condition characterized by the convergence of pulmonary vascular dysfunction and right ventricular (RV) stress. Despite its prevalence, the pathophysiological mechanisms of development and progression of PH-HFpEF remain largely unknown. Consequently, there are no current therapies that target PH-HFpEF other than optimization of treatment for HFpEF and some limited adaptation of therapies for pulmonary artery hypertension (PAH). This review examines PH-HFpEF through the lens of heart-lung interactions, integrating evidence across hemodynamic, molecular, and cellular scales. We highlight how chronic venous pressure overload, impaired pulmonary vascular reserve, and increased pulsatile load reshape RV afterload and contribute to RV-pulmonary arterial uncoupling, particularly during physiological stress such as exercise. We further discuss how endothelial dysfunction, context-dependent signaling pathways, and systemic comorbidities modify pulmonary vascular remodeling and RV adaptation in ways that differ from PAH. Emerging roles for extracellular vesicles and other circulating mediators as vehicles of cardiopulmonary signaling are considered, alongside current experimental and clinical tools for studying these processes. By examining physiological and molecular insights in parallel, this review identifies key gaps in disease modeling, phenotyping, and mechanistic understanding, while emphasizing the need for approaches that link cardiopulmonary function to underlying biology. Such strategies are essential for advancing disease phenotyping and developing targeted therapies for PH-HFpEF.