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The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.<\/jats:p>","DOI":"10.1152\/ajpheart.00068.2024","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T10:46:10Z","timestamp":1713523570000},"page":"H1498-H1514","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction"],"prefix":"10.1152","volume":"326","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0548-5403","authenticated-orcid":false,"given":"Vaishnavi","family":"Aradhyula","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Toledo College of Medicine and Life Sciences, 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