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Despite its prevalence, the pathophysiological mechanisms of development and progression of PH\u2010HFpEF remain largely unknown. Consequently, there are no current therapies that target PH\u2010HFpEF other than optimization of treatment for HFpEF and some limited adaptation of therapies for pulmonary artery hypertension (PAH). This review examines PH\u2010HFpEF through the lens of heart\u2013lung 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\u2010pulmonary arterial uncoupling, particularly during physiological stress such as exercise. We further discuss how endothelial dysfunction, context\u2010dependent 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\u2010HFpEF.<\/jats:p>","DOI":"10.1002\/cph4.70168","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T13:54:48Z","timestamp":1778853288000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Heart\u2013Lung Interactions in Pulmonary Hypertension due to Heart Failure With Preserved Ejection Fraction"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6436-6907","authenticated-orcid":false,"given":"Pratima","family":"Prabala","sequence":"first","affiliation":[{"name":"Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center and Department of Biomedical Engineering University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5750-2034","authenticated-orcid":false,"given":"Farhan","family":"Raza","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Division University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7612-5796","authenticated-orcid":false,"given":"Naomi C.","family":"Chesler","sequence":"additional","affiliation":[{"name":"Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center and Department of Biomedical Engineering University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.123.323119"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.14212"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt184"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvw054"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.122.028121"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2023.06.031"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.119.14330"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1115\/1.4068886"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200710\u20101458oc"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.3236"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.25326"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.049"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci74773"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw241"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.03.077"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2019.03.021"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2015.02.002"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.121.17957"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2021.01.015"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2025.111113"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.26430\/chungarica.2022.52.2.105"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010\u20100323oc"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac389"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011833"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054475"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.14507"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.3187"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2018.05.006"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.126.079918"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.630"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/4727283"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2016.08.22"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.653576"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01321\u20102024"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.124.069340"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2024277"},{"key":"e_1_2_11_38_1","doi-asserted-by":"crossref","unstructured":"Jaeschke L. 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