{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:34:48Z","timestamp":1791646488436,"version":"4.3.4"},"reference-count":69,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Comprehensive Physiology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The clinical trajectory of pulmonary vascular disease (PVD) is governed by the functional and molecular integration of the right ventricle (RV) and pulmonary vasculature\u2014the cardiopulmonary unit. Right ventricular\u2010pulmonary arterial (RV\u2010PA) coupling (Ees\/Ea) is the principal determinant of survival. This review synthesizes contemporary pathophysiology and therapeutics through the lens of RV\u2010PA coupling, reflecting the recognition of active heart\u2010lung crosstalk. Advancing beyond traditional reviews, this article (1) formalizes a phenotype\u2010guided treatment algorithm based on coupling derangement, (2) integrates emerging concepts of molecular crosstalk mediated by extracellular vesicles, and (3) positions sotatercept as a \u201ccoupling drug\u201d targeting both components of the cardiopulmonary unit. We detail maladaptive pathways\u2014including metabolic reprogramming, inflammation, fibrosis, and sex hormone signaling\u2014that degrade RV contractility (Ees) under chronic pressure overload. The pharmacotherapeutic landscape is critically evaluated: from established vasodilators that indirectly support the RV by reducing afterload (Ea) to transformative disease\u2010modifying agents like sotatercept that reverse vascular remodeling and the emerging frontier of direct RV\u2010targeted therapies. We argue that the future of PVD management lies in a precision\u2010based strategy using deep phenotyping to classify patients by dominant coupling derangements and matching them with mechanism\u2010based therapies. The paradigm must shift beyond symptomatic vasodilation toward regimens explicitly designed to restore the physiological balance of the cardiopulmonary unit, carefully distinguishing between validated standards of care and investigational approaches.<\/jats:p>","DOI":"10.1002\/cph4.70160","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T05:05:36Z","timestamp":1777698336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Restoring the Cardiopulmonary Unit: A Coupling\u2010Centric Review of Pharmacotherapy in Pulmonary Vascular Disease"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6700-3570","authenticated-orcid":false,"given":"Niloofar","family":"Khoshnam Rad","sequence":"first","affiliation":[{"name":"Thoracic Research Center, Imam Khomeini Hospital Complex Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayebeh","family":"Lakzaei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Vali\u2010e\u2010Asr Hospital Zanjan University of Medical Sciences  Zanjan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamidreza","family":"Abtahi","sequence":"additional","affiliation":[{"name":"Thoracic Research Center, Imam Khomeini Hospital Complex Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayebe","family":"Mohammad Alizade","sequence":"additional","affiliation":[{"name":"Thoracic Research Center, Imam Khomeini Hospital Complex Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202110\u20102274OC"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.124.012518"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD012785.pub2"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0183\u20102023"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.019351"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fddsv.2022.1022971"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221910579"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.734720"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2014.11.079"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16277"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1374100"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13247748"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00060.2025"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9030824"},{"key":"e_1_2_14_16_1","doi-asserted-by":"crossref","unstructured":"Figuinha V. 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