{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:41:07Z","timestamp":1793320867322,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["HL-121500"],"award-info":[{"award-number":["HL-121500"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MSCA-RISE-2014","award":["645648"],"award-info":[{"award-number":["645648"]}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR053897"],"award-info":[{"award-number":["R01AR053897"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in the caudal direction and reducing the length of fibers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients and mechanically ventilated rats with normal and increased titin compliance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H2O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i.e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts, end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force, and diaphragm weakness ensues.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201709-1917oc","type":"journal-article","created":{"date-parts":[[2018,3,26]],"date-time":"2018-03-26T15:10:41Z","timestamp":1522077041000},"page":"472-485","source":"Crossref","is-referenced-by-count":108,"title":["Positive End-Expiratory Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers"],"prefix":"10.1093","volume":"198","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4010-013X","authenticated-orcid":false,"given":"Johan","family":"Lindqvist","sequence":"first","affiliation":[{"name":"Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0920-6139","authenticated-orcid":false,"given":"Marloes","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robbert","family":"van der Pijl","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona"},{"name":"Department of Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pleuni E.","family":"Hooijman","sequence":"additional","affiliation":[{"name":"Department of Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albertus","family":"Beishuizen","sequence":"additional","affiliation":[{"name":"Department of Intensive Care, Medisch Spectrum Twente, Enschede, the Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Elshof","sequence":"additional","affiliation":[{"name":"Department of Intensive Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"de Waard","sequence":"additional","affiliation":[{"name":"Department of Intensive Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armand","family":"Girbes","sequence":"additional","affiliation":[{"name":"Department of Intensive Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique","family":"Spoelstra-de Man","sequence":"additional","affiliation":[{"name":"Department of Intensive Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong-Hua","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charissa","family":"van den Brom","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Bogaards","sequence":"additional","affiliation":[{"name":"Department of Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyi","family":"Shen","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Strom","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"Granzier","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Kole","sequence":"additional","affiliation":[{"name":"Department of Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 J. 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