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This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2\u03b1 phosphatase, PPP1R15A.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvae214","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T15:27:25Z","timestamp":1726759645000},"page":"2249-2260","source":"Crossref","is-referenced-by-count":46,"title":["GDF15 antagonism limits severe heart failure and prevents cardiac cachexia"],"prefix":"10.1093","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8515-8282","authenticated-orcid":false,"given":"Minoru","family":"Takaoka","sequence":"first","affiliation":[{"name":"Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8424-1252","authenticated-orcid":false,"given":"John A","family":"Tadross","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and Medical Research Council, University of Cambridge , Cambridge ,","place":["UK"]},{"name":"Department of Histopathology, East Midlands & East of England Genomic Laboratory, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0417-9653","authenticated-orcid":false,"given":"Ali B A K","family":"Al-Hadithi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Villena-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares (CNIC) , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6043-0713","authenticated-orcid":false,"given":"Jasper","family":"Tromp","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Centre Groningen , Groningen ,","place":["the Netherlands"]},{"name":"Saw Swee Hock School of Public Health, National University of Singapore & the National University Health System ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shazia","family":"Absar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Au","sequence":"additional","affiliation":[{"name":"Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge , Cambridge CB2 0QQ 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