2026-04-29T04:09:36Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/265412025-12-18T13:01:34Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Takaoka, Minoru author Tadross, John A author Al-Hadithi, Ali B A K author Zhao, Xiaohui author Villena-Gutiérrez, Rocío author Tromp, Jasper author Absar, Shazia author Au, Marcus author Harrison, James author Coll, Anthony P author Marciniak, Stefan J author Rimmington, Debra author Oliver, Eduardo author Ibáñez, Borja author Voors, Adriaan A author O'Rahilly, Stephen author Mallat, Ziad author Goodall, Jane C author 2024-12-31 Heart failure and associated cachexia is an unresolved and important problem. 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 eIF2α phosphatase, PPP1R15A. 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. 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. Cardiovasc Res. 2024 Dec 31;120(17):2249-2260. https://hdl.handle.net/20.500.12105/26541 39312445 Cardiovascular Research Cachexia GDF15 Heart failure Integrated stress response PPP1R15A GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.