2026-04-29T04:08:34Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/265412025-12-18T13:01:34Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud
author
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
2025-03-20T12:19:28Z
2025-03-20T12:19:28Z
2024-12-31
Cardiovasc Res. 2024 Dec 31;120(17):2249-2260.
https://hdl.handle.net/20.500.12105/26541
39312445
Cardiovascular Research
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.
eng
Cachexia
GDF15
Heart failure
Integrated stress response
PPP1R15A
GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
research article
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GDF15 antagonism limits_Cardiovasc Res_2024.pdf