GDF15 antagonism limits severe heart failure and prevents cardiac cachexia

• Published in: Cardiovascular research 2024-12, Vol.120 (17), p.2249-2260
• Main Authors: Takaoka, Minoru, Tadross, John A, Al-Hadithi, Ali B A K, Zhao, Xiaohui, Villena-Gutiérrez, Rocío, Tromp, Jasper, Absar, Shazia, Au, Marcus, Harrison, James, Coll, Anthony P, Marciniak, Stefan J, Rimmington, Debra, Oliver, Eduardo, Ibáñez, Borja, Voors, Adriaan A, O'Rahilly, Stephen, Mallat, Ziad, Goodall, Jane C
• Format: Article
• Language: English
• Subjects: Aged; Animals; Bone Marrow Transplantation; Cachexia - etiology; Cachexia - genetics; Cachexia - metabolism; Cachexia - physiopathology; Cachexia - prevention & control; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - physiopathology; Disease Models, Animal; Editor's Choice; Female; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Heart Failure - drug therapy; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Failure - prevention & control; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myocardium - metabolism; Myocardium - pathology; Original; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; Severity of Illness Index; Signal Transduction - drug effects; Weight Loss - drug effects
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvae214

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.