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GDF15 antagonism limits severe heart failure and prevents cardiac cachexia
Minoru Takaoka1, John A Tadross2,3, Ali B A K Al-Hadithi1
1Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK.
Aims:
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.
Methods And Results:
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.
Conclusion:
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.
Insights
Cardiac cachexia is worsened by a GDF15-dependent pathway. Blocking GDF15 activity in heart failure may prevent weight loss and improve cardiac function, offering a novel therapeutic strategy.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Heart failure and associated cachexia remain significant clinical challenges.
- The integrated stress response (ISR) plays a role in cellular stress and adaptation.
- PPP1R15A is an ISR-induced eIF2α phosphatase implicated in stress response pathways.
Purpose of the Study:
- To investigate the role of PPP1R15A deficiency in a novel mouse model of heart failure.
- To identify factors contributing to cardiac cachexia in this model.
- To explore the therapeutic potential of targeting specific pathways in heart failure-induced cachexia.
Main Methods:
- Generation of mice lacking functional PPP1R15A via irradiation and bone marrow reconstitution.
- Assessment of cardiac function and body weight changes.
- Measurement of Gdf15 expression in the heart and GDF15 levels in circulation.
- Evaluation of GDF15 activity blockade on cachexia and heart failure progression.
- Analysis of GDF15 relevance to lean mass and protein intake in human heart failure patients.
Main Results:
- Mice lacking PPP1R15A developed dilated cardiomyopathy and severe weight loss post-irradiation.
- Wild-type mice showed no adverse effects.
- Increased Gdf15 expression in the heart and elevated circulating GDF15 levels were observed in affected mice.
- Blocking GDF15 activity ameliorated cachexia and slowed heart failure progression.
- GDF15 levels correlated with lean mass and protein intake in human heart failure patients.
Conclusions:
- Cardiac stress activates a GDF15-dependent pathway contributing to weight loss and cardiac dysfunction.
- Targeting GDF15 represents a potential therapeutic strategy for mitigating cardiac cachexia.
- Intervention against GDF15 may improve clinical outcomes in patients with severe systolic heart failure.
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