GDF15 Antagonism Limits Severe Heart Failure and Prevents Cardiac Cachexia

Sample size: 20 publication 10 minutes Evidence: high

Author Information

Author(s): 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

Primary Institution: University of Cambridge

Hypothesis

The study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A.

Conclusion

Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

Supporting Evidence

Mice lacking functional PPP1R15A exhibited dilated cardiomyopathy and severe weight loss following irradiation.
Blockade of GDF15 activity prevents cachexia and slows the progression of heart failure.
GDF15 levels were inversely correlated with protein intake in patients with heart failure.
Patients with cachexia exhibited greater plasma GDF15 than those who did not fit the criteria.
Blocking GDF15 activity significantly prevented the decrease in left ventricular function.
Plasma GDF15 was elevated following irradiation in both genotypes, but significantly higher in Ppp1r15aΔC/ΔC mice.
Analysis of heart tissue showed significant fold changes in inflammatory and ISR gene expression in Ppp1r15aΔC/ΔC mice.
Blocking GDF15 maintained food intake and triglyceride levels in the study model.

Takeaway

This study found that a protein called GDF15 makes mice lose weight and worsen heart function when they have heart failure, but blocking GDF15 can help them feel better.