Background:
Cachexia is wasting of normal body tissue and occurs in chronic medical diseases. It is a common complication of heart failure (HF) that is associated with very high mortality. Growth differentiation factor 15 (GDF15) regulates food intake and can cause cancer cachexia. GDF15 is a sensitive biomarker in humans, though its biologic function in HF is unknown. This study investigated the role of GDF15 in HF.
Methods:
We utilized a genetic mouse model of dilated cardiomyopathy (DCM) caused by a mutation in the phospholamban gene (PLN
R9C
). PLN
R9C
mice have dysregulated cardiac calcium handling (a common feature of nearly all forms of HF) and develop progressive DCM that leads to HF and premature death. Q-PCR and ELISA were performed to assess expression, tissue distribution and circulating levels of GDF15 in PLN
R9C
and age-matched wild type (WT) mice. A double transgenic mouse was created by crossing our DCM model with a constitutive
Gdf15
knock-out (KO). Using this novel model, we quantified food intake, and assessed fat and lean tissue mass by tissue weight at necropsy and by dual-energy X-ray absorptiometry (DXA). Cardiac function was assessed using echocardiography, and histochemistry performed to quantify cardiac fibrosis. Survival was assessed by Kaplan-Meier.
Results:
GDF15 mRNA (43-fold; p<0.01) and protein (54-fold; p<0.01) were increased in LV tissue, and circulating GDF15 was elevated (8.3-fold; p=0.03) in PLN
R9C
mice.
Gdf15
was expressed at low levels and was not increased in other organs in PLN
R9C
mice. PLN
R9C
mice developed cachexia (reduced fat and lean mass by tissue weight, reduced fat mass by DXA vs. WT; p<0.01 for all) and consumed less food (p<0.01 vs. WT).
Gdf15
KO in PLN
R9C
preserved fat and lean tissue mass and resulted in higher food intake (p≤0.01 for all).
Gdf15
KO had no effect on cardiac structure or function by echocardiography and PLN
R9C
/
Gdf15
KO mice displayed only a small reduction in cardiac fibrosis relative to PLN
R9C
mice (3%; p<0.01). Despite this,
Gdf15
KO prolonged survival in PLN
R9C
(29±3 vs. 25±3 weeks; p<0.01).
Conclusions:
GDF15 is a novel cardiac hormone produced in HF that triggers anorexia and cachexia in HF by an extra-cardiac mechanism.
GROWTH DIFFERENTIATION FACTOR-15 IS ASSOCIATED WITH MORTALITY IN PATIENTS WITH SEVERE ACUTE HEART FAILURE OR CARDIOGENIC SHOCK
