Growth Differentiation Factor 15 (GDF15) Causes Cardiac Cachexia in Heart Failure Restricted; Files Only

Lee, Da Young (Spring 2021)

Permanent URL: https://etd.library.emory.edu/concern/etds/3197xn31n?locale=en
Published

Abstract

Background & Aims

Cachexia is the wasting of normal body tissues and occurs in chronic medical diseases. It is a common complication of heart failure (HF) that is associated with high mortality. Growth differentiation factor 15 (GDF15) regulates food intake and can cause cancer cachexia. GDF15 is a sensitive biomarker in human HF, though its biologic function in HF is unknown. This study investigates the role of GDF15 in HF using a genetic mouse model of dilated cardiomyopathy (DCM).

Methods

Q-PCR and ELISA were performed to assess the expression, tissue distribution and circulating levels of GDF15 in DCM 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 direct tissue weights 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) with advanced DCM. Gdf15 mRNA was not increased in any other organs. DCM mice developed cachexia as assessed by reduced fat and lean mass by tissue weight and reduced fat mass by DXA in association with reduced food intake (vs. WT; p<0.01 for all). DCM mice with Gdf15 KO had preserved fat and lean tissue mass and consumed more food (p≤0.01 for all) than regular DCM mice. Gdf15 KO had no effect on cardiac structure or function by echocardiography and KO mice displayed only a small reduction in cardiac fibrosis relative to regular DCM mice (3%; p<0.01). Despite this, Gdf15 KO prolonged survival in DCM mice (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. 

Table of Contents

Introduction.................................................................................................................................1-9

Figure 1. Heart failure is a complex, chronic condition......................................................1

Table 1. Disease prevalence in the United States................................................................2

Figure 2. Postulated mechanism of cardiac cachexia in HF................................................4

Figure 3. GDF15 as a prognostic biomarker in numerous disease......................................6

Figure 4. PLNR9C/+ mice develop cardinal features of HF...................................................7

Figure 5. PLNR9C/+ mice develop cardiac cachexia.............................................................8

Table 2. GDF15 is upregulated in cardiomyopathy of varying etiologies..........................9

Figure 6. Postulated mechanisms of cardiac cachexia in HF..............................................5

Methods....................................................................................................................................10-14 Results......................................................................................................................................15-23

GDF15 is upregulated in PLNR9C/+ hearts....................................................................15-17

Figure 7. Mean Gdf15 normalized level is upregulated in PLNR9C/+ hearts...........16

Figure 8. GDF15 is upregulated in PLNR9C/+ hearts............................................17

GDF15 alters body composition in PLNR9C/+ mice........................................................17-19

Figure 9. GDF15 alters body composition in PLNR9C/+ mice................................18

GDF15 reduces food intake..........................................................................................19-20

Figure 10. GDF15 reduces food intake..................................................................20

GDF15 KO increases survival...........................................................................................20

Figure 11. GDF15 KO increases survival..............................................................20

GDF15 does not affect cardiac structure or function in chronic HF............................21-23

Figure 12. GDF15 does not affect cardiac structure or function in chronic HF....22

Figure 13. PLNR9C/+ mice develop severe cardiac fibrosis................................23 Discussion.................................................................................................................................24-27 Reference..................................................................................................................................28-40 

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