Abstract 18598: Contributions of Alpha-Ketoglutarate Dependent Oncometabolism to HFpEF in Two Mouse Models

Abstract

Introduction: Switching from fatty acid oxidation to less efficient but more expeditious glycolysis is associated with oncometabolism and more recently cardiac hypertrophy. Hypothesis: We hypothesized that such a switch drives HFpEF in two diverse mouse models. Methods: WT/129J mice at age 4-weeks were subjected to biweekly p407 i.p. injections and a single i.v. injection of AAV9-cTnT-LDLR. A separate group of injected mice were fed a diet supplemented with alpha-ketoglutarate (2% αKG) at onset. 4-week-old Alport mice received either αKG diet or normal chow. Glucose uptake was measured by whole-body PET-CT imaging of 18F-FDG in four groups: (1) untreated (n=5), (2) LDLR/P407 at 1, 2, 4, 7 and 8-week treatment (n=3-5), (3) LDLR/P407 + αKG mice at 4-week treatment (n=5), and (4) 9-12-week Alport mice (n=5). Echocardiography was performed on all the groups (n=4-17). Mechanical and energetic measurements on skinned cardiac pupillary muscles were performed on late-stage Alport , 8-week-treated LDLR/P407 , 4-week-treated LDR/P407 + αKG mice, and untreated controls (n=4-9). Survival of LDLR/P407, LDLR/P407/αKG and control groups (n=8-13) were recorded. Results: PET-CT scans showed increased cardiac glucose uptake in Alport (FC=3, p< 0.05) and LDLR/P407 mice at 1, 2, 4 (FC = 2, p<0.05), and 8 weeks (FC=3.2, p<0.001). αKG diet increased cardiac glucose uptake in LDLR/P407 at 4 weeks compared to normal chow (FC=2.15, p<0.05). Doppler and echocardiography showed worse diastolic dysfunction (E/E’) (FC = 1.8, P<.05) in LDLR/P407 αKG mice at 4-weeks versus control chow and reduced heart size (volume) (FC = 0.41, P<0.05) and worse diastolic dysfunction in Alport mice fed αKG diet. Alport hearts favored a DRX state (FC= 1.52, p <.0001) while 8-week-LDLR/P407 hearts favored SRX (FC=1.1, p< 0.05). The SRX state was exacerbated by αKG diet in 4-week-LDLR/P407 relative to normal chow. Life spans of LDLR/P407 mice fed αKG diet were significantly shortened (p<0.001). Conclusions: The results support roles for oncometabolism in promoting HF and sudden death in Alport and LDLR/P407 mice, effects that were exacerbated by an αKG diet, and possibly caused by enhanced hypertrophic growth. The results suggest an αKGDH and phenotype-dependent redistribution of myosin energetic states