Contributions Of A Glycolytic Switch To Hfpef In Two Mouse Models

Background: Switching from fatty acid oxidation to less efficient but more expeditious glycolysis is associated with oncometabolism and more recently cardiac hypertrophy. We hypothesized that such a switch drives HFpEF in two diverse mouse models. Method: 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% aKG) at onset. 4-week-old Alport mice received either aKG diet or normal chow. Glucose uptake was measured by whole-body PET-CT imaging of 18F-FDG in four groups: (1) untreated mice (n=5), (2) LDLR/P407 mice at 1, 2, 4, 7 (n = 3) and 8 weeks treatment (n=5), (3) LDLR/P407 + aKG mice at 4-weeks treatment (n=5), and (4) 9-12-weeks Alport mice (n=5). Echocardiography was performed on untreated mice (n=14), 4-week LDLR/P407 treatment mice (n=17), and 4-week LDLR/P407 + aKG treatment mice (n=5). Mechanical and energetic measurements on skinned cardiac pupillary muscles were performed on late-stage Alport (n=8), 8-week-treated LDLR/P407 (n=9), 4-week-treated LDR/P407 + aKG mice (n=2), and untreated controls (n=8). Survival of LDLR/P407 (n=13), LDLR/P407/aKG (n=8) and control groups 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). aKG 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. 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 aKG diet in 4-week-LDLR/P407 relative to normal chow. aKG diet significantly shortened life spans of LDLR/P407 mice (p<0.001). Conclusion: The results support roles for oncometabolism in promoting HF and sudden death in Alport and LDLR/P407 mice, effects that were exacerbated by an aKG supplement, possibly via enhanced hypertrophic growth. Results suggest an αKGDH-dependent and phenotype-dependent redistribution of myosin energetic states.