Ketone metabolism is upregulated during heart failure (HF) in mice and humans. However, the functional significance of the upregulated ketone metabolism in the failing heart is poorly understood.
Objective: To determine whether a ketogenic diet is protective against pressure-overload-induced heart failure and to demonstrate the underlying mechanism.
Methods and Results: C57BL/6J wild-type mice were fed a ketogenic diet (90% Fat (Keto-Fat) or 90% Protein (Keto-Pro)) or isocaloric control diet (Con) for 4 weeks, starting 2 days after transverse aortic constriction (TAC) surgery. There was no difference in the pressure gradient among the 3 groups (Con 66, Keto-Fat 73, and Keto-Pro 68 mmHg, p = 0.9). Both Keto-Fat and Keto-Pro diets ameliorated cardiac hypertrophy (LV weight/TL ratio: 12.5 ± 0.6, 9.7 ± 1.8* and 11.0± 0.4* mg/mm, *P < 0.01 vs. Con) and HF (Lung weight/TL ratio: 27.1± 4.9, 17.9± 10.2*, and 20.2± 4.5* mg/mm; and LVEDP, 25.3± 12.2, 15.2± 7.6*, and 22.7± 4.8* mmHg, *P < 0.05 vs. Con). Individual cardiomyocyte hypertrophy was also attenuated by the ketogenic diets (Fold change: 2.4* and 2.1*, *P < 0.01 vs. Con), as evaluated by WGA staining. However, both ketogenic diets failed to reduce cardiac fibrosis (%fibrosis: 12.8, 12.4, and 12.5, respectively). These results suggest that a 4-week ketogenic diet, especially the Keto-Fat diet, is protective against TAC-induced cardiac hypertrophy and heart failure, but not cardiac fibrosis. Mechanistically, endogenous GSK-3b activity was decreased 1-week post-TAC, as evidenced by an increased ratio of Ser9-phosphorylation to total GSK-3b, and cardiac-specific knockdown of GSK-3b (GSK-3b cHKO) exacerbated cardiac hypertrophy in mice fed a Con diet (LVW/TL ratio:14.7± 0.7, p < 0.01 vs. WT mice fed a Con diet). Although both ketogenic diets, especially the Keto-Fat diet, reversed GSK-3b activity, only the Keto-Fat, but not the Keto-Pro, diet exhibited cardioprotection in GSK-3b cHKO mice (LVW/TL ratio, 11.5 ± 0.5* and 15.3 mg/mm, *p < 0.05 vs Con).
Conclusion: These results suggest that ketogenic diets are cardioprotective against pressure-overload-induced heart failure, and that reversal of GSK-3b inactivation is involved in low-carbohydrate/high-protein-diet-mediated cardioprotection.