Ketogenic Diet is Cardioprotective Against Heart Failure

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.

Professional Heart Daily: Ketogenic Diet is Cardioprotective Against Pressure-overload-induced Heart Failure