Table 1.

Studies Relevant to Augmenting Ketosis in Human Heart Failure

First Author and Year	Population	Intervention	Main Findings
Human studies
Cox, 2016⁴⁹	8 endurance athletes	Crossover study of ketone monoester and dextrose vs. carbohydrate drink	Athletes after ingesting drink containing ketone monoester cycled on average 411 m further over 30 minutes.
Verma, 2016⁵⁰	10 patients with diabetes and established cardiovascular disease	Before/after study with empagliflozin	Empagliflozin reduced LV mass and improved lateral E’ velocity.
Gormsen, 2017⁵¹	8 healthy subjects	Randomized, crossover trial of sodium-3-OHB infusion vs. saline	Ketone infusion decreased myocardial glucose uptake and increased myocardial blood flow by 75%.
Nielsen, 2019⁶	16 HFrEF patients (EF≤40%)	Randomized, crossover trial of 3-OHB infusion vs. isotonic saline	3-OHB infusion increased cardiac output, reduced systemic and pulmonary vascular resistance, and marginally decreased biventricular filling pressures.
McMurray, 2019⁹	4744 HFrEF patients (EF≤40%)	Randomized, crossover trial of dapagliflozin vs. placebo	Dapagliflozin reduced risk of worsening heart failure or cardiovascular death, irrespective of underlying diabetes mellitus.
Animal studies
Joubert, 2017⁵²	Lipodystrophic (seipin knockout) mice	Dapagliflozin only	Dapagliflozin treatment significant improved diastolic function in the hypertrophic heart.
Lee, 2017⁵³	Normoglycemic male Wistar rats after coronary ligation	Dapagliflozin therapy and control arm	Dapagliflozin reduced cardiac fibrosis.
Verma, 2018⁵⁴	Mice with diabetes	Empagliflozin and control arms	Empagliflozin increased cardiac ATP production, but not through ketone oxidation.
Abdurrachim, 2019⁵⁵	Rats with obesity, diabetes, hypertension and HF	Empagliflozin and control arms	Empagliflozin lowered myocardial ketone utilization; no effect observed on LV hypertrophy or fibrosis.
Horton, 2019⁷	TAC/MI mice and tachycardia-induced cardiomyopathy dogs	Ketogenic and normal chow for mice; 3-OHB infusion vs. no infusion in dogs with HF	Ketogenic chow improved LV remodeling in mice; 3-OHB infusion significantly improved systolic dysfunction and LV remodeling in the canine model.
Santos-Gallego, 2019⁵⁶	HF after left anterior descending artery ligation in nondiabetic pigs	Empagliflozin versus control	Empagliflozin improved systolic function and cardiac remodeling. Empagliflozin-treated pigs switched substrate utilization to ketones, FAs, and branched chain amino acids.
Yurista, 2019⁵⁷	Rat models without diabetes after MI	Empagliflozin and control chow arms	Empagliflozin significantly improved EF, attenuated hypertrophy, diminished fibrosis, and reduced oxidative stress after MI. Empagliflozin increased myocardial expression of the ketone body transporters and ketogenic enzymes.

3-OHB, 3-hydroxybutyrate; EF, ejection fraction; FA, fatty acid; g, gram; h, hour; HF, heart failure; kg, kilogram; LV, left ventricle; MI, myocardial infarction; TAC, transaortic constriction.