Butyrate rescues cardiac metabolic dysfunction in hypertensive heart failure with preserved ejection fraction

Diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) is characterized by metabolic inflexibility. Unlike systolic heart failure, where ketone bodies support energy homeostasis, the failing heart in HFpEF lacks well-characterized alternative fuels to meet its high ATP demand. Here, we show that butyrate, a microbiota-derived short-chain fatty acid, serves as an ancillary energy source and improves diastolic function. Although cardiac power was preserved in rats with HFpEF, both experimental and human HFpEF hearts exhibited an impaired expression of proteins in mitochondrial electron transport chain and oxidative phosphorylation. Additionally, accumulation of 3-hydroxy-butyrate (BOH) in rat and also human HFpEF indicated that ketones do not rescue the cardiac energetic deficit. In HFpEF patients from the UK Biobank, higher BOH levels were associated with increased mortality, particularly those with hypertension. Applying 13C-butyrate to isolated perfused hearts with and without HFpEF resulted in isotope incorporation in butyryl-CoA and downstream TCA intermediates and thus proving its active metabolization. Butyrate was efficiently oxidized by cardiomyocytes and was overtaking BOH and amino acids in supporting respiration. Finaly, chronic butyrate supplementation improved survival, enhanced diastolic function, and reduced fibrosis and inflammation in HFpEF rats despite persistent hypertension. These findings identify butyrate as a compensatory fuel and a promising therapeutic candidate in energetically compromised HFpEF.