Gut microbiota-derived butyrate supports myocardial energetics and improves diastolic dysfunction in hypertensive HFpEF

Background/Introduction

Heart failure with preserved ejection fraction (HFpEF) is characterised by diastolic dysfunction and impaired mitochondrial oxidative phosphorylation. Unlike heart failure with reduced ejection fraction, adaptive ketone utilisation appears limited in HFpEF, suggesting the presence of metabolic bottlenecks.

Purpose

We investigated whether the microbiota-derived short-chain fatty acid butyrate serves as an alternative cardiac fuel and improves myocardial energetics and function in hypertensive HFpEF.

Methods

Hypertensive double transgenic rats developing HFpEF were comprehensively phenotyped using echocardiography, invasive pressure–volume analysis and region-resolved quantitative proteomics to characterise structural, functional and metabolic remodelling. Myocardial substrate utilisation was investigated by in situ ¹³C-butyrate tracing in isolated perfused rat hearts and extended to human endomyocardial biopsies to confirm translational relevance. Chronic sodium-butyrate supplementation was administered for three weeks to the HFpEF rat to evaluate metabolic and functional effects in vivo. To assess the clinical significance of ketone metabolism, circulating 3-hydroxybutyrate (BOH) concentrations were analysed in 23,255 individuals with HFpEF from the UK Biobank, and their association with all-cause mortality was examined using multivariable Cox regression models.

Results

HFpEF hearts exhibited region-specific downregulation of mitochondrial electron transport chain proteins and reduced maximal respiratory capacity, consistent with impaired oxidative metabolism. BOH accumulated in rodent and human HFpEF hearts, and a reduced acetoacetate/BOH ratio suggested impaired ketone oxidation. In the UK Biobank, higher circulating BOH levels were independently associated with increased all-cause mortality, particularly in hypertensive individuals.

In contrast, ¹³C tracing demonstrated active myocardial uptake and oxidation of butyrate, with incorporation into butyryl-CoA and downstream citric acid (TCA) cycle intermediates in both rodent and human myocardium. Chronic butyrate supplementation increased cardiac butyryl-CoA and succinyl-CoA levels, improved global longitudinal strain, enhanced diastolic compliance, reduced fibrosis and inflammation, and significantly improved survival despite persistent severe hypertension and cardiac hypertrophy.

Conclusion

These findings identify butyrate as a compensatory cardiac fuel that bypasses mitochondrial metabolic bottlenecks in HFpEF, suggesting its potential as a therapeutic candidate to ameliorate cardiac metabolic dysfunction.