Abstract Body: Healthy hearts can flexibly switch between energy substrates. This capacity is lost in failing hearts and is implicated in the development of heart failure with preserved ejection fraction (HFpEF). Currently, HFpEF lacks effective therapies, reflecting its complex and poorly defined pathophysiology. Microbially derived short-chain fatty acids (SCFAs) are key regulators of cardiovascular health via modulation of anti-inflammatory and cardiometabolic pathways.
Here, we combined proteomic and metabolomic profiling of the myocardium with and without chronic SCFA butyrate supplementation, kinetic metabolic modeling and echocardiographic analysis of cardiac function in hypertensive transgenic rats overexpressing the human renin and angiotensinogen genes. The model recapitulates key clinical HFpEF features. Our goal is to clarify how SCFA metabolism modulates myocardial energetics and supports cardiac function in HFpEF.
We identified a profound energetic deficit, reduced ATP production, and mitochondrial uncoupling measured as a reduction of oxygen consumption in HFpEF cardiomyocytes (95.7% vs 136% to basal levels). Interestingly, HFpEF hearts showed comparable cardiac power output (17.52 mW) as healthy hearts (14.45 mW). Further, downregulation of proteins involved in the electron transport chain, fatty acid oxidation, and glycolysis were observed. In the posterior apex of HFpEF hearts, the reactome pathways aerobic respiration, mitochondrial electron transport, and complex I biogenesis were the most significantly downregulated. Additionally, branched chain amino acid (BCAA) catabolism and collagen degradation were reduced, suggesting impaired substrate flexibility and matrix turnover. The upregulation of β-hydroxybutyrate dehydrogenase 2 (BDH2, 18.6 vs 18.2 log2 LFQ intensity) proposed a compensatory shift toward alternative energy substrates.
Chronic butyrate supplementation rescued mortality (100% vs 60% in untreated) in the HFpEF model, besides persisting hypertension and concentric hypertrophy. Pressure-volume loop analysis showed in part a normalized loop geometry and improved diastolic compliance after butyrate. Butyrate enhanced myocardial longitudinal strain in a segmental manner and reduced cardiac fibrosis and inflammation. Previously, ketone bodies have been indicated as a potential energy source in HFpEF. Our study identifies the SCFA butyrate as a novel and efficient alternative to serve energy requirements in HFpEF.