Butyrate Rescues Metabolic and Diastolic Dysfunction in Hypertensive Heart Failure with Preserved Ejection Fraction

S. Kedziora (Berlin)¹, S. Geisberger (Berlin)², O. Popp (Berlin)², A. Frovola (Berlin)², A. Uhrbach (Berlin)², K. Kräker (Berlin)³, N. Tagiyeva (Berlin)², M. Kelm (Berlin)⁴, N. Berndt (Nuthetal)⁵, Y. D. Zhang (Berlin)², G. Mastrobuoni (Berlin)², P. Lorenz (Berlin)³, T. U. P. Bartolomaeus (Berlin)¹, P. Fahjen (Berlin)², G. N. Kaufhold (Berlin)², P. Parakkat (Berlin)², A.-M. Chitroceanu (Berlin)⁶, F. Edelmann (Berlin)⁷, G. Schiattarella (Berlin)⁸, S. K. Forslund (Berlin)⁹, N. Wilck (Berlin)¹, M. Gotthardt (Berlin)¹⁰, P. Mertins (Berlin)¹¹, R. Dechend (Berlin)¹², S. Sawamiphak (Berlin)¹¹, D. N. Müller (Berlin)¹¹, S. Kempa (Berlin)¹¹, N. Haase (Berlin)^13
1Charité - Universitätsmedizin Berlin Experimental & Clinical Research Center (ECRC) Berlin, Deutschland; ²Max-Delbrueck Center for Molecular Medicine Berlin, Deutschland; ³Charité - Universitätsmedizin Berlin Berlin, Deutschland; ⁴Deutsches Herzzentrum der Charite (DHZC) Klinik für Angeborene Herzfehler - Kinderkardiologie Berlin, Deutschland; ⁵Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DIfE) Molekulare Toxikologie Nuthetal, Deutschland; ⁶Deutsches Herzzentrum der Charité, Charité – Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany Klinik für Kardiologie, Angiologie und Intensivmedizin Berlin, Deutschland; ⁷Charité - Universitätsmedizin Berlin Leiter des Clinical Study Center CVK Berlin, Deutschland; ⁸Charité - Universitätsmedizin Berlin CCR Center for Cardiovascular Research Berlin, Deutschland; ⁹Max Delbrück Center for Molecular Medicine Berlin, Deutschland; ¹⁰Max-Delbrück-Centrum für Molekulare Medizin Translationale Kardiologie und Funktionelle Genomforschung Berlin, Deutschland; ¹¹Max-Delbrück-Centrum für Molekulare Medizin Berlin, Deutschland; ¹²HELIOS Klinikum Berlin-Buch Klinik und Poliklinik für Kardiologie und Nephrologie Berlin, Deutschland; ¹³Max-Delbrueck Center for Molecular Medicine Experimental and Clinical Research Center (ECRC) Berlin, Deutschland

Background: Heart failure with preserved ejection fraction (HFpEF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. 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. We hypothesize that butyrate, a microbiota-derived short-chain fatty acid, serves as an auxiliary energy source and improves diastolic function.

Methods: We conducted proteomic and metabolomic profiling before and after chronic butyrate, and ¹³C-butyrate tracing, as well as kinetic modeling in transgenic rats that overexpress the human renin and angiotensinogen genes. This model exhibits the characteristic features of hypertensive HFpEF (dTGR).

Results: Despite preserved cardiac power, HFpEF hearts displayed an energetic deficit marked by mitochondrial uncoupling, suppressed oxidative metabolism, and reduced fatty acid and glucose oxidation, while the polyol pathway was increased. Ketone oxidation was impaired, as indicated by β-hydroxybutyrate (BOH) accumulation and reduced acetoacetate. In HFpEF patients from the UK Biobank, higher circulating BOH levels were consistently associated with increased mortality, particularly in those with hypertension (n=4,287; HR 1.32, 95% CI 1.24–1.40, p<0.001). Mechanistically, butyrate was efficiently metabolized by cardiomyocytes, surpassing BOH and amino acids in supporting respiration. In a preclinical therapeutic proof of concept study, chronic butyrate supplementation (200mM in the drinking water) improved survival, enhanced diastolic function, and reduced fibrosis and inflammation in HFpEF rats despite persistent hypertension and hypertrophy.

Conclusion: These findings identify butyrate as a compensatory fuel and therapeutic candidate in energetically compromised HFpEF.