Myocardial Tricarboxylic Acid Cycle Suppression Disrupts The Epigenetic Landscape In Human Heart Failure With Preserved Ejection Fraction

Heart Failure with Preserved Ejection Fraction (HFpEF) represents the greatest unmet therapeutic need in cardiology and is intimately related to obesity and metabolic syndrome. Using a bedside-to-bench approach, we investigated the hypothesis that suppressed tricarboxylic acid cycle (TCA) enzymes and metabolic intermediates in HFpEF influence epigenetic histone post-translational modifications (PTMs) that regulate genes involved in mitochondrial OxPhos and fatty acid metabolism. Endomyocardial biopsies were obtained from human HFpEF patients (n=32) and donor controls (n=12) and integrated proteomics, metabolomics, ChIP-seq, and RNAseq analyses were performed. Small molecule histone PTM modulators were screened in vitro in neonatal rat ventricular cardiomyocytes (NRVMs) to identify potential therapeutic targets. Proteomics demonstrates reduced TCA cycle enzyme abundance consistent with our recently published metabolomics data showing reduced succinate, fumarate, and malate. Histone PTM profiling found H3K27ac and H3K36me3 upregulated (p<0.001) and inversely correlated with TCA cycle intermediates succinate and fumerate. ChIP-seq promoter gene ontology analysis revealed enrichment of mitochondrial metabolism and fatty acid uptake ontologies (CD36), as well as major cardiac transcription factors such as GATA4. Small-molecule inhibitor proteomics screens of histone writers in neonatal rat ventricular myocytes showed that H3K27ac inhibition upregulates all TCA cycle enzymes 1.5-4 fold and may rescue TCA cycle function. Our multi-omics approach suggests an association between H3K27ac, H3K36me3, and TCA cycle intermediates. Inhibition of myocardial H3K27ac deposition represents a novel therapeutic target for HFpEF.