Abstract Body (Do not enter title and authors here): Introduction: Recent transcriptomic and metabolomic studies have suggested heart failure with preserved ejection fraction (HFpEF) myocardium exhibits metabolic insufficiency. Here we integrated targeted gene expression and proteomics to identify which fuel use pathways are likely compromised in HFpEF.
Hypothesis: We hypothesize HFpEF has depressed gene/protein/metabolite levels related to metabolism of fatty acids, branched chain amino acids, and anaplerosis.
Methods: Myocardial septal biopsies from HFpEF patients and non-failing controls were studied by Western blot for key proteins in fuel metabolism and cross-related to metabolomics (38 HFpEF, 20 control) and bulk RNAseq (41 HFpEF, 24 control). Protein abundance between groups was tested using Welch’s t-test.
Results: Protein levels of CPT1 and CPT2 enzymes needed for acylcarnitine formation and rate-limiting for fatty acid metabolism, were similar in HFpEF vs controls. Proteins related to fatty acid uptake (ACSL1, P=0.002) and oxidation (ACAD [ACADM, P=0.02; ACADVL, P=0.009], HADH [HADHA, P<0.0001; HADHB, P=0.0006]), and master regulators PPARa (P<0.0001) and PGC1a (P=0.01), were significantly lower in HFpEF vs controls. Key enzymes in ketone metabolism had lower protein expression in HFpEF (SLC16A1 [ketone transporter, P=0.0002], BDH1 [P=0.003], ACAT [P=0.002]). Both BCAT2 (P=0.002) and BCKDH (P=0.0006) were lower in HFpEF, suggesting impaired oxidation of branched-chain amino acid (BCAA) and branched-chain ketoacids, concordant with metabolomic data. Proteins in anaplerotic pathways that replenish TCA intermediates were also lower in HFpEF, [ME (converts malate to pyruvate, P<0.0001), GOT (converts aspartate to oxaloacetate, P=0.036), and GLUD1 (converts glutamate to α-ketoglutarate, P<0.0001). Protein expression of the PCC family and MUT, responsible for replenishment of succinyl CoA, did not differ between groups.
Conclusions: Multi-omic analysis of metabolic pathways in HFpEF suggests significant metabolic insufficiency, with reduced expression of key proteins and their mRNAs involved with fatty acid, ketone, BCAA, and anaplerotic metabolism. This reveals the HFpEF heart as particularly energy challenged and suggests potential metabolic therapy targets.