Abstract Body: Background: HFpEF represents >50% of all HF cases. While numerous animal models have been developed, the ZSF1-obese rat recapitulates many of the clinical features of HFpEF including hypertension, metabolic syndrome, and diastolic dysfunction.
Objectives: Using an integrated systems-biology approach, we aimed to identify metabolic and transcriptional signatures which may provide mechanistic insight into pathways important for the development of HFpEF.
Methods: Male, 14 w old ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls underwent extensive physiological phenotyping and LV tissue harvesting for unbiased-metabolomics, RNA-seq, and mitochondrial phenotyping. Comparisons were made to uncover changes driven by hypertension alone vs those elicited by hypertension + metabolic syndrome.
Results: Hypertension-specific effects (ZSF1-lean vs WKY) identified a metabolic shift from β-oxidation to increased glycolysis accompanied by dysregulated purine and pyrimidine metabolism. Interestingly, hypertension alone elicited few transcriptional changes (233 genes) as compared to those seen in the ZSF1-obese rat (5,691 genes); FC ≥ 2.0 and FDR ≤ 0.05. The robust transcriptional signature of ZSF1-obese HFpEF rats revealed upregulation of inflammatory processes and downregulation of mitochondrial structure/function and metabolic processes, the latter of which was confirmed by significantly worsened metabolic remodeling. Integrated omics analysis highlighted downregulation of the majority of energy producing pathways, likely contributing to the diastolic dysfunction in ZSF1-obese HFpEF rats. As our omics datasets highlighted mitochondrial processes, assessment of mitochondrial substrate-mediated respiration and Ca²⁺ handling demonstrated ZSF1-obese rats have an ~25% reduction in respiratory rates (p<0.05) and failed to uptake repeated Ca²⁺ boluses (p<0.01). Cardiomyocyte ultrastructure analysis was supportive of these findings, revealing cristae disorganization, decreased mitochondrial area and size, and significant lipid droplet accumulation in HFpEF hearts.
Conclusions: Our integrated omics approach provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial structure/function and energy metabolism as a potential target.