Abstract 16434: Temporal Metabolomic and Transcriptomic Changes in a Large-Animal Model of Hfpef

• Published in: Circulation (New York, N.Y.) N.Y.), 2020-11, Vol.142 (Suppl_3 Suppl 3), p.A16434-A16434
• Main Authors: Gibb, Andrew A, Murray, Emma K, Eaton, Deborah M, Huynh, Anh T, Tomar, Dhanendra, Garbincius, Joanne F, Kolmetzky, Devin W, Berretta, Remus M, Wallner, Markus, Houser, Steve R, Elrod, John W
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.142.suppl_3.16434

Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of HF cases, with no effective treatments. We previously reported that a feline aortic banding model recapitulates many of the multi-factorial features of HFpEF, includingLV hypertrophy, left atrial enlargement, elevated LV filling pressures, impaired pulmonary mechanics and fibrosis. Importantly, this model lacks obesity and hypertension enabling the discovery of cardiac centric targets independent of comorbidities. We examined early changes in metabolism and transcription to gain mechanistic insight into HFpEF development. Male short-hair kittens (2mo old) underwent aortic banding or sham operation. Cardiac function was assessed at baseline and 1mo post-banding prior to tissue collection and downstream analyses. Following banding, we observed significant cardiac hypertrophy and initiation of LV fibrosis in the absence of changes in cardiac function. We observed LV mitochondrial dysfunction, indicated by impaired complex-I and -II respiration prompting the examination of cardiac metabolism by unbiased metabolomics. 82 metabolites were significantly different (≥ 1.25 fold, p ≤ 0.1) between 1mo banded and sham hearts, with an overrepresentation of amino acid (aa) and lipid species. Pathway enrichment analysis highlighted an increase in aa metabolism (e.g. serine, proline) that is associated with ECM remodeling and tissue fibrosis. Additionally, an increase in lipid species (i.e. acyl-carnitines) suggests reduced fatty acid utilization and a shift towards glycolysis. Correlations of metabolomics data with mitochondrial function and cardiac phenotyping revealed strong associations between mitochondrial function and the cardiac energy state, as well as aa and LV fibrosis. RNA-seq and enrichment analyses revealed a significant inflammatory response early in disease progression and a decrease in protein/histone acetylation. Collectively, this systems-based approach provides new insights into the cellular biology underlying HFpEF-like disease progression. The metabolic and transcriptional signature that precede the clinical features of HFpEF, will provide new pre-clinical research directions and may yield novel therapeutic targets.