Abstract 933: Integrated Omics Analysis of Diabetic Heart Failure in Human Myocardium

Abstract

Background: Patients with diabetes mellitus (DM) have a higher risk of heart failure (HF). While metabolic dysregulation has been well-established in HF and DM separately, molecular mechanisms associated with diabetic HF are incompletely understood. Thus, we sought to test the overarching hypothesis that cardiac metabolic programming is distinct in diabetic HF compared to DM and HF individually. Methods: RNA-sequencing and targeted metabolomics profiles were completed on human myocardial tissue from 54 unique individuals received from the Duke Human Heart Biorepository and the University of Colorado. Multi-omics profiles of cardiac tissue from 4 groups were compared: a) controls with no clinical evidence of DM or HF (n = 12), b) DM-only (n = 15), c) HF-only (n = 10), and d) HF+DM (n = 17). Results: After using statistical criteria to prioritize genes, we looked for genes that function together or modulate the same activity. Genes encoding producers of reactive oxygen species (ROS), DUOX2, DUOXA2, and DUOXA1, were differentially upregulated in diabetic-HF, compared to DM or HF alone (FDR HF+DM vs DM-only/HF-only = 6.6 x 10 -7 /2.2 x 10 -4 , 7.7 x 10 -3 /6.7 x 10 -3 , and 3.6 x 10 -6 /0.013, respectively). Modulators of mTOR signaling, ERBB3, ERBB4, and PIK3R3, were also differentially regulated in diabetic-HF (FDR HF+DM vs DM-only/HF-only = 1.4 x 10 -3 /0.010, 0.012/7.4 x 10 -3 , and 0.011/9.3 x 10 -3 , respectively). Gene set enrichment analysis supported our focus on these genes; top enriched gene sets included mTOR signaling and processes related to oxidative stress response. In our metabolomics data, long chain acylcarnitines (AC) and ceramides (Cer) are decreased in diabetic-HF. For example, C20:1 AC can be converted to C20:1 Cer and accumulation of both is diminished in diabetic-HF (FDR = 0.0032 and 0.035, respectively). Conclusions: We found that diabetic-HF was characterized by a distinct omics profile consistent with increased ROS production, diminished AC and Cer accumulation, and modulation of mTOR signaling. The fact that ceramide accumulation has been previously associated with oxidative stress and also linked to ERBB and PI3K pathways suggests that these data may reveal a unique regulation of these pathways in diabetic-HF.