Abstract 15621: Proteomic and Metabolomic Analyses Elucidates Common and Differential Themes in Etiological Paradigms of Heart Failure
Heart failure (HF) leads to atrial structural remodeling and increased susceptibility to sustained atrial fibrillation (AF). How the heart adapts to increased energy demand inherent to AF remains poorly understood. Protein and metabolite changes in HF induced AF were investigated.
Methods: We applied proteomic and metabolomic analysis of human left atrial (LA) tissue from unused donors (n = 11) and explanted hearts with HF in the presence (n = 7 (DCM) and n = 5 (IHD)) and absence of AF (n = 10 (DCM) and n = 8 (IHD)). Protein extracts were subjected to 2-dimensional gel electrophoresis using DIGE. Differentially expressed proteins (p < 0.05) were identified by mass spectrometry. LA metabolites were analyzed by NMR spectroscopy.
Results: NMR spectroscopy revealed a decrease in glucose and lactate in HF vs. donor irrespective of AF or the underlying pathophysiology. This was paralleled by decreased protein expression of glycolytic enzymes, α-enolase, pyruvate kinase and the β subunit of pyruvate dehydrogenase (DH). Additionally, enzymes involved with oxidative phosphorylation (ATP synthase, ubiquinol cytochrome c reductase and NADH DH) were all significantly decreased in the HF groups vs. donor in both the presence and absence of AF. Myosin light chain 1, atrial, was significantly reduced in HF + AF and HF only vs. donor in both DCM and IHD. Interestingly, an increase in β-hydroxybutyrate (p = 0.06), the major substrate in ketone body metabolism, was only observed in the HF + AF group from the DCM group vs. HF only. This was strengthened by proteomic data, with an increase in expression of 3-oxoacid CoA-transferase 1, the key enzyme for ketolytic energy production, observed in the HF + AF vs. HF only or donor. Decreased carnitine + GPC were only observed in the HF + AF vs. HF only or donors in the DCM group. Decreased expression of the antioxidants PRX-2 and PRX-3 was found in the HF groups (AF and non-AF) from IHD only vs. donor.
Conclusions: HF substantially alters the atrial proteome and metabolome both in the presence and absence of AF with common and differential changes observed between DCM and IHD tissues. This study of failing human LA tissue provides insights into molecular mechanisms underlying AF, highlighting extensive metabolic changes.
- © 2013 by American Heart Association, Inc.