Abstract

Introduction: Several studies have implicated energetic deficits in chronic heart failure. Recently, our group has described a state of myocardial substrate deficiency across a broad spectrum of lipid species in non-diabetic end-stage heart failure. We hypothesized that lipid substrate depletion in end-stage heart failure would be associated with dysregulation of short chain acyl-CoA intermediates implicated in important metabolic pathways. Methods: Left ventricular samples were obtained at the time of orthotopic heart transplantation for failing cases with idiopathic dilated cardiomyopathy (DCM) n=16, and brain-dead organ donors without a history of heart failure (NF) n=18. Samples were snap frozen at -80°C for further analysis with liquid chromatography in tandem mass spec LC MS/MS. Stable isotope labeled essential nutrient in cell culture (SILEC) internal standards for acyl-CoAs were generated using 13 C 3 15 N 1 pantotheonate in Hepa1c1c7 cells. Results: In the myocardium of failing as compared to NF, we identified a significant decrease in Succinyl-CoA (Avg 10.5 versus 17.7 pmol/mg, p = 0.004 ), Propionyl-CoA (0.9 versus 1.8 pmol/mg, p=0.004) and a concomitant increase in β-hydroxybutyryl -CoA (BHB-CoA Avg 0.57 versus 0.29 pmol/mg, p =0.008 ). The ratio of myocardial Succinyl-CoA to Acetyl-CoA, a potential marker of tricarboxylic acid cycling, is significantly decreased in end-stage heart failure ( 0.84 versus 1.93, p= 0.005 ). The figure depicts the levels of myocardial acyl-CoA species in the non-diabetic cohort. Conclusion: We have identified important differences in myocardial acyl CoA species—an increase in the ketogenic BHB-CoA and decreased Succinyl-CoA and Propionyl-CoA in end-stage human heart failure. These data, along with the recently identified state of myocardial lipodeficiency, are strongly supporting the concept of a bio-energetic deficit in end-stage heart failure.

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