Abstract 19466: Metabolomic and Gene Expression Changes in End-Stage Heart Failure are Reversed by Left Ventricular Assist Device

Abstract

Introduction: Heart muscle tissue in advanced heart failure (HF) is reported to be ‘energy-depleted’ and inflexible to metabolic changes. Left ventricular assist devices (LVAD) and ventricular unloading with LVAD is known to regress cardiac hypertrophy, reduce fibrosis and partially improve function. The metabolic alterations with HF and LVAD support are not fully understood. We hypothesize that HF is associated with metabolic changes that are reversible with LVAD placement. Methods: We analyzed gene and protein expression and performed metabolomics analyses in failing left ventricular (LV) tissue obtained at the time of heart explant or LVAD placement (HF, n = 13) and removal (post-LVAD, n = 7). Control LV tissue was procured from patients undergoing heart-lung transplantation for severe right HF (control, n = 4). P<0.05 was considered significant. Results: In HF samples, expression levels of mitochondrial transcription factors and coactivators were decreased, while LVAD increased expression of PGC1α, PGC1β, ERRγ and TFAM to levels of control samples. Gene and protein expression of mitochondrial complex subunits NDUFS6, SDHA, UQCRC1, Cox5a, ATP5a1 were reduced in HF, but increased after LVAD. LVAD rescued reduced expression of fatty acid oxidation genes CPT2, ACADvl, ACADm, HADHA and PPARα, as well as pyruvate and glucose metabolism genes ME3, MCT1, PDHB, GPT and PFK. Targeted metabolomics analysis showed a reduction in short- and medium-chain acylcarnitines (C2-C10) in failing LV indicating decreased substrate catabolism, with these analytes universally restored to normal post-LVAD. Pyruvate levels tended to increase (P=0.07), whereas all measured Krebs cycle intermediates including citrate, α-ketoglutarate, succinate, fumarate and malate were reduced in the HF samples compared to normal controls. LVAD normalized pyruvate levels, and normalized the levels of all Krebs cycle intermediates. Conclusion: Both the gene expression and metabolomics profiles for mitochondrial, fatty acid, pyruvate and glucose metabolism pathways indicate that HF is associated with a global defect in substrate utilization. Complete reversal by ventricular unloading demonstrates the reversibility of metabolic defects.