Abstract 19732: Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance and Normalizes Cardiac Metabolism in Advanced Heart Failure
Impaired myocardial metabolism in advanced heart failure (HF) results in a shift from fatty acid to glucose utilization for generation of ATP. Impaired fatty acid oxidation might lead to accumulation of toxic lipid intermediates, impaired insulin signaling and progression of cardiac dysfunction. We hypothesized that mechanical unloading through implantation of a ventricular assist device (VAD) reverses metabolic derangements in patients with HF. Myocardium and serum was obtained from 36 patients with HF before VAD implantation and at explantation. Clinical data were obtained from institutional medical records. mRNA expression was analyzed by RT-PCR and protein levels analyzed by western blot. Triglycerides (TG), diacylglycerols (DAG) and ceramides were extracted. Insulin levels were measured by ELISA and insulin resistance calculated using the HOMA-IR method. The cohort had a mean BMI of 27.1±5.1 kg/m2, age of 51±12.0 years and VAD duration of 185±156.2 days. VAD implantation reduced fasting glucose (144±47.1 to 112±43.8 mg/dL), HbA1c (7.5±2.4 to 6.3±1.5 %), and insulin resistance (HOMA-IR: 4.5±0.56 to 3.2±0.45) (all p<0.05). Expression of lipid metabolism genes CD36, CPT1 and ACO increased and cardiac triglycerides decreased (5.1±1.09 to 3.6±0.67 mg/g) after VAD implantation. Myocardial levels of DAG also decreased while ceramide content remained unchanged. Expression of the glucose uptake gene, GLUT4, decreased; PDK4, a critical inhibitor of cellular glucose oxidation also decreased suggesting more glucose oxidation. Improved insulin signaling was noted by increased phosphorylation of insulin signaling mediators IRS, Akt, and FoxO after VAD implantation suggesting activation of the insulin/PI3kinase/Akt signaling cascade. Membrane localization of protein kinase C (PKC) isoforms, known inhibitors of insulin signaling, also decreased after VAD implantation. In conclusion, mechanical unloading after VAD implantation leads to correction of systemic and local metabolic derangements in advanced HF. This is evidenced by increased myocardial fatty acid oxidation, reduction in toxic lipid intermediates and improved insulin signaling events with subsequent improvement of markers of insulin sensitivity and glucose utilization.
- © 2010 by American Heart Association, Inc.