Background Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose utilization for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. Methods and Results We analyzed myocardium and serum of 61 patients with heart failure (BMI 26.5±5.1 kg/m2, age 51±12 years) obtained during left ventricular assist device (LVAD) implantation and at explantation (mean duration 185±156 days) and from 9 controls. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and FOXO, were detectable in heart failure compared to controls. LVAD implantation improved whole body insulin resistance (HOMA-IR: 4.5±0.6 to 3.2±0.5; p<0.05) and decreased myocardial levels of diacylglycerol and ceramide while triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/PI3kinase/Akt signaling cascade after LVAD implantation was confirmed by increased phosphorylation of Akt and FOXO, which was accompanied by decreased membrane localization of protein kinase C isoforms after LVAD implantation. Conclusions Mechanical unloading after LVAD implantation corrects systemic and local metabolic derangements in advanced heart failure leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.

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Fewer than one-half of patients with ambulatory HF rated HF as the greatest limitation to their QOL, suggesting that this important outcome will be difficult to affect by HF-targeted therapies alone, particularly in those with higher LVEFs and comorbidities. Patients with HF with better LVEF represent a distinct subtype with better overall QOL.

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