Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance, and Normalizes Cardiac Metabolism in Patients With Advanced Heart Failure

Abstract

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.

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…1C). Conversely, KLF15 has been shown to be substantially down-regulated in rodent models of heart failure (20,21), a pathologic state where myocardial lipid utilization is reduced (5,6). Consistent with this rodent data, we found KLF15 to be significantly reduced in failing human hearts with a significant recovery of expression after mechanical unloading with a left ventricular assist device (Fig.…”

“…Human Left Ventricular Samples-Human left ventricular RNA samples were obtained as described previously (6). In brief, myocardial specimens were collected before and after left ventricular assisted device (LVAD) implantation and explantation as a bridge to transplantation for end-stage HF patients.…”

“…In brief, myocardial specimens were collected before and after left ventricular assisted device (LVAD) implantation and explantation as a bridge to transplantation for end-stage HF patients. Control heart samples were obtained from non-failing hearts as described previously (6 Mitochondrial Physiology and Electron Microscopy-Myocardia of four individual WT or KO mice were pooled for each experiment. The data presented are from four independent experiments.…”

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

“…They may also reflect changes in the composition and function of cellular membranes within tissues, because in addition to the generation of plasma ceramides by secreted sphingomyelinases, ceramides are also secreted by parenchymal tissues 21, 22. Given observations that ceramides accumulate in the myocardium in the setting of metabolic cardiomyopathy and HF, and given that accumulation of ceramides promotes cardiomyocyte oxidative stress and mitophagy, it is possible that enhanced ability to export very–long‐chain ceramides from tissues underlies the inverse relationships between plasma ratios of C24:0/C16:0 and CHD and mortality 23, 24. Future studies will be required to elucidate the relation of plasma ratios to ceramide content in specific tissues and how this affects the pathogenesis of vascular disease and related outcomes.…”

Dietary high-fat lard intake induces thyroid dysfunction and abnormal morphology in rats

“…However, excess dietary fat intake promotes ectopic accumulation of triglycerides and free fatty acids in non-adipose depots, known as lipotoxicity, which contributes to chronic cellular dysfunction and injury [2][3][4] . In recent years, lipotoxicity has been well documented in the pathogenesis of many diabetes-related metabolic diseases [5][6][7][8][9] .…”