TY - JOUR
T1 - Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure
AU - Chokshi, Aalap
AU - Drosatos, Konstantinos
AU - Cheema, Faisal H.
AU - Ji, Ruiping
AU - Khawaja, Tuba
AU - Yu, Shuiqing
AU - Kato, Tomoko
AU - Khan, Raffay
AU - Takayama, Hiroo
AU - Knöll, Ralph
AU - Milting, Hendrik
AU - Chung, Christine S.
AU - Jorde, Ulrich
AU - Naka, Yoshifumi
AU - Mancini, Donna M.
AU - Goldberg, Ira J.
AU - Schulze, P. Christian
PY - 2012/6/12
Y1 - 2012/6/12
N2 - Background-Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use 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 the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m 2; age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. 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 with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. Conclusions-Mechanical unloading after left ventricular assist device 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.
AB - Background-Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use 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 the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m 2; age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. 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 with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. Conclusions-Mechanical unloading after left ventricular assist device 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.
KW - heart failure
KW - lipids
KW - metabolism
KW - myocardium
KW - ventricular assist device
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U2 - 10.1161/CIRCULATIONAHA.111.060889
DO - 10.1161/CIRCULATIONAHA.111.060889
M3 - Article
C2 - 22586279
AN - SCOPUS:84862137804
SN - 0009-7322
VL - 125
SP - 2844
EP - 2853
JO - Circulation
JF - Circulation
IS - 23
ER -