title: 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 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.
  
  
  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.
authors.affiliation: Columbia University Medical Center, Center for Advanced Cardiac Care, Department of Medicine, Division of Cardiology, 622 W 168th St, PH 10, Room 203, New York, NY 10032, USA.
authors.forename: Aalap
authors.initials: A
authors.lastname: Chokshi
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Drosatos
authors.forename: Faisal H
authors.initials: FH
authors.lastname: Cheema
authors.forename: Ruiping
authors.initials: R
authors.lastname: Ji
authors.forename: Tuba
authors.initials: T
authors.lastname: Khawaja
authors.forename: Shuiqing
authors.initials: S
authors.lastname: Yu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kato
authors.forename: Raffay
authors.initials: R
authors.lastname: Khan
authors.forename: Hiroo
authors.initials: H
authors.lastname: Takayama
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.forename: Christine S
authors.initials: CS
authors.lastname: Chung
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jorde
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Naka
authors.forename: Donna M
authors.initials: DM
authors.lastname: Mancini
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
mesh_terms: D000328:Adult; D000368:Aged; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000601:surgery*; D006353:Heart-Assist Devices; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D002518:Ceramides; D004075:Diglycerides; D005227:Fatty Acids; D007328:Insulin; D014280:Triglycerides; D011493:Protein Kinase C