Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure

Aalap Chokshi, Konstantinos Drosatos, Faisal H. Cheema, Ruiping Ji, Tuba Khawaja, Shuiqing Yu, Tomoko Kato, Raffay Khan, Hiroo Takayama, Ralph Knöll, Hendrik Milting, Christine S. Chung, Ulrich P. Jorde, Yoshifumi Naka, Donna M. Mancini, Ira J. Goldberg, P. Christian Schulze

Research output: Contribution to journalArticle

139 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)2844-2853
Number of pages10
JournalCirculation
Volume125
Issue number23
DOIs
StatePublished - Jun 12 2012
Externally publishedYes

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Heart-Assist Devices
Insulin Resistance
Heart Failure
Insulin
Poisons
Fatty Acids
Ceramides
Diglycerides
Lipids
Protein Kinase C
Myocardium
Protein Isoforms
Membrane Proteins
Triglycerides
Phosphatidylinositol 3-Kinase
Body Mass Index
Adenosine Triphosphate
Phosphorylation
Glucose
Serum

Keywords

  • heart failure
  • lipids
  • metabolism
  • myocardium
  • ventricular assist device

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. / Chokshi, Aalap; Drosatos, Konstantinos; Cheema, Faisal H.; Ji, Ruiping; Khawaja, Tuba; Yu, Shuiqing; Kato, Tomoko; Khan, Raffay; Takayama, Hiroo; Knöll, Ralph; Milting, Hendrik; Chung, Christine S.; Jorde, Ulrich P.; Naka, Yoshifumi; Mancini, Donna M.; Goldberg, Ira J.; Schulze, P. Christian.

In: Circulation, Vol. 125, No. 23, 12.06.2012, p. 2844-2853.

Research output: Contribution to journalArticle

Chokshi, A, Drosatos, K, Cheema, FH, Ji, R, Khawaja, T, Yu, S, Kato, T, Khan, R, Takayama, H, Knöll, R, Milting, H, Chung, CS, Jorde, UP, Naka, Y, Mancini, DM, Goldberg, IJ & Schulze, PC 2012, 'Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure', Circulation, vol. 125, no. 23, pp. 2844-2853. https://doi.org/10.1161/CIRCULATIONAHA.111.060889
Chokshi, Aalap ; Drosatos, Konstantinos ; Cheema, Faisal H. ; Ji, Ruiping ; Khawaja, Tuba ; Yu, Shuiqing ; Kato, Tomoko ; Khan, Raffay ; Takayama, Hiroo ; Knöll, Ralph ; Milting, Hendrik ; Chung, Christine S. ; Jorde, Ulrich P. ; Naka, Yoshifumi ; Mancini, Donna M. ; Goldberg, Ira J. ; Schulze, P. Christian. / Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. In: Circulation. 2012 ; Vol. 125, No. 23. pp. 2844-2853.
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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. 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.",
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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 P.

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.

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KW - heart failure

KW - lipids

KW - metabolism

KW - myocardium

KW - ventricular assist device

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