Mechanical unloading promotes myocardial energy recovery in human heart failure

Anisha A. Gupte, Dale J. Hamilton, Andrea M. Cordero-Reyes, Keith A. Youker, Zheng Yin, Jerry D. Estep, Robert D. Stevens, Brett Wenner, Olga Ilkayeva, Matthias Loebe, Leif E. Peterson, Christopher J. Lyon, Stephen T C Wong, Christopher B. Newgard, Guillermo Torre-Amione, Heinrich Taegtmeyer, Willa A. Hsueh

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background-Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results-We compared metabolomic, gene transcript, and protein data from 6 paired samples of failing human left ventricular tissue obtained during left ventricular assist device insertion (heart failure samples) and at heart transplant (post-left ventricular assist device samples). Nonfailing left ventricular wall samples procured from explanted hearts of patients with right heart failure served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in heart failure tissue: 2.6-fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-Activated receptor ? coactivator 1a (PGC1A, 1.3-fold) and estrogen-related receptor a (ERRA, 1.2-fold) and ? (ERRG, 2.2-fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with left ventricular assist device improved all of these metabolic and transcriptional defects. Conclusions-These observations underscore an important pathophysiologic role for severely defective metabolism in heart failure, while the reversibility of these defects by left ventricular assist device suggests metabolic resilience of the human heart.

Original languageEnglish (US)
Pages (from-to)266-276
Number of pages11
JournalCirculation: Cardiovascular Genetics
Volume7
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

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Heart-Assist Devices
Heart Failure
Metabolomics
Pyruvic Acid
Peroxisome Proliferator-Activated Receptors
Citric Acid Cycle
Patient Rights
Organelle Biogenesis
Enzymes
Estrogen Receptors
Energy Metabolism
Transcription Factors
Fatty Acids
Transplants
Genes
Proteins

Keywords

  • Heart failure
  • Metabolism
  • Mitochondria

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Gupte, A. A., Hamilton, D. J., Cordero-Reyes, A. M., Youker, K. A., Yin, Z., Estep, J. D., ... Hsueh, W. A. (2014). Mechanical unloading promotes myocardial energy recovery in human heart failure. Circulation: Cardiovascular Genetics, 7(3), 266-276. https://doi.org/10.1161/CIRCGENETICS.113.000404

Mechanical unloading promotes myocardial energy recovery in human heart failure. / Gupte, Anisha A.; Hamilton, Dale J.; Cordero-Reyes, Andrea M.; Youker, Keith A.; Yin, Zheng; Estep, Jerry D.; Stevens, Robert D.; Wenner, Brett; Ilkayeva, Olga; Loebe, Matthias; Peterson, Leif E.; Lyon, Christopher J.; Wong, Stephen T C; Newgard, Christopher B.; Torre-Amione, Guillermo; Taegtmeyer, Heinrich; Hsueh, Willa A.

In: Circulation: Cardiovascular Genetics, Vol. 7, No. 3, 2014, p. 266-276.

Research output: Contribution to journalArticle

Gupte, AA, Hamilton, DJ, Cordero-Reyes, AM, Youker, KA, Yin, Z, Estep, JD, Stevens, RD, Wenner, B, Ilkayeva, O, Loebe, M, Peterson, LE, Lyon, CJ, Wong, STC, Newgard, CB, Torre-Amione, G, Taegtmeyer, H & Hsueh, WA 2014, 'Mechanical unloading promotes myocardial energy recovery in human heart failure', Circulation: Cardiovascular Genetics, vol. 7, no. 3, pp. 266-276. https://doi.org/10.1161/CIRCGENETICS.113.000404
Gupte, Anisha A. ; Hamilton, Dale J. ; Cordero-Reyes, Andrea M. ; Youker, Keith A. ; Yin, Zheng ; Estep, Jerry D. ; Stevens, Robert D. ; Wenner, Brett ; Ilkayeva, Olga ; Loebe, Matthias ; Peterson, Leif E. ; Lyon, Christopher J. ; Wong, Stephen T C ; Newgard, Christopher B. ; Torre-Amione, Guillermo ; Taegtmeyer, Heinrich ; Hsueh, Willa A. / Mechanical unloading promotes myocardial energy recovery in human heart failure. In: Circulation: Cardiovascular Genetics. 2014 ; Vol. 7, No. 3. pp. 266-276.
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AU - Yin, Zheng

AU - Estep, Jerry D.

AU - Stevens, Robert D.

AU - Wenner, Brett

AU - Ilkayeva, Olga

AU - Loebe, Matthias

AU - Peterson, Leif E.

AU - Lyon, Christopher J.

AU - Wong, Stephen T C

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