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Circ Cardiovasc Genet. 2014 Jun;7(3):266-76. doi: 10.1161/CIRCGENETICS.113.000404. Epub 2014 May 13.

Mechanical unloading promotes myocardial energy recovery in human heart failure.

Author information

  • 1From the Methodist Diabetes and Metabolism Institute, Houston Methodist Research Institute, Houston, TX (A.A.G., D.J.H., C.J.L., W.A.H.); Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX (Z.Y., S.T.C.W.); Center for Biostatistics, Houston Methodist Research Institute, Houston, TX (L.E.P.); Department of Medicine, Houston Methodist Hospital, Houston, TX (D.J.H., W.A.H.), Department of Radiology, Houston Methodist Hospital, Houston, TX (S.T.C.W.); Methodist DeBakey Heart and Vascular Institute, Houston, TX (A.M.C.-R., K.A.Y., J.D.E., M.L., G.T.-A.); Weill Cornell Medical College, New York, NY (A.A.G., D.J.H., A.M.C.-R., K.A.Y., Z.Y., J.D.E., M.L., L.E.P., C.J.L., S.T.C.W., G.T.-A., W.A.H.); Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center (R.D.S., B.W., O.L., C.B.N.); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (S.T.C.W.); Catedra de Cardiologia, Instituto Tecnologico de Monterrey, Monterrey, Mexico (G.T.-A.); The University of Texas Medical School at Houston, Houston, TX (H.T.).
  • 2From the Methodist Diabetes and Metabolism Institute, Houston Methodist Research Institute, Houston, TX (A.A.G., D.J.H., C.J.L., W.A.H.); Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX (Z.Y., S.T.C.W.); Center for Biostatistics, Houston Methodist Research Institute, Houston, TX (L.E.P.); Department of Medicine, Houston Methodist Hospital, Houston, TX (D.J.H., W.A.H.), Department of Radiology, Houston Methodist Hospital, Houston, TX (S.T.C.W.); Methodist DeBakey Heart and Vascular Institute, Houston, TX (A.M.C.-R., K.A.Y., J.D.E., M.L., G.T.-A.); Weill Cornell Medical College, New York, NY (A.A.G., D.J.H., A.M.C.-R., K.A.Y., Z.Y., J.D.E., M.L., L.E.P., C.J.L., S.T.C.W., G.T.-A., W.A.H.); Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center (R.D.S., B.W., O.L., C.B.N.); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (S.T.C.W.); Catedra de Cardiologia, Instituto Tecnologico de Monterrey, Monterrey, Mexico (G.T.-A.); The University of Texas Medical School at Houston, Houston, TX (H.T.). wahsuehmd@gmail.com.

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 γ coactivator 1α (PGC1A, 1.3-fold) and estrogen-related receptor α (ERRA, 1.2-fold) and γ (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.

© 2014 American Heart Association, Inc.

KEYWORDS:

heart failure; metabolism; mitochondria

PMID:
24825877
[PubMed - in process]
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