Circulation: Cardiovascular Genetics HCG Mechanical Unloading Promotes Myocardial Energy Recovery in Human Heart Failure Gupte/Hamilton, Metabolism in human heart failure CIRCCVG/2013/000404-T CIRCCVG/2013/000404-T 10.1161/CIRCGENETICS.113.000404 7 06/17/14 3 Sine Kristina 617-542-5100 617-542-6539 Grosser, Tilo University of Pennsylvania Dr. Willa A. Hsueh wahsueh@tmhs.org Dr. The Methodist Hospital Research Institute Director, Diabetes Research Center, The Methodist Hospital Research Institute, 6670 Bertner Street, R8-111 Houston Texas 77030 UNITED STATES 713-824-1401 713-790-3026 1095 Anisha A. Gupte Houston Methodist Research Institute aagupte@houstonmethodist.org 27512 Dale Hamilton The Methodist Hospital djhamilton@tmhs.org 121314 Andrea M Cordero-Reyes The Methodist Hospital tmhamc2@tmhs.org 121287 Keith A. Youker The Methodist Hospital Research Institute kayouker@tmhs.org 80236 Zheng Yin Houston Methodist Research Institute ZYin@tmhs.org 153585 Jerry D. Estep Methodist DeBakey Heart & Vascular Center, Methodist Hospital jestep@tmhs.org 69289 Robert Stevens Duke University Medical Center robert.d.stevens@duke.edu 153586 Brett R. Wenner Duke University Medical Center brett.wenner@gmail.com 175644 Olga Ilkayeva Duke University Medical Center Ilkay001@mc.duke.edu 153592 Matthias Loebe Methodist DeBakey Heart & Vascular Center MLoebe@houstonmethodist.org 175597 Leif Peterson Houston Methodist Research Institute LEPeterson@tmhs.org 153593 Christopher J. Lyon The Methodist Hospital Research Institute CJLyon@tmhs.org 27523 Stephen Wong Houston Methodist Research Institute STWong@tmhs.org 153594 Christopher B. Newgard Duke University Medical Center chris.newgard@duke.edu 153595 Guillermo Torre-Amione The Methodist Hospital gtorre@tmhs.org 121310 Heinrich Taegtmeyer The University of Texas Medical School at Houston heinrich.taegtmeyer@uth.tmc.edu 18847 Willa A. Hsueh The Methodist Hospital Research Institute wahsueh@tmhs.org 1095 08/02/2013 08/02/2013 03/24/2014 04/02/2014 05/13/2014 06/17/2014 Original Article <P><B><I>Background</I></B>—Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. </P><P><B><I>Methods and Results</I></B>—We compared metabolomic, gene transcript, and protein data from six paired failing human left ventricular (LV) tissue samples obtained during left ventricular assist device (LVAD) insertion (heart failure (HF) samples) and at heart transplant (post-LVAD samples). Non-failing left ventricular (NFLV) wall samples procured from explanted hearts of patients with right HF served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in HF 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 gamma co-activator1α (<I>PGC1A</I>, 1.3 fold) and estrogen-related receptor α (<I>ERRA</I>, 1.2 fold) and γ (<I>ERRG</I>, 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 LVAD improved all of these metabolic and transcriptional defects. </P><P><B><I>Conclusions</I></B>—These observations underscore an important pathophysiologic role for severely defective metabolism in HF, while the reversibility of these defects by LVAD suggests metabolic resilience of the human heart.</P> 2 0 0 5 5 yes CircGenetics_CIRCCVG-2013-000404-T.xml CircGenetics_CIRCCVG-2013-000404-T_file1.docx

CircGenetics_CIRCCVG-2013-000404-T_fig1.ppt

CircGenetics_CIRCCVG-2013-000404-T_supp1.pdf 000404_clinical perspective.docx CircGenetics_CIRCCVG-2013-000404-T_supp3.pdf CircGenetics_CIRCCVG-2013-000404-T_merge.pdf CircGenetics_CIRCCVG-2013-000404-T_Hsueh_1095_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Hsueh_1095_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Peterson_153593_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Peterson_153593_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Loebe_175597_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Loebe_175597_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Wong_153594_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Wong_153594_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Hamilton_121314_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Hamilton_121314_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Newgard_153595_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Newgard_153595_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Taegtmeyer_18847_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Taegtmeyer_18847_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Ilkayeva_153592_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Ilkayeva_153592_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Gupte_27512_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Gupte_27512_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Cordero-Reyes_121287_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Cordero-Reyes_121287_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Wenner_175644_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Wenner_175644_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Estep_69289_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Estep_69289_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Stevens_153586_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Stevens_153586_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Yin_153585_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Yin_153585_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Lyon_27523_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Lyon_27523_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Torre-Amione_121310_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Torre-Amione_121310_copyright.pdf CircGenetics_CIRCCVG-2013-000404-T_Youker_80236_disclosure.pdf CircGenetics_CIRCCVG-2013-000404-T_Youker_80236_copyright.pdf Bill authors $70 per pg; no excess pgs. Article has supplemental material (1 PDF) and a clinical perspective. Drs. Gupte and Hamilton contributed equally to this work. Rec'd 8/2/13 (Invited from Circulation) Please set the flag 'exportcadmusahafundingtypecodes' with the funding type code of the sources you wish to list. Subject Codes: [110] Congestive [107] Biochemistry and metabolism ksine