title: Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.
abstract: Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content.
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors: Junko
authors: J
authors: Shibayama
authors: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America; ARUP Laboratories, Salt Lake City, Utah, United States of America.
authors: Tatiana N
authors: TN
authors: Yuzyuk
authors: Metabolomics Core Research Facility, University of Utah, Salt Lake City, Utah, United States of America; Department of Biochemistry, University of Utah, Salt Lake City, Utah, United States of America.
authors: James
authors: J
authors: Cox
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors: Aman
authors: A
authors: Makaju
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors: Mickey
authors: M
authors: Miller
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America; Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States of America.
authors: Justin
authors: J
authors: Lichter
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors: Hui
authors: H
authors: Li
authors: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors: Jane D
authors: JD
authors: Leavy
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America; Department of Biochemistry, University of Utah, Salt Lake City, Utah, United States of America.
authors: Sarah
authors: S
authors: Franklin
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America; Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States of America.
authors: Alexey V
authors: AV
authors: Zaitsev
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002952:Citric Acid Cycle / Q000502:physiology; D003401:Creatine / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004285:Dogs; D004734:Energy Metabolism / Q000502:physiology*; D008401:Gas Chromatography-Mass Spectrometry; D006019:Glycolysis; D006333:Heart Failure / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055432:Metabolomics / Q000379:methods*; D009206:Myocardium / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D018754:Ventricular Dysfunction / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D003402:Creatine Kinase; D003401:Creatine