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Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.

Shibayama J, Yuzyuk TN, Cox J, Makaju A, Miller M, Lichter J, Li H, Leavy JD, Franklin S, Zaitsev AV - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Metabolomic and proteomic profile of glucose metabolism.Data from Control, SHF, and DHF hearts. Detected metabolites and enzymes are indicated with bold font. Metabolome is presented in arbitrary units while proteome is presented as fold change compared to Control. Filled bars: metabolites. Open bars: proteins. G1-P: glucose 1-phosphate, G6-P: glucose 6-phosphate, F6-P: fructose 6-phosphate, F1,6-P: fructose 1,6-bisphosphate, GAP: glycealdehydo 3-phosphate, DHAP: dihydroxyacetone phosphate, 1,3-PG: 1,3-bisphosphoglycerate, 3-PG: 3-phosphoglycerate, 2-PG: 2-phosphoglycerate, PEP: phosphoenolpyruvate. P*<0.05.
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pone.0118974.g008: Metabolomic and proteomic profile of glucose metabolism.Data from Control, SHF, and DHF hearts. Detected metabolites and enzymes are indicated with bold font. Metabolome is presented in arbitrary units while proteome is presented as fold change compared to Control. Filled bars: metabolites. Open bars: proteins. G1-P: glucose 1-phosphate, G6-P: glucose 6-phosphate, F6-P: fructose 6-phosphate, F1,6-P: fructose 1,6-bisphosphate, GAP: glycealdehydo 3-phosphate, DHAP: dihydroxyacetone phosphate, 1,3-PG: 1,3-bisphosphoglycerate, 3-PG: 3-phosphoglycerate, 2-PG: 2-phosphoglycerate, PEP: phosphoenolpyruvate. P*<0.05.

Mentions: It is known that HF leads to switching in substrate preference from fatty acids to glucose [21]. The metabolomic profile of glucose pathway with its enzyme expression is shown in Fig. 8. The myocardial levels of glucose were not different between Control, SHF, and DHF. However, the average values of all the intermediates of glycolysis pathway that were detected by GC/MS decreased in both models of HF.


Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.

Shibayama J, Yuzyuk TN, Cox J, Makaju A, Miller M, Lichter J, Li H, Leavy JD, Franklin S, Zaitsev AV - PLoS ONE (2015)

Metabolomic and proteomic profile of glucose metabolism.Data from Control, SHF, and DHF hearts. Detected metabolites and enzymes are indicated with bold font. Metabolome is presented in arbitrary units while proteome is presented as fold change compared to Control. Filled bars: metabolites. Open bars: proteins. G1-P: glucose 1-phosphate, G6-P: glucose 6-phosphate, F6-P: fructose 6-phosphate, F1,6-P: fructose 1,6-bisphosphate, GAP: glycealdehydo 3-phosphate, DHAP: dihydroxyacetone phosphate, 1,3-PG: 1,3-bisphosphoglycerate, 3-PG: 3-phosphoglycerate, 2-PG: 2-phosphoglycerate, PEP: phosphoenolpyruvate. P*<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4366225&req=5

pone.0118974.g008: Metabolomic and proteomic profile of glucose metabolism.Data from Control, SHF, and DHF hearts. Detected metabolites and enzymes are indicated with bold font. Metabolome is presented in arbitrary units while proteome is presented as fold change compared to Control. Filled bars: metabolites. Open bars: proteins. G1-P: glucose 1-phosphate, G6-P: glucose 6-phosphate, F6-P: fructose 6-phosphate, F1,6-P: fructose 1,6-bisphosphate, GAP: glycealdehydo 3-phosphate, DHAP: dihydroxyacetone phosphate, 1,3-PG: 1,3-bisphosphoglycerate, 3-PG: 3-phosphoglycerate, 2-PG: 2-phosphoglycerate, PEP: phosphoenolpyruvate. P*<0.05.
Mentions: It is known that HF leads to switching in substrate preference from fatty acids to glucose [21]. The metabolomic profile of glucose pathway with its enzyme expression is shown in Fig. 8. The myocardial levels of glucose were not different between Control, SHF, and DHF. However, the average values of all the intermediates of glycolysis pathway that were detected by GC/MS decreased in both models of HF.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus