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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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High-energy phosphates and related adenine nucleotides.Metabolites were measured by HPLC in Control, SHF and DHF hearts. A-C. Chromatograms of extracts from ventricular tissue in Control (A), SHF (B), and DHF (C). D-I. Quantitative analysis of the levels of creatine (Cr), phosphocreatine (PCr), ATP, ADP, AMP, and NAD+, respectively, normalized by wet tissue weight. J. PCr/ATP ratio. K. Total pool of myocardial creatine (creatine + PCr). L. Total pool of adenine nucleotides (ATP+ADP+AMP). *p<0.05.
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pone.0118974.g003: High-energy phosphates and related adenine nucleotides.Metabolites were measured by HPLC in Control, SHF and DHF hearts. A-C. Chromatograms of extracts from ventricular tissue in Control (A), SHF (B), and DHF (C). D-I. Quantitative analysis of the levels of creatine (Cr), phosphocreatine (PCr), ATP, ADP, AMP, and NAD+, respectively, normalized by wet tissue weight. J. PCr/ATP ratio. K. Total pool of myocardial creatine (creatine + PCr). L. Total pool of adenine nucleotides (ATP+ADP+AMP). *p<0.05.

Mentions: Molecules involved in energy turnover (ATP, ADP, AMP, creatine, PCr, and NAD+) were measured in Control, SHF, and DHF animals using HPLC (Fig. 3). The upper three panels (A-C) show the representative chromatograms in Control, SHF and DHF, respectively. Other panels show the average values of the six measured metabolites and three derived parameters (total creatine pool (creatine + PCr, ∑Cr); total adenine nucleotide pool (ATP+ADP+AMP, ∑Ad); and PCr/ATP ratio). The energy profile in SHF animals was very similar to that in Control. In fact, among the 6 metabolites involved in energy turnover, only the level of creatine trended lower (p = 0.053) in SHF than in Control. The PCr/ATP ratio, ∑Cr, and ∑Ad, were not significantly different between SHF and Control hearts. In contrast, DHF group exhibited significant reduction in the levels of creatine, PCr, ATP, PCr/ATP ratio, ∑Cr, and ∑Ad. Neither SHF nor DHF showed significant alterations in the levels of ADP, AMP, and NAD+. We also estimated the level of free ADP (ADPf) using the equilibrium expression for creatine kinase [7] and computed ratios of ATP/ADPf as well as ATP/ADP (see S1 Fig.). APDf and ATP/ADPf were not significantly different between the three groups. ATP/ADP ratio was significantly increased in SHF, but was not different in DHF as compared to Control. Lastly, the levels of the intermediates of the adenine nucleotide degradation pathway (adenine, adenosine, xanthine and hypoxanthine) detected by GS/MS trended towards reduced levels, but none of them were significantly different in SHF and DHF from Control (see Fig. 1). Summarizing above, we conclude that DHF hearts exhibited energy deficit, whereas in SHF hearts the energy balance was largely preserved.


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)

High-energy phosphates and related adenine nucleotides.Metabolites were measured by HPLC in Control, SHF and DHF hearts. A-C. Chromatograms of extracts from ventricular tissue in Control (A), SHF (B), and DHF (C). D-I. Quantitative analysis of the levels of creatine (Cr), phosphocreatine (PCr), ATP, ADP, AMP, and NAD+, respectively, normalized by wet tissue weight. J. PCr/ATP ratio. K. Total pool of myocardial creatine (creatine + PCr). L. Total pool of adenine nucleotides (ATP+ADP+AMP). *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0118974.g003: High-energy phosphates and related adenine nucleotides.Metabolites were measured by HPLC in Control, SHF and DHF hearts. A-C. Chromatograms of extracts from ventricular tissue in Control (A), SHF (B), and DHF (C). D-I. Quantitative analysis of the levels of creatine (Cr), phosphocreatine (PCr), ATP, ADP, AMP, and NAD+, respectively, normalized by wet tissue weight. J. PCr/ATP ratio. K. Total pool of myocardial creatine (creatine + PCr). L. Total pool of adenine nucleotides (ATP+ADP+AMP). *p<0.05.
Mentions: Molecules involved in energy turnover (ATP, ADP, AMP, creatine, PCr, and NAD+) were measured in Control, SHF, and DHF animals using HPLC (Fig. 3). The upper three panels (A-C) show the representative chromatograms in Control, SHF and DHF, respectively. Other panels show the average values of the six measured metabolites and three derived parameters (total creatine pool (creatine + PCr, ∑Cr); total adenine nucleotide pool (ATP+ADP+AMP, ∑Ad); and PCr/ATP ratio). The energy profile in SHF animals was very similar to that in Control. In fact, among the 6 metabolites involved in energy turnover, only the level of creatine trended lower (p = 0.053) in SHF than in Control. The PCr/ATP ratio, ∑Cr, and ∑Ad, were not significantly different between SHF and Control hearts. In contrast, DHF group exhibited significant reduction in the levels of creatine, PCr, ATP, PCr/ATP ratio, ∑Cr, and ∑Ad. Neither SHF nor DHF showed significant alterations in the levels of ADP, AMP, and NAD+. We also estimated the level of free ADP (ADPf) using the equilibrium expression for creatine kinase [7] and computed ratios of ATP/ADPf as well as ATP/ADP (see S1 Fig.). APDf and ATP/ADPf were not significantly different between the three groups. ATP/ADP ratio was significantly increased in SHF, but was not different in DHF as compared to Control. Lastly, the levels of the intermediates of the adenine nucleotide degradation pathway (adenine, adenosine, xanthine and hypoxanthine) detected by GS/MS trended towards reduced levels, but none of them were significantly different in SHF and DHF from Control (see Fig. 1). Summarizing above, we conclude that DHF hearts exhibited energy deficit, whereas in SHF hearts the energy balance was largely preserved.

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