The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Damian J. Tyler - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial Krebs Cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, Kieran Clarke, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial Krebs Cycle activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
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REAL-TIME ASSESSMENT OF Krebs Cycle METABOLISM WITH HYPERPOLARISED [2-13C]PYRUVATE
Heart, 2010Co-Authors: Helen J. Atherton, Marie A. Schroeder, Michael S. Dodd, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Damian J. TylerAbstract:The Krebs Cycle is fundamental to cardiac energy production, and is often implicated in energetic imbalances characteristic of heart disease. To date, Krebs Cycle flux has been measured using 13C-magnetic resonance spectroscopy with isotopomer analysis; however, this approach is limited to the study of steady-state metabolism …
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real time assessment of Krebs Cycle metabolism using hyperpolarized 13c magnetic resonance spectroscopy
The FASEB Journal, 2009Co-Authors: Marie A. Schroeder, Helen J. Atherton, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Mark A Cole, Lisa C Heather, Damian J. TylerAbstract:The Krebs Cycle plays a fundamental role in cardiac energy production and is often implicated in the energetic imbalance characteristic of heart disease. In this study, we measured Krebs Cycle flux in real time in perfused rat hearts using hyperpolarized magnetic resonance spectroscopy (MRS). [2-13C]Pyruvate was hyperpolarized and infused into isolated perfused hearts in both healthy and postischemic metabolic states. We followed the enzymatic conversion of pyruvate to lactate, acetylcarnitine, citrate, and glutamate with 1 s temporal resolution. The appearance of 13C-labeled glutamate was delayed compared with that of other metabolites, indicating that Krebs Cycle flux can be measured directly. The production of 13C-labeled citrate and glutamate was decreased postischemia, as opposed to lactate, which was significantly elevated. These results showed that the control and fluxes of the Krebs Cycle in heart disease can be studied using hyperpolarized [2-13C]pyruvate.—Schroeder, M. A., Atherton, H. J., Ball, D. R., Cole, M. A., Heather, L. C., Griffin, J. L., Clarke, K., Radda, G. K. Tyler, D. J. Real-time assessment of Krebs Cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy.
Helen J. Atherton - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial Krebs Cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, Kieran Clarke, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial Krebs Cycle activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
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REAL-TIME ASSESSMENT OF Krebs Cycle METABOLISM WITH HYPERPOLARISED [2-13C]PYRUVATE
Heart, 2010Co-Authors: Helen J. Atherton, Marie A. Schroeder, Michael S. Dodd, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Damian J. TylerAbstract:The Krebs Cycle is fundamental to cardiac energy production, and is often implicated in energetic imbalances characteristic of heart disease. To date, Krebs Cycle flux has been measured using 13C-magnetic resonance spectroscopy with isotopomer analysis; however, this approach is limited to the study of steady-state metabolism …
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real time assessment of Krebs Cycle metabolism using hyperpolarized 13c magnetic resonance spectroscopy
The FASEB Journal, 2009Co-Authors: Marie A. Schroeder, Helen J. Atherton, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Mark A Cole, Lisa C Heather, Damian J. TylerAbstract:The Krebs Cycle plays a fundamental role in cardiac energy production and is often implicated in the energetic imbalance characteristic of heart disease. In this study, we measured Krebs Cycle flux in real time in perfused rat hearts using hyperpolarized magnetic resonance spectroscopy (MRS). [2-13C]Pyruvate was hyperpolarized and infused into isolated perfused hearts in both healthy and postischemic metabolic states. We followed the enzymatic conversion of pyruvate to lactate, acetylcarnitine, citrate, and glutamate with 1 s temporal resolution. The appearance of 13C-labeled glutamate was delayed compared with that of other metabolites, indicating that Krebs Cycle flux can be measured directly. The production of 13C-labeled citrate and glutamate was decreased postischemia, as opposed to lactate, which was significantly elevated. These results showed that the control and fluxes of the Krebs Cycle in heart disease can be studied using hyperpolarized [2-13C]pyruvate.—Schroeder, M. A., Atherton, H. J., Ball, D. R., Cole, M. A., Heather, L. C., Griffin, J. L., Clarke, K., Radda, G. K. Tyler, D. J. Real-time assessment of Krebs Cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy.
G. K. Radda - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial Krebs Cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, Kieran Clarke, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial Krebs Cycle activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
-
REAL-TIME ASSESSMENT OF Krebs Cycle METABOLISM WITH HYPERPOLARISED [2-13C]PYRUVATE
Heart, 2010Co-Authors: Helen J. Atherton, Marie A. Schroeder, Michael S. Dodd, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Damian J. TylerAbstract:The Krebs Cycle is fundamental to cardiac energy production, and is often implicated in energetic imbalances characteristic of heart disease. To date, Krebs Cycle flux has been measured using 13C-magnetic resonance spectroscopy with isotopomer analysis; however, this approach is limited to the study of steady-state metabolism …
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real time assessment of Krebs Cycle metabolism using hyperpolarized 13c magnetic resonance spectroscopy
The FASEB Journal, 2009Co-Authors: Marie A. Schroeder, Helen J. Atherton, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Mark A Cole, Lisa C Heather, Damian J. TylerAbstract:The Krebs Cycle plays a fundamental role in cardiac energy production and is often implicated in the energetic imbalance characteristic of heart disease. In this study, we measured Krebs Cycle flux in real time in perfused rat hearts using hyperpolarized magnetic resonance spectroscopy (MRS). [2-13C]Pyruvate was hyperpolarized and infused into isolated perfused hearts in both healthy and postischemic metabolic states. We followed the enzymatic conversion of pyruvate to lactate, acetylcarnitine, citrate, and glutamate with 1 s temporal resolution. The appearance of 13C-labeled glutamate was delayed compared with that of other metabolites, indicating that Krebs Cycle flux can be measured directly. The production of 13C-labeled citrate and glutamate was decreased postischemia, as opposed to lactate, which was significantly elevated. These results showed that the control and fluxes of the Krebs Cycle in heart disease can be studied using hyperpolarized [2-13C]pyruvate.—Schroeder, M. A., Atherton, H. J., Ball, D. R., Cole, M. A., Heather, L. C., Griffin, J. L., Clarke, K., Radda, G. K. Tyler, D. J. Real-time assessment of Krebs Cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy.
Julian L. Griffin - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial Krebs Cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, Kieran Clarke, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial Krebs Cycle activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
-
REAL-TIME ASSESSMENT OF Krebs Cycle METABOLISM WITH HYPERPOLARISED [2-13C]PYRUVATE
Heart, 2010Co-Authors: Helen J. Atherton, Marie A. Schroeder, Michael S. Dodd, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Damian J. TylerAbstract:The Krebs Cycle is fundamental to cardiac energy production, and is often implicated in energetic imbalances characteristic of heart disease. To date, Krebs Cycle flux has been measured using 13C-magnetic resonance spectroscopy with isotopomer analysis; however, this approach is limited to the study of steady-state metabolism …
-
real time assessment of Krebs Cycle metabolism using hyperpolarized 13c magnetic resonance spectroscopy
The FASEB Journal, 2009Co-Authors: Marie A. Schroeder, Helen J. Atherton, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Mark A Cole, Lisa C Heather, Damian J. TylerAbstract:The Krebs Cycle plays a fundamental role in cardiac energy production and is often implicated in the energetic imbalance characteristic of heart disease. In this study, we measured Krebs Cycle flux in real time in perfused rat hearts using hyperpolarized magnetic resonance spectroscopy (MRS). [2-13C]Pyruvate was hyperpolarized and infused into isolated perfused hearts in both healthy and postischemic metabolic states. We followed the enzymatic conversion of pyruvate to lactate, acetylcarnitine, citrate, and glutamate with 1 s temporal resolution. The appearance of 13C-labeled glutamate was delayed compared with that of other metabolites, indicating that Krebs Cycle flux can be measured directly. The production of 13C-labeled citrate and glutamate was decreased postischemia, as opposed to lactate, which was significantly elevated. These results showed that the control and fluxes of the Krebs Cycle in heart disease can be studied using hyperpolarized [2-13C]pyruvate.—Schroeder, M. A., Atherton, H. J., Ball, D. R., Cole, M. A., Heather, L. C., Griffin, J. L., Clarke, K., Radda, G. K. Tyler, D. J. Real-time assessment of Krebs Cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy.
Michael S. Dodd - One of the best experts on this subject based on the ideXlab platform.
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impaired in vivo mitochondrial Krebs Cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Circulation-cardiovascular Imaging, 2014Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, Kieran Clarke, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, James A West, Damian J. TylerAbstract:Background— Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results— Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs Cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions— The in vivo decrease in Krebs Cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs Cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
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impaired in vivo mitochondrial Krebs Cycle activity following myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy
Heart, 2013Co-Authors: Michael S. Dodd, Helen J. Atherton, Julian L. Griffin, G. K. Radda, Lisa C Heather, Carolyn A Carr, Daniel J Stuckey, K Clarke, Damian J. TylerAbstract:An increasing body of evidence links alterations in cardiac metabolism with the progression of heart disease. Using the recently developed technique of hyperpolarized 13 C magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed following myocardial infarction (MI). Hyperpolarization of 13C containing compounds can increase their signal by >10,000 fold over conventional methods. MI with reperfusion surgery was performed on eleven female Wistar rats. Four sham animals were also prepared. Animals were given two hyperpolarized scans, of either [1- 13 C] or [2- 13 C] pyruvate, at 1, 6 and 22 weeks post-MI. [1- 13 C] or [2- 13 C] pyruvate were hyperpolarized and dissolved in a GE prototype polarizer. 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner. Spectra were acquired every second for a 1min following injection, using a 5 o RF excitation pulse. Signal was localised to the heart using a custom 13 C RF surface coil. Metabolic alterations were correlated with ejection fraction (EF) assessed by echocardiography, at each timepoint to yield information on the interplay between cardiac function and mitochondrial metabolism. One week post-MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of EFs observed. This is an early adaptive phase post-MI, where scar formation and remodelling of the heart are occurring. Six weeks post-MI, a novel finding in this study was impaired in vivo mitochondrial Krebs Cycle activity, in addition to decreased flux into acetylcarnitine, which correlated with the EF. These changes were seen in the absence of any alterations in pyruvate dehydrogenase (PDH) flux. Thus, in vivo alterations in Krebs Cycle flux may indicate an early maladaptive phase in the metabolic derangement following MI. By 22 weeks post-MI, alterations were also seen in PDH flux, which positively correlated with EF, highlighting a reduction in glucose oxidation and Krebs Cycle activity in the infarcted heart. At 22 weeks, biochemical analysis was performed on excised hearts, to further characterize the metabolic alterations accompanying MI. Enzyme activities of PDH, citrate synthase, isocitrate dehydrogenase and carnitine acetyltransferanse positively correlated with EF. Metabolomic analysis revealed reduced levels of Kerbs Cycle intermediates. The correlation between function and metabolism raises an interesting paradox; is the reduction in PDH and Krebs Cycle activity due to a reduction in contraction and therefore a reduced energy requirement, or does the altered PDH and Krebs Cycle activity lead to reduced energy levels meaning cardiac contraction is impaired? This study highlights the importance of assessing metabolism at multiple timepoints in vivo , and demonstrates the potential of hyperpolarized MRS for investigating the metabolic effects of progressive diseases, potentially in a clinical setting.
-
REAL-TIME ASSESSMENT OF Krebs Cycle METABOLISM WITH HYPERPOLARISED [2-13C]PYRUVATE
Heart, 2010Co-Authors: Helen J. Atherton, Marie A. Schroeder, Michael S. Dodd, Daniel R. Ball, Julian L. Griffin, Kieran Clarke, G. K. Radda, Damian J. TylerAbstract:The Krebs Cycle is fundamental to cardiac energy production, and is often implicated in energetic imbalances characteristic of heart disease. To date, Krebs Cycle flux has been measured using 13C-magnetic resonance spectroscopy with isotopomer analysis; however, this approach is limited to the study of steady-state metabolism …
