Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.
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 ((13)C)-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 (13)C-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.
['Dodd|Michael S|MS|', 'Atherton|Helen J|HJ|', 'Carr|Carolyn A|CA|', 'Stuckey|Daniel J|DJ|', 'West|James A|JA|', 'Griffin|Julian L|JL|', 'Radda|George K|GK|', 'Clarke|Kieran|K|', 'Heather|Lisa C|LC|', 'Tyler|Damian J|DJ|']
D000108:Acetylcarnitine D000818:Animals D015415:Biomarkers D019343:Citric Acid D002952:Citric Acid Cycle D004195:Disease Models, Animal D005260:Female D018698:Glutamic Acid D019028:Magnetic Resonance Imaging, Cine D009682:Magnetic Resonance Spectroscopy D055432:Metabolomics D008929:Mitochondria, Heart D009203:Myocardial Infarction D009206:Myocardium D011237:Predictive Value of Tests D011768:Pyruvate Dehydrogenase Complex D017208:Rats, Wistar D013318:Stroke Volume D013997:Time Factors D016277:Ventricular Function, Left
myocardial infarction magnetic resonance spectroscopy heart metabolism citric acid cycle