Impaired In Vivo Mitochondrial Krebs Cycle Activity After Myocardial Infarction Assessed Using Hyperpolarized Magnetic Resonance Spectroscopy

Abstract

M yocardial infarction (MI) is the leading cause of heart failure in the developed world and results in high levels of mortality and morbidity in patients. 1 MI is caused by a partial or complete obstruction of a coronary artery, resulting in significant reductions in coronary blood flow and in ischemia.2 MI injury results in loss of heart tissue, causing the heart to remodel structurally and metabolically. However, this remodeled state is unsustainable, and the heart eventually fails, where the myocardial wall thins, the left ventricular (LV) cavity dilates, and cardiac output decreases.2 After a MI, the progression into heart failure can be characterized by profound changes in myocardial energy metabolism. 1,3 Editorial see p 854 Clinical Perspective on p 904Fatty acid oxidation contributes 60% to 70% of the energy required for the resting heart, with glucose and lactate making up the majority of the remaining needs.1,2,4,5 The tightly regulated reciprocal relationship between glucose oxidation through pyruvate dehydrogenase (PDH) and fatty acid oxidation breaks down after an MI. [5][6][7] This is accompanied by alterations in both Krebs cycle enzyme activities and electron chain complexes and contributes to a generalized reduction in the capacity for ATP production. [8][9][10][11][12] In vitro experiments of MI have revealed that there are alterations in the electron transport chain as early as 2 weeks after MI, 8 and that alterations in cardiac mitochondrial metabolism continue out to 6 months. However, the exact nature and timing of in vivo mitochondrial dysfunction after an MI are unclear, and information about this would provide a greater understanding of the development of metabolic abnormalities after an MI.The use of hyperpolarized 13 C-magnetic resonance spectroscopy (MRS) 13 allows the study of in vivo mitochondrial metabolism by measuring the flux of 13 C-labeledBackground-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...

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure

“…26, 27 Specifically, the increased myocardial acetyl-CoA coupled with decreased levels of metabolites incorporated in the second span of the Krebs cycle (succinyl-CoA, succinate and fumarate) suggest the end-stage failing human myocardium has deficiencies in the Krebs cycle. This also includes a depleted pool of intermediate metabolites which feed the Krebs cycle through anaplerosis (propionyl-CoA), supporting recent observations that a disruption in Krebs cycle activity is an important signature of progression to HF.…”

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

“…The technique provides unique insights into important questions regarding myocardial metabolism, substrate preference, pharmacological intervention, and the ability to differentiate between normal and pathological metabolism [22][23][24][25][26][27][28][29][30][31][32][33]. Pyruvate is by far the most widely used hyperpolarized 13 C substrate and it can be served as a probe for mitochondrial oxidative flux [34].…”

Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐13C2]pyruvate

“…2,3,5,25 It has been demonstrated that the hyperpolarized [5-13 C]glutamate signal is modulated at an early stage of cardiac remodeling into heart failure and thus has potential as an imaging-based biomarker. 22,31 However, an understanding of the mechanism of the early change to [5][6][7][8][9][10][11][12][13] C]glutamate production will be essential for this parameter to have a role in the management of CVD.…”