Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats

2005 ◽  
Vol 288 (5) ◽  
pp. H2102-H2110 ◽  
Author(s):  
Peipei Wang ◽  
Steven G. Lloyd ◽  
Huadong Zeng ◽  
Arend Bonen ◽  
John C. Chatham
Keyword(s):  
Fatty Acids ◽  
Oxygen Consumption ◽  
Cardiac Function ◽  
Energy Production ◽  
Cardiac Metabolism ◽  
Low Flow ◽  
Control Group ◽  
Atp Production ◽  
Oxidation Rates ◽  
Zucker Diabetic Fatty Rats

The goal of this study was to determine whether changes in cardiac metabolism in Type 2 diabetes are associated with contractile dysfunction or impaired response to ischemia. Hearts from Zucker diabetic fatty (ZDF) and lean control rats were isolated and perfused with glucose, lactate, pyruvate, and palmitate. The rates of glucose, lactate, pyruvate, and palmitate oxidation rates and glycolysis were determined during baseline perfusion and low-flow ischemia (LFI; 0.3 ml/min for 30 min) and after LFI and reperfusion. Under all conditions, ATP synthesis from palmitate was increased and synthesis from lactate was decreased in the ZDF group, whereas the contribution from glucose was unchanged. During baseline perfusion, the rate of glycolysis was lower in the ZDF group; however, during LFI and reperfusion, there were no differences between groups. Despite these metabolic shifts, there were no differences in oxygen consumption or ATP production rates between the groups under any perfusion conditions. Cardiac function was slightly depressed before LFI in the ZDF group, but during reperfusion, function was improved relative to the control group despite the increased dependence on fatty acids for energy production. These data suggest that in this model of diabetes, the shift from carbohydrates to fatty acids for oxidative energy production did not increase myocardial oxygen consumption and was not associated with impaired response to ischemia and reperfusion.

Calcium regulation of glycolysis, glucose oxidation and fatty acid oxidation in the aerobic and ischemic heart

1995 ◽  
Vol 73 (11) ◽  
pp. 1632-1640 ◽  
Author(s):  
Brett Schönekess ◽  
Peter G. Brindley ◽  
Gary O. Lopaschuk
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Pyruvate Dehydrogenase Complex ◽  
Dry Weight ◽  
Low Flow ◽  
Acid Oxidation ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Oxidation Rates

Although Ca2+is an important regulator of energy metabolism, the effects of increasing extracellular [Ca2+] on energy substrate preference are not clear. We determined the relationship between [Ca2+], fatty acids, and ischemia on rates of glycolysis, glucose oxidation, and palmitate oxidation in isolated working rat hearts. Hearts were perfused with Krebs–Henseleit buffer containing 11 mM glucose, 100 μU/mL insulin, and either 1.25 or 2.5 mM Ca2+, in the presence or absence of 1.2 mM palmitate. Rates of glycolysis and glucose oxidation or palmitate oxidation were measured in the hearts using [5-3H,14C(U)]glucose or [1-14C]palmitate, respectively. In the absence of fatty acids, glycolysis and glucose oxidation rates were similar, regardless of whether [Ca2+] was 1.25 or 2.5 mM. Addition of 1.2 mM palmitate to the perfusate of hearts perfused with 1.25 mM Ca2+significantly decreased rates of both glycolysis (from 4623 ± 438 to 1378 ± 238 nmol∙min−1∙g−1dry weight) and glucose oxidation (from 1392 ± 219 to 114 ± 22 nmol∙min−1∙g−1dry weight). When [Ca2+] was increased from 1.25 to 2.5 mM in hearts perfused with 1.2 mM palmitate, glycolysis and glucose oxidation increased by 164 and 271%, respectively, with no change in palmitate oxidation rates. Increasing [Ca2+] from 1.25 to 2.5 mM increased the contribution of glucose to ATP production from 9.3 to 18.7%. When hearts were subjected to low-flow ischemia (by reducing coronary flow to 0.5 mL∙min−1) oxidative metabolism was essentially abolished. Under these conditions, glycolytic rates were not dependent on either [Ca2+] or the presence or absence of fatty acids. These results demonstrate that perfusate [Ca2+] is an important determinant of myocardial glucose metabolism in aerobic hearts, and that glycolysis and glucose oxidation are more responsive to changes in [Ca2+] than is fatty acid oxidation.Key words: β-oxidation, glucose oxidation, pyruvate dehydrogenase complex.

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

2006 ◽  
Vol 291 (3) ◽  
pp. H1036-H1046 ◽  
Author(s):  
Lufang Zhou ◽  
Marco E. Cabrera ◽  
Isidore C. Okere ◽  
Naveen Sharma ◽  
William C. Stanley
Keyword(s):  
Oxygen Consumption ◽  
Energy Expenditure ◽  
Myocardial Oxygen Consumption ◽  
Experimental Studies ◽  
Cardiac Metabolism ◽  
Substrate Selection ◽  
Abrupt Increase ◽  
Model Simulations ◽  
Atp Production ◽  
Parallel Activation

In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD+ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD+ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10–15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD+ but had minimal effects on the mitochondrial NADH/NAD+, myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD+ ratio that is independent of substrate supply.

scholarly journals Treatment with Nitrate, but Not Nitrite, Lowers the Oxygen Cost of Exercise and Decreases Glycolytic Intermediates While Increasing Fatty Acid Metabolites in Exercised Zebrafish

2019 ◽  
Vol 149 (12) ◽  
pp. 2120-2132 ◽  
Author(s):  
Elizabeth R Axton ◽  
Laura M Beaver ◽  
Lindsey St. Mary ◽  
Lisa Truong ◽  
Christiana R Logan ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Oxygen Consumption ◽  
Mitochondrial Function ◽  
Energy Production ◽  
Ketone Bodies ◽  
Oxygen Cost ◽  
Nitrate Treatment ◽  
Glycolytic Intermediates ◽  
Treated Fish ◽  
Nitrate And Nitrite

ABSTRACT Background Dietary nitrate improves exercise performance by reducing the oxygen cost of exercise, although the mechanisms responsible are not fully understood. Objectives We tested the hypothesis that nitrate and nitrite treatment would lower the oxygen cost of exercise by improving mitochondrial function and stimulating changes in the availability of metabolic fuels for energy production. Methods We treated 9-mo-old zebrafish with nitrate (sodium nitrate, 606.9 mg/L), nitrite (sodium nitrite, 19.5 mg/L), or control (no treatment) water for 21 d. We measured oxygen consumption during a 2-h, strenuous exercise test; assessed the respiration of skeletal muscle mitochondria; and performed untargeted metabolomics on treated fish, with and without exercise. Results Nitrate and nitrite treatment increased blood nitrate and nitrite levels. Nitrate treatment significantly lowered the oxygen cost of exercise, as compared with pretreatment values. In contrast, nitrite treatment significantly increased oxygen consumption with exercise. Nitrate and nitrite treatments did not change mitochondrial function measured ex vivo, but significantly increased the abundances of ATP, ADP, lactate, glycolytic intermediates (e.g., fructose 1,6-bisphosphate), tricarboxylic acid (TCA) cycle intermediates (e.g., succinate), and ketone bodies (e.g., β-hydroxybutyrate) by 1.8- to 3.8-fold, relative to controls. Exercise significantly depleted glycolytic and TCA intermediates in nitrate- and nitrite-treated fish, as compared with their rested counterparts, while exercise did not change, or increased, these metabolites in control fish. There was a significant net depletion of fatty acids, acyl carnitines, and ketone bodies in exercised, nitrite-treated fish (2- to 4-fold), while exercise increased net fatty acids and acyl carnitines in nitrate-treated fish (1.5- to 12-fold), relative to their treated and rested counterparts. Conclusions Nitrate and nitrite treatment increased the availability of metabolic fuels (ATP, glycolytic and TCA intermediates, lactate, and ketone bodies) in rested zebrafish. Nitrate treatment may improve exercise performance, in part, by stimulating the preferential use of fuels that require less oxygen for energy production.

scholarly journals Metabolic Complications in Cardiac Aging

2021 ◽  
Vol 12 ◽  
Author(s):  
Thomas Sithara ◽  
Konstantinos Drosatos
Keyword(s):  
Fatty Acids ◽  
Cardiac Function ◽  
Ketone Bodies ◽  
Atp Synthesis ◽  
Cardiac Metabolism ◽  
Cardiovascular Complications ◽  
Acid Oxidation ◽  
Metabolic Complications ◽  
Cardiac Aging ◽  
Relative Contribution

Aging is a process that can be accompanied by molecular and cellular alterations that compromise cardiac function. Although other metabolic disorders with increased prevalence in aged populations, such as diabetes mellitus, dyslipidemia, and hypertension, are associated with cardiovascular complications; aging-related cardiomyopathy has some unique features. Healthy hearts oxidize fatty acids, glucose, lactate, ketone bodies, and amino acids for producing energy. Under physiological conditions, cardiac mitochondria use fatty acids and carbohydrate mainly to generate ATP, 70% of which is derived from fatty acid oxidation (FAO). However, relative contribution of nutrients in ATP synthesis is altered in the aging heart with glucose oxidation increasing at the expense of FAO. Cardiac aging is also associated with impairment of mitochondrial abundance and function, resulting in accumulation of reactive oxygen species (ROS) and activation of oxidant signaling that eventually leads to further mitochondrial damage and aggravation of cardiac function. This review summarizes the main components of pathophysiology of cardiac aging, which pertain to cardiac metabolism, mitochondrial function, and systemic metabolic changes that affect cardiac function.

Triacylglycerol turnover in isolated working hearts of acutely diabetic rats

1994 ◽  
Vol 72 (10) ◽  
pp. 1110-1119 ◽  
Author(s):  
Maruf Saddik ◽  
Gary D. Lopaschuk
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Acid Oxidation ◽  
Atp Production ◽  
Oxidation Rates ◽  
Rat Hearts

Although myocardial triacylglycerol may be a potentially important source of fatty acids for β-oxidation in diabetes, few studies have measured triacylglycerol turnover directly in hearts from diabetic animals. In this study, myocardial triacylglycerol turnover was directly measured in isolated working hearts from streptozotocin-induced acutely diabetic rats. Hearts were initially perfused in the presence of 1.2 mM [14C]palmitate and 11 mM glucose for 1 h (pulse) to label the endogenous lipid pools, followed by a 10-min washout perfusion. Hearts were then perfused for another hour (chase) with buffer containing 11 mM glucose ± 1.2 mM [3H]palmitate. During the chase, both 14CO2 and 3H2O production (measures of endogenous and exogenous fatty acid oxidation, respectively) were determined. A second series of hearts were perfused using the same protocol, except that unlabeled palmitate was used during the pulse and 11 mM [14C(U),5-3H]glucose ± unlabeled palmitate was present during the chase. Both glycolysis (3H2O production) and glucose oxidation (14CO2 production) rates were measured in this series. Myocardial triacylglycerol levels were significantly higher in the diabetic rat hearts (77.5 ± 4.6 vs. 33.7 ± 4.1 μmol fatty acid/g dry mass in control hearts). In diabetic rat hearts chased with 1.2 mM palmitate, triacylglycerol lipolysis was increased, although endogenous [14C]palmitate oxidation rates were similar to control hearts and contributed 10.1% of overall ATP production. The majority of fatty acids derived from triacylglycerol lipolysis were released into the perfusate. In the absence of palmitate, both triacylglycerol lipolysis and endogenous [14C]palmitate oxidation rates were significantly increased in diabetic rat hearts, compared with control. Under these conditions, triacylglycerol fatty acid oxidation contributed 70% of steady-state ATP production in diabetic rat hearts, compared with 34% in control hearts. These results demonstrate that in diabetic rat hearts myocardial triacylglycerol lipolysis is significantly increased and can readily be used as a source of fatty acids for mitochondrial β-oxidation.Key words: heart, triacylglycerols, fatty acid oxidation, glucose oxidation, glycolysis.

scholarly journals Esmolol for cardioprotection during resuscitation with adrenaline in an ischaemic porcine cardiac arrest model

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Hilde Karlsen ◽  
Harald Arne Bergan ◽  
Per Steinar Halvorsen ◽  
Kjetil Sunde ◽  
Eirik Qvigstad ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiac Output ◽  
Single Dose ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Low Flow ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Tetrazolium Chloride ◽  
Va Ecmo

Abstract Background The effectiveness of adrenaline during resuscitation continues to be debated despite being recommended in international guidelines. There is evidence that the β-adrenergic receptor (AR) effects of adrenaline are harmful due to increased myocardial oxygen consumption, post-defibrillation ventricular arrhythmias and increased severity of post-arrest myocardial dysfunction. Esmolol may counteract these unfavourable β-AR effects and thus preserve post-arrest myocardial function. We evaluated whether a single dose of esmolol administered prior to adrenaline preserves post-arrest cardiac output among successfully resuscitated animals in a novel, ischaemic cardiac arrest porcine model. Methods Myocardial infarction was induced in 20 anaesthetized pigs by inflating a percutaneous coronary intervention (PCI) balloon in the circumflex artery 15 min prior to induction of ventricular fibrillation. After 10 min of untreated VF, resuscitation with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated and the animals were randomized to receive an injection of either 1 mg/kg esmolol or 9 mg/ml NaCl, prior to adrenaline. Investigators were blinded to allocation. Successful defibrillation was followed by a 1-h high-flow VA-ECMO before weaning and an additional 1-h stabilization period. The PCI-balloon was deflated 40 min after inflation. Cardiac function pre- and post-arrest (including cardiac output) was assessed by magnetic resonance imaging (MRI) and invasive pressure measurements. Myocardial injury was estimated with MRI, triphenyl tetrazolium chloride (TTC) staining and serum concentrations of cardiac troponin T. Results Only seven esmolol and five placebo-treated pigs were successfully resuscitated and available for post-arrest measurements (p = 0.7). MRI revealed severe but similar reductions in post-arrest cardiac function with cardiac output 3.5 (3.3, 3.7) and 3.3 (3.2, 3.9) l/min for esmolol and control (placebo) groups, respectively (p = 0.7). The control group had larger left ventricular end-systolic and end-diastolic ventricular volumes compared to the esmolol group (75 (65, 100) vs. 62 (53, 70) ml, p = 0.03 and 103 (86, 124) vs. 87 (72, 91) ml, p = 0.03 for control and esmolol groups, respectively). There were no other significant differences in MRI characteristics, myocardial infarct size or other haemodynamic measurements between the two groups. Conclusions We observed similar post-arrest cardiac output with and without a single dose of esmolol prior to adrenaline administration during low-flow VA-ECMO in an ischaemic cardiac arrest pig model.

scholarly journals Mismatched light and temperature cues disrupt locomotion and energetics via thyroid-dependent mechanisms

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Amélie Le Roy ◽  
Frank Seebacher
Keyword(s):  
Oxygen Consumption ◽  
Thyroid Hormone ◽  
Swimming Performance ◽  
Day Length ◽  
Seasonal Temperature ◽  
Dependent Manner ◽  
Atp Production ◽  
Oxidation Rates ◽  
Mitochondrial Efficiency ◽  
Short Days

Abstract Animals integrate information from different environmental cues to maintain performance across environmental gradients. Increasing average temperature and variability induced by climate change can lead to mismatches between seasonal cues. We used mosquitofish (Gambusia holbrooki) to test the hypotheses that mismatches between seasonal temperature and light regimes (short days and warm temperature and vice versa) decrease swimming performance, metabolic rates and mitochondrial efficiency and that the responses to light and temperature are mediated by thyroid hormone. We show that day length influenced thermal acclimation of swimming performance through thyroid-dependent mechanisms. Oxygen consumption rates were influenced by acclimation temperature and thyroid hormone. Mitochondrial substrate oxidation rates (state three rates) were modified by the interaction between temperature and day length, and mitochondrial efficiency (P/O ratios) increased with warm acclimation. Using P/O ratios to calibrate metabolic (oxygen consumption) scope showed that oxygen consumption did not predict adenosine triphosphate (ATP) production. Unlike oxygen consumption, ATP production was influenced by day length in a thyroid-dependent manner. Our data indicate that oxygen consumption alone should not be used as a predictor of ATP production. Overall, the effects of thyroid hormone on locomotion and energetics were reversed by mismatches such as warm temperatures on short days. We predict that mid to high latitudes in North America and Asia will be particularly affected by mismatches as a result of high seasonality and predicted warming over the next 50 years.

scholarly journals Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency

2019 ◽  
Vol 115 (11) ◽  
pp. 1606-1616 ◽  
Author(s):  
Kim L Ho ◽  
Liyan Zhang ◽  
Cory Wagg ◽  
Rami Al Batran ◽  
Keshav Gopal ◽  
...  
Keyword(s):  
Energy Production ◽  
Glucose Oxidation ◽  
Cardiac Metabolism ◽  
Cardiac Efficiency ◽  
Or Efficiency ◽  
Additional Energy ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Failing Heart ◽  
Cardiac Energy

AbstractAimsThe failing heart is energy-starved and inefficient due to perturbations in energy metabolism. Although ketone oxidation has been shown recently to increase in the failing heart, it remains unknown whether this improves cardiac energy production or efficiency. We therefore assessed cardiac metabolism in failing hearts and determined whether increasing ketone oxidation improves cardiac energy production and efficiency.Methods and resultsC57BL/6J mice underwent sham or transverse aortic constriction (TAC) surgery to induce pressure overload hypertrophy over 4-weeks. Isolated working hearts from these mice were perfused with radiolabelled β-hydroxybutyrate (βOHB), glucose, or palmitate to assess cardiac metabolism. Ejection fraction decreased by 45% in TAC mice. Failing hearts had decreased glucose oxidation while palmitate oxidation remained unchanged, resulting in a 35% decrease in energy production. Increasing βOHB levels from 0.2 to 0.6 mM increased ketone oxidation rates from 251 ± 24 to 834 ± 116 nmol·g dry wt−1 · min−1 in TAC hearts, rates which were significantly increased compared to sham hearts and occurred without decreasing glycolysis, glucose, or palmitate oxidation rates. Therefore, the contribution of ketones to energy production in TAC hearts increased to 18% and total energy production increased by 23%. Interestingly, glucose oxidation, in parallel with total ATP production, was also significantly upregulated in hearts upon increasing βOHB levels. However, while overall energy production increased, cardiac efficiency was not improved.ConclusionsIncreasing ketone oxidation rates in failing hearts increases overall energy production without compromising glucose or fatty acid metabolism, albeit without increasing cardiac efficiency.

Allosteric, transcriptional and post-translational control of mitochondrial energy metabolism

2019 ◽  
Vol 476 (12) ◽  
pp. 1695-1712 ◽  
Author(s):  
Qutuba G. Karwi ◽  
Alice R. Jörg ◽  
Gary D. Lopaschuk
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Energy Production ◽  
Energy Regulation ◽  
Energy Substrates ◽  
Mitochondrial Energy Metabolism ◽  
Atp Production ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

AbstractThe heart is the organ with highest energy turnover rate (per unit weight) in our body. The heart relies on its flexible and powerful catabolic capacity to continuously generate large amounts of ATP utilizing many energy substrates including fatty acids, carbohydrates (glucose and lactate), ketones and amino acids. The normal health mainly utilizes fatty acids (40–60%) and glucose (20–40%) for ATP production while ketones and amino acids have a minor contribution (10–15% and 1–2%, respectively). Mitochondrial oxidative phosphorylation is the major contributor to cardiac energy production (95%) while cytosolic glycolysis has a marginal contribution (5%). The heart can dramatically and swiftly switch between energy-producing pathways and/or alter the share from each of the energy substrates based on cardiac workload, availability of each energy substrate and neuronal and hormonal activity. The heart is equipped with a highly sophisticated and powerful mitochondrial machinery which synchronizes cardiac energy production from different substrates and orchestrates the rate of ATP production to accommodate its contractility demands. This review discusses mitochondrial cardiac energy metabolism and how it is regulated. This includes a discussion on the allosteric control of cardiac energy metabolism by short-chain coenzyme A esters, including malonyl CoA and its effect on cardiac metabolic preference. We also discuss the transcriptional level of energy regulation and its role in the maturation of cardiac metabolism after birth and cardiac adaptability for different metabolic conditions and energy demands. The role post-translational modifications, namely phosphorylation, acetylation, malonylation, succinylation and glutarylation, play in regulating mitochondrial energy metabolism is also discussed.

Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

2004 ◽  
Vol 287 (1) ◽  
pp. H351-H362 ◽  
Author(s):  
Steven G. Lloyd ◽  
Peipei Wang ◽  
Huadong Zeng ◽  
John C. Chatham
Keyword(s):  
Myocardial Ischemia ◽  
Protective Effect ◽  
Citrate Synthase ◽  
Substrate Oxidation ◽  
Low Flow ◽  
Control Group ◽  
Lactate Oxidation ◽  
Carbohydrate Utilization ◽  
Atp Production ◽  
Oxidative Energy Metabolism

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used 1H and 13C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and 13C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a ∼50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and ∼30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia.

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