http://msg2018.weebly.com/uploads/1/6/1/0/16101502/jaswal_2011_targeting_fatty_acid_and_carbohydrate_oxidation___a_novel_therapeutic_intervention_in_the_ischemic_and_failing_heart__.pdf

Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart.

Myocardial ischemia revisited. The osmolar load, membrane damage, and reperfusion

Myocardial metabolism in ischemic heart disease: basic principles and application to imaging by positron emission tomography

Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.

Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation

Acute myocardial ischemia induced by coronary occlusion in dogs is most severe in the subendocardial region, whereas more collateral blood flow is often present in the subepicardial region. Initially, all ischemic myocytes are reversibly injured, but beginning at 15 to 20 minutes after the onset, and continuing for 3 to 6 hours, there is a wave front of cell death from the subendocardial region to the less ischemic subepicardial region, such that by 6 hours, the final transmural extent of the infarct is established. Thus, ischemic myocardium cannot be salvaged by reperfusion after greater than or equal to 6 hours of coronary occlusion in open-chest anesthetized dogs. In the severely ischemic subendocardial region, most of the creatine phosphate is lost within the first 3 minutes of ischemia in vivo, and adenosine triphosphate (ATP) is depleted to 35% of control by 15 minutes (when cellular injury is still reversible), and to less than 10% of control at 40 minutes (when injury is irreversible). Tissue ATP content and other indexes of subcellular damage have also been compared after different periods of ischemia using a model of total myocardial ischemia in vitro. As long as the ATP of the tissue was not depleted below 5 mumols/g dry weight, incubated slices of injured myocardium resynthesized high-energy phosphates and excluded inulin. However, lower tissue ATP was associated with depressed high-energy phosphate resynthesis and failure of cell volume regulation. Overt membrane damage, as measured by an increased inulin-diffusible space, was detected only after the tissue ATP decreased to less than 2.0 mumols/g of dry weight. Thus, marked ATP depletion is associated with the onset of structural and functional indexes of irreversible injury. However, whether irreversibility is caused by the marked ATP depletion or by other concomitant metabolic consequences of ischemia is not known. Myocardial ischemic cellular injury is reversible despite depletion of 70% of the control ATP. Nevertheless, when myocyte injury is reversible, there is slow repletion of adenine nucleotides. This slow metabolic recovery may explain the delayed recovery of contractile function observed after reperfusion of ischemic myocardium.

Pathobiology of acute myocardial ischemia: Metabolic, functional and ultrastructural studies

The relationship between coronary flow and adenosine triphosphate ATP production was determined in isolated rat hearts and in situ pigs hearts. The major source of ATP in ischemic hearts was oxidative phosphorylation. Oxidation of glucose accounted for most of the residual oxygen consumption in ischemic hearts when the concentration of fatty acids was low, but at 1.2 mM palmitate fatty acids were oxidized in preference to carbohydrate, as in aerobic hearts. The rates of ATP production from both glycolysis and oxidative metabolism were decreased in proportion to the reduction in coronary flow in oxygen-deficient hearts. Glycolysis was reduced to below aerobic rates when coronary flow was about 0.5 ml/min/g tissue in both rat hearts perfused with bicarbonate buffer and blood-perfused pig hearts. Tissue level of high energy phosphates reflected the rates of ATP production and declined in proportion to the reduction in coronary flow. In addition, tissue lactate and H+ accumulated in proportion to the restriction in flow.

Relationship between coronary flow and adenosine triphosphate production from glycolysis and oxidative metabolism.

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Relationship between coronary flow and adenosine triphosphate production from glycolysis and oxidative metabolism.