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18th World Congress on Heart Disease



Gary Lopaschuk, Ph.D., University of Alberta, Edmonton, AB, Canada


Alterations in cardiac energy metabolism contribute to the impaired heart function observed in heart failure patients. The failing heart is both energy compromised, as well as inefficient at producing energy. Defects in the rates of O2 consumption and mitochondrial electron transport activity occur in advanced stages of heart failure, which decrease ATP generation. This results in an increase in glycolysis as a source of ATP production. Unfortunately, while glycolysis increases, the second part of the glucose metabolic pathway, glucose oxidation, decreases because it is a mitochondrial dependent process. As a result, an increased uncoupling of glycolysis from glucose oxidation enhances H+ and lactate production. This can decrease cardiac efficiency, as ATP produced by the heart is directed away from use by the contractile proteins towards use in clearance of the H+ís. One promising strategy to increase cardiac efficiency in the failing heart is to directly stimulate glucose oxidation, thereby improving the coupling of glycolysis to glucose oxidation. This can be achieved with agents like dichloroacetate, which stimulate pyruvate dehydrogenase, the rate-limiting enzyme involved in glucose oxidation, and improves cardiac efficiency and function in the failing heart. Alternatively, glucose oxidation can be stimulated indirectly by inhibiting fatty acid oxidation. Fatty acid oxidation inhibitors such as trimetazidine and perhexiline increase glucose oxidation in the heart, and have been shown to be beneficial in treating heart failure. As a result, enhancing glucose oxidation is a potential novel therapeutic approach to treating heart failure.




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