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Metabolic efficiency in remodeled failing hearts

  • Author / Creator
    Masoud, Waleed GT
  • Heart failure is a serious cardiovascular disease that develops following a variety of insults to the heart including hypertrophy and myocardial infarction. While it is clear that heart failure is associated with changes in cardiac energy metabolism, it remains unclear if, and how, such changes might contribute to left ventricular (LV) contractile dysfunction. Two distinct hypotheses have been advanced to link changes in energy metabolism with heart failure: 1) there is a state of energetic crisis / starvation, where rates of energy metabolism decrease and thereby cause LV failure, or 2) there is inefficiency in energy utilization where more energy is required to produce external work. Inefficiency may be due to mismatched rates of glycolysis and glucose oxidation that leads to intracellular proton accumulation resulting in Na+ and Ca2+ overload. Recently, drug-induced modulation of rates of carbohydrate and fat metabolism has been proposed as a new approach for the treatment of LV dysfunction and heart failure. Such metabolic modulation can also be achieved experimentally by the use of genetically-modified experimental animals. This thesis compared the metabolic profile of remodeled post-infarction mouse hearts with normal hearts, studied the response of these hearts to ex vivo ischemia reperfusion (IR) and the ability of metabolic modulation to limit the deterioration of metabolic efficiency and LV dysfunction following myocardial infarction. Using coronary artery ligation, we created a mouse model of post-infarction remodeled heart failure that we verified using in vivo echocardiographic examination. Using ex vivo heart perfusion in the isolated working mode, we provided evidence that CAL hearts are metabolically inefficient rather than energy starved and that mismatched glucose metabolism is a possible contributor to metabolic inefficiency. Using malonyl CoA decarboxylase deficient (MCD-KO) mice that are known to have better matching of glucose metabolism, we confirmed that this metabolic intervention improved glucose matching, metabolic efficiency and limited functional deterioration in CAL hearts. We also studied the response of CAL hearts to ex vivo IR. We showed that CAL hearts have better functional recovery and limited functional deterioration following IR in comparison to SHAM hearts. This was associated with reduced ischemic glycogenolysis, lack of acceleration in fatty acid oxidation during reperfusion and increased triacylglycerol accumulation in reperfused CAL hearts. We provided evidence that mitochondrial mass, Ca2+ handling proteins and AMPK activity are unchanged and are unlikely to contribute to the observed response of CAL hearts to IR. This thesis also studied the potential for further protection of CAL hearts after IR via pharmacologic improvement of the match of glucose oxidation using dichloroacetate (DCA). We showed that in presence of lactate, DCA did not stimulate glucose oxidation, improve functional recovery or improve the match of glucose metabolism. We also showed that in absence of lactate, DCA was able to stimulate glucose oxidation but this was not enough to improve the matching of glucose metabolism. This thesis also discussed differences between mouse and rat heart metabolism that may explain the lack of response to DCA in mouse hearts. Similarly, we studied the possible improvement of metabolic efficiency in CAL hearts via acute ex vivo MCD inhibition but this acute intervention was not sufficient to produce benefit.

  • Subjects / Keywords
  • Graduation date
    2015-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R39S1KS1S
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Pharmacology
  • Supervisor / co-supervisor and their department(s)
    • Clanachan, Alexander S (Pharmacology)
    • Lopaschuk, Gary D (Pediatrics/Pharmacology)
  • Examining committee members and their departments
    • Seubert, John M (Pharmacy and Pharmaceutical Sciences/Pharmacology)
    • Kassiri, Zamaneh (Physiology)
    • Pierce, Grant N (Physiology)
    • Light, Peter E (Pharmacology)