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Metabolic efficiency in remodeled failing hearts Open Access

Descriptions

Other title
Subject/Keyword
Cardiac metabolism
Ex vivo measurement of cardiac metabolic rates
Isolated working mouse heart
In vivo evaluation of heart function
Metabolic efficiency
Mismatched glycolysis and glucose oxidation
Post-infarction remodeled hearts
Ex vivo evaluation of heart funtion
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Masoud, Waleed GT
Supervisor and department
Clanachan, Alexander S (Pharmacology)
Lopaschuk, Gary D (Pediatrics/Pharmacology)
Examining committee member and department
Light, Peter E (Pharmacology)
Kassiri, Zamaneh (Physiology)
Pierce, Grant N (Physiology)
Seubert, John M (Pharmacy and Pharmaceutical Sciences/Pharmacology)
Department
Department of Pharmacology
Specialization

Date accepted
2015-01-15T14:50:39Z
Graduation date
2015-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R39S1KS1S
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Jugdutt BI, Dhalla NS, eds. Cardiac Remodeling. : Springer New York, Masoud WT, Clanachan AS, Lopaschuk GD. The Failing Heart: Is it an Inefficient Engine or an Engine Out of Fuel? 2013:65-84Masoud WG, Ussher JR, Wang W, Jaswal JS, Wagg CS, Dyck JR, Lygate CA, Neubauer S, Clanachan AS, Lopaschuk GD. Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation. Cardiovascular Research, 2014 Jan;101:30-38“Failing Hearts From Mice Subjected to Coronary Artery Ligation Are Not Energy Deficient, But Rather Utilize Energy Inefficiently and Benefit from Metabolic Intervention” Waleed G.T. Masoud, John Ussher, Wei Wang, Cory Wagg, Alexander S. Clanachan and Gary D. Lopaschuk. A poster presentation at ISHR conference May 2012 (international conference).  http://www.usouthal.edu/ishr/NAM/indices2012/pdf/2012ISHR_0002.pdf

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