Myocardial Energy Metabolism in Cardiomyopathies

  • Author / Creator
    Greenwell, Amanda Ashleigh
  • As the most metabolically demanding organ in the body, the heart must continually produce extraordinary amounts of energy to sustain constant contractile function. To accommodate for alterations in fuel source availability, the healthy mature heart is omnivorous and possesses the capacity to flexibly metabolize numerous fuel substrates including fatty acids, carbohydrates, ketone bodies and amino acids delivered to it through the coronary circulation. Accordingly, disturbances in this metabolic flexibility contribute to the development of numerous cardiovascular disorders, including various cardiomyopathies that often precede the development of heart failure. Although perturbation of myocardial energy metabolism represents a shared feature of cardiomyopathies with diverse origins and basic disease mechanisms, the specific metabolic profile and, thus, potential targets for therapeutic intervention are often unique to the particular cardiomyopathy type. Herein, we investigated the alterations in myocardial intermediary energy metabolism present in the cardiomyopathies associated with Barth syndrome and obesity/type 2 diabetes. Furthermore, we determined whether pharmacological optimization of cardiac substrate utilization, or modulation of the systemic nutrient environment to mitigate cardiovascular risk factors, represent viable targets for the treatment of cardiac dysfunction in Barth syndrome and obesity/type 2 diabetes.

    Barth syndrome is a rare, X-linked disorder caused by mutations in the TAFAZZIN gene that results in impaired mitochondrial cardiolipin remodeling, mitochondrial dysfunction, and the infantile development of cardiomyopathy. Utilizing a mouse model of human Barth syndrome (TazKD mice; doxycycline-inducible short hairpin RNA-mediated Tafazzin knockdown), myocardial glucose oxidation rates were demonstrated to be markedly reduced in the tafazzin-deficient isolated working heart. Notably, impaired myocardial glucose oxidation was associated with the development of adverse hypertrophic left ventricular remodeling in TazKD mice. To assess whether pharmacological enhancement of myocardial glucose oxidation could mitigate pathological cardiac remodeling in Barth syndrome, TazKD mice were treated with dichloroacetate (70 mM) added to the drinking water for four weeks. Despite decreasing inhibitory phosphorylation of cardiac pyruvate dehydrogenase, suggestive of increased glucose oxidation, dichloroacetate failed to improve cardiac hypertrophy in TazKD mice. Therefore, stimulation of myocardial glucose oxidation may not represent an effective strategy to mitigate cardiomyopathy development and progression in Barth syndrome.

    In obese, prediabetic mice, transition to a ketogenic diet for eight weeks failed to induce significant body weight loss and improve obesity-induced impairments in glucose homeostasis. Furthermore, although maintenance on a ketogenic diet did not impair cardiac function, it increased cardiac lipid accumulation which may indicate the presence of pathological molecular alterations. In consideration of the present findings, caution should be exercised when considering a ketogenic diet as a non-pharmacological strategy to reduce cardiovascular risk factors in obesity and diabetes.

    Myocardial ketone body oxidation was blunted in isolated working hearts from mice with experimental type 2 diabetes, however, this decreased reliance on ketone bodies as an energy substrate may not be detrimental for the myocardium given that further inhibition by treatment with pimozide neglected to impair cardiac function. Our results offer fundamental insight regarding a potential adaptive role for decreased cardiac ketone body utilization in diabetic cardiomyopathy.

    In summary, the studies presented herein support that although alterations of myocardial energy metabolism represent a common feature of cardiomyopathies, modulation of intermediary metabolic pathways may not always represent an effective therapeutic approach. Furthermore, the results of the present studies provide fundamental insight into the myocardial metabolic profile characteristic of Barth syndrome and diabetic cardiomyopathies, which may serve to guide the development of targeted therapies.

  • Subjects / Keywords
  • Graduation date
    Spring 2023
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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.