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Determinants of Reperfusion Injury in the Diabetic Heart

Harding, Idris John; (2019) Determinants of Reperfusion Injury in the Diabetic Heart. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Ischaemic cardiac injury is a leading cause of morbidity and mortality. Recent advances in management of acute cardiac ischaemia have seen early mortality fall and increased survival of myocardial infarction. An increase in prevalence of left ventricular systolic dysfunction and congestive cardiac failure have accompanied increased survival of acute events. Chronic congestive cardiac failure confers high morbidity and late mortality from ischaemic disease. Given the correlation between infarct volume and likelihood of post-infarct heart failure, reduction of infarct size has emerged as an important therapeutic target. A range of experimental treatments collectively termed “preconditioning” have been shown to reduce vulnerability to experimental myocardial infarction in animals but reproducing these results in human cohorts suffering spontaneous myocardial infarction has proved challenging. One of the explanations advanced for lack of translation has been the high prevalence of diabetes in the human population undergoing myocardial infarction, and a direct interaction between the diabetic state and preconditioning treatments has been proposed. Here, I investigate if animal model of diabetes can be used to predict and overcome failure of preconditioning treatments in the diabetic population. Using a rat model of type 2 diabetes, alongside rat strains at lower risk of developing diabetes, the impact of blood insulin content and blood glucose content on susceptibility to myocardial infarction and amelioration by preconditioning treatments was quantified. Experimental infarction was induced by temporary coronary occlusion in an ex vivo Langendorff preparation; both direct and remote ischaemic preconditioning treatments were studied. A raised threshold for successful preconditioning in diabetes was confirmed for direct ischaemic preconditioning and identified for the first time in remote ischaemic preconditioning. Relationships between myocardial exposure to glucose and extent of ischaemia-reperfusion injury were described in both diabetic and non-diabetic animals, and the damage attributable to high glucose exposure in non-diabetic hearts rescued by partial blockade of cellular glucose uptake.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Determinants of Reperfusion Injury in the Diabetic Heart
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10083449
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