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Title: The influence of age and type 2 diabetes on cardioprotective interventions against myocardial ischaemia-reperfusion injury
Author: Whittington, H. J.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The background of the thesis is based on the conflicting results between bench and bedside regarding the susceptibility to myocardial infarction with old age and diabetes. In laboratories all over the world, strategies have been developed to protect the myocardium from this insult, including the use of ischaemic conditioning (short periods of ischaemia and reperfusion prior to or following lethal ischaemia) or the use of a variety of pharmacological agents. However, surprisingly, translating these effective cardioprotective treatments into the clinic has proved problematic. The main issue seems to be the fact that the experimental investigations have mainly used young, healthy animals while the human patients present often with a number of other risk factors, or comorbidities, such as type 2 diabetes and old age. Therefore the aim of this thesis was to investigate the susceptibility to ischaemia-reperfusion injury and the proficiency of cardioprotective strategies to protect the heart in the setting of ageing and type 2 diabetes. Utilizing a model of type 2 diabetes, the Goto-Kakizaki rat and its normoglycaemic control Wistar rat, within the range of 3 to 18 months of age, the Langendorff isolated heart model and in vivo coronary artery occlusion and reperfusion were employed to investigate the susceptibility to ischaemia-reperfusion injury. Mechanical or pharmacological cardioprotective strategies were also investigated in this setting and the mechanisms of the failed cardioprotection were examined further using in vitro techniques focusing on known pro survival signalling pathways within the myocardium. The ageing diabetic heart demonstrated an increased vulnerability to injury and was less amenable to protection by ischaemic conditioning. Pharmacological agents namely, metformin and sitagliptin appear to differentially protect the diabetic and non-diabetic heart, and this could be due to the underlying intracellular changes associated with ageing and diabetes.
Supervisor: Mocanu, M. M. ; Yellon, D. Y. ; Hausenloy, D. J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available