Schulman, Daniel; (2002) The impact of age on the ability of preconditioning and pharmacological intervention to protect the heart from ischaemic and reperfusion injury. Doctoral thesis (Ph.D), University College London.

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Abstract

Introduction: Ischaemic heart disease is the main cause of morbidity and mortality in the United Kingdom, with the greatest proportion of suffers being elderly. Current treatments are not altogether successful, and there is a need for development of improved therapeutic strategies. One area of interest is ischaemic preconditioning as well as the pharmacological prevention of ischaemic and reperfiision injury through upregulation of various reperfusion induced salvage kinases (e.g. p42/p44 MAPK). However, the effect of senescence on the ability of these treatments to influence outcome of ischaemia / reperfusion injury has been overlooked, and the aims of this study has been to address aspects of changed signalling mechanisms and cardioprotection in the aged heart in addition to exploring the role of p42/p44 MAPK in protecting the heart from reperfusion injury. Methods; Whole heart in vitro rat models of myocardial infarction have been used to investigate differences in ischaemic and pharmacological preconditioning in rats of three age groups (young adults, middle age, old). Using similarly aged rats, experiments on isolated mitochondria have investigated age related changes in mitochondrial membrane potential in response to treatment with the mitochondrial KATP channel opener, diazoxide. Further studies in both rat (young and old) and rabbit in vitro and in vivo models of myocardial infarction have determined the role of the agents urocortin and cardiotrophin-1 in protecting the heart from reperfusion injury through activation of the p42/p44 mitogen activated protein kinase (MAPK) pathway. Results; Progressive age has been shown to negatively affect the ability of preconditioning to protect the heart from myocardial infarction, and mitochondrial studies have supported these findings. The importance of the p42/p44 MAPK pathway has been demonstrated in the protection of young adult rats from reperfusion injury, though this effect has been lost in the aged rat heart. Conclusion: Ischaemic and pharmacological preconditioning, as well as pharmacological intervention at reperfusion are both able to reduce infarct size in the adult heart, however the influence of senescence leads to the abrogation of all modalities of cardioprotection investigated in this study.

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