Targeting the reperfusion injury salvage kinase pathway in the clinical setting.
Doctoral thesis, UCL (University College London).
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Ischaemic heart disease contributes the largest burden and despite advances in revascularisation therapy significant morbidity and mortality exist in both the elective and emergency treatment setting. Short episodes of sub-lethal ischaemia and reperfusion applied before a period of prolonged ischaemia (preconditioning) and reperfusion stuttered with short episodes of ischaemia (postconditioning) are powerful, endogenous, cardioprotective phenomena which offer the potential to reduce myocardial injury and infarction by as much as 50%. Despite many years of research these mechanical, invasive techniques have not been adopted to routine practice. A pharmacological mimetic, targeting the same protective pathways as pre- and post- conditioning would have great potential in reducing myocardial injury in a number of clinical settings and could be easily administered and adopted to the clinical arena. Chapter 1 of this thesis summarises the research to date in this rapidly evolving field concentrating on two pharmacological conditioning mimetics, atorvastatin and erythropoietin and the clinical assessment of cardioprotection and myocardial salvage. Chapter 2 details the hypotheses to be investigated. Chapter 3 describes two studies undertaken in coronary artery bypass surgery with high dose atorvastatin as a potential cardioprotective agent. Chapter 4 describes a study testing the use of erythropoietin in patients presenting with acute myocardial infarction requiring emergency angioplasty and using cardiac magnetic resonance outcome measures. Chapter 5 highlights the difficulties in translating pre-clinical animal studies to the human clinical setting and discusses potential methods to improve this. In summary, this thesis examines the pre-existing research regarding atorvastatin and erythropoietin as cardioprotective agents. Novel clinical studies testing the use of these agents in the settings of coronary artery bypass surgery and acute myocardial infarction are presented. The findings are discussed and reviewed in the context of ongoing advances in the field of cardioprotection.
|Title:||Targeting the reperfusion injury salvage kinase pathway in the clinical setting|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Hatter Cardiovascular Institute|
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