Morris, Susan D.; (1998) Myocardial protection : From cell culture to human in vitro models. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Background: In the Western world acute myocardial infarction remains one of the most important causes of mortality in adults. Although advances such as thrombolysis and primary angioplasty have revolutionised treatment, myocardial infarction remains a major challenge. This is in part because benefits diminish as treatment is delayed. Hence the potential for exploiting the endogenous protective mechanisms within the myocardium is of prime clinical importance. Any potential agent which induces a state of enhanced resistance to ischaemia warrants investigation as it may potentially lead to the development of novel therapeutic approaches to cardioprotection in clinical practise. Aim: The broad aim of this thesis is to investigate possible pharmacological therapeutic approaches to cardioprotection. Methods: Two routes to myocardial protection were studied: The potential role for up regulating stress proteins in order to protect the myocardium was examined in an isolated rat neonatal cardiomyocyte model. A tyrosine kinase inhibitor known to induce stress proteins in non cardiac cells was studied in detail. The cardioprotective effects of angiotensin converting enzyme inhibitors were studied in a superfused isometrically contracting human atrial trabeculae model. Results: It is possible to specifically up regulate 70 kDa heat stress proteins and induce a state of enhanced resistance to myocardial injury. Furthermore, in a human atrial model of ischaemia, angiotensin converting enzyme inhibitors exert cardioprotective effects, possibly via B2 bradykinin receptors. Conclusions: These results demonstrate that the endogenous protective mechanisms within the myocardium may be amenable to therapeutic manipulation. In the future both routes to protecting the myocardium could be of use in a clinical setting. For example a prolonged state of protection via induction of stress proteins could be superimposed with a shorter classical preconditioning type of protection when needed, for example prior to high risk coronary angioplasty or coronary artery bypass surgery.

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