Cooper, Marie; (1999) An in-vitro assessment of myocardial ischaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ischaemic heart disease is the most common causes of death in the United Kingdom. In addition to the mortality associated with this disease there are the human and economic costs associated with chronic illness. Many strategies for the treatment and prevention of heart disease are in use and under investigation. The consequences of myocardial infarction have been well described but the causes and mechanisms underlying the disease and its sequeli remain largely unknown. In order to investigate the mechanisms of ischaemic injury and the interventions that might lead to new or improved therapeutic strategies a number of model systems have been devised. The work described in this thesis concerns the construction and validation of a new model system. In order to investigate the mechanisms of ischaemic injury at the cellular level a model has been constructed based on the adult cardiac myocyte in culture. In the first series of experiments described in this thesis the characteristics of adult cardiomyocytes in culture were investigated and a model of ischaemia / reperfusion injury was devised. The model was tested to determine the effects of the individual components of the ischaemic milieu, in living tissues, on cells in culture. Combinations of these components that would cause reproducible lethal and sub-lethal stimuli analogous to those observed in other models and in living tissues were also investigated. It was also determined that cells in culture retained the responses to injury found in the in-vivo heart and that these responses could be modified by similar interventions. The second series of experiments described in this study dealt with the potential for gene-transfer to myocardial cells as a strategy for modifying the response of these cells to ischaemic injury. This work was divided into three parts. The first was concerned with finding the optimal gene delivery vehicle for use in cells in culture that would also have utility in other model systems such as the in-vitro or in-vivo heart. In this section of the work, both viral and non-viral gene delivery systems were investigated. The second part of the work involved an assessment of the modification of response to injury of gene transfer techniques per se. The final part of the work was to have looked at the action of the transfer of specific genes on the response to ischaemic injury in the in-vitro model.

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