This project aims at causal analysis and development of a therapeutic strategy for acute reperfusion injury. The first aim is to elucidate the mechanisms responsible for mechanical cellular injury. The second aim is to develop a therapeutic strategy to limit this Injury.
Ischemic heart disease is the leading cause of death in Europe. The extent of myocardial necrosis caused by acute coronary occlusion depends on damage developed during ischemia and during reperfusion, following spontaneous or therapeutic recanalization. There is increasing evidence that during the acute phase of reperfusion severe cellular damage, additional to the one manifested during ischemia, develops due to mechanical causes.
The project will combine methods and skills of three different laboratories within the European Union, two of which were partners in a previous, successful BIOMED-I project, to attain its objectives. The workplan considers the following 6 intermediate targets:
1. Sarcolemmal fragility is increased in reoxygenated cardiomyocytes. The importance of lipid peroxidation and disruption of the cytoskeletal anchoring of the sarcolemma will be investigated.
2. The role of uncontrolled force generation in reoxygenated cardiomyocytes, caused by elevated cytosolic Ca2+ levels, will be analyzed.
3. The causes for increased susceptibility of the myofibrils to develop hypercontracture will be studied in reoxygenated cardiomyocytes.
4. based on the previous causal analysis a composite strategy of therapeutic means will be developed for ischemic-reperfused myocardium in vivo (pig model).
5. In cardiomyocytes, saved from mechanical injury during early reperfusion, the consequences of gene expression in long-term recovery will be studied.
6. It will be investigated whether prevention of early reperfusion injury may eventually find its natural limit by nuclear injury, analogues to the natural process of apoptosis.
It is hoped that the answers to these questions will lead to the development of treatments able to improve survival and quality of life of patients with ischemic heart disease.