J Mol Cell Cardiol 18, (Supplement 4) 109 (1986)

CHALLENGES AND PROSPECTS FOR 'E"IE

Howard E. Morgan M.D.

Department of Physiology, Milton S Hershey Medical Center, Hershey, Pa. 17033, USA.

What are the problems for current research into the mechanisms of ischaemic damage and the prospects for the future? i) Studies of ischaemia and reperfusion remain descriptive and a rigorous approach to the mechanism of changes has not been taken. In large part, this problem may be related to the fact that knowledge of the fundanental cell biology is still too inadequate to allow approp- riate mechanistic questions to he asked. Such mechanistic studies also require new technologies that are not yet avail- able or not familiar to many investiga- tors in this field. 2 ) Experimental models may be used that in scme instances mimic severe ischaemia but in others simulate high flow anoxia. Although these conditions may he super- ficially similar, large differences probably exist with regard to the mechanism of cell damage. Rigorous evaluation of the animal or isolated tissue models of ischaemia is needed. This evaluation rmast include considerat- ion of the heterogeneity produced by the death of a small fraction of cells or by an area of no-reflow during reperfusion. 3) New and specific forms of therapy require a detailed understanding of cellular and molecular mechanisms and represent the major prospect for the

future. In the evaluation of therapeutic agents, failure to distinguish between a delay in oell death and permanent salvage has been ce[nmon. Thus, it is now appar- ent that the anti-inflammatory agent flurbiprofen will limit infarct size at 6 hours but not at 24 hours, and that the calcium blocker verapamil is effect- ive at 24 but not 48 hours.

In man the topiCs to be addressed with regard to limitation of infarct size are considered to he I) whether limitation of infarct size will improve function, 2) whether reperfusion ultimately is essential for salvage, 3) over what periods an agent must he adalinistered and for how long procedures to revasol]~ise the myocardium can be delayed, and 4) the measurment of infarct size, as well as risk zone size, in relation to the clinical evaluation of drug effect- iveness. These measurements cannot currently be done.

In summary, the major challenges which exist are to define the molecular mechanisms of ischaemic damage, to design more specific pharmacologic agents to correct these abnormalities, and to evaluate the most efficacious agents in man.

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