The surgical correction of the majority of acquired and congenital cardiac defects requires that the myocardium undergo a period of global ischemia with the effects of this ischemia lessened by the infusion of cold, potassium-containing cardioplegia. Current cardioplegic solutions result in numerous undesirable side effects which include reversible and occasionally irreversible conduction system injury, cell swelling which affects contractility, reversible sarcolemmal phospholipid injury which affects cell volume regulation, intracellular enzyme denaturation as well as nucleoside washout upon reperfusion. Of fundamental importance to further improving intraoperative myocardial preservation techniques and the subsequent long term results achieved by cardiac operative procedures is a more detailed understanding of the basic pathogenesis of both reversible as well as irreversible injury during global ischemia. The planned research proposal has two interrelated specific aims designed to further our understanding of the basic pathogenesis of total ischemia, and to allow this process to be monitored in on-line fashion using new tissue microelectrodes capable of monitoring a variety of interstitial ionic and molecular events. Basic investigations of the pathogenesis of total ischemia will further investigate recent findings from our laboratory showing that during total ischemia, ultrastructural and metabolic evidence for irreversible injury appears first in the subendocardium and coincides closely with the eventual onset of ischemic contracture. Relevant to cardiac surgery is the finding that these changes occurred in a model system completely free of collateral flow and wall tension. Specific studies will be performed to determine why the metabolic rate of the subendocardium is increased and how to control this metabolic rate prior to a planned period of global ischemia. In order to develop an on-line means to determine the degree of ischemic injury occurring during cardiac operations, totally new tissue microelectrodes based on microfilamentous carbon rods will be developed which are capable of monitoring in on-line fashion tissue ionic and molecular fluxes which can be correlated with the progression of ischemic injury. The proposed microelectrode technology represents a totally new means to achieve this goal. Interstitial ionic and molecular fluxes (potassium, calcium, magnesium, hydrogen ions, NAD and hypoxanthine) occurring during varying degrees of reversible ischemia will be correlated with measureable markers such as high energy phosphate depletion and ultrastructural changes. These two interrelated projects rely heavily on basic investigative work but have definite clinical relevance. The research personnel involved in the planned work represent a unique combination of individuals with basic science investigative experience and the planned studies all relate to the clinical problem of improving surgical results.
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