While cardioplegic arrest is a common requirement for cardiac surgery, transient left ventricular (LV) dysfunction can occur following reperfusion and rewarming. The overall goal of this project is to define basic mechanisms responsible for LV dysfunction following cardioplegic arrest and to identify unique strategies at the cellular and molecular level which will protect the fundamental contractile unit of the heart, the myocyte, during cardioplegic arrest. Past studies have demonstrated that myocardial preconditioning protects the myocardium from a subsequent prolonged ischemic insult. Potential mechanisms for preconditioning include opening of the ATP sensitive potassium (Katp) channels and activation of the myocyte adenosine receptor system. Recent reports have identified a link between the adenosine receptor and the Katp channel; activation of protein kinase C (PKC). Based on these findings and preliminary results from our laboratory, the following hypotheses will be tested: (1) Katp activation will improve myocyte contractile processes following cardioplegic arrest and that a contributory mechanism for this effect is improved ionic homeostasis, (2) Adenosine receptor activation followed by cardioplegic arrest will improve myocyte contractile processes and the intracellular mechanisms for this effect are similar to that of Katp activation and cardioplegic arrest, (3) The specific intracellular trigger for myocyte protection during cardioplegic arrest is PKC stimulation, which in turn activates the Katp channel, (4) Katp opening or adenosine treatment with cardioplegic arrest provide particular beneficial effects in the setting of pre-existing LV dysfunction. Using LV myocytes isolated from normal and heart failure pigs, and an isolated myocyte system developed by this laboratory, the effects and mechanisms for each treatment will be defined. In order to facilitate the transfer of the findings from this project to clinical applications, this project will isolate LV myocytes from patients undergoing cardiac surgery in order to develop a predictive model which will identify the patients which will benefit from these treatment strategies.
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