The objective of the research outlined in this proposal is to determine the unique ionic conditions responsible for ventricular fibrillation in the setting of acute regional myocardial ischemia. Following occlusion of the left anterior descending coronary artery (LAD), we believe that discrete myocardial regions are created in which extracellular potassium is elevated to approximately l0mM, but pH is lowered by no more than 02 pH units. As a result of this specific ionic combination, slow-channel mediated responses occur and cause impulses to propagate with very slow conduction (ie, a conduction velocity of less than 10cm/sec). Premature responses occurring in close proximity to these discrete regions, either as a the result of spontaneous reentry or as the result of abnormal automaticity induced by injury currents, may then reenter to cause ventricular tachycardia and ventricular fibrillation. Our hypothesis also predicts that the known anti-fibrillatory effects of the calcium channel blocking agents, such as verapamil, will be due to the ability of these agents to prevent very slow conduction by lessening the likelihood that these ionic discrete regions will be created via alterations in the time course of ionic change and by direct blockade the slow calcium channel mediated currents which are responsible for the very slow conduction. In preparation for these experiments, we have designed ion-selective and voltage sensors using a Kapton/polyimide substrate dagger electrode that will permit the accurate three dimensional mapping of K+, pH, and activation throughout the ischemic zone and we have developed unique software programs and hardware systems necessary to analyze and display these data. Experimental studies will be performed in open-chested, domestic swine whose hearts have been instrumented with a carotid-to-LAD shunt. Flow through the LAD will be controlled by a peristaltic roller pump and brief periods (8min) of ischemia will be initiated by halting this pump.
Our specific aims are to: (1) identify and characterize regions of the heart demonstrating these critical K+/pH combinations; (2) measure conduction velocity within these regions to characterize and quantify the degree of conduction slowing produced; (3) test the susceptibility of these regions to initiate and/or sustain premature beats that lead to reentry and ventricular fibrillation; and (4) determine the action on calcium channel blockade (e.g, verapamil) on the location of the regions, on the conduction velocity across these regions, and on the response of these regions to premature stimuli.
