ELECTRICAL RESTITUTION AND VENTRICULAR FIBRILLATION

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DESCRIPTION (adapted from the applicant's description): The mechanism for ventricular fibrillation (VF) is still poorly understood. The currently accepted notion is that the onset of VF involves the disintegration of a single spiral wave into many self-perpetuating waves and that such a process requires that the slope of the restitution relation between the action potential duration (APD) and its previous diastolic interval is equal to or greater than 1. The same theory anticipates that a single spiral wave will be stable (not disintegrate) if the slope of the APD restitution relation is less than 1. Using a new dynamic measurement protocol, the investigators have shown that the slope of the APD restitution relation is equal to or greater than 1 in canine endocardium, and that Ca channel blockers and hyperkalemia reduce the slope of the restitution relation and suppress VF in normal three-dimensional myocardium. Three aims (in reality, hypotheses) are now proposed. 1) Increasing repolarizing K currents also reduces the slope of the APD restitution relation and suppresses VF. This is to be tested via simulation using the Luo-Rudy membrane model and 2-D sheets of coupled LRd-type elements, and via experimental interventions that increase repolarizing K currents. Hypothesis 2) states that reductions in the slope of the APD restitution relation also suppress VF in the setting of acute myocardial infarction. To test this hypothesis, restitution relations for both APD and conduction velocity will be determined during ischemia in perfused canine ventricle and in intact Langendorff-perfused canine hearts, and the effects of ischemia on the induction and maintenance of VF will be determined. Interventions that reduce the slope of the APD restitution relation will then be delivered to determine whether they convert the VF into a periodic rhythm. Hypothesis 3) is that VF can also be induced in two-dimensional myocardium and can be modulated by alterations in the slope of the APD restitution relation. To address this, the restitution relations for conduction velocity and APD will be determined in canine and equine epicardium, prior to and after excision of large 2-dimensional sheets of epicardial tissue. Attempts will be made to induce VF using rapid pacing and the success or failure of each attempt will be correlated with the slope of the APD restitution relation. If VF is induced, the effects on the VF of interventions known to reduce the slope of the APD restitution relation will be determined. These studies will help to define the relative role of APD restitution kinetics in the development of VF, vis-a-vis other known or suspected modulators of VF, in both normal and ischemic myocardium. New strategies to reduce the slope of the APD restitution relation and thereby suppress VF may suggest novel pharmacological therapies for the prevention of VF and sudden cardiac death.