Recent studies suggest that antiarrhythmic drugs (AADs) may protect against potentially lethal ventricular arrhythmias independent of quantitative suppression of chronic ventricular ectopic activity (VEA); i.e.; a dissociation between """"""""antifibrillatory/antitachycardia"""""""" and """"""""antidyrhythmic"""""""" drug actions. In addition, there are conflicting data on the best end-points for antiarrhythmic management of patients at risk for potentially lethal arrhythmias. Therefore, this project was designed for the ultimate goal of developing better guiding principles for the use of AADs. The studies are based on the premise that fundamental information on relationships between forms of VEA, clinical settings in which they occur, and responses of ventricular arrhythmias to therapy, must be accumulated and analyzed before the ultimate aim can be achieved. Three major hypotheses will be tested: (1) that concentration-response relationships between AADs and potentially lethal arrhythmias differ from those for various forms of non-lethal VEA; (2) that antiarrhythmic effectiveness varies as a function of clinical setting in which a specific arrhythmia occurs; and (3) that concentration-response relationships vary as a function of free drug concentrations. The hypotheses will be tested in 4 patient categories, based on our preliminary data: (1) patients who have chronic VEA of different forms; (2) patients with acute myocardial infarction with VEA studied longitudinally - acutely, during convalescence, about 3 weeks after the acute event; (3) patients who have recurrent sustained ventricular tachycardia (VT) and a background of chronic VEA; and (4) survivors of prehospital cardiac arrest. In patients without life-threatening arrhythmias, the relationship between free and total plasma concentrations of AADs on forms and frequencies of ventricular arrhythmias will be studied. Three standard drugs with different binding kinetics will be used: the highly bound drug quinidine; the poorly bound drug procainamide; and a drug with concentration-related binding, disopyramide. In patients with life-threatening arrhythmias, 3 end-points of therapy will be evaluated: (1) concentration-related changes in frequencies or forms of chronic VEA; (2) changes in inducibility of VT, and simultaneous changes in VEA, during drug testing in the electrophysiology laboratory; and (3) the influence of free and total plasma levels of AADs on long-term arrhythmia control. Clarification of the relationships between forms of arrhythmias, clinical settings, and responses measured in terms of various end-points of therapy will provide fundamental information needed to define the role of AADs in patients who have potentially lethal or non-lethal forms of ventricular arrhythmias.
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