The majority of deaths associated with ischemic heart disease occur suddenly due to disturbances in rhythm leading to ventricular fibrillation (VF). The proposed research is directed at delineating the anatomic substrates and electrophysiologic derangements responsible for sustained ventricular tachycardia (VT), nonsustained VT and VF after transmural and non-transmural myocardial infarction using in vivo and in vitro procedures. Studies will also be performed to define the anatomic and electrophysiologic alterations responsible for the abnormalities in the fast Fourier transform derived frequency content of the signal averaged ECG detected in patients with, compared to those without, sustained VT. This approach offers promise for the non-invasive identification of patients at increased risk for developing sustained ventricular arrhythmias. A 3-dimensional mapping system will be used to identify the mechanisms responsible for VT as well as assess the underlying alterations responsible for the abnormalities in the ferquency content of the signal averaged ECG. In vitro electrophysiologic analyses and detailed morphometric studies will be performed to identify the functional and structural basis for delayed conduction through the border regions of the infarct which contribute to the maintenance of VT localized by previous mapping. Based on previous studies in animals and man implicating enhanced adrenergic neural influences in the occurrence of sudden cardiac death post myocardial infarction, a detailed analysis of the electrophysiologic effects of catecholamines will be performed both in vivo using detailed mapping procedures, as well as in vitro. Since previous studies using tissue homogenates of ischemic tissue indicate an increase in both Alpha-1 and Beta-adrenergic receptors, quantitative autoradiography of both receptor types will be performed first to assess whether increased regional receptor density is altered after infarction and second, whether the changes lead to enhanced or decreased responsitivity to catecholamines assessed by mapping studies in vivo and in vitro. The influence of selected antiarrhythmic agents on inducibility of ventricular arrhythmias following infarction, the electrophysiologic mechanisms responsible, and the associated alterations in the fast Fourier transform derived frequency content of the signal averaged ECG will provide essential data relative to the ability of frequency analysis to evaluate the efficacy of therapy non-invasively.
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