Recent observations indicate that intramural tissue is critical to sustained monomorphic ventricular tachycardia (VT) in patients with prior myocardial infarction. Improved, noninvasive detection of risk of sustained VT requires bioelectrical and biophysical characterization of the myocardium responsible for VT; knowledge of the time course of activation and recovery of the myocardium critical to VT during sinus beats; and a valid computer simulation of the anatomic and electrophysiologic substrate in humans responsible for VT. Accordingly, the proposed research will determine in patients the mechanisms of VT and test the hypothesis that differences in intramural activation and recovery during sinus rhythm and in response to programmed stimulation determine whether VT is sustained, nonsustained, monomorphic, polymorphic, or degenerates to ventricular fibrillation (VF). The planned studies will permit the unique opportunity to integrate the electrophysiologic and anatomic data acquired directly from human myocardium critical to VT with detailed, patient-specific computer-based simulations enabling direct testing of putative mechanisms of human VT. Analysis of transmural ventricular activation and recovery during sinus rhythm, programmed stimulation, and induced VT from patients with prior myocardial infarction (n=20) undergoing VT surgery or cardiomyopathy undergoing cardiac transplantation (n=10) will enable determination of the mechanisms that underlie each type of VT in ischemic and nonischemic heart disease; and the time course of activation of the tissue critical to each VT type during sinus rhythm. Forward and inverse problem solutions will be utilized to determine whether activation and recovery of the transmural components of the myocardium critical to VT are detected on the epicardium during sinus rhythm, data that are essential to ultimately establish that activation of arrhythmogenic tissue in the heart is responsible for the distinguishing spectral, temporal, and spatial features detected in signal-averaged ECGs from patients with VT. Magnitude and phase spectra of the dipole moments inferred from the epicardium for transmural tissue critical to VT will also be analyzed to determine whether or not there are distinguishing spectral, temporal, and spatial features, similar to those identified on the body surface, that permit separation of patients with VT from those without VT (n=10). Results of the research will improve procedures for VT ablation by characterizing and localizing the tissue critical to VT; and enhance the pathophysiologic foundation needed to refine methods of signal-averaged ECG analysis that will improve identification of risk of VT or VF.