Computer Model of Mechanisms Underlying Dynamic Electrocardiographic T-wave Changes

Abstract

<p>Sudden death from arrhythmia is a major cause of mortality in the United States. Unfortunately, no current diagnostic test can accurately predict risk for sudden arrhythmic death. Because ventricular arrhythmias often result from abnormalities of repolarization, assessment of myocardial repolarization using the electrocardiogram (ECG) can aid in prediction of arrhythmia risk. Non-linear, rate-dependent changes in myocardial repolarization can promote the development of arrhythmia, but few studies examine how these dynamic changes in repolarization affect the ECG. This dissertation describes the use of a computer model to investigate the effect of dynamic changes in myocardial repolarization on the ECG T wave.</p><p>To simulate action potential conduction from the endocardium to the epicardium of the free wall of the canine left ventricle, 1-dimensional multicellular computer fiber models were created. Each fiber model was composed of endocardial, midmyocardial, and epicardial cells. For each cell type, existing mathematical models were modified to approximate experimental data for four types of dynamic repolarization behavior: (1) dynamic restitution, the response to steady-state pacing; (2) S1-S2 restitution, the response to a premature or postmature stimulus; (3) short-term memory (STM), the response to an abrupt change in pacing rate; and (4) repolarization alternans, beat-to-beat alternation in cellular repolarization time. Repolarization times were obtained from endocardial, midmyocardial, and epicardial regions in the fiber model and compared to parameters measured from a computed transmural ECG.</p><p>Spatial differences in repolarization created two voltage gradients that influenced the ECG: an endocardial-midmyocardial (endo-mid) gradient and a midmyocardial-epicardial (mid-epi) gradient. Epicardial dynamic restitution changes altered the mid-epi gradient, influencing the rising phase of the ECG T wave, and endocardial dynamic restitution changes altered the endo-mid gradient, influencing the falling phase of the T wave. Changes in epicardial or endocardial repolarization due to S1-S2 restitution or STM caused transient changes in the rising or falling phase of the T wave, respectively.</p><p>During repolarization alternans, an alternating, asymmetric distribution of extracellular potential around the fiber influenced the measurement of T-wave alternans (TWA) in the ECG. Presence of a resistive barrier in the fiber model altered the magnitude of repolarization alternans as well as the TWA amplitude in the ECG with effects dependent on barrier location. The resistive barrier also modified the relationship between cellular repolarization alternans magnitude and TWA amplitude.</p><p>The results presented in this dissertation explain basic mechanisms by which dynamic changes in myocardial repolarization affect the ECG T wave. These mechanisms form the foundation for the development of techniques to identify arrhythmogenic, dynamic changes in the myocardium using the ECG. Future studies in higher-dimensional, more complex models will build upon these results by considering the influence of additional voltage gradients, more realistic tissue geometries, and heterogeneities in the volume conductor.</p>