| dc.description.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>
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