Applications in
Computational Biology:
Focus on Excitable Media and
Cardiac Electrophysiology
Catheter
ablation of reentrant atrial arrhythmias. Certain types of
predictable atrial arrhythmias can be treated by radiofrequency catheter
ablation, in which a catheter is inserted into the heart and, following a
diagnostic session to locate the path of the reentrant waves, energy is applied
to form non-conducting lesions that can eliminate the aberrant conduction
pathways. However, catheter ablation techniques to treat chronic reentrant
atrial fibrillation (AF) have been largely unsuccessful. I have postulated that
a major determinant of failure is the extreme variability in atrial structure
among chronic AF patients, who usually have various types of
structure-affecting heart disease, so that no single catheter ablation strategy
will be successful; rather, therapy must be individualized using
patient-specific atrial geometry data. To date, I have been performing the
fundamental research necessary to bring patient-specific ablation therapy to
the animal laboratory and, ultimately, to human patients. Using both an
existing generic anatomical model of the human atria and patient-specific
anatomical provided by Dr. Steven J. Evans, a clinical electrophysiologist at
Beth Israel Medical Center, I have been testing the efficacy of different
ablation strategies in silico to determine how ablation lesions can be
successfully placed for specific individual anatomic structures. In one
reentrant AF scenario, I found that using left atrial ablation lines (shown as
unexcited dark blue tissue in Figure 1) around the pulmonary veins did not
prevent reentry formation from a premature stimulus (see Figure 1A), whereas
the addition of a right atrial ablation line connecting the superior and
inferior venae cavae with all other conditions the same successfully prevented
reentry (Figure 1B). This work is designed to lead directly to testable
ablation strategies and to novel clinical paradigms in the treatment of AF.
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A 205 ms |
B 1190 ms |
C 1970 ms |
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D 205 ms |
E 1190 ms |
F 1275 ms |
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Figure 1. Efficacy of different locations of ablation lines
in terminating reentry. Electrical potential is shown, ranging from blue (-80
mV) to red (20 mV). (a) Using left lines only (isolating pulmonary veins and
connecting to each other and to the mitral valve annulus), reentry was
sustained for 7 seconds, the length of the simulation. (b) Adding right lines
(connecting superior vena cava to inferior vena cava and inferior vena cava
to tricuspid valve annulus) terminated the reentry in just over one second.
The lines of block can be seen as areas with fixed-value voltages
corresponding to blue in color. |
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Movie of successful catheter ablation intervention with the addition of a right atrial lesion.
Geometrical effects of pulmonary veins on reentry stability. The pulmonary veins in the left atrium have received much attention lately as a possible source of atrial arrhythmias. It has been hypothesized that the pulmonary veins can spontaneously produce activations which result in fibrillation. However, experiments have not confirmed this hypothesis. In modeling work conducted recently with experimental collaborators, I developed mathematical models of pulmonary vein electrical activity that accurately reproduce experimental data from left atrial (Figure 2A) and pulmonary vein (Figure 2B) physiology and I have shown that another mechanism can explain the role of pulmonary veins in arrhythmias while also remaining consistent with the experimental observation that pulmonary veins do not produce spontaneous activations at physiologically relevant heart rates. In this scenario, observed heterogeneous conduction in the pulmonary veins can lead to conduction block and, subsequently, the formation of reentry. I have explained this mechanism thus far using an idealized model of a single pulmonary vein connected to a 2D sheet of left atrial tissue (Figure 2C) in which cell-to-cell connections along both the longitudinal and circumferential directions have a certain probability of being removed. If too few connections are removed, propagation proceeds normally, and if too many connections are removed, propagation along the vein fails. However, in between there is a range of probabilities that produce either nonsustained or sustained reentrant waves. Currently I am working to determine the range of connection removal probabilities in which sustained reentry can be induced in a realistic human atrial structure.
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Figure 2. Pulmonary veins and
reentry. (A) Representative normal left atrial experimental (black) and
model (red) action potentials. (B) Representative normal pulmonary vein
experimental (black) and model (red) action potentials. (C) Reentry
within a pulmonary vein due to patchy propagation results in activation of
the left atrium. |
A |
B |
C |
Movie of initiation of pulmonary vein-induced activation of the left atrium as a result of a premature stimulus from the left atrium.
Movie of a self-terminating pulmonary vein-induced arrhythmia in the left atrium.
Movie of a sustained pulmonary vein-induced arrhythmia in the left atrium.
Movie of propagation failure within the pulmonary vein due to insufficient connectivity.
