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.

A 205 ms
B 1190 ms
C 1970 ms
D 205 ms
E 1190 ms
F 1275 ms

Figure 1

Movie of unsuccessful catheter ablation intervention using only left atrial lesions.

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.


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.

Movie of normal pulmonary vein-induced activation of the left atrium.

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.