Comparison of Detailed and Simplified Models of Human Atrial Myocytes to Recapitulate Patient Specific Properties

<div><p>Computer studies are often used to study mechanisms of cardiac arrhythmias, including atrial fibrillation (AF). A crucial component in these studies is the electrophysiological model that describes the membrane potential of myocytes. The models vary from detailed, describing numerous ion channels, to simplified, grouping ionic channels into a minimal set of variables. The parameters of these models, however, are determined across different experiments in varied species. Furthermore, a single set of parameters may not describe variations across patients, and models have rarely been shown to recapitulate critical features of AF in a given patient. In this study we develop physiologically accurate computational human atrial models by fitting parameters of a detailed and of a simplified model to clinical data for five patients undergoing ablation therapy. Parameters were simultaneously fitted to action potential (AP) morphology, action potential duration (APD) restitution and conduction velocity (CV) restitution curves in these patients. For both models, our fitting procedure generated parameter sets that accurately reproduced clinical data, but differed markedly from published sets and between patients, emphasizing the need for patient-specific adjustment. Both models produced two-dimensional spiral wave dynamics for that were similar for each patient. These results show that simplified, computationally efficient models are an attractive choice for simulations of human atrial electrophysiology in spatially extended domains. This study motivates the development and validation of patient-specific model-based mechanistic studies to target therapy.</p></div

The conduction velocity as a function of DI for each of the 5 patients.

<p>No raw data was available for the CV restitution curves, though the points calculated from the inverse activation time data can be seen in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005060#pcbi.1005060.g002" target="_blank">Fig 2</a>. Only the polynomial fit to these is shown here, along with the model curves.</p

Model APD curves can be fitted to clinical data.

<p>The clinically determined APD and its polynomial fit are shown as open and closed symbols, respectively, for the 5 patients. The results from the fitting procedure is shown in blue (FK) and red (KKT).</p

Spiral wave patterns in 2D for the fitted parameters sets.

<p>The top row shows snapshots of the activation pattern following the initiation of a spiral wave in the KKT model using the fitted parameter set for each patient. The membrane voltage is shown using a color scale. The middle row show snapshots of the activation patterns obtained using the FK model with white (black) corresponding to depolarized (repolarized) tissue. In the bottom row we have plotted the corresponding tip trajectories of the KKT model (red) and FK model (blue). Note that the trajectory location is arbitrary, and that some spirals were spatially translated to facilitate comparison between the models. Scalebar: 2 cm.</p

Computational Mapping Identifies Localized Mechanisms for Ablation of Atrial Fibrillation

<div><p>Atrial fibrillation (AF) is the most common heart rhythm disorder in the Western world and a common cause of hospitalization and death. Pharmacologic and non-pharmacologic therapies have met with limited success, in part due to an incomplete understanding of the underlying mechanisms for AF. AF is traditionally characterized by spatiotemporally disorganized electrical activation and, although initiating triggers for AF are described, it is unclear whether AF is sustained by spatially meandering continuous excitation (re-entrant waves), localized electrical sources within the atria, or some other mechanism. This has limited therapeutic options for this condition. Here we show that human AF is predominantly caused by a small number (1.8±0.9) of localized re-entrant waves or repetitive focal beats, that remain stable with limited spatial migration over prolonged periods of time. Radiofrequency ablation that selectively targeted the sites of these sources was able to immediately terminate fibrillation and eliminate the arrhythmia with high success. Our results show that human AF, despite apparent spatiotemporal disorganization, is often perpetuated by a few spatially-constrained and temporally conserved sources whose targeted ablation can eliminate this complex rhythm disorder.</p> </div

Clinical AP morphology compared to model AP morphologies obtained by fitting the model parameters.

<p>The average clinical AP morphology, corresponding to the largest DI value, is shown as a dashed line while the FK model is shown in blue and the KKT model is in red.</p

Clinical restitution data for patient 3.

<p>(A). The APD as a function of DI as determined from the MAP electrode (symbols) and the polynomial fit to the data (solid line). (B) CV as a function of CL using the activation times of the basket electrodes. (C) DI as a function of CL from the MAP data. (D) CV restitution curve computed using the data in (B) and (C). The symbols correspond to the values of the DI in (B).</p

Stable Localized sources underlie human atrial fibrillation.

<p><b>A</b>. Isochrones show an LA rotor in paroxysmal AF, with electrograms during AF (ECG lead I and CS electrodes; scale bar 1 second). Activation times are color-coded (black indicates non-activated, diastole). <b>B</b>. Spatially constrained migration locus of the rotational center, computed every 25–45 ms and joined using third-order Bézier curve fitting. <b>C</b>. Isochrones 90 minutes later, indicating temporal conservation of the rotor. <b>D</b>. Isochrones of a RA rotor in persistent AF. <b>E</b>. Migration locus. <b>F</b>. Isochrones 1 hour later. <b>G</b>. LA repetitive focal beat in paroxysmal AF. <b>H</b>. Conservation of focal beat 1 hour later. In each case, ablation only at the source locus terminated AF within <5 minutes. Scale bar 1 cm.</p

Determination of AP shape from clinical data.

<p>(A) MAP data in one of our patients (2) for different CLs (in ms). Time is rescaled and runs from 0 (stimulus) to 1 (repolarization). (B) Clinical data, corrected for pacing artifacts averaged over all CLs, shown as symbols and the corresponding polynomial fit.</p

AF Termination by ablation of a Stable RA Rotor.

<p><b>A</b>. Isochrones show a RA rotor and concurrent LA focal beat during persistent AF. <b>B</b>. Spatially constrained rotational center locus. <b>C</b>. Ablation lesions at lateral RA rotor on patient specific geometry (performed 2 hours after initial recording of rotor). A total of 11 lesions were applied (shown), with AF termination to sinus rhythm at 5.5 minutes. The red lesion indicates where ablation terminated AF. <b>D</b>. Electrograms AF terminating to sinus rhythm with localized ablation at rotor (total duration 5.5 minutes) (ECG lead I, intracardiac electrodes in RA, LA and CS). <b>E</b>. Isochrones of sinus rhythm. After ablation, the patient remains AF-free at 12 months on implanted cardiac monitor. Scale bar 1 cm.</p