Paroxysmal Lone Atrial Fibrillation Is Associated With an Abnormal Atrial Substrate

Figures

• 

  FIGURE 1. Electrical Remodeling in Individual Atrial Myocytes (A) Progressive electrical remodeling of ionic currents and fluxes (different color lines) in response to progressively faster pacing (shorter cycle lengths). Conductances are at baseline (γx ≈1) for pacing at 60 beats/min (cycle length of 1,000 ms). (B) Calcium transients (CaTs) (red) and moving average intracellular calcium (Cai) (black) illustrate the impact of remodeling to a maintain a homeostatic Cai level (calcium target, dashed horizontal line) at different cycle lengths. (C) Electrical remodeling, following pacing at different cycle lengths, alters action potential duration (APD) restitution. (D) Electrical remodeling following 250-ms pacing (dotted line) results in shorter action potentials and altered CaTs compared with the healthy state (solid line) (calcium target, dashed horizontal line). (E) For all currents and fluxes (different color lines), steady-state remodeling at different cycle lengths (symbols) maintains a linear relationship between conductances, described by equation 1.

• 

  FIGURE 2. Spiral Wave Stabilization in a Homogeneous Atrial Tissue The size of the tissue corresponds to 512 × 512 cells. (A) The trajectory of the spiral tip over the first simulation hour illustrates stabilization after the first approximately 1,000 seconds. (B, C) Snapshots of voltage, Cai, and electrical conductance scaling factor γCaL for (B) stable and (C) unstable spirals. The initially induced spiral wave is unstable, leading to breakups and extinction. As remodeling progresses, the spiral wave stabilizes. (B) Note that the spiral tip follows the electrical remodeling spatial pattern, which was induced by the stable spiral wave (right and inset). Black traces show spiral tip position shortly before and after each snapshot. (D) The position of the spiral tip trajectories (y-axis projection) is initially wide (spanning the entire tissue), with brief pauses (denoting wave breakups) before stabilizing. (E) The pseudo-electrocardiogram of tissue voltage activity similarly indicates periods of unstable and stable spirals. Orange lines denote rapid (100 ms) pacing followed by cross-stimulation. (F) Electrical (γCaL , green lines) remodeling approaches steady-state levels relatively early,…

• 

  FIGURE 3. Long-Term Progression of AF in a Heterogeneous Atrial Tissue Further details of the same simulation are shown in Figures 4 to 6. The tissue size corresponds to 1024 × 1024 cells. (A) Pseudo-electrocardiogram of tissue voltage activity. Orange lines mark episodes of fast pacing (100 ms). B) Progression of atrial fibrillation (AF) interval duration. Note the log scale on the y-axis. (C) Electrical (γCaL) and (D) intercellular coupling (γD) remodeling dynamics during progression from transient to persistent fibrillatory activity. (E) Spatial map of calcium target (Catgt) in the heterogeneous tissue. (F, G) Examples of electrical activity (time points denoted in the plots above) during an episode of fast pacing and during re-entrant activity.

• 

  FIGURE 4. The First Episode of Spontaneous Initiation of Re-entry in Heterogeneous Tissue (A) Spiral tip tracks during the first episode of re-entry. (B) Pseudo-electrocardiogram and pacing episodes. (C, D) Tissue activity and remodeling states during the initiation of re-entry. (C) Pacing in the lower left corner. (D) Re-entry initiation around a remodeling “peak,” which defines a local intracellular calcium (Cai) heterogeneity leading to a temporary local conduction block. Data are also shown in Video 5.

• 

  FIGURE 5. Increasing Complexity and Organization of AF Over Time (A) The number of spiral wave tips present in the atrial tissue (with red trace showing moving average). The pacing markers (same as Figure 3A) are overlaid for reference. (B) Increase in the dominant frequency of atrial fibrillation (AF) activity. The vertical dotted line marks the transition to permanent re-entrant activity. The final permanent episode is split into 1,000-second intervals. The red curve represents the moving average of the frequency, increasing over time. Note that the y-axis was chose to clearly delineate the average, such that some data points are outside the plot. (C) Moving average of distance between peaks in the pseudo-electrocardiogram, a measure of fractionation or complexity of activation. (D) Spiral tip density heatmap of each third of the simulation. (E, F) Snapshots of voltage, intracellular calcium (Cai), γCaL , and γD at time periods corresponding to (E) early and (F) late chaotic electrical dynamics. Black and white lines show spiral tip position shortly before and after each snapshot. Insets in panel F illustrate the remodeling pattern underlying the stable spiral location.

• 

  FIGURE 6. Fibrillatory Activity in Heterogeneous Tissue (A) Dense spiral tracks during fibrillatory activity. The orange track highlights the stable re-entrant activity in the emergent tissue niche. (B) Chaotic tissue pseudo-electrocardiogram. (C) Snapshot of tissue activity and remodeling state. Points 1, 2, and 3 mark the cell locations highlighted in panel E. (D) Map of average voltage activation frequency, calculated from the 20 seconds of activity shown in panels A and B. The white arrowhead points to the high activation rate spot created by stable spiral wave location, which rapidly paces the local region. (E) Normalized voltage (blue) and calcium (red) activity at the 3 locations. Cell 1 exhibits the most remodeling, with the highest activation frequency and very low calcium activity. Cells 2 and 3 are less remodeled, showing high calcium peaks and longer APDs. Both are activated chaotically and exhibit APD and calcium peak irregular periodicities. Note the dissociation between voltage and calcium, a hallmark characteristic of atrial fibrillation. Abbreviations as in Figure 1.