Fig 1.
3D electro-anatomical human SAN model.
A: Action potential profiles of atrial (cyan), SAN (red), and paranodal area (blue) cells. Gray box: Epicardial (Bi and Bii) and endocardial (Ci and Cii) views of the 3D anatomy consisting of atrial tissue (cyan), SAN (red), paranodal area (blue), insulating border (yellow tissue encasing of the SAN in Bii and Cii), and SEPs. Left panels (Bi, Ci) show the anatomy without border-SEPs. Right column (Bii, Cii) shows the anatomy with the insulating border-SEPs. D: Cell-cell coupling centre to periphery diffusion gradient inside the SAN. The diffusion increases from the SAN’s centroid towards the atrium. The paranodal area (blue) is shown for anatomical reference. E: An instance of uniform distribution of SAN action potential cycle lengths in a range of 800 ms to 1000 ms with a mean of 850 ms. An instance of SAN cell cycle lengths is illustrated in S1 Fig. The paranodal area’s cycle length was kept at 1400 ms throughout.
Fig 2.
SAN activation times and leading pacemaker sites under basal conditions.
I, A-D: Colour coded SAN activation times are shown in four cases. Leading pacemaker site’s (white sphere within the SAN) coordinates and period of atrial pacing, P, for each case are shown. Paranodal area (blue in panels C and D) when present is shown. Atrial tissue (Fig 1) and atrial activation are omitted from the panels for clarity. II. Locations of LPS in anatomical variants. The location of minimum diffusion with the SAN is coincident with the SAN only LPS. III. Cycle lengths of individual SAN cells.
Fig 3.
Atrial pacing by the paranodal area.
The SAN was replaced by atrial tissue in this simulation. The paranodal area (blue) with activation wave fronts (beige iso-surfaces) are shown, but the surrounding atrial tissue is omitted from the panels for clarity. Top row shows epicardial view, whereas bottom row shows endocardial view. The leading pacemaker site (black star) is within the paranodal area as shown in the snapshots. The period of atrial pacing was found to be 1564 ms.
Fig 4.
SAN micro re-entry without SEPs.
A: Epicardial as well as transmural views of SAN (red), paranodal area (blue), and non-conducting intra-SAN fibrosis (gray). The morphology of the fibrosis is further illustrated by the transmural left and right views. Locations of the omitted SEPs are shown by circular symbols to provide further anatomical landmarks. B: Evolution of micro re-entry. Top row (Bi) shows data from simulation without insulating border. Bottom row (Bii) shows data from simulation with insulating border without SEPs. Bi data show dissipation of re-entry due to absence of insulating border. Sixth panel illustrates the mechanism. Bii shows data with the insulating border configuration where the re-entry persisted unhindered. Sixth panel illustrates the mechanism.
Fig 5.
Evolution of micro re-entry in the full model with SEPs.
A: Anatomy (similar to Fig 4A) of the SAN, SAN fibrosis, and locations of functional SEPs. B: Consecutive time frames of the micro re-entry in terms of voltage distribution interspersed with panels illustrating the important events that occur during one period of the re-entry. E1 illustrates the SAN propagation initiating excitation in the atrium. E2 illustrates the directions of propagation from the atrium into the SAN, as well as the annihilation and continuing of the SAN re-entry. E3 marks the completion of one period of the re-entry.
Fig 6.
Macro re-entry around the SAN.
A: Modified 3D model with atrial fibrosis between the SAN and epicardial surface. B: Simulation of macro re-entry. Bi shows data where insulating border was omitted, where the initiated macro re-entry induced atrial fibrillation. Bii shows data when insulating border-SEPs configuration was included where atrial flutter was observed. In each, Bi and Bi, top row shows time frames from the simulation and bottom row illustrates the mechanism. The periods for SAN and atrial pacing in each simulation is also given.
Fig 7.
Effects of atrial tachycardia on SAN excitation. A: Transmural and epicardial views of the initiated scroll wave (green isosurfaces) and the transmural filament (black line) of the scroll wave. Whereas the full model is shown, 5 anatomical cases were simulated. B: Data for 5 anatomical cases in five columns. The atrial anatomy is omitted for clarity. First row shows representative number and shape of filaments. Second and third rows show dominant frequency (DF) maps of 5 s of data. Slices through the SAN (second row) and through the paranodal area (third row) are shown. C: Time course of filament numbers. The data were smoothed by moving window averaging for clarity.
Fig 8.
Shift of leading pacemaker site due to altered SAN micro-structure.
I: Top row shows data for the control case (Fig 2) while bottom row shows data for the altered SAN micro-structure case. A: model anatomies with colour coded SAN diffusion distribution. The location of the lowest cell-cell coupling is given, which lies within the SAN. B: LPS location in the SAN only case where border was omitted. C: LPS location in the full model case. In columns B and C, the white dots represent location of the leading pacemaker sites while the SAN activation time is colour coded as denoted by the colour bars. The coordinates of the leading pacemaker location are given below the respective panels. II: Vector diagram of the leading pacemaker locations, and locations of minimum diffusion gradients. The minimum diffusion gradients (purple spheres) are joined to the LPS of SAN only (black spheres) and full model (gray spheres). The control LPS are above the biochemically affected LPS.
Fig 9.
Fibrosis within the old human SAN.
The dashed red lines delineate SAN pacemakers. The left panel shows a representative slice from a young heart while the right panel shows a slice from an old heart. The Masson’s trichrome staining shows cell cytoplasm (pink) and connective tissue or fibrosis (blue, blue-green). Whereas the left panel’s SAN region is dominated by pink staining, the right panel has diffuse fibrosis.