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1Nora Eccles Harrison Cardiovascular Research and Training Institute, 2Department of Bioengineering; and 3Scientific Computing Institute, University of Utah, Salt Lake City, Utah; and 4Dipartimento di Biologia Evolutiva e Funzionale, Universita di Parma, Parma, Italy
Submitted 14 December 2007 ; accepted in final form 4 February 2008
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ABSTRACT |
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propagation patterns; excitation mapping
Experimental data published during the last 20 years show that epicardial and intramural ventricular pacing in canine hearts result in complex patterns of epicardial excitation, with multiple distinct areas of relatively slow and fast propagation (2, 4, 12, 23, 30, 32). Published computer simulations of the spread of excitation in the ventricles, mostly based on eiconal equations, propose possible electrophysiological mechanisms for many of these complex patterns (8, 9, 13, 33), but some of the suggested mechanisms have not yet received experimental confirmation.
In the present experimental study, we observed three distinct patterns of epicardial propagation, elicited by ventricular pacing. During epicardial pacing, propagation on the ventricular surface was anisotropic and relatively slow near the pacing site (
0.6 m/s along fibers, 0.3 m/s across fibers, with local accelerations), became very fast in neighboring regions, where large areas of tissue activated in a few milliseconds, and became slow again (<1 m/s) where excitation spread across the epicardial projection of the septum. Subsequently, propagation became very fast again when excitation reached the nonpaced ventricle. The three patterns were also observable during intramural pacing, with some variations. The purpose of this work was to investigate the mechanisms underlying the various patterns of epicardial propagation, in particular the role of myocardial anisotropy, fiber architecture, and the conduction system.
First Specific Aim
Numerous experimental studies show that, in canine hearts, a family of concentric, quasi-elliptical isochrones appears on the ventricular surface in the vicinity of an epicardial pacing site (2, 4, 12, 22, 32). Arisi et al. (2) referred to this region as the "primary area". The major axis of the elliptical isochrones was approximately parallel to the direction of the local subepicardial fibers, and the minor axis was perpendicular to fiber direction. A previous study from our group also showed that, at 20–30 ms after the stimulus, the elliptical isochrone patterns become asymmetric because of the appearance of conspicuous bulges (32) in the contours. These features were observed on the left (LV) and right ventricles (RV) (32). Simulation studies produced these epicardial bulges and attributed them to electrotonic attraction from the helix-shaped intramural portions of the wave front, resulting from the counterclockwise (CCW) epi-endocardial rotation of the intramural fiber direction (8, 16). To the best of our knowledge, however, this proposed mechanism has not been validated experimentally. The first specific aim of the present investigation was to provide experimental data that would confirm or disprove the mechanism suggested by the simulations.
Second Specific Aim
In 1992, Arisi et al. (2) studied the spread of excitation on the RV surface of exposed dog hearts during RV epicardial pacing. These authors observed an abrupt acceleration, up to 
2 m/s, just outside of the "primary area," in the regions toward which excitation moved across fibers away from the pacing site. Similar features were also observed on the LV (29). Arisi et al. (2) hypothesized that excitation, starting from the epicardial pacing site, reached the endocardium, traversed a Purkinje-ventricular junction (PVJ) in a retrograde direction, entered the Purkinje network, and reentered the ventricular muscle through one or more PVJs. From there, one or more excitation wave fronts moved in an endo-epicardial direction and reached the epicardium at one or more breakthrough (BKT) sites. The second specific aim of this work was to test the hypothesis that the involvement of the Purkinje conduction system produces the observed abrupt increases in the epicardial apparent propagation speed and the appearance of BKT sites. We addressed this issue by recording epicardial and intramural isochrone maps before and after inactivating the conduction system in the relevant ventricle.
Third Specific Aim
Another observed distinct pattern of propagation consisted of a relative deceleration of propagation where the excitation wave front, elicited by ventricular pacing, crossed the epicardial projection of the interventricular septum, both anteriorly and posteriorly. The third specific aim of this investigation was to test the hypothesis that the slower propagation speed is due to the fact that, in those regions, the intramural excitation wave front is approximately perpendicular to the surface, whereas it is more parallel to the surface in the high-velocity regions.
Fourth Specific Aim
In previous studies by our group (32), point stimulation at increasing intramural depths produced epicardial potential patterns at 10–14 ms after the stimulus, with a central negative area and two peripheral maxima. The axis joining the two maxima was parallel to the orientation of the myocardial fibers near the pacing site for all pacing depths. However, the magnitude of the two maxima was asymmetric. For an observer looking at the heart from the outside, the magnitude of the right maximum was invariably lower than that of the left maximum, and the difference increased with increasing pacing depth. Moreover, the distance between the right maximum and the epicardial projection of the pacing site increased as a function of pacing depth, except for subendocardial pacing. In the 1994 study, we hypothesized that the asymmetry of the maxima was due to the "imbrication" angle (28), i.e., to the epi-endocardial obliqueness of fiber direction, whereby one end of the ellipsoidal intramural wave front points slightly toward the epicardium, and the other end points toward the endocardium. We are not aware of any published experimental validation of this hypothesis. The fourth specific aim of the present investigation was to test this hypothesis, by recording intramural isochrone and potential maps, in an attempt to visualize the intramural obliqueness of the ellipsoidal wave front. An additional purpose was to ascertain whether some other predictable effects of the obliqueness of the intramural fibers, namely, the migration of the epicardial BKT sites as a function of pacing depths and pacing locations, could be demonstrated in epicardial maps.
To achieve these goals, we recorded between 500 and 1,540 unipolar epicardial or intramural electrograms from 22 exposed or isolated dog hearts, using epicardial electrode arrays and/or intramural plunge electrodes, during ventricular pacing from epicardial or intramural sites. In five animals, recordings were made before and after inactivation of the conduction system. We then displayed the results as epicardial or intramural isochrone or potential maps.
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METHODS |
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All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University of Utah and are in compliance with the Guide for the Care and Use of Laboratory Animals (22a). Twenty-two mongrel dogs, weighing 15–30 kg, were anesthetized with 30 mg/kg iv pentobarbital sodium, plus additional amounts as needed. The heart was exposed through a median sternotomy (13 dogs) or a left thoracotomy (5 dogs) and suspended in a pericardial cradle. An additional four hearts were rapidly excised and perfused with blood from a support dog in a modified Langendorff procedure, as described previously (17), and suspended in a warm chamber at 37°C.
Epicardial Mapping
For epicardial mapping, flexible electrode arrays were applied to the ventricular surface. These arrays were constructed by attaching silver wires (0.003 in.), fully insulated except near the tip, to nylon stockings (sock arrays) or rectangular pieces of nylon cloth (grid arrays), as described previously (1, 29). The "sock" arrays were fabricated by marking 242, 490, or 630 regularly spaced points on a plaster cast of a medium-sized dog heart. The spatial coordinates of the points were digitized using a Microscribe 3D Digitizer (Immersion, San Jose, CA). The foot of a nylon stocking was slipped over the cast, and silver wires were attached at all of the marked sites. Spacing between electrodes was 8, 5, and 4 mm. Anatomical landmarks, such as the major coronary vessels, were permanently marked on the sock to provide alignment of the array when it was placed around a dog heart (Fig. 1, A and B). The "grid" arrays carried 525 or 1,200 wires spaced 2 mm along rows and columns of a regular grid and covered part of the ventricular surface (Fig. 1, C and D).
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With a view to documenting the relationships between epicardial and intramural activation, we performed five experiments in which we inserted between 74 and 154 needles into the LV and/or RV walls of isolated dog hearts, prepared as described above (Fig. 2). In one experiment, we inserted 56 needles in the free wall of the LV of an exposed dog heart after applying a 242-electrode sock on its surface. Each needle carried 10 electrodes along the shank, spaced 1.6 mm apart on the LV and 1.0 mm apart on the RV. In two of these experiments, we recorded electrical signals from the needles before and after perfusing the LV cavity with Lugol solution. In these experiments, we did not insert needles in the internal portions of the septum.
Pacing Protocol
The right atrium was paced with a bipolar hook at a rate just above the spontaneous sinus rate. Ventricular stimulation was achieved by delivering unipolar cathodal stimuli to the ventricles via any electrode on the flexible epicardial array or with unipolar or bipolar stimuli delivered through intramural needle electrodes. The indifferent electrode for unipolar stimulation was placed subcutaneously in the chest wall for in situ studies and at the aortic root for isolated hearts. Stimuli were 2 ms in duration, and their intensity was just above threshold. Pacing cycle lengths ranged from 330 to 430 ms. Simultaneous stimulation of the ventricle and the right atrium was performed to prevent ventricular captures from the atria.
Data Acquisition, Analysis, and Display
Potential differences between groups of 192, 256, or 490 electrodes and a common reference electrode placed on the left hind leg for in situ experiments or on the aortic root of isolated hearts were simultaneously amplified, sampled at 1,000 Hz per channel, digitized with a linear 12-bit analog-to-digital converter, and stored on a MicroVax or Macintosh computer. These operations were repeated when necessary until signals were collected from all electrode sites (up to 1,540). Signals from successive groups were time aligned and merged into a single data set. Unipolar electrograms of poor quality or low signal-to-noise ratio were eliminated from the data set. In addition, unipolar signals from needle electrodes with a QRS down-stroke with a substantially smaller modulus of the derivative than the other signals from the same needle, suggesting they were located at the tip of the needle and recording from within the ventricular cavity or outside the epicardium, were not included for analysis.
Excitation times were estimated as the time of maximum negative slope of the unipolar electrogram (24, 27). Excitation time and isopotential maps were graphically displayed as sets of linearly interpolated contour lines (http://www.sci.utah.edu/map3d) (18). In potential maps, the position of the excitation wave front was taken as the location of the dense "band" of equipotential lines associated with the high-potential gradient. For data relating to the entire epicardial surface, as explored by the 242-, 490-, or 630-electrode sock, excitation isochrones were displayed on planar, orthogonal projections of rotatable three-dimensional (3D) images. For intramural data, excitation isochrones and potential distributions were displayed on 10 surfaces parallel to the epicardium (Fig. 2C). The epicardial surface was generated by triangulating all of the electrode sites from the outermost electrode on each needle (marked no. 10 in Fig. 2B). Similarly, 10 parallel surfaces were constructed (Fig. 2C). Isochrone lines and potential contours were also mapped on transmural, horizontal (parallel to the atrioventricular groove) (Fig. 2E), and vertical (apico-basal) (Fig. 2D) sections.
Average estimates of conduction speeds were determined from 2-mm resolution epicardial maps by measuring the distance (mm) between electrodes located along a line perpendicular to isochronal lines and dividing it by the difference in activation time (ms). Epicardial propagation velocity vectors and their magnitude were estimated over very short distances using the computational technique described by Bayly et al. (3). Attempting to estimate propagation speed using activation times determined only on the surface of the heart presents limitations because the wave front(s) propagate(s) within the myocardial volume. Excitation coming from the depth may reach the epicardium at one or more sites and then propagate in all directions until it encounters an anatomic boundary or another wave front. If the interelectrode distance in the array is >2 mm, one or more epicardial BKT sites may be missed (1). Thus, in the areas where there are multiple wave fronts, estimating epicardial speed by dividing the normal distance between two successive isochrone lines by the time interval between them will yield inaccurate results, even falsely estimating an infinite local speed. Moreover, the angle with which an excitation wave coming from the depth reaches the epicardium will affect the estimated speed as determined on the surface. If an excitation wave reaches the surface parallel to the epicardium, the epicardial velocity may appear to be infinite. Finally, the curvature of a wave approaching the epicardium from the depth so that it hits the boundary at a 90° angle (6) will also affect the propagation speed as estimated on the surface. Because of these complex effects, we acknowledge that, when we assess the epicardial propagation speed by either method, the results are only the "apparent speed," as seen on the surface.
Fiber direction near the pacing site was deduced, for all pacing depths, from the direction of the axis connecting the two potential maxima in epicardial potential maps, at 5–10 ms after the stimulus. This method has been shown to be at least as accurate as histological studies in previous experiments (12, 25, 31) and computer simulations (7, 21). Limitations of this method include assessing the fiber direction too long after stimulation so that encountered fiber rotation begins to modify the orientation of the maxima or poor quality of the signals masking the true center of the maxima.
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RESULTS |
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Epicardial excitation time maps, depicting the sequence of excitation over the entire ventricular surface after epicardial ventricular stimulation, showed three distinct patterns of propagation, which were consistently observed for 243 epicardial pacing sites in 17 dogs. Figure 3 illustrates a typical example of these patterns on planar orthogonal projections of 3D isochronal epicardial maps recorded with a 490-lead sock during RV pacing. The images in Fig. 3 were obtained with the 490-electrode sock shown in Fig. 1, A and B, with an average interelectrode distance of 4–5 mm.
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A characteristic feature of the primary area was a consistent deformation of the 20- to 30-ms isochrones from the symmetric, quasi-elliptical shape of the early isochrones (10–20 ms) into an asymmetric configuration with two "bulges". A typical example is shown in Fig. 4A, which was obtained with a spatial resolution of 2 mm. The figure demonstrates the outward CCW stretching of the isochrones at 18–36 ms (black arrows). For an observer looking at the heart from the outside, the two bulges were located in the upper (basal) left and lower (apical) right quadrants of the isochronal pattern centered at the pacing site, with axes along and across the major axis of the ellipse. Two "dimples" in the contours (white arrows) marked the passage from a bulging quadrant to a nonbulging quadrant of the isochrones. The bulges resulted from a CCW acceleration of the wave-front motion in the corresponding quadrants. The acceleration was documented and quantified by epicardial speed maps, which we constructed for seven epicardial pacing sites in three dogs. Figure 4B shows a typical distribution of epicardial propagation speeds on the LV surface during epicardial pacing from the site marked with a star. Two blue areas of relatively slow speed are located on both sides of the pacing site. These areas are asymmetrically elongated, with the right one expanding upward and the left one downward. The figure shows that the highest speeds in the primary area were not found along a straight line parallel to epicardial fiber direction and passing through the pacing site (the red dashed line in Fig. 4, A and B), but along a line shaped like an inverted "S" (white dashed line in Fig. 4A and solid line in Fig. 4B) that was slightly shifted CCW relative to the fiber direction. The epicardial bulges were observed in both ventricles in the upper left and lower right quadrants of the primary area in all cases studied, irrespective of the location of the pacing site, and persisted after inactivation of the conduction system in the relevant ventricle (not shown).
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To estimate the size of the primary area, we assumed that the electrodes were equally spaced on the 490-electrode sock array; hence each electrode represented a fixed area. We then estimated the size of the area by counting the number of electrodes contained within the isochrone that marked the abrupt passage to the high-velocity areas (like the isochrone highlighted with a thick line in Fig. 3A). Expressed as a percentage of the total number of epicardial electrodes, the primary area was generally larger on the LV (14 ± 6%) than on the RV (8 ± 3%, P < 0.001, n = 49). The total time of activation for the primary area was shorter on the RV (31 ± 7 ms) than on the LV (48 ± 9 ms, n = 112, P < 0.0001).
Pattern 2: High-propagation velocities. The second pattern of propagation was distinguished by higher apparent propagation speeds (up to 2–3 m/s), an irregular shape of the isochrone lines, and by the presence of BKT sites. It must be pointed out that the number of BKT sites observable in Fig. 3 is smaller than the real number because many BKTs are missed when the distance between electrodes is >2 mm (1). This pattern of propagation was encountered by moving farther than 1 or 1.5 cm in either of the across-fiber directions from the pacing site (see example in Fig. 3, A and E) and occurred on at least one side of the pacing site, for all epicardial pacing sites.
This pattern was observed over the epicardium of the paced ventricle outside the primary area and also on the opposite ventricle (see areas marked 2, 3, and 5 in Fig. 3). An example of this pattern of high propagation velocity with BKT sites found on the epicardium of the nonpaced ventricle, which was also the latest region reached by the excitatory process, is shown in Fig. 3D (area labeled no. 5). For the RV-paced beat in Fig. 3D, most of the LV surface was excited in only 9 ms. This area with high velocities did not appear if the Purkinje network of the nonpaced ventricle had been previously inactivated (not shown).
To assess if the high apparent velocity was attributable to the involvement of the conduction system (specific aim 2), we mapped the epicardial potential distributions during ventricular activation using an electrode array with 2-mm interelectrode distances before and after Purkinje inactivation. Representative isopotential maps measured from epicardial stimulation of the RV are shown in Fig. 6. At 46 ms after stimulation, the wave front (black line) had moved from the pacing site (marked with a star) to the position shown in Fig. 6A. Figure 6B shows the position of the wave front at 46 ms after pacing, but after Purkinje inactivation. Differences in the location of the wave front between Fig. 6, A and B, are due to the fact that the position of the epicardial sock moved slightly during the Lugol perfusion. One millisecond later, a distinct, small excited area of BKT appeared at 16 mm from the main wave front (Fig. 6C, arrow). This and the subsequent BKT areas did not appear after Purkinje inactivation (Fig. 6D). During the following instants, the new excited BKT area expanded in all directions, including toward the advancing main wave front, and the two wave fronts finally merged at 50–51 ms. In the meantime, additional BKT sites appeared in the surrounding regions (Fig. 6E, arrows). During the same time interval (46–51 ms), the main wave front barely moved in the maps obtained after Lugol (Fig. 6, B, D, F, H, and J), thus demonstrating the marked effects of the RV Purkinje system on BKT sites.
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Figure 7A shows the sequence of activation before Lugol perfusion in a LV transmural plane that intersects the epicardium along the thick black line shown in Fig. 7E. A red star marks the epicardial stimulation site. Excitation spread from epicardium to endocardium, underwent a fast acceleration along the deep and subendocardial layers, and returned to the epicardium in the left portion of the section.
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The earliest areas of activation in Fig. 7C (atrial drive) are close to the endocardium, appear at 17 ms after QRS onset, and most likely indicate early, Purkinje-initiated activation sites. After Purkinje inactivation, the earliest excitation areas appear at 40 ms after QRS onset, in a different location (Fig. 7D). Figure 7F shows the activation time difference between panels B (no Purkinje) and A (with Purkinje). All of the values in Fig. 7F are positive and increase from right to left. This showed that, in the Purkinje-activated heart, excitation reached all sites in the transmural plane earlier than in the Purkinje-inactivated heart, except in the area near the pacing site (primary area), where the differences are close to zero.
Pattern 3: Slowing across the septum. The third distinct pattern of propagation was found over the epicardial projection of the septum (Fig. 3, C and E, areas labeled with no. 4). This area was marked by isochronal lines that became more densely spaced as the wave front passed from one ventricle to the other on both the anterior (Fig. 3E) and posterior (Fig. 3C) epicardial projections of the septum. Average surface speeds of propagation across these regions were 0.7 ± 0.2 m/s (n = 42).
Figure 8C shows activation isochrones in a transmural cross section of the heart during LV pacing (site marked with a red star). The internal portions of the interventricular septum are not represented, because no needles were inserted there. Figure 8 shows that the slowing of epicardial propagation where the wave front crossed the septum during ventricular pacing was the epicardial expression of an intramural, advancing wave front that was approximately perpendicular to the heart surface in the anterior crossing region, or at 
45° in the posterior crossing region, whereas it was more parallel to the epicardium in the remaining regions, except near the pacing site, where the propagation speed was also relatively low. This configuration of the wave front where it crossed the septum was observed for all pacing depths, whether pacing was initiated from the LV or the RV. The slower propagation across the septum was not observed during atrial drive. Figure 8D shows the distribution of excitation isochrones in the same section, but during atrial pacing. It demonstrates the presence of two subendocardial sites that become excited very early, at 5 ms from the onset of ventricular activation (arrows). The two early sites most probably reveal the presence of two PVJs, which are located near the junction of the LV wall with the septum. Excitation spreading from these PVJs during atrial drive gave rise to two endo-epicardial waves that reached the septal epicardium at a narrow angle (posterior septum) or were quasi-parallel to the epicardium (anterior septum). Therefore, the apparent propagation speed at the epicardium was very high. In Fig. 8C (paced beat), excitation coming from the pacing site did not seem to reach these PVJs, but moved across the septum without Purkinje involvement.
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The three patterns of propagation were also observed in epicardial excitation time maps relating to intramural pacing. However, the boundary separating the primary area from areas of high-propagation velocity became less clear-cut for deeper pacing. Areas showing relatively slow propagation across the septum and very fast propagation over the opposite ventricle were clearly present for all pacing depths.
Five differences were observed between epicardial primary areas produced by epicardial and deep pacing.
First, the major axis of the central elliptical isochrones was no longer parallel to the direction of epicardial fibers, but progressively rotated CCW with increasing pacing depth on both the RV and the LV. Figure 9, A–D, shows an example of this for pacing of the LV. The rotation of the epicardial isochrones was always significantly less than the rotation of the fibers near the increasingly deep pacing sites, as previously reported for the pulmonary conus (12). In our experiments, fiber direction near the pacing site was assessed from a straight line drawn through the positions of the two initial epicardial potential maxima produced by pacing at any intramural depth (Fig. 9, E–H). For potential patterns where only a single potential maximum was visible on the epicardial area, a line connecting the site of insertion of the needle with the potential maximum indicates the fiber direction at the relevant pacing depth. At pacing depths of 8–11 mm, the rotation of the isochrones was 50% of the rotation of fibers (32 ± 9 vs. 64 ± 15°). Figure 9C shows an example for pacing at 11.2 mm deep, where the line through the long axis of the earliest elliptical isochrone has rotated 29° CCW compared with the earliest line in panel A. The line indicating fiber direction in Fig. 9G has rotated 59° relative to panel E. For more superficial pacing (3–6 mm), isochrone rotation was 60% of fiber rotation. The amount of rotation could not be assessed for subendocardial pacing (Fig. 9D), as the elliptical shape of the earliest isochrone was no longer observable and there was no clear-cut major axis.
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Fifth, for deep pacing, the early isochrone lines on the epicardium were no longer centered about the site of insertion of the pacing needle, as invariably occurred for epicardial pacing, but became progressively shifted, so that the site of insertion often was located outside of the earliest epicardial isochrone lines. Figure 12A shows the shift of the center of the concentric elliptical isochrones, away from the site of insertion of the pacing needle, for midwall and endocardial LV pacing. This feature was observed on both ventricles even after inactivation of the Purkinje network (see example in Fig. 12B). The shift of the isochrones was consistent with the shift of the BKT, in the sense that it occurred to the left (of the observer) and toward the apex when the pacing site was in the lower hemisphere, to the right (and toward the base) when we paced in the upper 25% of the ventricular mass (Fig. 12C). Features described in points 3–5 are predictable effects of the epi-endocardial obliqueness of the fibers.
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DISCUSSION |
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Epicardial Pacing
Primary area. It has been well demonstrated that the elliptical shape of the concentric isochrone lines surrounding an epicardial pacing site is an expression of the anisotropic conduction velocity of the heart muscle (4, 5, 12). The asymmetric bulges that appear in the elliptical isochrone contour maps (Fig. 4A) have been predicted by computer simulations (8, 16). Our results provide experimental confirmation of their origin and show that they coincide with relatively higher propagation speed in the relevant quadrants. The higher speed can be attributed to the epi-endocardial CCW rotation of fiber direction in the ventricular walls (28). The intramural wave front elicited by epicardial pacing assumes a helical shape in the thickness of the wall. This brings about a CCW rotation of the intersections between the 3D helical wave front and the successive surfaces, parallel to the epicardium (Fig. 5). One consequence of the CCW rotation of the wave front profiles at increasing depths is that some portions of the deep wave front overtake the epicardial wave front, in the regions where epicardial excitation spreads slowly across fibers. As a consequence, in these deep regions, some protruding portions of the wave front can expand upwards, toward the epicardium, while the remaining portions expand toward the endocardium. The results indicate that the intersection of the wave front with the epicardium in the area of the bulge forms an acute angle, in the direction of propagation (see example in Fig. 5G, arrow 1), whereas the right intersection of the same wave front with the epicardium (see example in Fig. 5F, arrow 2) will form an obtuse angle. In theory, both angles would result in the apparent epicardial speed of propagation being higher than the normal (perpendicular to the wave front), intramural velocity. However, Colli Franzone et al. (6) demonstrated that the wave fronts must hit the boundary, in this case the epicardium, at a right angle. Thus, in the immediate vicinity of the ventricular surface, the left portion of the wave front will abruptly bend toward the epicardium. This will result in a highly positive curvature, entailing a higher speed, compared with a planar wave front (11). This relatively higher speed brings about the formation of epicardial bulges in the relevant quadrant.
Conversely, the obtuse intersection of the wave front with the epicardium acquires a negative curvature, giving rise to a slower speed, compared with a planar wave. This correlates with the absence of a bulge in the upper right epicardial quadrant and a relatively shorter distance between successive isochrones on the epicardium. Thus the presence of a subepicardial portion of the 3D wave front, which is shifted CCW, relative to its epicardial intersection, accelerates the leftward expansion of the epicardial isochrone (bulge) and delays the right expansion (no bulge) (specific aim 1).
Boundary of primary area. In agreement with the hypothesis published by Arisi et al. in 1992 (2), our results show that, in the "high-velocity" areas, multiple excitation wave fronts come from subendocardial PVJs, because the high-velocity areas and the multiple BKT sites disappear after Purkinje inactivation (specific aim 2). Thus the boundary between pattern 1 of propagation (quasi-elliptical isochrones) and pattern 2 (high velocity) is the line along which an excitation wave front spreading directly from the pacing site encounters a wave front coming from one or more PVJs. However, this transition does not occur simultaneously along a specific isochrone line. For example, in the regions where excitation advances along fibers, the transition may occur later than across fibers. In this study, we defined the boundary of the epicardial primary area as the isochrone line that first encounters a wave front coming from an epicardial BKT site, because, after that time instant, the excited area becomes a combination of regions activated directly by a wave coming from the pacing site and other regions activated through the conduction system. Thus it can no longer be defined as the "primary area".
The intramural events during the transition from the primary to "secondary" or "high-speed" regions showed that the marked subepicardial acceleration (with apparent speed reaching up to 3 m/s) disappears after Purkinje inactivation. The highest speed values are observed in regions in which one or more PVJs are located. The map showing the time differences between excitation times before and after Purkinje inactivation (Fig. 7F) shows that, after Purkinje inactivation, excitation advancing through working myocardium reaches the entire section (except the primary area) later than propagation with Purkinje involvement. Thus, before Purkinje inactivation, the entire section, except the primary area, is activated by Purkinje-initiated excitation waves (specific aim 2).
Slowing Across the Septum
The results confirm our hypothesis that the slower propagation in the epicardial areas where the wave front crosses the epicardial projection of the septum is associated with an intramural wave front that is perpendicular to the epicardium, or moderately tilted, whereas it is rather parallel to the surface in most of the remaining regions (specific aim 3). We are not aware of any published mathematical simulation that reproduces this feature. The results suggest this difference is due to Purkinje involvement near the septal wall during normal activation sequences, whereas the PVJs near the septum are not activated during a paced beat, as shown in Fig. 8C.
Intramural Pacing: Effects of Epi-Endocardial Obliqueness of Fibers
Isochrone maps and equipotential contour maps traced on properly oriented transmural sections and recorded during endocardial pacing revealed the intramural epi-endocardial obliqueness of fiber direction [imbrication angle (28)]. The major axis of the elliptical isochrone lines was clearly tilted toward the epicardium in transmural planes and not parallel to the epicardial surface. Epicardial BKT sites were clearly shifted to the left or right relative to the site of insertion of the pacing needle, depending on which hemisphere of the heart the needle was inserted. Streeter's diagrams (28) predict that, in the apical "hemisphere" of the LV, endocardial pacing should provoke a shift of the BKT site toward the apex and the left of the observer, whereas endocardial pacing in the upper (basal) hemisphere should result in a shift to the right. This prediction is confirmed by our experimental results. In Fig. 13D, the left intramural potential maximum is closer to the epicardium than the right one and generates a stronger epicardial maximum, whereas the right epicardial maximum is weaker and not distinguishable from the background noise. This finding is consistent with our hypothesis that the asymmetry of the voltage of the maxima and the shift of the BKT sites are due to epi-endocardial obliqueness of the intramural direction of propagation (specific aim 4).
In summary, this study provides new information on the intramural electrical events underlying the multiple patterns of excitation elicited by epicardial and intramural pacing in normal dog hearts. This study presents new results that provide an electrical propagation counterpart for the widely known purely anatomical work of Streeter (28) on normal ventricular fiber geometry. Consequently, this study shows that knowledge of the details of ventricular fiber structure are quite important for understanding the epicardial ventricular electrical events that occur following pacing at different locations throughout both ventricles and their intramural counterparts. This information has practical relevance because it is now possible to map epicardial electrical events noninvasively, in human patients and experimental animals, using electrocardiographic imaging (14, 34) or semi-invasively, using transthoracic epicardial mapping (26) in view of ventricular pacing therapy.
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ACKNOWLEDGMENTS |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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D. J. Dosdall, P. B. Tabereaux, J. J. Kim, G. P. Walcott, J. M. Rogers, C. R. Killingsworth, J. Huang, P. G. Robertson, W. M. Smith, and R. E. Ideker Chemical ablation of the Purkinje system causes early termination and activation rate slowing of long-duration ventricular fibrillation in dogs Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H883 - H889. [Abstract] [Full Text] [PDF]
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