INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

A SINGLE SHOCK delivered during a portion of the T wave can induce ventricular fibrillation (VF) (17, 35). Thus ventricular vulnerability is bounded in terms of the timing of premature shocks that will induce VF. Upper and lower boundaries also exist for the strength of the shock. A shock must exceed the VF threshold to induce VF (34). If a shock is so strong that it exceeds the upper limit of ventricular vulnerability (ULV), then VF is not induced, regardless of the timing of the shock (9). This ULV exists in animals (9, 15, 28) and humans (2, 13).

Winfree (37) proposed a mechanism that explains both the induction of VF by a strong premature stimulus and the existence of the ULV. The mechanism, called the critical point mechanism by others (11), describes how a premature shock (S2) induces reentry in excitable tissue. According to this theory, the application of an S2 shock creates varying tissue effects that depend on the level of refractoriness and the strength of the S2 shock field at each tissue site. Reentry will form around a tissue site where a spatially varying S2 field encompasses a particular value, called the critical field strength, and where the tissue refractoriness also varies spatially and encompasses a particular level of recovery, called the critical recovery level. This tissue site, called the critical point, occurs where the critical level of the S2 potential gradient field intersects tissue that is critically refractory. Reentry should initiate wherever a critical point is formed as long as the surrounding area of myocardium is large enough to support the reentrant circuit.

The critical point hypothesis for the ULV states that S2 shocks stronger than the VF threshold but weaker than the ULV induce reentry, and subsequent VF, via the critical point mechanism (28, 36). Because the critical potential gradient areas are moved farther away from the S2 shocking electrodes as S2 strength is increased, the hypothesis predicts that the locations where VF is initiated will change with increasing shock strength. At or above a particular S2 shock strength, reentry will not occur because the critical point will be positioned very close to or beyond a heart border. This S2 shock strength is the ULV (36, 37).

Although the critical point mechanism for the induction of reentry and VF has been experimentally validated (11), the critical point hypothesis for the ULV has not. Shibata et al. (28) mapped the initiation of VF by shocks using 56 bipolar epicardial electrodes. Although they showed that increases in S2 shock strength move VF initiation sites away from the shocking electrodes until the ULV is reached, they did not map the S2 potential gradient field. A detailed study mapping the earliest post-S2 cardiac activations and the S2 shock potential gradient fields for shocks at and below the ULV has not previously been reported.

The purpose of this study was to examine the critical point hypothesis for the ULV by testing several predictions. The hypothesis predicts that, for a single S2 shock electrode configuration, the direction of activation and recovery preceding the shock (i.e., the S1 pacing site) should not affect the ULV shock strength but should affect the time points in the T wave at which VF is induced. The hypothesis predicts that the sites of earliest activation following S2 shocks should move away from the S2 electrodes as shock strength is increased. For shocks just below the ULV, the earliest postshock activation should appear where the potential gradient field is weakest in the ventricles. The potential gradients measured at the initiation points should be similar, regardless of location or S1 pacing site. In addition, the level of refractoriness at the time of the S2 should be similar at the initiation points, regardless of S1 pacing site. This study was accomplished by determining the ULV for three spatially distinct S1 pacing sites and a single S2 shock electrode configuration while mapping epicardial activations at 528 sites and shock potential gradients at 264 sites.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Animal Preparation

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The heart was exposed by median sternotomy, and a pericardial cradle was created. A stainless steel mesh defibrillation electrode (~3-cm² area) was sewn to the epicardial surface of the left ventricular apex (LVA). The electrode was a cloverleaf shape with four leaflets to conform to the apical surface. A single-coil catheter defibrillation electrode (~3.5-cm length, ~3.5-mm diameter) was inserted into an internal or external jugular vein and positioned in the distal superior vena cava (SVC) with its tip at the entrance to the right atrium. Three stainless steel wires were sewn to the epicardium for S1 pacing: one near the LVA, one overlying the right ventricular outflow tract (RVOT) close to the pulmonic valve ring, and one posteriorly at the LV base (LVB). The return electrode for the S1 electrodes was connected to the chest retractor. The S1 and S2 electrode positions are diagrammed in Fig. 1. Two chlorided solid Ag beaded wires were inserted into the right and left thighs through small skin incisions to act as grounds for the mapping system.

View larger version (63K): [in this window] [in a new window]   Fig. 1.   Diagram showing anterior and posterior views of the heart with approximate positions of S1 and S2 electrodes and sock recording electrodes. S1 pacing was performed from each of the epicardial S1 positions referenced to the chest retractor. S2 shocks were delivered between left ventricular apex (LVA) patch electrode and superior vena cava (SVC) catheter electrode. , 1 of 528 unipolar recording sites. LAD, left anterior descending coronary artery, PDA, posterior descending coronary artery; RVOT, right ventricular outflow tract; LVB, left ventricular base.

S1 Pacing and S2 Shock Delivery

All S2 and defibrillation shocks were delivered from an external defibrillator (HVS-02, Ventritex, Sunnyvale, CA). A biphasic truncated exponential waveform was used in which both phases were 6 ms in duration. The LVA patch electrode was the first-phase anode. To mimic a single capacitor discharge, the leading-edge voltage of the second phase was set equal to the trailing edge of the first phase. For each shock, the voltage and current waveforms were acquired at a 20-kHz sampling rate with a waveform analyzer (model 6100, Data Precision, Danvers, MA). Shock parameters were then measured (voltage and current) or calculated (energy, impedance, and time constant) and recorded.

Epicardial Recording Electrodes

View larger version (47K): [in this window] [in a new window]   Fig. 2.   A: top, side, and bottom views of a multicontact electrode plaque. Side view shows the 3 layers of the plaque: solder layer, circuit-board layer, and recording layer with embedded Ag wire recording electrodes. B: recording face of a plaque with 24 Ag-AgCl recording sites. Exploded view shows group of 4 sites oriented as a square with 2.54-mm side lengths. Within each square, cardiac activations were measured at 2 sites in unipolar mode from + electrodes. Bipolar recordings were made during shocks between + and  electrodes across each diagonal for potential gradient calculations.

An elastic recording sock (Xspan, Baxter Healthcare, Deerfield, IL) was constructed to which the 44 multicontact electrode plaques were secured with small snaps. The recording sock was stretched to cover both ventricles with the plaques against the epicardial surface. Multiple sutures were placed along the atrioventricular (AV) groove to hold the sock in place. At the end of each study, the plaques were removed from the sock and cleaned. A new sock was used for each animal study. Care was taken to maintain consistent plaque positioning and orientation across animals.

Recording Methods

All electrode recordings were made at a sampling rate of 2 kHz using a 528-channel mapping system (38). Unipolar cardiac activations were recorded until 10 ms before shock delivery. The mapping system was then switched to bipolar recording until 5 ms after the end of the shock, when unipolar recording was resumed. Unipolar cardiac signals were band-pass filtered from 0.05 to 500 Hz except in the 50-ms window after a shock. During that postshock period, the high-pass filter was set to 5 Hz to rapidly reduce any postshock offset and to return the signal to baseline. The bipolar signals recorded during the shock were band-pass filtered from direct current to 4 kHz.

The gain settings for recording shocks were determined at the beginning of each study by delivering a 180- and a 380-V S2 shock after S1 pacing trains with the S1-S2 coupling interval set to the S1-S1 interval to prevent VF. The S2 peak voltages were determined for each channel for each shock (16). Optimal gains for any S2 strength were estimated from a linear equation relating peak voltage and S2 strength for each channel.

ULV Testing

Initially, the S2 shock was set to 60 V of leading-edge voltage (LEV) and the S1-S2 interval was set to the S1-T_pk interval (Fig. 3). If the S2 test shock did not induce VF, the S1-S2 interval was incremented by 10 ms (S1-T_pk + 10 ms). If the S2 shock again did not induce VF, the S1-S2 interval was decremented by 20 ms (S1-T_pk  10 ms). Testing continued by alternating between scanning later and earlier than T_pk in 10-ms steps until VF was induced or until the minimum and maximum scanning intervals were reached. When either the maximum or minimum scanning interval was obtained and more than one step was needed to obtain the other limit, successive incrementing or decrementing of the S1-S2 interval was used to complete the T-wave scan. At least 15 s were allowed to elapse between S2 delivery and restarting the S1 train when VF was not induced (33). If VF was induced, the animal was defibrillated with one or more rescue shocks (equal to or 50-400 V higher than the S2) delivered through the S2 electrodes. After a recovery period of at least 4 min following defibrillation, testing was resumed.

View larger version (19K): [in this window] [in a new window]   Fig. 3.   Scanning protocol for upper limit of variability (ULV) testing. A portion of T wave is shown at bottom. In this case, testing is started with S2 = 60 V. The first S2 shock (shock 1) is timed to occur at peak of T wave (Tpk). Ventricular fibrillation (VF) was not induced, and the S1-S2 interval was incremented by 10 ms for the next shock (shock 2). VF was not induced and S1-S2 was decremented by 20 ms (3 ). After shock 3 failed to induce VF, S1-S2 was incremented by 30 ms. VF was induced when shock 4 was delivered. After defibrillation, S2 was set to 100 V and scanning was restarted (top). The first shock at the new S2 strength (shock 5) was timed to intersect the T wave where VF was previously induced. Back-and-forth scanning was continued from this point until VF was again induced (shock 7).

If VF was not induced at any S1-S2 coupling interval, the S2 shock strength was decremented by 40 V, and the scanning sequence was restarted. If VF was induced, testing at that S2 strength was halted, the S2 strength was incremented by 40 V, and the scanning sequence was restarted. The first S1-S2 coupling interval to be tested at the new S2 strength was the interval that first induced VF at the previous S2 shock strength (Fig. 3). The ULV was determined when a single increment or decrement of the S2 shock strength changed the result of the T-wave scan compared with the preceding scan. For example, ULV testing was halted when VF was induced at one S2 shock strength but not at the next higher S2 shock strength. The ULV was considered the lowest S2 shock strength that did not induce VF at any point in the T-wave scanning interval.

The ULV was determined for all three S1 pacing sites. The ULV was measured three times for each S1 site, first using a 40-V step size as described above, next with a 20-V step size, and last with a 10-V step size for the S2 shock. The starting voltage for the second and third ULV determinations was either the ULV or one step below the preceding ULV. The first ULV is called ULV40 (40-V step size), the second ULV20 (20-V step size), and the third ULV10 (10-V step size). A randomized Latin-square design was used to determine the testing order of the three S1 pacing sites for each animal. Within an animal, the S1 pacing site tested was changed after each T-wave scanning sequence. For the second and third ULV determinations, the S2 shock strength was not incremented after VF was induced, but scanning was continued to determine all S1-S2 intervals that induced VF at that S2 strength.

At the end of the study, the animal was killed with electrically induced VF. The catheter electrode position was verified, and the heart was excised, rinsed, weighed, tagged, and placed in 10% Formalin.

Data Analysis

Global shock variables. The ULVs for each S1 site were compared on the basis of the first-phase LEV and leading-edge current and on the total energy of the two phases combined. Data were analyzed by repeated-measures ANOVA to control for interanimal variability.

Timing intervals. Timing intervals measured from the S2 electrodes were compared for shocks that induced VF from the ULV40 group for the three S1 sites.

Early site locations. To determine the earliest sites of activation following the S2 shocks, cardiac activations were visualized and animated on a three-dimensional representation of the electrode sock obtained from a magnetic resonance image of the sock on a fixed pig heart (Fig. 1). All VF induction episodes that occurred during determination of ULV40 were analyzed. For ULV20 and ULV10, VF episodes for S2 shocks whose strength was one step below the ULV were analyzed. Earliest sites of postshock activation were also determined for each shock of ULV strength that was given at the same S1-S2 interval as a lower-strength shock that induced VF. Although these ULV strength shocks did not induce VF, they usually induced at least one ectopic beat.

View larger version (30K): [in this window] [in a new window]   Fig. 4.   Sock electrode positions plotted as  on horizontal axis and  along vertical axis.  is the rotational angle around the heart. The "line" at which  = 0 divides the sock into right and left halves along the anterior midline. At top, the middle of the right ventricular outflow tract (RVOT) is positioned along the  = 0 line.  is the distance from the tip of the LVA. Each square represents 1 of 528 unipolar recording sites. The approximate position of the SVC catheter is shown at top left. The LVA patch is positioned along the lower border of the sock. The approximate positions of the three S1 pacing sites are shown as filled circles. RCA, right coronary artery.

Early site activations. The local electrogram recorded at each early site was displayed from the next-to-last (19th) S1 paced beat to several beats following the S2 shock. The times of local activation following the last S1 stimulus (VR) and after the S2 shock (V1) were determined for each early site. The activation time was considered to be the time when the derivative was maximally negative. In addition, the time of the maximum positive derivative of the local recorded T wave following the last S1 stimulus was found at each early site. This time (RS1) was used as a reference point for recovery of the underlying tissue (22). On the basis of these measured time points, several intervals were calculated and compared. Early site activation data were analyzed by repeated-measures ANOVA and analysis of covariance.

Early site potential gradients. The two-dimensional potential gradient magnitudes were calculated for every shock. For shocks that were one step weaker than the ULV, the potential gradients measured at the early activation sites were compared for the three S1 pacing sites. Early site potential gradient data were analyzed by ANOVA and analysis of covariance.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

A total of 301 S2 shock episodes were analyzed. In five animals, all three ULVs were determined. In four animals, only the ULV40 was obtained. In one animal, only ULV40 and ULV20 were determined. In one animal, the mapping system gain bank used immediately after S2 shock delivery was set improperly so that the sites of early activations following shock delivery could not be determined. This animal was excluded from early site analysis. Thus, for early site determinations, 294 S2 shock episodes were analyzed.

Global Shock Variables

Timing Intervals

The timing of VF inductions relative to the peak of the T wave (T_pk-S2 interval) as a function of the S2 shock LEV during determination of ULV40 is shown in Fig. 5. A positive T_pk-S2 interval indicates that the S2 shock was delivered after the peak. At the lowest shock level (60 V), VF was frequently induced by the first (T_pk) or second (T_pk + 10) S2 shock given. As the S2 shock strength increased, there was a clear separation of the timing of VF inductions as a function of the S1 pacing site. At one step below the ULV for the LVA and LVB pacing sites, S2 shocks induced VF at later points in the T wave than the peak (T_pk-S2 LVA: 32.4 ± 17 ms; LVB: 20.6 ± 21 ms). However, for the RVOT S1 site, S2 shocks induced VF at points significantly earlier in the T wave than the peak (T_pk-S2 19.1 ± 19 ms).

View larger version (21K): [in this window] [in a new window]   Fig. 5.   Plot of mean Tpk-S2 interval at which VF was induced vs. S2 leading-edge voltage (LEV) for all animals combined. Tpk-S2 was measured using the electrogram recorded between the LVA patch and the SVC catheter. The Tpk-S2 interval was the time between Tpk and an S2 shock that induced VF at a specific S2 strength. The Tpk-S2 = 0 line represents the peak of the T wave. Initial S2 shocks were 60 V and were delivered at Tpk. Lines show change in Tpk-S2 interval with increasing S2 shock strength for LVA (squares), LVB (triangles), and RVOT (circles) S1 pacing sites. Filled symbols represent mean Tpk-S2 intervals; open symbols represent 1 SD above or below mean. Values without SD points represent single-animal data.

During determination of ULV20 and ULV10, full T-wave scanning was performed. VF was induced at only a single time point in 27 of the 33 full T-wave scans that were analyzed one step (20 or 10 V) below the ULV. In the remaining six T-wave scans, VF was induced at only two times in the T wave. For five of the six cases, these two VF induction points were either 10 or 20 ms apart. In the remaining case, the VF induction points were separated by 50 ms.

Early Site Locations

Examples of activation sequences for S1 paced beats from the LVA, LVB, and RVOT are shown in Fig. 6. For the LVA pacing site, activation proceeded along the anterior and posterior surfaces simultaneously. The entire epicardium was activated in 74 ms in this example, with the last portion activated in the high RVOT. For LVB S1 pacing, activation began in the high posterior base and propagated symmetrically around the right and left lateral epicardium. The last area to be activated was in the high RVOT, similar to that for LVA. However, for LVB pacing, it took 97 ms to activate the entire epicardium. For RVOT S1 pacing, the activation sequence was almost exactly opposite to that for LVB pacing and took nearly the same amount of time to activate the epicardium (98 ms).

View larger version (69K): [in this window] [in a new window]   Fig. 6.   Examples of activation sequences for a single paced beat for all three S1 pacing sites. Isochronal maps show representative activation sequences following an S1 stimulus from LVA (A), LVB (B), and RVOT sites (C). Anterior (left) and posterior (right) views are shown; shaded areas represent the atria. The LAD (anterior view) and circumflex with posterior descending coronary arteries (posterior view) are indicated by thick shaded lines. The initial site of recorded activation is shown as time 0 (arrow) in each panel. Isochrone lines are shown at intervals of 10 ms and indicate times at which underlying tissue became activated relative to the earliest recorded activation time. For S1 pacing from the LVA site (A), the last recorded activation occurred in the high RVOT 74 ms after the earliest activation. For S1 pacing from the LVB site (B), the last recorded activation occurred in the high RVOT 97 ms after the earliest activation. For S1 pacing from the RVOT site (C), the last recorded activation occurred in the posterior LVB 98 ms after the earliest activation.

Figure 7 shows an example of the activation sequences for the first two postshock cycles leading to VF following a 140-V S2 shock after LVB S1 pacing in the same animal as in Fig. 6 (views shifted 90° with respect to Fig. 6B). After the shock, activations were initiated from two early sites. Activation first appeared on the epicardium in the right lateral wall along the base 22 ms after the start of the shock. A second wave front appeared on the opposite side of the heart in the lateral LVB 30 ms after the start of the S2. The potential gradients measured at first and second early sites were 2.3 and 3.7 V/cm, respectively. The time between the last preshock activation following the 20th S1 at the early site and the time of S2 delivery (VR-S2, see below) was 157 ms for the first site and 141 ms for the second site. The activation wave front in the RV proceeded clockwise around a line of block while the LV wave front proceeded counterclockwise around a similar line of block. In both the RV and the LV, as the activation fronts completed propagation around the ends of the lines of block, wave fronts appeared in the nearby previously activated tissue at the end of the block, indicating reentry into these areas. The second cycle wave fronts appeared in the RV and LV at 107 and 121 ms, respectively, after the S2 while the first cycle wave fronts completed activation of nearby previously unactivated myocardium. The maps for the second cycle show that the lines of block extended further, but the activation fronts still propagated around the block and reentered the previously activated tissue. In this case, after the second cycle, wave fronts propagated from the original sites, but these wave fronts broke into numerous smaller segments that activated the remainder of the epicardium. Subsequently, other small wave fronts appeared on the epicardial surface in other areas that could not be directly linked on the epicardium to the original propagating activation front. Multiple activation wavelets were present on the epicardial surface, and VF ensued. Two bilateral reentrant rotors were seen in this example, with the plane of rotation appearing parallel with the epicardial surface. In other cases with identifiable reentry near the early site, the circuit was more distorted, with the plane of rotation apparently angled into the myocardium. Frequently, activation was followed by wave front propagation away from the early site; however, one or more wave fronts could not be identified as reentering. When this occurred, activations originated at the early site repeatedly until multiple small wave fronts were present and VF ensued. It could not be distinguished whether the earliest wave fronts represented activations propagating from an automatic focus or from a rotor deep within the myocardium.

View larger version (91K): [in this window] [in a new window]   Fig. 7.   Anterolateral views of RV (left) and LV (right) showing beats 1 (A) and 2 (B) after a 140-V shock that induced VF in the same animal as in Fig. 6. Shaded areas represent the atria. The LAD can be seen at bottom right of anterolateral RV view and at top left of anterolateral LV view (thick shaded lines). S1 pacing was from the LVB site, located at top right of anterolateral LV view. Isochrone lines are spaced in 10-ms increments; numbers indicate activation times of underlying tissue after the beginning of S2 shock. Arrows indicate initial sites of activation for beats 1 and 2. At 22 ms after the S2, an activation front initiated in the lateral RV base (beat 1). A 2nd front initiated at 30 ms after the S2 in the lateral LVB. After initial activation, the 2 bilateral wave fronts propagated around lines of block (thick lines) and reentered tissue that was previously activated (curving arrows). At 107 and 121 ms after the S2 (beat 2), the 2nd postshock cycle began on the lateral RV and LV walls, respectively. Wave fronts for 2nd cycle proceeded in the same direction around extended lines of block in a reentrant fashion. After beat 2, wave fronts broke down into smaller fragments and VF occurred.

Figure 8 shows all early site positions following the S2 for LVA, LVB, and RVOT S1 pacing sites, respectively, in a single animal. For LVA pacing at lower- strength S2 shocks (400 V below ULV), three early sites of activation were observed about midway between the apex and the base, one in the RV and two in the LV. As the S2 shock strength increased, the sites moved to more basal positions and the number of early sites decreased. With pacing from the posterior LVB, bilateral early sites were slightly more posterior. However, as the shock strength increased, those sites moved to anterior and basal positions similar to that with LVA pacing. With the S1 pacing site at the RVOT, however, the sites originated anteriorly. The early sites moved to more lateral and basal positions with increasing S2 shock strength. At one step below the ULV, two early sites were located at the edge of the AV groove.

View larger version (29K): [in this window] [in a new window]   Fig. 8.   Plots of all early site locations for a single animal in terms of (, ) coordinates (see Fig. 4). Early site locations are shown for LVA (A), LVB (B), and RVOT pacing sites (C). Numbers represent S2 shock voltage relative to ULV. Arrows indicate movement of early site locations as S2 strength is increased closer to ULV level. As S2 shock strength increased, the number of early sites decreased. At 40 V below ULV, there was a single early site in the RVOT area for LVA (A) and LVB pacing (B). For RVOT pacing with S2 40 V below ULV, there were 2 early sites near each other at the right lateral RV base (C). Movements and final locations of early sites at strengths just below ULV were consistent across animals.

The progression of early sites was similar across all animals for each S1 pacing site. The distance from the tip of the LVA to the epicardial early site is plotted in Fig. 9 as a function of the S2 voltage relative to the ULV for all animals and each S1 site. There was a consistent increase in the distance from the S2 shocking electrode to the epicardial early site location as S2 shock strength increased, regardless of S1 pacing site.

View larger version (21K): [in this window] [in a new window]   Fig. 9.   Plot of polar distance from LVA to epicardial early site (y-axis) vs. S2 shock strength relative to ULV (x-axis). Polar distance () was measured as the distance in spherical coordinates from the tip of the LVA to the epicardial electrode. The y-axis range from 30 to 100 mm represents the range of epicardial electrode distances. Filled symbols represent mean values across animals for each S1 pacing site; open symbols represent 1 SD above or below mean. For each S1 pacing site as S2 strength increased, the early sites moved progressively away from the LVA S2 shock electrode.

The early site positions in all animals for shocks just below the ULV are shown in Fig. 10. In most cases, the early sites of activation for LVA and LVB S1 pacing arose in the RVOT. On the other hand, the early sites were located in slightly different locations across animals for pacing from the RVOT. Whereas some early sites were present over the RVOT, the majority were located along the AV groove at various points around the heart. Note that in the two animals in which the VF induction time corresponded to the earliest scanning time for RVOT S1 pacing, the early sites at one step below the ULV were located in the RVOT closer to the pacing site. In the remaining seven animals, the early sites were not present in the RVOT.

View larger version (48K): [in this window] [in a new window]   Fig. 10.   Positions on heart of all early sites for S2 shocks 1 step below ULV strength (ULV at 10, 20, and 40 V) in all animals. Left, anterior view; right, posterior view (see Fig. 1). , S1 pacing locations. Early sites for RVOT tend to group along lateral RV and posterolateral RV base. Sites for LVA and LVB group in RVOT.

Early Site Potential Gradients

View larger version (103K): [in this window] [in a new window]   Fig. 11.   Four views of electrode sock showing sites of earliest postshock activation leading to VF and the potential gradient fields for 380-V (A), 220-V (B), and 60-V (C) S2 shocks delivered between LVA patch and SVC catheter electrodes for same animal as in Fig. 8. Pacing was from LVA S1 site. Each potential gradient measurement site is represented by a shaded patch. Scale (bottom) shows corresponding potential gradient level (in V/cm) for each level of shading: low potential gradient regions are represented by lighter shades; darkest shade represents values greater than ~10.5 V/cm. White "holes" represent sites with missing values. For S2 = 60 V (C), the potential gradient field was <10 V/cm at most measurement sites. In this case there were 3 early sites () all in the midtransverse region. For S2 = 220 V (B), the potential gradient field exceeded ~10.5 V/cm in almost the entire lower one-half of the heart. Two early sites were present at more basal positions compared with the early site locations for S2 = 60 V. For S2 = 380 V (A), the potential gradient field was strong in all but a few areas of the heart. Weak potential gradient areas were present in RVOT and along RV and LV base. At this shock level, there were 2 early sites, 1 in high RVOT and 1 in posterolateral RV base in top row of electrodes. In this case, the ULV was achieved when S2 was increased by another 80 V (S2 = 420 V).

The average potential gradient magnitudes at the early sites are plotted in Fig. 12 as a function of S2 LEV for all three S1 pacing sites. The potential gradients at the early sites increase with increasing S2 shock strength for each S1 site (P < 0.001 for each slope vs. zero, analysis of covariance, r = 0.4). The gradients for each S1 site increase at the same rate (P > 0.10 for slope comparisons, analysis of covariance).

View larger version (31K): [in this window] [in a new window]   Fig. 12.   Plot of early site potential gradient magnitudes vs. S2 shock strength relative to ULV level. Each filled symbol represents mean value across animals for a specific S2 shock level and S1 pacing site; open symbols represent 1 SD for each S1 pacing site.

Figure 13 shows an example of the location of the early sites relative to the potential gradient field after shocks one step below the ULV for all three S1 pacing sites in the same animal as in Figs. 8 and 10. The early sites at this shock level arose in regions of the heart remote from the S2 electrodes, where the potential gradient field was weak. The early site potential gradient data measured at one step below the ULV are summarized in Table 2. Among S1 pacing sites, the early site potential gradient magnitudes were not significantly different for ULV40, ULV20, or ULV10. The same was true when the data for ULV40, ULV20, and ULV10 were combined (LVA: 7.0 ± 3.9 V/cm; LVB: 6.9 ± 4.3 V/cm; RVOT: 7.9 ± 4.1 V/cm; P = 0.53 between S1 sites, ANOVA). For the ULV40 group, the maximum measured potential gradients on the heart were 264 ± 128, 266 ± 142, and 243 ± 142 V/cm for the LVA, LVB, and RVOT pacing sites, respectively. The respective minimum measured potential gradients were 1.0 ± 0.8, 1.7 ± 1.0, and 1.4 ± 1.0. Thus the early sites were located in low potential gradient regions but were not the minimum values on the epicardium.

View larger version (91K): [in this window] [in a new window]   Fig. 13.   Comparison of early site locations and potential gradient fields for each S1 site when S2 strength was 40 V less than ULV in same animal as in Figs. 8 and 11. Each potential gradient measurement site is represented by a shaded patch. Scale (right) shows corresponding potential gradient level (in V/cm) for each level of shading: low potential gradient regions are represented by lighter shades; darkest shade represents values greater than ~10.5 V/cm. White holes represent sites with missing values. Early site locations are indicated by an arrow and asterisk. Regardless of pacing site, distribution of potential gradient values was similar in each case. For LVA (A) and LVB (B), single early sites were located in RVOT. However, for RVOT (C), a single early site was present along lateral RV base.

Early Site Activations

To further assess the timing of S2 delivery relative to the timing of local recovery, the RS1-S2 interval was calculated as the time between the maximum positive slope of the T wave following the last S1 stimulus at each early site and the time of S2 delivery. A negative RS1-S2 interval indicates that the S2 shock was delivered earlier than the maximum positive slope of the local T wave. Across animals, the RS1-S2 interval was not significantly (P > 0.14) different from zero for any S1 pacing site (LVA: 8.0 ± 19 ms; LVB: 7.6 ± 17 ms; RVOT: 2.0 ± 12 ms). Additionally, there were no significant differences (P = 0.41, repeated-measures ANOVA) among pacing sites for this interval. Because the RS1 point for unipolar electrograms has been shown to correlate with the refractory period of the underlying tissue, (22) these data suggest that early sites were located where the tissue was in a particular state of refractoriness at the time of the S2.

The S2-V1 interval is the time delay between the beginning of the S2 shock and the time of the first recorded post-S2 activation at the early site. The S2-V1 interval is plotted in Fig. 14 as a function of shock strength relative to the ULV for all S1 pacing sites. As S2 shock strength increased, the S2-V1 interval increased for all three S1 pacing sites. However, the S2-V1 interval increased at a faster rate for the RVOT S1 pacing site compared with the LVA and LVB pacing sites (P < 0.01, analysis of covariance). At one S2 step below the ULV (40, 20, and 10 V combined), the S2-V1 interval was significantly (P < 0.05) longer for RVOT (82.2 ± 27 ms) than for LVA (64.1 ± 21 ms) and LVB (61.8 ± 21 ms). S2-V1 intervals were not significantly different for LVA versus LVB. For all S1 pacing sites, the early site potential gradient and early site S2-V1 interval showed slight positive correlation (r = 0.44).

View larger version (30K): [in this window] [in a new window]   Fig. 14.   Plot of time delay between beginning of S2 shock and time of first recorded post-S2 activation at early site (S2-V1 interval) vs. S2 shock strength relative to ULV. Each data point (filled symbol) is average value across animals at a specific relative S2 shock strength; open symbols are 1 SD above or below mean. As S2 shock strength increased to ULV, average S2-V1 interval increased for all three S1 pacing sites. Interval for RVOT increased at a significantly faster rate than that for LVA and LVB (P < 0.01, analysis of covariance).

The potential gradient measured at each early site is plotted in Fig. 15 against the RS1-S2 interval at the same site. Early sites where the S2-V1 interval was <25 ms are shown with a different marker. As seen in Fig. 15, the earliest sites of activation with the shortest S2-V1 intervals had a smaller divergence of potential gradient (mean 2.8 ± 1.6 V/cm) and RS1-S2 (mean 12.6 ± 11.1 ms) values. These points of earliest activation arose where, simultaneously, there was a similar degree of relative refractoriness and similar potential gradient at the time of the S2 shock.

View larger version (19K): [in this window] [in a new window]   Fig. 15.   Plot of epicardial potential gradient magnitude at each early site vs. time of maximum positive derivative of local recorded T wave following last S1 stimulus at each early site (RS1-S2 interval) at same site for all pacing sites in all animals. Small shaded points represent early sites at which S2-V1 interval exceeded 25 ms. , data for early sites at which S2-V1 interval was 25 ms or earlier. Clustering of data points for sites with short latency (S2-V1  25 ms) indicates that across animals and pacing configurations, the earliest postshock activations arose where there was a similar potential gradient and similar state of relative refractoriness at time of S2 shock.

ULV Shocks

The potential gradients measured at these early sites for ULV level shocks are summarized in Table 3 for each of the S1 pacing sites. There were no significant differences in the early site potential gradients at the ULV between S1 pacing sites (P = 0.67). However, the early site potential gradients measured at the ULV were significantly (P < 0.01) higher than those measured for shocks that were one step below the ULV (ULV: 8.9 ± 4.8 V/cm vs. ULV-step: 7.3 ± 4.1 V/cm).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Global Shock Variables and Shock Timing

In the current study, the ULV was determined using a single S2 shock electrode configuration and three S1 pacing sites that were placed in distinct areas of the heart. Regardless of this disparity in the origin of ventricular activation, the measured ULVs at resolutions of 10, 20, and 40 V were not significantly different with the use of repeated-measures analysis to adjust for interanimal variation. These findings are consistent with the predictions of the critical point hypothesis for the ULV.

In a few animals, there was a variation in the measured ULVs during the step-up testing for the ULV40 (Table 1). No particular S1 pacing site appeared to result in a different ULV. These results may be reflective of the dose-response relationship between shock strength and the ULV (29). Step-up testing will determine a point in a lower and potentially flatter portion of the curve. Thus there may be more variation in the measured ULV shock strength. Up/down testing with sequentially smaller step sizes will determine a more accurate measure of the 50% point on the dose-response curve. At that point, the slope is steeper and there is less potential for random variation of the ULV (32). When we performed further testing for the ULV in the ULV20 and ULV10 sets, the ULVs converged closer between S1 pacing sites in those animals.

Whereas the global shock strength at the ULV did not appear to be affected by the choice of S1 pacing site, the timing of VF inductions for shocks below the ULV was altered by this choice. For all three S1 sites, S2 shocks were delivered starting at the same point in the T wave. However, as shock strength increased, the VF induction points in the T wave diverged on the basis of the origin of ventricular activation (Fig. 5). S2 shocks had to be delivered earlier than the peak of the T wave for RVOT pacing but later than the peak for LVA and LVB pacing.

On the basis of the critical point theory, the time points in the electrical cycle at which an S2 induces VF should depend on the S1 pacing site. The critical point hypothesis predicts that properly timed S2 shocks slightly weaker than the ULV initiate VF because the critical potential gradient level is present in one or more areas of the heart. The critical potential gradient should be located in these same areas of the heart as long as the S2 shock strength, S2 configuration, and intrinsic factors remain unaltered. As a result, the critical point hypothesis predicts that after shocks slightly weaker than the ULV, VF will be initiated in one of these areas regardless of the S1 pacing site. However, the S1 pacing site will affect the timing of S2 shocks that induce VF because the time at which one of the regions becomes activated and critically recovered depends on the sequence of ventricular activation. The critical potential gradient area will activate soon after the S1 and pass through the critical degree of recovery early in the T wave if the S1 site is nearby. However, pacing from a distant S1 site will cause the area to activate later after the S1 and pass through the critical degree of recovery later in the T wave. Therefore, the critical point hypothesis predicts that VF will be induced for S2 shocks delivered early in the T wave for S1 sites close to a critical area and later in the T wave for sites distant from a critical area.

These findings have important implications concerning testing methods used to determine the ULV. In this study, the entire T wave was scanned with S2 shocks at a particular shock strength. This method requires the delivery of a large number of shocks, thus decreasing its clinical practicality. In clinical practice, others have employed techniques using a single point in the T wave or a limited scanning interval to determine the ULV (5, 13). The use of such techniques in the current study would probably have altered the results. If only a small segment on the upstroke of the T wave were scanned (see Fig. 5), the ULV for S1 pacing from the RVOT site would probably have been similar to that found with full T-wave scanning. However, for the LVA or LVB S1 sites, VF induction times at later points in the T wave would have been untested. Therefore, the measured ULV would have been lower than the absolute ULV. Thus, whereas a point in the upstroke of the T wave may be optimal for testing with RVOT S1 pacing, the same point would be much less desirable for LVA or LVB S1 pacing.

Early Sites

Early site locations. In this study, as predicted by the critical point hypothesis, shocks well below the ULV induced activations leading to VF at multiple apical sites on the heart, closer to the LVA shocking electrode. As shock strength increased, the earliest sites of activation moved away from the S2 shocking electrode and decreased in number. The movement of early sites for increasing shock strengths is similar to that shown by Shibata et al. (28) using a similar S2 configuration but a different waveform in dogs. As in their study, we observed oppositely rotating bilateral reentrant wave fronts for some lower-strength shocks. We have shown further that the early sites for initiating these wave fronts originated where the potential gradients were low and of similar value. The early sites also originated where the tissue was in a similar state of recovery following prior S1 pacing (similar VR-S2 interval).

Early sites at the ULV. Repetitive activity following ULV-strength S2 shocks has been noted previously (28). However, the origin of these postshock activations after ULV-level shocks has not been documented. In this study, we found that most activations following ULV- level S2 shocks arose in the same areas of the heart where the early sites occurred for S2 shocks just weaker than the ULV. These activations following ULV- level shocks either self-extinguished or were halted by collisions with other early site wave fronts. The results indicate that whereas a single mechanism may be responsible for initiating the postshock activations, there may be several mechanisms that prevent their continuation. As we have shown, increases in the S2 shock strength moved the early sites away from the S2 shocking electrodes. When a single rotational wave front was observed but failed to reenter, the increased S2 strength may have moved the early site just close enough to a tissue border that an activation front was induced but reentry could not proceed (36). In cases with multiple beats from a single early site, the reentrant circuit may have drifted (8) into a border and extinguished, although active "drifting" was not observed, perhaps due to the mapping resolution in this study. Recent modeling combines the critical point mechanism with bidomain theory. In that model, the critical potential gradient remains present, regardless of shock strength. However, due to anisotropy and its spatial effects on stimulation, higher-strength shocks may create rotors that are too close together to survive (24). With any of these mechanisms, small local variations in potential gradient or refractoriness may result in continuing reentrant activity rather than cessation after one or two beats. Thus a probability factor exists that may explain the dose-response relationship for the ULV (29). High-resolution three-dimensional mapping close to the tissue borders needs to be performed to determine the exact mechanism for the ULV.

Early site activations. Two intervals from the early site electrograms were used to assess the timing of the S2 shock relative to the local recovery time for S2 shocks just below the ULV. The interval from the time of local activation to the time of the S2 (VR-S2 interval) was not significantly affected by the S1 pacing site. If it is assumed that the refractory periods are the same at all early sites, then the results would indicate that the earliest sites of activation always arose in areas where the tissue was at a similar degree of relative refractoriness.

Early site potential gradients. The potential gradients measured at the earliest sites of activation for shocks just below the ULV averaged 5-9 V/cm. As predicted by the critical point hypothesis for the ULV, the S1 pacing site did not have an effect on the early site potential gradients, even though the early sites arose in a different region of the heart for the RVOT pacing site. Frazier et al. (11) reported potential gradients of ~5 V/cm at the critical point of reentry induced in a small region of the RVOT. A different shock waveform, S1 site, and S2 electrode configuration were used in that study. However, the potential gradients measured at the early sites in this study would be expected to be slightly different. With the critical point mechanism, activations would initiate in an area adjacent to the singularity point, where the potential gradient field is slightly weaker than at the critical point itself.

Limitations

We used multielectrode plaques to record from the epicardial surface. This was performed to reduce potential gradient measurement error caused by errors in interelectrode distance measurements. Although this optimized potential gradient measurements, it restricted our ability to map evenly across the epicardial surface. Our ability to track activations back to the earliest sites would have been improved by reducing the interplaque distances and increasing the number of recording electrodes; however, this was not possible due to technical limitations.

In this study, we used the leading-edge S2 potential gradient magnitude as the parameter to describe the local shock "force" affecting the tissue. In theory, the formation of critical point reentry is most dependent on the cellular state of the tissue at the instant the S2 stimulus is removed. As long as the regions of varying cellular states exist in the proper spatial orientation with an intervening singularity point, reentry will ensue spontaneously. The use of this single parameter was based on previous studies involving the critical point and potential gradient measurements during S2 shock delivery (6, 11). This single parameter measured at the beginning of the S2 may not be the best predictor of cellular response. Differing cell responses based on S2 intensity, duration, polarity, and orientation have been documented (19). Other parameters such as the mean potential gradient, trailing-edge potential gradient, or potential gradient combined with shock duration and/or polarity may be better predictors of cellular response and reentry formation.

Interestingly, although we used a biphasic waveform in this study, it is unknown whether the results would have been different had a monophasic S2 shock been utilized. The similarity of results between our study and that of Shibata et al. (28) in terms of early site location and movement with S2 shock strength suggests that waveform polarity may not play a significant role, because they used a monophasic S2 shock. However, it is unknown whether the early site potential gradients would have been different had a monophasic waveform been used.

In summary, in this study the ULV was determined by using a single S2 shock electrode configuration and three separate S1 pacing sites. The measured ULVs were not affected by the S1 pacing site in terms of global shock strength variables (LEV, current, and total shock energy). However, the choice of S1 pacing site changed the time points in the T wave at which VF was induced for shocks below the ULV. These results were predicted by the critical point hypothesis for the ULV.

Epicardial mapping of cardiac activations revealed that shocks at strengths far below the ULV induced activations in areas closer to the S2 shocking electrode. As shock strength was increased, the early sites were moved away from the shocking electrode to more remote areas where the potential gradient field remained weak. When slightly stronger shocks were delivered, one or several early activations originated from the same remote areas but halted and did not result in VF.

For this S2 configuration, shocks at strengths just weaker than the ULV initiated activations in the RVOT when pacing was from the LVA or LVB. However, the early sites were located at the lateral aspect of the RV when pacing was performed from the RVOT. Regardless of the pacing origin, shocks just below the ULV level induced activations for which the potential gradient magnitude was ~5-9 V/cm, and the level of tissue recovery was similar at the time of the shock. However, for shocks that were much weaker than the ULV, the early site potential gradient magnitudes were lower.

On the basis of the critical point hypothesis, predictions were made regarding the effect of S1 pacing site on the ULV shock strength, the timing of VF inductions in the T wave, the locations of earliest post-S2 epicardial activations, and the potential gradients and level of tissue recovery at the early sites. The results support most of these predictions. The few predictions not verified in this study, such as the prediction of a constant potential gradient at the early sites, indicate either that the critical point hypothesis is correct but the lack of intramural electrodes in this study did not allow us to identify the true early site or that other factors in addition to the critical point, such as bidomain effects and the direction of activation and recovery, are influential. The results indicate that the critical value of the potential gradient may not be a constant but may change with location in the heart. The ULV appears to result from movement of the critical potential gradient to remote areas where other factors, such as the proximity of heart borders, restrict the formation of reentry around the critical point.