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(Circulation. 1999;99:949-962.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Differential Effects of a Segment of Slow Conduction on Reentrant Ventricular Tachycardia in the Rabbit Heart
From the Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Netherlands.
Correspondence to Prof Dr M.A. Allessie, Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands.
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Abstract |
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Background—The purpose of this study was to compare differential effects of a segment of slow conduction during ventricular tachycardia (VT) due to depression of the action potential and electrical uncoupling.
Methods and Results—In 33 Langendorff-perfused rabbit hearts, a ring of anisotropic left ventricular subepicardium was created by a cryoprocedure. Reentrant VT was produced by incremental pacing. Slow conduction in a segment of the ring was created by selective perfusion of the LAD with 10 mmol/L potassium or 0.75 mmol/L heptanol. As a result, VT cycle length increased from 193±34 to 235±37 ms (potassium) and 227±42 ms (heptanol). Reset curves were made by applying premature stimuli proximal to the area of depressed conduction. In a ring of uniform anisotropic tissue, the reset curve was almost completely flat. Electrical uncoupling of part of the ring (nonuniform anisotropy) resulted in a mixed reset curve. In both substrates, early premature beats failed to terminate VT. Depression of part of the ring by increasing K+ resulted in a completely sloped reset curve, indicating a gap of partial excitability. Under these conditions, in 19 of 24 hearts, premature beats terminated VT by conduction block in the high K+ area.
Conclusions—The nature of the area of slow conduction determines the type of reset response and the ability to terminate VT.
Key Words: tachycardia • conduction • ventricles • electrophysiology
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Introduction |
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Many clinical as well as experimental studies have provided evidence that ventricular tachycardia (VT) after myocardial infarction is based on reentry.1 2 3 4 Areas of slow intraventricular conduction are thought to play an essential role in the arrhythmogenic substrate and are a preferential target for radiofrequency ablation.5 6 7 Tissue anisotropy, the presence of collagenous septa between muscle bundles, and depression of the active membrane properties have been kept responsible for areas of slow conduction.8 9 10 11 12 13 14 15 However, the nature of slow conduction in clinical reentrant VT is not exactly known, and it is incompletely understood how differences in the nature of slow conduction may affect the characteristics of VT.
Some years ago, we developed an animal model of reentrant VT in uniform anisotropic subepicardium (the frozen heart model).16 Although this model has been useful to study the role of anisotropy and the response to programmed electrical stimulation and antiarrhythmic drugs,16 17 18 19 20 21 22 23 extrapolation of these data to clinical arrhythmias remained questionable because of the absence of an area of pathological slow conduction. In the present study, a segment of slow conduction was introduced in the reentrant circuit by selective perfusion of the left anterior descending coronary artery (LAD) by high potassium or heptanol. In this way, we could differentiate the effects of an area of slow conduction on reentrant VT, depending on whether it was due to depression of the active membrane currents or to electrical uncoupling.
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Methods |
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Preparation
Animals were handled according to Dutch law, and the study was approved by the university animal investigation committee. Thirty-three Flemish rabbits of both sexes weighing between 3.5 and 4.7 kg were used for this study. The rabbits were anesthetized with Hypnorm (0.5 mL/kg), and after heparinization (1000 IU), they were killed by cervical dislocation. The thorax was opened by a midsternal incision, the heart quickly removed, and the aorta connected to a Langendorff perfusion system. To obtain a thin layer of perfused subepicardium, a cryotechnique was used as described previously.16 17 18 19 20 21 22 23 The 1-mm-thick left epicardial layer was then transformed into a ring by a transmural cryolesion in the middle of the left ventricular wall.17 The size of this cryolesion was
20x10 mm,
and it was oriented parallel to the LAD. In this way, a subepicardial
ring of uniform anisotropic tissue was created with an isthmus of 5 to
10 mm between the LAD and the central cryolesion (Figure 1
).
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Cannulation of the LAD
After reentrant VT was produced in the ring by rapid pacing, the
proximal part of the LAD was visualized by dissecting the overlying
epicardium. A polyethylene tube (diameter, 0.67 mm) connected to a
separate perfusion system at 37°C was stretched to get an outer tip
diameter of 0.3 to 0.5 mm. Under microscopic control, the
polyethylene tube was inserted into the LAD through the aortic cannula.
The LAD was selectively perfused by setting the pressure in the LAD
slightly higher than the aortic pressure. The average flow in the LAD
was 3±1.9 mL/min. As long as the LAD was perfused with normal
perfusate, the VT was stable and the impulse circulated around
the ring with a constant cycle length. A segment of slow conduction
could be produced in the reentrant circuit by selective perfusion of
the LAD with high K+ (10 mmol/L) or heptanol
(0.75 mmol/L). Because the LAD perfused a full segment of the ring
(Figure 1
, right), the circulating impulse was forced to
propagate through this segment of depressed conduction.
Mapping and Stimulation
The epicardium of the left ventricle was mapped with a
spoon-shaped mapping electrode containing 248 silver electrodes
(diameter, 0.3 mm), with an interelectrode distance of 2.3
mm. After amplification and filtering (bandwidth, 1 to 400 Hz), the
signals were multiplexed, analog-to-digital–converted (1000 Hz, 8
bits), and stored on videotape.24 Custom-made software was
used to detect the negative intrinsic deflection of the electrograms
and to generate color-coded activation maps. A computer-controlled
stimulator (Medtronic SP3084) was used to pace the ventricles through a
pair of electrodes selected from the mapping array. Premature stimuli
(4 times diastolic threshold) were applied proximal to the
area of slow conduction. A sensing electrode adjacent to the pacing
site was used to synchronize the stimulator. The last activation
preceding the stimulus was defined as V1. The 2
beats following the premature stimulus were defined as
V2 and V3. The coupling
interval between V1 and the stimulus (S) was
varied in steps of 5 ms. The effective refractory period (ERP) was
defined as the shortest V1-S interval that
induced a propagated response. The exact coupling interval was
determined after correction for small differences in activation time
between pacing and sensing sites. The shortest
V1-V2 interval closely
orthodromic to the pacing site was taken as the functional refractory
period. The excitable gap was defined as the difference between the VT
cycle length and the ERP.
Experimental Protocol
After cannulation of the LAD, sustained monomorphic VT was
monitored for 30 minutes. During this time, the mapping electrode was
positioned on the heart and several maps were made to check the quality
of the electrograms and the reproducibility of the maps. When the
tachycardia was stable, the potassium concentration in the
LAD perfusate was progressively increased in 2-minute steps of
1 mmol/L until VT terminated (33 hearts). Infusion of high
K+ was then stopped, and VT was reinitiated by
rapid pacing. After VT cycle length had returned to its control value,
the LAD was perfused with 10 mmol/L K+ (24
hearts). At this concentration, the conduction in the LAD segment was
depressed without terminating the tachycardia. A complete
reset curve was made by applying single premature stimuli orthodromic
to the area of depressed conduction. In case the
tachycardia was interrupted, it was immediately
reinitiated. The LAD area was then perfused with normal
perfusate, and the reset curve was repeated. In 12 hearts,
reset curves were made during perfusion of the LAD with heptanol
(0.75 mmol/L). Because at higher concentrations, heptanol also
blocks the fast sodium channels,25 26 termination of VT by
higher concentrations of heptanol was not studied systematically.
Data Analysis
The whole experiment was recorded on tape. Activation maps
were generated automatically and edited when necessary. Isochrones
were drawn manually at 10-ms intervals. Conduction velocity through the
area of slow conduction was calculated from the distance between 
5
isochrones. The total conduction time was measured between 2
electrodes proximal and distal to the LAD area. Results are expressed
as mean±SD. The effects of heptanol and potassium were studied in
different series in which each preparation served as its own control.
Statistical analysis was done with the paired Student's
t test. Differences between groups were tested with the
unpaired t test. A value of P<0.05 was taken as
statistically significant.
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Results |
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Effects of a Segment of Slow Conduction on VT
Epicardial mapping of the left ventricle showed that all VTs were based on clockwise or counterclockwise reentry around the ring of myocardium. VT was strictly monomorphic, the beat-to-beat variation in cycle length being <2 ms. Spontaneous termination of VT was not observed. In 29 of 33 hearts, the isthmus between the LAD and the cryolesion in the free wall of the left ventricle was perfused by the LAD. In this area, conduction velocity was slow because the circulating wave front propagated perpendicular to the fiber orientation. The average VT cycle length was 191±35 ms (range, 142 to 263 ms), interindividual differences being mainly due to differences in size and location of the central cryolesion.16 Depending on the length of the isthmus (range, 0.6 to 2.7 cm; mean, 1.5±0.5 cm), the total conduction time through this part of the circuit varied between 21 and 119 ms (mean, 70±29 ms). The conduction velocity through the isthmus was 23.5±8.5 cm/s (14 to 40 cm/s). In 4 of 33 hearts, the LAD area was localized at the base of the left ventricle where the impulse propagated more obliquely to the fiber orientation. Consequently, the conduction velocity was higher (>35 cm/s).
Figures 2 and 3 show the effects of depression of LAD
conduction by infusion of increasing dosages of potassium or heptanol.
During control, the differences in conduction velocity around the ring
were due to the normal anisotropic properties of the
subepicardium.16 Figure 2 shows that a clockwise VT
with a cycle length of 187 ms became slower by infusion of high
potassium in the LAD (gray segment). At a concentration of 10
mmol/L K+, VT cycle length had increased from 187
to 230 ms. At 14 mmol/L, the tachycardia had become
more than twice as slow (cycle length, 429 ms). The total conduction
time through the LAD segment (electrodes a through h) increased
markedly from 101 ms during control to 160 and 376 ms during perfusion
with 10 and 14 mmol/L K+. The apparent
conduction velocity through the isthmus decreased from 21 to 13 and 6
cm/s, respectively. The unipolar electrograms recorded from the LAD
area became broader and lost much of the steepness of their negative
deflections. During infusion with 10 mmol/L of potassium,
transverse conduction was still uniform, and the isochrones in the
LAD area remained equally distributed. However, infusion by 14
mmol/L of K+ produced nonuniformity in conduction
and local crowding of isochrones. Local conduction times as long as
84 ms (between t=116 and 200 ms) were recorded between electrodes
2.3 mm apart. In the nondepressed part of the circuit, the
conduction time between electrodes h and a shortened from 86 ms during
control (187 minus 101 ms) to 70 ms (t=160 to 230) and 53 ms (t=376 to
429), respectively, during perfusion of the LAD by 10 and 14
mmol/L of K+. This shortening in conduction time
in the normal part of the reentrant circuit was due to a slight change
in exit site of the circulating impulse from the segment of depressed
conduction.
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Figure 3 shows the effects of selective perfusion of the LAD
segment by heptanol 0.75 and 1.0 mmol/L. Because of slowing of
conduction in the LAD area, the VT cycle length increased from 173 to
218 and 246 ms, respectively. The conduction time of the depressed
segment (electrodes c through h) prolonged from 84 ms (t=23 to 107 ms)
to 128 ms (t=25 to 153) and 162 ms (t=23 to 185 ms). The effective
transverse conduction velocity through the isthmus slowed from 24 to 14
and 10.4 cm/s, respectively. Conduction was depressed nonuniformly,
some areas being affected more than others. Heptanol did not broaden
the extracellular waveforms, but the amplitude and steepness of the
electrograms decreased markedly, and in some areas, they became
fragmented.
Table 1 gives the effects of
selective perfusion of the LAD by high potassium or heptanol for all
experiments. Perfusion by 10 mmol/L potassium increased the
conduction time through the LAD segment by 71%, from 72±29 to 123±52
ms (P<0.001). However, the cycle length of the
tachycardia increased by 23%, from 193±34 to 235±37 ms
(P<0.001). Thus, even a high degree of depressed conduction
in a segment composing 20% of the circuit caused a relatively small
increase in VT cycle length. In none of the 24 hearts was VT terminated
by 10 mmol/L K+. Perfusion of the LAD by
heptanol 0.75 mmol/L prolonged the conduction time of the LAD zone
from 64±32 to 106±51 ms (66%) (P<0.001). Again, the
increase in VT cycle length was smaller and averaged 25% (from
181±29 to 227±42 ms) (P<0.001). The effects of
K+ and heptanol on VT cycle length were similar,
and the slowing of conduction was also comparable.
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Termination of VT by Regional High Potassium
Table 2 gives the measurements
during termination of VT by LAD infusion of high
K+ for all experiments (33 hearts). VT was
terminated at an average potassium concentration of 12.2±1.3
mmol/L (range, 11 to 16 mmol/L), prolonging the VT cycle length
from 191±35 to 278±69 ms (range, 172 to 495 ms)
(P<0.001). The wide range in cycle length at which VT
terminated was caused primarily by differences in the length of the
isthmus of depressed conduction. In 3 experiments, VT cycle length
before termination was >350 ms. In these cases, the depressed LAD
segment was >2 cm long. On average, the conduction time through the
LAD segment before termination of VT increased by 140%, from 70±29 to
169±86 ms (range, 39 to 476 ms). This reflects a slowing in apparent
conduction velocity from 23±8 to 10±4 cm/s. In all cases, VT was
terminated by conduction block of the circulating impulse in the
isthmus of depressed conduction.
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Often, oscillations in VT cycle length occurred before
termination of VT. In only 8 of 33 experiments did the
tachycardia terminate abruptly (Figure 4, top). In the other hearts, various
types of cycle-length oscillations were seen before
termination. In 6 hearts, the last 2 cycles before termination showed a
long-short pattern (second panel). In 9 cases, the
oscillations were more complex and did not follow a fixed
pattern (third panel). However, in these cases, the
tachycardia terminated with a last short interval at the
entrance of the segment of slow conduction. In 10 hearts, the
tachycardia showed a regular 2:1 alternation in cycle
length before termination of VT (bottom). Again, VT terminated with a
last short interval. Thus, in 23 hearts with different patterns of
oscillation, VT always terminated with a last sequence of
long-short intervals. In 2 hearts, 2 short cycles followed each other
before termination of VT.
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Figure 5 shows an example of the maps
that were recorded during the cycle-length oscillations
before termination of VT. During control, the clockwise VT had a stable
cycle length of 177 ms (not shown), the LAD area being traversed in 74
ms. The gradual increase in K+ concentration in
the LAD segment (gray area) caused a concentration-dependent slowing of
conduction and a progressive slowing of the tachycardia.
Approximately 45 seconds before termination, oscillations
in VT cycle length developed. The magnitude of these
oscillations gradually increased to a maximum of 71 ms
before termination. The maps in Figure 5 show that the
oscillations were caused by beat-to-beat alterations in
pathway of the circulating impulse within the segment of depressed
conduction. Because of the development of 2:1 conduction block along
the inner boundary of the circuit (thick line), every other cycle the
circulating wave front had to propagate through the outer portion of
the depressed segment. During the long cycles, the circulating impulse
traversed the LAD segment in 165 ms (from t=59 to 224 ms), compared
with a conduction time of 102 ms during the short cycles (t=71 to 173
ms). This resulted in clear alternations in VT cycle length between 222
and 293 ms. The VT was interrupted when complete conduction block
occurred in the area of depressed conduction (right map). In other
cases of cycle-length oscillations, alternations in pathway
through the segment of slow conduction could be demonstrated. When
oscillations in cycle length were small, the mapping
resolution of 2.3 mm was insufficient to directly demonstrate
changes in pathway of the circulating impulse. However, in these cases,
changes in electrogram morphology also pointed to beat-to-beat changes
in direction of propagation.
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Reset of VT With and Without a Segment of Slow Conduction
In 24 hearts, reset curves were made both during control and after
perfusion of the LAD with 10 mmol/L K+. In
12 hearts, the reset curve was also measured after LAD infusion with
0.75 mmol/L heptanol. Figure 6 shows
the activation maps obtained during reset of the
tachycardia under these circumstances. The pacing site was
chosen proximal to the area of slow conduction. The electrograms below
the maps were recorded between the pacing site and the area of
depressed conduction. Infusion of 0.75 mmol/L heptanol or 10
mmol/L potassium increased VT cycle length to a similar extent (from
205 to 245 and 252 ms). During control, the LAD area was
activated from t=67 to 134 ms (conduction time, 67 ms). After
perfusion with heptanol or high K+, the
conduction time through this area increased by 103 (from t=67 to 170
ms) and 117 ms (from t=67 to 184 ms). From the electrograms at the
bottom of the maps, it can be seen that during control and after
electrical uncoupling by heptanol, even the earliest premature beats
(coupling interval, 80 ms) did not terminate VT. In contrast, when
conduction was depressed by high potassium, late premature beats
(V1-S interval, 165 ms) already terminated the
tachycardia.
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During control, the earliest premature beat invaded 31% of the
circuit antidromically before it collided with the
clockwise-circulating wave front. The
V2-V3 cycle length of the
new reentrant tachycardia initiated by the premature beat
was 212 ms, compared with a normal VT cycle length of 205 ms. In the
total of 24 control experiments with a VT cycle length of 193±34 ms,
the maximal V2-V3 return
cycle was 202±36 ms (P<0.05). This implies that the
earliest premature wave front propagated at almost normal speed around
the circuit, with a total conduction delay of only 9±7 ms. Together
with the observation that early premature stimuli did not terminate VT,
this is good evidence that in a normal anisotropic circuit, no segments
with considerably prolonged refractory periods or decreased safety
factor for conduction exist.
After perfusion of the LAD with heptanol, VT could not be terminated by
early premature beats. However, the earliest premature impulse (80 ms)
now invaded the circuit retrogradely for as much as 69% before it
collided with the circulating wave front (Figure 6, lower
middle panel). In fact, the whole free wall of the left ventricle was
now activated by the premature wave front rather than by the
circulating impulse. The presence of an area of slow conduction thus
largely determines how much of the ventricles are activated
antidromically during pacing and thus the degree of fusion of the QRS
complex. Because of slow conduction of the premature wave front in the
area of electrical uncoupling, the
V2-V3 return cycle length
was 23 ms longer than the normal VT cycle length (268 compared with 245
ms). In the whole group of 12 heptanol experiments, the
V2-V3 return cycle was
prolonged from 227±42 to 243±48 ms (P<0.05). The fact
that VT did not terminate means that despite the electrical uncoupling,
the excitability and safety for conduction were still
homogeneously distributed around the circuit.
In contrast, when a segment of slow conduction was produced by high
potassium, late premature stimuli already terminated the
tachycardia (Figure 6, right panels). In this
example, the conduction time through the LAD segment increased by 117
ms (from t=67 to 184), and a premature beat with a coupling interval of
165 ms terminated the tachycardia by orthodromic conduction
block in the LAD segment. This differential effect of the 2 types of
depressed conduction was apparent even though conduction was depressed
to a similar degree by heptanol and K+. In a
total of 24 potassium experiments (VT cycle length, 235±37 ms), the
shortest premature stimulus that did not terminate VT had a
V1-S coupling interval of 133±22 ms and was
followed by a prolonged
V2-V3 return cycle of
274±47 ms (P<0.05).
Figure 7 illustrates the marked slowing
of conduction of an early premature beat in the segment with high
K+. In this example, the VT cycle length was 217
ms, and the LAD segment perfused by high K+ was
activated from t=57 to 140 (conduction time, 83 ms). Reset of
the tachycardia by a stimulus with a coupling interval of
150 ms resulted in a V2-V3
return cycle of 270 ms. The upper right map shows that the premature
impulse needed 141 ms to cross the LAD segment (from t=57 to 198). This
slowing of conduction obviously caused longer
V1-V2 intervals distal to
the area of slow conduction. The right lower panel shows the spatial
distribution of the V1-V2
intervals. This interval map shows that at the exit of the segment of
slow conduction, the premature impulse (150 ms) had lost almost all its
prematurity (V1-V2
intervals, 203 ms). Thus, in the normal part of the ring, the
tachycardia was reset by only 14 ms (VT cycle length, 217
ms).
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Figure 8 shows the complete reset curves
of the tachycardia shown in Figure 6. During
control, the reset curve was almost completely flat, and only the
earliest premature stimuli (<100 ms) caused a slight prolongation in
V2-V3 cycle length. Local
electrical uncoupling by heptanol increased VT cycle length from 205 to
245 ms and resulted in a mixed reset curve. Prolongation of the return
cycle now started already at a longer coupling interval (120 ms), and
the degree of prolongation was more pronounced (up to 268 ms).
Perfusion of the LAD by high K+ prolonged VT
cycle length to 252 ms and produced a completely sloped reset curve.
Even late premature stimuli were already followed by a prolonged
V2-V3 return cycle. This
indicates that despite the increase in VT cycle length, only a
partially excitable gap existed in the depressed segment of the
circuit. The maximal prolongation of the
V2-V3 interval was 297 ms.
All premature stimuli between 110 and 165 ms terminated VT, indicating
that the local depression of conduction by high
K+ created a marked spatial
heterogeneity in refractoriness and safety factor for
conduction in the reentrant circuit.
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In Table 3, the quantitative differences
in reset characteristics of the different substrates of VT are given.
During control and after infusion of heptanol, VT could not be
terminated by single premature stimuli in any of the hearts. In
contrast, during high potassium perfusion, single premature stimuli
terminated the tachycardia in 19 of 24 hearts. Because of
the prolongation of VT cycle length, the ERP in the normal part of the
circuit prolonged by 25%, from 92±14 to 115±23 ms in the heptanol
group and from 94±16 to 119±12 ms in the potassium group. Because VT
cycle length prolonged more than the refractory period, the excitable
gap also widened. However, the portion of the VT cycle length that was
excitable remained the same (48% and 51% in the control groups,
compared with 49% in the heptanol and potassium groups). Because of
some stimulus latency and conduction delay in the small zone between
the pacing site and the LAD area, the shortest attainable
V1-V2 interval at the
entrance of the area of slow conduction was somewhat longer than the
ERP. During perfusion with high potassium or heptanol, the entrance of
the LAD area could be reset to an amount similar to that during control
(43% to 45%). After heptanol infusion, the exit of the segment of
slow conduction was also reset to an extent similar to that during
control (39% and 37%, respectively). During high
K+ perfusion, however, the slowing of premature
impulses in the depressed segment limited the degree of reset at the
exit of the area of slow conduction to 20% to 27% of the VT cycle
length.
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Termination of VT by Single Premature Stimuli
Two different mechanisms of termination of VT were observed in 19
of 24 hearts by perfusion of the LAD with high
K+. In 16 hearts, termination was a result of
complete block of the premature wave front in the depressed segment. In
7 hearts, an antidromic echo wave emerged from the area of slow
conduction, which extinguished the tachycardia (Figure 9). In 4 hearts, both mechanisms were
observed. The site of block was almost always located at the entrance
of the depressed segment, where the premature beat exhibited its
largest prematurity. The shortest
V1-V2 interval that could
be attained before block occurred was 182±23 ms (n=16). Because VT
cycle length was 235±41 ms, the excitable gap in the area of depressed
conduction must have been <53±38 ms. Because in the normal part of
the circuit, the excitable period was 119±30 ms, under these
conditions a marked heterogeneity in functional
refractory period existed in the ring of ventricular
myocardium.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The model of reentrant VT comprising a segment of slow conduction is a modification of the ring of perfused anisotropic myocardium as described by Brugada et al.17 The introduction of an area of slow conduction in the anatomic circuit makes this experimental model more closely resemble the clinical substrate of VT.1 2 27 Selective perfusion of the LAD with high potassium or heptanol mimics some of the changes that occur during myocardial ischemia and infarction.9 10 11 12 13 14 15 28 It allows us to differentiate the effects of slow conduction due to depression of the action potential or electrical uncoupling. The major finding of the present study is that the nature of an area of slow conduction in a reentrant circuit largely determines the behavior of the tachycardia. Slow conduction due to a diminished availability of rapid Na+ channels could be distinguished from slow conduction due to electrical uncoupling. This distinction was based on differences in reset curve and termination of VT by programmed electrical stimulation. Such a diagnosis of the nature of the area of slow conduction might be of importance for prevention and treatment of the reentrant tachycardia.
Differential Effects of a Segment of Slow Conduction on Reset
Characteristics
In uniform anisotropic rings of myocardium without an
area of slow conduction, a fully excitable gap was present during
reentrant VT (cycle length approximately twice the refractory period).
Because the partially excitable gap was rather short (usually <20 ms),
only the earliest premature beats propagated with some minor conduction
delay of 9±7 ms. Consequently, in this substrate, the reset curve was
almost complete flat. In contrast, in the presence of a segment of slow
conduction, the reset curve was either mixed (electrical uncoupling) or
completely sloped (depression of sodium channels). Clinically different
reset patterns have also been described.29 30 31 A flat
reset curve is generally associated with a circuit containing a large
fully excitable gap. A sloped reset curve is attributed to the presence
of a partially excitable gap or conduction delay between the pacing
site and the reentrant circuit.32 33 34 35 In a study by
Almendral et al36 in 32 patients with chronic myocardial
infarction, the 3 different reset patterns were approximately equally
distributed. In another clinical study, Gottlieb et al37
found that termination of VT by premature stimuli was more likely if
the reentrant VT exhibited a sloped reset curve. VT cycle length did
not determine the type of response during reset of the
tachycardia. Our study shows that termination of VT by
premature stimulation is not due to the presence of a segment of slow
conduction per se. Only if the active membrane properties are depressed
are a sloped reset curve and termination of VT observed. It is possible
that slowing of the reactivation kinetics of the sodium channels by
partial depolarization of the membrane and consequent development of
postrepolarization refractoriness may have contributed to the sloped
reset curve.
Segment of Slow Conduction Due to Depressed Sodium
Channels
Perfusion of the LAD by 10 mmol/L of K+
reduced the local conduction velocity in the circuit by 40%. At the
same time, VT cycle length prolonged by 23%. In the depolarized
segment, the safety factor for conduction was significantly reduced and
the refractory period markedly prolonged. This is due to a reduction of
the number of available sodium channels by a less negative takeoff
potential, prolongation of the action potential by high
K+, and slowing of the reactivation kinetics
leading to postrepolarization refractoriness.38 As a
result, a high degree of spatial heterogeneity in
safety factor and refractory period existed along the circuit, with a
functional refractory period of 126±14 ms in the normal part and
182±23 ms in the depressed part of the circuit. Late premature stimuli
could still advance the tachycardia, proving that an
excitable gap existed at each and every point along the circuit,
including the segment of depressed conduction. The fact that late
premature stimuli already prolonged the return cycle, however,
indicated that in the area of slow conduction, excitability was only
partially recovered. High-resolution mapping of the reset response
provided direct evidence for such a partially excitable gap. Late
premature impulses conducted with considerable delay through the
depressed segment, whereas moderately premature beats terminated VT by
complete conduction block in the depressed segment.
Slow Conduction Due to Electrical Uncoupling
Heptanol has been shown to increase the intercellular resistance
by blockade of the gap junctions.39 40 The active membrane
properties are less affected, although at higher dosages (1.3
mmol/L), heptanol can also block the sodium channels.26
Therefore, we did not use concentrations of heptanol >0.75
mmol/L. At this concentration, conduction was slowed to an extent
similar to that with administration of 10 mmol/L
K+. Jalife et al41 compared the
effects of heptanol and high K+ in sheep Purkinje
fibers. They showed that after complete conduction block was produced
by heptanol, the cells were still fully excitable and the shapes of the
generated action potentials were relatively normal. This is in
agreement with our observation that during VT, early premature beats
were not blocked in the heptanol-treated segment of the circuit.
Obviously, in a segment of slow conduction due to electrical
uncoupling, neither the stimulating efficacy nor the excitability of
the ventricular cells is reduced. Consequently, the spatial
heterogeneity in the refractory period of the circuit
was not increased. During reset of VT, however, the return cycle
prolonged already at less premature stimuli, indicating a prolonged
period of partial excitability. This observation is difficult to
explain by an increased junctional resistance alone. Some studies have
suggested that changes in cell-to-cell communication may also have an
indirect effect on the action potential25 42 43 and that
heptanol may change the capacitance of the membrane.39 43
Therefore, it remains uncertain whether the prolongation of the
partially excitable period is due to electrical uncoupling alone or
whether a change in availability or kinetics of the fast sodium
channels may also play a role.
Limitations of the Study
Our attempts to mimic the pathophysiological
substrate of clinical reentrant VT is clearly still an
oversimplification. In acute ischemia, the elevated
extracellular potassium is only one of the factors that depress the
active membrane properties, and other changes in ionic composition and
metabolic compounds are involved as
well.11 12 13 14 15 An important limitation of the present
model is that we have deliberately reduced the ventricles to a
2-dimensional subepicardial substrate of VT. Cryoablation of the
endocardial and midmyocardial layers of the left ventricle eliminated
the possible participation of these structures in our studies. This is
in contrast to the arrhythmogenic substrate after chronic myocardial
infarction, which has a more complex 3D architecture. Also, the
pathological changes in the heterogeneous scar of a healed
myocardial infarction are certainly not adequately reproduced by local
perfusion with heptanol, and it cannot be excluded that heptanol may
have some depressive effect on the sodium channels. Finally, high
potassium not only modifies the fast sodium channels but also affects
K+ conductances and ionic pumps.
Clinical Implications
In the clinical setting, the different components of a reentrant
circuit are not easily accessible, and the exact nature of the area of
slow conduction in the reentrant circuit therefore remains largely
unknown. In our experimental reentrant substrate of VT comprising a
segment of slow conduction, the response of VT to programmed electrical
stimulation differed depending on whether the segment of slow
conduction was based on depression of the active membrane properties or
on electrical uncoupling of the myocardial cells. Termination of VT by
a single premature stimulus and a sloped reset curve were
characteristic for the presence of a segment of slow conduction due to
depression of the fast sodium channels. In this setting, cycle-length
oscillations frequently occurred before termination of VT.
These oscillations resulted from slight changes in the
exact pathway of the circulating impulse through the segment of slow
conduction. Although the limitations of the study as outlined above do
not allow direct extrapolation of our observations to clinical
reentrant VT, they may serve as a basis to diagnose the nature of an
area of slow conduction.
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Acknowledgments |
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This study was made possible by a scholarship from the Deutsche Forschungsgemeinschaft to Dr Kai Haberl (HA 2069/1-1). We thank Jan Hollen and Fritz Schmitz for their technical assistance.
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Footnotes |
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Dr Haberl is currently affiliated with the Klinikum Grosshadern, Medizinische Klinik I, Forschungslabor B, Marchioninistrasse 15, D-81377 Munchen, Germany.
Received December 9, 1997; revision received October 2, 1998; accepted October 2, 1998.
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References |
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