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Interdependence of Modulated Dispersion and Tissue
Structure in the Mechanism of Unidirectional Block
Kenneth R. Laurita, David S. Rosenbaum
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Abstract—We previously showed that a premature stimulus can significantly alter vulnerability to arrhythmias by
modulating spatial gradients of ventricular repolarization (ie, modulated dispersion). However, it is not clear if such
changes in arrhythmia vulnerability can be attributed to the formation of an electrophysiological substrate for
unidirectional block and what the potential role is of tissue structure in this process. Therefore, the main objective of
the present study was to examine the concomitant effect repolarization gradients and tissue structure have on
unidirectional block. Optical action potentials were recorded from 128 ventricular sites (1 cm2) in 8 Langendorffperfused guinea pig hearts. Propagation was confined to the epicardial surface using an endocardial cryoablation
procedure, and a 12-mm barrier with a 1.5-mm isthmus was etched with a laser onto the epicardium. A premature
stimulus (S2) was delivered over a range of S1S2 coupling intervals to modulate repolarization gradients in a predictable
fashion. When a second premature stimulus (S3) was delivered from the center of the isthmus, the occurrence and
orientation of unidirectional block were highly dependent on repolarization gradients created by the S2 beat. In this
model, a local repolarization gradient of 3.2 ms/mm was required for unidirectional block at this isthmus. In addition,
the formation of unidirectional block was critically dependent on the presence of the source-sink mismatch imposed by
the isthmus. These results may explain how the interplay between spatial heterogeneities of repolarization and tissue
structure form a substrate for unidirectional block and reentry. (Circ Res. 2000;87:922-928.)
Key Words: optical mapping 䡲 source-sink mismatch 䡲 repolarization 䡲 reentry 䡲 premature stimulation
W
e previously found that intrinsic properties of cellular
repolarization vary systematically between cells across
the epicardial surface of the guinea pig heart despite the
presence of normal cell-to-cell coupling.1 From this work and
other studies,2– 4 it is abundantly apparent that repolarization
properties vary extensively throughout the heart. However,
the implication such diversity has on the formation of
arrhythmogenic substrates in the heart is not well appreciated.
Early studies have established a close association between
heterogeneity of repolarization and cardiac arrhythmogenesis.5– 8 Furthermore, we have shown that vulnerability to
arrhythmias is significantly influenced by spatial gradients of
repolarization that form, disappear, and reform on the epicardial surface during premature stimulation in a coupling
interval– dependent manner (ie, modulated dispersion).9
However, the mechanism underlying such dynamic formation
of the arrhythmogenic substrate was not clear.
It is also well recognized that impulse propagation is
highly dependent on the structural arrangement of tissue10,11
and wavefront geometry.12,13 For example, tissue branching14
and propagation through a narrow isthmus15 can create an
abrupt change in electrical load, resulting in an imbalance
between the current available upstream and the actual current
required to excite cells downstream (ie, source-sink mis-
match). The source-sink mismatch imposed by an isthmus or
abrupt tissue expansion has been shown, in experimental
models and theoretical studies, to significantly influence the
safety factor of propagation11,12,16 and the initiation of reentrant excitation.17 It is clear that such source-sink mismatches
play an important role in impulse propagation. However,
what is less clear is the relative importance functional
heterogeneity of repolarization properties between cells and
source-sink mismatch have in the formation of unidirectional
block, a fundamental requirement of reentrant excitation.
This question has important implications to the mechanisms
of arrhythmias in the atria10,18 and ventricle,19,20 where discontinuities of tissue structure caused by valvular orifices,
muscle bundles, veins, arteries, and scar tissue are known to
coexist with regional heterogeneities of cellular ionic
properties.
The main objective of the present study was to investigate
the relative importance of dynamically modulated repolarization gradients and the source-sink mismatch imposed by a
fixed isthmus in the determination of unidirectional block.
Because of limitations of conventional recording techniques,
it is difficult to track the dynamic changes in spatial gradients
of repolarization and their direct effect on the electrophysiological substrate for reentry. Therefore, high-resolution action
Received August 21, 2000; revision received September 7, 2000; accepted September 7, 2000.
From the Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio.
Correspondence to Kenneth R. Laurita, PhD, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Rammelkamp, 6th floor,
Cleveland, Ohio 44109-1998. E-mail [email protected]
© 2000 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
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Laurita et al
Mechanisms of Unidirectional Block
923
potential mapping with voltage-sensitive dye was used to
measure spatial gradients of cellular repolarization and the
propagation of an extrastimulus in the wake of such gradients.
The mechanism of unidirectional block could not be explained by repolarization gradients or source-sink mismatch
alone but was critically dependent on both influences.
Materials and Methods
Experimental Preparation
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All experiments were carried out in accordance with Public Health
Service guidelines for the care and use of laboratory animals. Guinea
pigs (n⫽8) were anesthetized (30 mg/kg pentobarbital, IP), and their
hearts were rapidly excised and perfused as Langendorff preparations (perfusion pressure 70 mm Hg) with oxygenated (95% O2, 5%
CO2) Tyrode’s solution containing (mmol/L) NaCl 130, NaHCO3 25,
MgSO4 1.2, KCl 4.75, dextrose 5, and CaCl2 1.25 (pH 7.4, 31°C to
33°C). The right and left atria were excised to avoid competitive
simulation from the SA node and to provide access to the ventricles
for the cryoablation procedure (see below). Hearts were stained with
voltage-sensitive dye di-4-ANEPPS (10 ␮mol/L) by direct coronary
perfusion for 10 minutes.
Beating and perfused hearts were immersed in a Tyrode-filled
custom-built Lexan chamber. Gentle pressure was applied with a
movable piston to the posterior surface of the heart during action
potential recordings, allowing the heart to contract freely except for
within the mapping field. Because gentle pressure may cause
transient ischemia, recordings were brief and action potentials were
continually monitored for signs of ischemia (eg, triangulated action
potentials). If ischemia was evident, the experiment was not included
in the analysis. Cardiac rhythm was monitored using 3 silver disk
electrodes fixed to the chamber in positions corresponding to ECG
limb leads I, II, and III. The ECG signals were filtered (0.3 to 300
Hz), amplified (1000⫻), and displayed on a digital recorder (WINDOGRAF, Gould Inc). The optical mapping system used in this
study has been described in detail elsewhere.1,21,22 In the present
study, an optical magnification of 1.8⫻ was used, corresponding to
a mapping field of 1⫻1 cm and 0.08 cm spatial resolution between
recording pixels.
Experimental Protocol
To confine propagation to the epicardial surface and avoid the
confounding influence of subepicardial breakthrough from the HisPurkinje system, the endocardial muscle layers were eliminated
using a cryoablation procedure described previously.22 To create a
source-sink mismatch, a linear barrier containing a 1.5-mm isthmus
was etched precisely (⫾1 ␮m) onto the epicardial surface (n⫽5)
using a 5W argon ion laser guided by computer controlled micropositioners (Figure 1).22 The width of the isthmus was based on findings
by Cabo et al,12 who demonstrated that isthmus widths between 1.3
and 2 mm were sufficient to cause unidirectional block in ventricular
myocardium. Software provided the ability to preprogram the position and size of barriers, ensuring reproducibility between experiments. The barrier extended in depth to the endocardial cryoablation
zone to create a line of anatomical block that was parallel to and 2
mm to the right of the left anterior descending coronary artery on the
anterior free wall of the left ventricle. In addition, the position of the
barrier was perpendicular to the orientation of repolarization typically found in guinea pig.1 In 3 additional control hearts, no barrier
was created.
Baseline pacing (S1S1⫽600 ms) and a single premature stimulus
(S2) were delivered at 2⫻ diastolic threshold using a Teflon-coated
silver bipolar electrode (DTU 101, Bloom Associates LTD) from the
same site near the base of the left ventricle corresponding to the basal
end of the laser barrier, when present (Figure 1). The location of
S1S2 stimulation was carefully chosen with respect to the barrier to
reduce the possibility of unequal conduction delays on either side of
the isthmus. Four different S1S2 coupling intervals were tested in
each experiment, decrementing from a coupling interval equal to the
baseline pacing cycle length down to a short coupling interval just
Figure 1. Diagram of the mapping field (1 cm2) and its position
relative to the intact heart. RV indicates right ventricle; LV, left
ventricle. The S3 impulse was always delivered just beyond the
effective refractory period of the S2 beat from the center of an
isthmus (S3) within a linear anatomical barrier (arrows). In hearts
without a barrier, the site of S3 stimulation was from the center
of the mapping field. Baseline pacing (S1) and the first premature stimulus (S2) were always delivered from the same site
(S1S2) near the base of the LV. White squares indicate the 2
regions from which the local repolarization gradient was
calculated.
above the refractory period of the S1 beat. For each S1S2 coupling
interval tested, a second premature stimulus (S3) was delivered at
2⫻ diastolic threshold from the center of the isthmus (or from the
center of the mapping field in the absence of a barrier) using a
Teflon-coated silver unipolar electrode (0.1 mm diameter) connected
to a second stimulator (DCI-1114, Digital Cardiovascular Instruments Inc). The S3 stimulus was always delivered just above the
effective refractory period (⬍2 ms) of the S2 beat.
Data Analysis
In all experiments and for each S1S2 coupling interval tested,
automated algorithms were used to determine depolarization time
and repolarization time relative to a single fiducial point (ie, the
stimulus).9 Repolarization time was defined as the maximum positive
curvature (maximum positive second derivative) during repolarization23 and corresponds to ⬇95% repolarization24 (ie, APD95%). To
quantify the local gradient of repolarization surrounding the isthmus,
the average repolarization times from 2 regions (3⫻3 pixels), each
immediately adjacent to either side of the isthmus without overlapping the barrier, were subtracted and divided by the center-to-center
distance between each region (⬇2 to 3 mm). Shown in Figure 1 are
the 2 regions chosen (white squares) from a representative experiment. The direction of the local repolarization gradient was defined
as either positive (left ventricle apex to right ventricle base repolarization sequence) or negative (right ventricle base to left ventricle
apex repolarization sequence). Local repolarization gradients were
determined for all coupling intervals tested. Successful propagation
was defined as cell-to-cell impulse propagation occurring across at
least 3 recording sites.
Results
Modulated Dispersion After a Premature Stimulus
Shown in Figure 2 is a representative example of depolarization and repolarization during premature stimulation in the
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November 10, 2000
during baseline pacing became earliest during the short
premature coupling interval and vice versa. Shown in the
Table are summary data of the local repolarization gradient at
baseline pacing and for premature stimuli delivered at an
intermediate and short coupling interval for every experiment
with a barrier. In hearts without a barrier (ie, control),
repolarization gradients were modulated in a similar fashion,
as previously reported.1
Modulated Dispersion and Unidirectional Block
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Figure 2. Contour maps of depolarization (top) and repolarization (bottom) during a premature stimulus delivered at a coupling interval equal to the baseline pacing cycle length (A), at an
intermediate coupling interval (B), and at a short coupling interval near the effective refractory period (C). All values shown are
in ms unless otherwise indicated. Local repolarization gradient
near the isthmus within the linear barrier (black rectangles) was
calculated for each S1S2 coupling interval tested.
presence of a barrier. For an S1S2 coupling interval equal to
the baseline drive train (Figure 2A), the impulse initiated by
S2 propagated simultaneously down either side of the barrier.
Significant gradients of action potential duration were present
across the epicardial surface (not shown), as evidenced by
gradients of repolarization orientated perpendicular to the
direction of depolarization and the barrier. A premature
stimulus introduced at an intermediate coupling interval
(Figure 2B) produced no significant change in the pattern of
depolarization compared with baseline pacing. However,
repolarization gradients were substantially reduced, resulting
in a local repolarization gradient of 0 ms/mm near the
isthmus. When a premature stimulus was introduced at a short
coupling interval near refractoriness (Figure 2C), the overall
pattern of depolarization was unchanged. In contrast, repolarization gradients reappeared and were reversed in direction
compared with baseline; ie, where repolarization was latest
To determine if coupling interval– dependent changes in
repolarization determine the occurrence of unidirectional
block, we examined the characteristics of propagation of an
S3 stimulus delivered from the center of an isthmus in the
wake of repolarization gradients established by an S2 beat.
Shown in Figure 3 are data from a representative experiment
where S1S2 coupling interval was shortened from 600 ms to
225 ms. The contour maps across the top show the pattern of
repolarization surrounding the isthmus after each S2 beat.
Shown below each repolarization map is a contour map
demonstrating depolarization of an S3 beat in the wake of
repolarization gradients established by each S2 beat. For an
S1S2 coupling interval equal to the baseline cycle length
(Figure 3A), a gradient of repolarization is present that delays
repolarization on the left side of the isthmus. An S3 impulse
delivered in the wake of this repolarization pattern failed to
propagate to the left side of the isthmus in the direction of the
repolarization gradient. However, propagation (velocity⫽0.44⫾0.11 m/sec) was successful to the right (ie, unidirectional block) and continued around both ends of the barrier
in a pattern like figure-of-eight reentry. This is also reflected
in the action potentials shown at the bottom of Figure 3 that
were recorded from equally spaced sites perpendicular to the
barrier. Propagation failed in the direction of site a but was
successful in the direction of site b, continuing around, much
later, to site a. Thus, during baseline pacing, the electrophysiological requirements for unidirectional block were present.
An S3 stimulus was again introduced from the same
location in the same heart, but in this case after a shorter (ie,
Influence of Premature Coupling Interval on the Local Repolarization Gradient and on
Unidirectional Block
Coupling Interval, ms
Local Repolarization Gradient,
ms/mm
Unidirectional Block
Experiment
No.
BASE
INTER
SHORT
BASE
INTER
SHORT
BASE
INTER
SHORT
1
600
270
160
⫹5.6
⫹1.6
⫺8.5
⫹
None
⫺
2
600
300
225
⫹7.5
⫺3.7
⫺12.1
⫹
None
⫺
⫺
3
600
270
230
⫹14.0
⫺0.1
⫺3.2
⫹
None
4
600
290
220
⫹9.3
⫹2.0
⫺5.9
⫹
None
⫺
5
600
230
200
⫹7.1
⫹1.4
⫺3.6
⫹
None
⫺
8.7⫾3.2
1.8⫾1.3
6.7⫾3.7
Mean⫾SD
Summary of experimental data demonstrating the effect of premature stimulation coupling interval on the local
repolarization gradient and the occurrence of unidirectional block in the presence of a lesion. Shown are results for
baseline stimulation (BASE), premature stimulation at an intermediate coupling interval when repolarization gradients
were minimum (INTER), and premature stimulation at a short coupling interval near refractoriness (SHORT). The
absolute value of the local repolarization gradient was used to determine the mean response. The direction of
unidirectional block is either toward the right ventricular base perpendicular to the barrier (positive, ⫹) or toward the
left ventricular apex perpendicular to the barrier (negative, ⫺).
Laurita et al
Mechanisms of Unidirectional Block
925
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Figure 3. Unidirectional block of an S3
impulse (S3) delivered from the center of
an isthmus within a linear barrier (white
rectangles). Three different premature
coupling intervals were tested: baseline
pacing (A) (600 ms), an intermediate coupling interval (B) (300 ms), and a short
coupling interval (C) (225 ms). Contour
maps on top show the pattern of repolarization of the S2 beat surrounding the
isthmus. Contour maps in the middle
show propagation of the S3 beat in the
wake of repolarization gradients established by the S2 beat. Shown at the bottom are action potentials of the S3 beat
recorded from equally spaced sites perpendicular to the barrier. The S3 stimulus
was always introduced just beyond the
effective refractory period of the S2 beat.
intermediate) S1S2 coupling interval (Figure 3B). It is evident that after this premature stimulus, gradients of repolarization were greatly attenuated, and repolarization was nearly
simultaneous on both sides of the isthmus. Under these
circumstances, propagation after the S3 stimulus never
blocked unidirectionally, but either propagated successfully
(velocity⫽0.39⫾0.12 m/sec) in both directions (Figure 3B)
or failed to capture the tissue at all (not shown). Thus, at an
intermediate coupling interval, the electrophysiological requirements for unidirectional block were eliminated because
of eradication of repolarization gradients. Finally, at a short
S1S2 coupling interval (Figure 3C), the repolarization gradient is restored to a similar magnitude as that seen during
baseline pacing; however, the orientation of the gradient is
reversed. In this case, the S3 impulse failed to propagate to
the right side of the barrier but successfully propagated
(0.45⫾0.10 m/sec) to the left and continued around both ends
of the barrier, meeting on the other side of the isthmus. Thus,
at a short S1S2 coupling interval, the electrophysiological
requirements for unidirectional block were restored; however,
at this coupling interval, unidirectional block occurred on the
opposite side of the isthmus, following the direction of the
repolarization gradient. Shown in the Table are the occurrence and direction of block as a function of S1S2 coupling
interval and local repolarization gradient. In the absence of a
barrier, unidirectional block was observed only once for all
coupling intervals tested (n⫽12, not shown).
Reentrant beats after the S3 stimulus were observed in 3 of
5 experiments performed with a barrier and in no experiment
when an isthmus was absent (ie, control). Shown in Figure 4
are examples of ECGs and action potentials recorded during
premature stimulation, the formation of unidirectional block,
and during multiple reentrant beats in 3 separate experiments.
The activation sequence, determined from all 128 action
potential recordings made during each episodes (not shown),
indicates that unidirectional block of the S3 impulse initiated
reentrant excitation.
Requirements for Unidirectional Block
When pacing from the center of the isthmus, the likelihood of
unidirectional block was highly dependent on the magnitude
and direction of the local repolarization gradient surrounding
the isthmus. Shown in Figure 5 are summary data for all
Figure 4. Shown is the ECG (top) and 1 optically recorded ventricular transmembrane potential (bottom) measured during the
initiation of several reentrant beats after premature stimulation in
3 different experiments. For each example, the last 2 beats of
drive train pacing (S1) and the first premature stimulus (S2) followed by the onset of several spontaneous beats are shown.
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November 10, 2000
Figure 5. Association between the local repolarization gradient
and the formation of unidirectional block in the presence of a
barrier. Unidirectional block occurred when local repolarization
gradients were ⬎3.2 ms/mm.
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experiments indicating the local repolarization gradient (ms/
mm) that was associated with the formation (right) or lack of
formation (left) of unidirectional block on either side of the
isthmus. Local repolarization gradients for all S1S2 coupling
intervals tested are shown. When pacing from the center of
the isthmus, unidirectional block was induced 14 times out of
20 coupling intervals tested. In each of the 14 cases of
unidirectional block, a local repolarization gradient ⬎3.2
ms/mm was present. However, block did not occur when the
repolarization gradient was ⬍3.7 ms/mm (n⫽5). Thus, in this
model there seems to be a distinct repolarization gradient
threshold that is required for unidirectional block. In contrast,
in the absence of a barrier over the same range of S1S2
coupling intervals tested (ie, control hearts), unidirectional
block of the S3 beat was observed only once for 12 coupling
intervals tested despite the presence of repolarization gradients (3.8⫾1.3 m/sec) ⬎3.2 ms/mm. Therefore, the sourcesink mismatch created by the isthmus seems to play a
significantly important role in the formation of unidirectional
block (␹2, P⬍0.005).
To test the relative importance of tissue structure and
repolarization gradients on the occurrence of unidirectional
block, in 2 experiments the S3 stimulus electrode was moved
from the center of the isthmus to one side, at the basal
entrance to the isthmus. In this configuration, the repolarization gradient is unchanged; however, the source-sink mismatch is no longer equal on both sides of the isthmus. On the
basal side of the isthmus, the source-sink mismatch is absent,
and on the apical side, it is present as the impulse propagates
through the isthmus. Shown in Figure 6 is a representative
example where a sufficiently large repolarization gradient
(panel A) resulted in unidirectional block of the S3 beat when
pacing from the center of the isthmus (panel B). The contour
map demonstrates successful propagation to the apical side of
the barrier, where repolarization was earliest (arrows), and
propagation failure to the basal side of the barrier, where
repolarization was latest. When the S3 stimulus was moved
from the center of the isthmus to the basal entrance of the
isthmus (panel C), propagation was successful toward the
base of the heart, against the repolarization gradient (arrows).
However, propagation failed toward the apex of the heart, in
the direction of the source-sink mismatch. Therefore, in this
configuration unidirectional block formed as a result of the
source-sink mismatch imposed by the isthmus, not the local
gradient of repolarization. These results additionally demonstrate that repolarization gradients, even in the presence of a
barrier, are not sufficient to create block unless a source-sink
mismatch is present.
Discussion
In this study, we report a potentially important mechanism for
the initiation of reentrant excitation on the basis of the direct
effect a premature stimulus has on modulating the electrophysiological substrate for reentry. We found that the electrophysiological requirements for unidirectional block were
modulated in a coupling interval– dependent manner by
pacing-induced modulation of repolarization gradients. Such
changes in the formation of unidirectional block may underlie
the mechanism of arrhythmia vulnerability associated with
modulated dispersion, as we have shown previously.9 In
addition, our results suggest that the source-sink mismatch
imposed by tissue structure also plays a critically important
role in the occurrence of unidirectional block.
Modulated Dispersion and
Arrhythmia Vulnerability
We previously showed that a premature stimulus can systematically modulate spatial gradients of action potential duration
and repolarization in a coupling interval– dependent manner,
which was explained on the basis of heterogeneities of
repolarization kinetics between ventricular cells.1 In the
present study we have shown a similar response in the
presence of a barrier, where repolarization gradients were
modulated in a systematic fashion perpendicular to the barrier
(Figure 2). Even though the modulated dispersion response,
Figure 6. Shown is the influence tissue structure has on the formation of unidirectional
block. When pacing from the center of the
isthmus (B), block occurred in the direction of
the repolarization gradient where repolarization
was latest (A). When pacing from the basal
entrance to the isthmus (C), the direction of
block reversed and occurred as the impulse
propagated through the isthmus, toward the
apex of the heart.
Laurita et al
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in general, was not altered in the presence of a barrier, we did
observe repolarization gradients that were greater in magnitude compared with control. This might be attributable to an
insulating effect of the barrier that reveals intrinsic regional
ionic properties. Nevertheless, in control hearts the local
repolarization gradient (3.8⫾1.3 ms/mm) generally failed to
produce unidirectional block, whereas comparable gradients
(6.4⫾4.2 ms/mm) did cause unidirectional block in the
presence of an isthmus. The results of the pullback experiment (Figure 6) provide additional evidence that the sourcesink mismatch created by the isthmus is critically important,
even if larger repolarization gradients are present because of
the barrier. In this experiment, the insulating effect of the
barrier is present, but the source-sink mismatch is absent on
one side of the isthmus. In this case, despite the larger
repolarization gradient in the presence of the barrier, block
only occurred in the direction of the source-sink mismatch
(Figure 6C). Therefore, even though the barrier creates
slightly larger gradients of repolarization, it is the source-sink
mismatch that seems to play a more important role. The fact
that large repolarization gradients could not be achieved in
the absence of a barrier is expected, because hearts are not
normally prone to arrhythmias. However, it is possible to
attain very large repolarization gradients and unidirectional
block without a barrier, such as those seen during discordant
repolarization alternans.25
We found that stimulus-induced changes in repolarization
gradients directly influenced the electrophysiological requirements for unidirectional block. As S1S2 coupling interval
was shortened to an intermediate value, dispersion of repolarization decreased such that unidirectional block of a
second premature beat was much less likely to occur. Additional shortening of S1S2 coupling interval to a value just
longer than the effective refractory period markedly increased
repolarization gradients, which, in-turn, restored the conditions necessary for the development of unidirectional block.
We previously found that vulnerability to ventricular fibrillation is also influenced in a coupling interval– dependent
fashion,9 where vulnerability decreased at intermediate coupling intervals when repolarization gradients were minimal. It
is possible that such changes in vulnerability to fibrillation
were a direct result of changes in the requirements for
unidirectional block. Taken together, these data provide
compelling evidence that in normal hearts a premature
stimulus can significantly modulate the electrophysiological
substrate for reentry.
Combined Role of Repolarization Gradients and
Tissue Structure in the Formation of
Unidirectional Block
In this study, we designed an experimental system that
allowed us to investigate the direct relationship between
repolarization gradients, a source-sink mismatch imposed by
an isthmus, and the formation of unidirectional block. In a
series of control experiments, we found that in hearts without
a barrier, unidirectional block of a second premature (S3) beat
was rarely observed despite the presence of significant
repolarization gradients generated by the S2 stimulus. Similarly, we found that the source-sink mismatch created when
Mechanisms of Unidirectional Block
927
stimulating from the center of an isthmus was not sufficient to
produce unidirectional block unless a significant repolarization gradient (ie, ⬎3.2 ms/mm) was present. Previously, it
was shown that abrupt tissue expansion during propagation
through an isthmus12 or at sites of tissue branching10,16 are
sufficient to cause slow conduction or block. For example,
Cabo et al12 showed that in the setting of uniform reduced
excitability, an isthmus width ⬍1.14 mm caused block. This
is comparable with our results, where an isthmus of 1.5 mm
did not create block in the presence of uniform reduced
excitability. We found that when pacing from the center of
the isthmus, unidirectional block could only be achieved
when the local repolarization gradient was ⬎3.2 ms/mm.
These data suggest a critically important interplay between
repolarization gradients and tissue structure in the formation
of unidirectional block.
When the site of S3 stimulation was moved from the center
of the isthmus to the entrance of the isthmus, an unequal
source-sink mismatch was created (Figure 6). In this situation, we found that unidirectional block occurred in the
direction of the source-sink mismatch, opposite to the direction of the repolarization gradient. Therefore, moving the S3
stimulus location must have increased the source-sink mismatch such that a repolarization gradient was not required to
obtain block. It is also possible that the lack of a source-sink
mismatch on the side of the pacing site made propagation
safer, thereby increasing the repolarization gradient required
for block. Indeed, this may be the case, because in the
absence of a source-sink mismatch (ie, in hearts without an
isthmus), block was rarely observed despite the presence of
significant repolarization gradients. In either case, these data
suggest that a source-sink mismatch can be an overriding
determinant of unidirectional block. These findings highlight
the important interplay between tissue structure and repolarization heterogeneities that, in conjunction, define the electrophysiological substrate for reentrant arrhythmias. On the
basis of these and other12 results, one would predict that in
situations where very large repolarization gradients are
present, such as in long-QT syndrome,26 only minimal or no
structural elements are required to form a substrate for block,
whereas in the presence of marked structures discontinuities
in tissue, the development of even small gradients of repolarization can contribute significantly to the substrate for
reentry. Other studies have shown that both repolarization
heterogeneities and tissue structure can play an important role
in the initiation of reentrant excitation.17,27,28 In particular,
Spach et al27 showed in atrial tissue how repolarization
heterogeneities interact with anisotropic conduction and discontinuities of axial resistance at muscle bundle junctions to
produce delayed conduction and unidirectional block,
respectively.
Implications
The geometrical characteristics of this experimental model
may be analogous to several clinical situations where structural discontinuities in myocardial tissue exist, such as those
imposed by a healing myocardial infarct,29 surgical suture
lines,30 accessory pathways,31 and the complex structure of
atrial endocardial tissue.10,18,32 In particular, the isthmus lo-
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Circulation Research
November 10, 2000
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cated between the tricuspid annulus and the eustachian ridge,
anterior to the inferior vena cava, has been shown to play a
critically important role in the initiation and maintenance of
atrial flutter.33 The occurrence of slow conduction and block
at the isthmus34 may be explained by the interplay between
tissue structure and heterogeneities of refractoriness. Such
source-sink mismatches imposed by propagation through an
isthmus may not necessarily result from distinct anatomical
structures but may also form during reentry. For example,
during figure-of-eight reentry, a central common pathway is
formed where propagation through an isthmus is associated
with spontaneous termination.19 Our results are not necessarily limited to source-sink mismatches imposed by an isthmus
but can be extrapolated to other forms of source-sink mismatch, such as that associated with wave front curvature.12,13,22
Additional studies are required to determine how such
source-sink mismatches interact with heterogeneities of repolarization and influence the initiation and maintenance of
reentrant excitation.
Acknowledgments
This work was supported by the Medical Research Service of the
Department of Veterans Affairs, National Institutes of Health (grant
HL54807), Whitaker Foundation, and American Heart Association.
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Interdependence of Modulated Dispersion and Tissue Structure in the Mechanism of
Unidirectional Block
Kenneth R. Laurita and David S. Rosenbaum
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Circ Res. 2000;87:922-928
doi: 10.1161/01.RES.87.10.922
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