(Circulation. 1999;99:1385-1394.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation
Presented in part at the 18th annual scientific sessions of the North American Society of Pacing and Electrophysiology, New Orleans, La, 1997.
From the Departments of Medicine and Biomedical Engineering and the Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, and the Veterans Affairs Medical Center, Cleveland, Ohio.
Correspondence to David S. Rosenbaum, MD, Case Western Reserve University, Department of Biomedical Engineering, Wickenden Building, Room 504, Cleveland, OH 44106-7207. E-mail dsr{at}pace.cwru.edu
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Abstract |
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Background—Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear.
Methods and Results—T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209±46 bpm) that was significantly lower (by 57±36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation.
Conclusions—Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.
Key Words: mapping • repolarization • fibrillation • electrical alternans • reentry • electrocardiogram
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Introduction |
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Electrical alternans is defined as a beat-to-beat change in the amplitude of the ECG that repeats once every other beat. Shortly after the ECG was introduced to clinical medicine, electrical alternans of the T wave was recognized as a precursor to ventricular arrhythmias.1 T-wave alternans was subsequently observed in a surprisingly wide variety of clinical2 3 4 5 6 and experimental7 8 9 10 11 12 conditions associated with ventricular arrhythmias. We have used sensitive ECG processing techniques to establish a close quantitative relationship between microvolt-level, visually inapparent T-wave alternans and vulnerability to ventricular arrhythmias in humans.13 Despite convincing evidence that T-wave alternans is closely associated with the development of reentrant ventricular arrhythmias and sudden cardiac death, it is not known how, or whether, T-wave alternans is causally linked to the underlying mechanism of ventricular arrhythmias.
There are 2 prevailing hypotheses on the mechanisms of T-wave alternans. One states that a spatial dispersion of refractoriness gives rise to alternations in propagation and repolarization. According to this hypothesis, repolarization alternans is secondary to propagation alternans, which occurs when the time between successive activations is shorter than the refractory period. This hypothesis was supported by an experimental study in which ECG alternans during regional ischemia was generated by alternating conduction block into the ischemic zone.14 However, such alternating conduction block has not been observed in the absence of regional ischemia. The second hypothesis states that T-wave alternans is caused primarily by alternations in repolarization of the action potential, which may give rise to secondary propagation alternans.11 12 15 16 17 18 However, the regional membrane changes that underlie the development of T-wave alternans in the intact heart and the possible role such changes play in the mechanism of ventricular arrhythmias are poorly understood because (1) conventional recording techniques cannot be used to monitor cellular membrane potential with sufficient spatial resolution during the development of ECG T-wave alternans and (2) experimental studies have focused on transient alternans during an abrupt change in cycle length (CL)9 19 20 or alternans during myocardial ischemia,8 10 11 12 21 whereas the majority of patients at risk for sudden cardiac death exhibit T-wave alternans at a relatively constant heart rate (HR) and in the absence of acute ischemia.13 Therefore, we used the technique of high-resolution optical action potential mapping in an intact heart model of pacing-induced T-wave alternans to determine if T-wave alternans is causally linked to the mechanism of reentry.
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Methods |
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Experimental Preparation
Male retired breeder guinea pigs (n=8) were anesthetized (pentobarbital sodium 30 mg/kg IP), and their hearts were rapidly excised and perfused as Langendorff preparations with oxygenated (95% O2, 5% CO2) Tyrode's solution containing (mmol/L) NaCl 130, NaHCO3 25.0, MgSO4 1.2, KCl 4.75, dextrose 5.0, and CaCl2 1.25 (pH 7.40, 27°C). Previously, it was shown that reduced temperature is an effective means of eliciting T-wave alternans in a controlled fashion.8 In a subset of experiments (n=5), the experimental protocol was repeated at 37°C to confirm that our experimental results could be reproduced at physiological temperatures. During all experiments, the endocardial surface was eliminated by use of a cryoablation procedure described previously.22 This procedure produces a thin (
800-µm-deep) viable rim of epicardium having normal
electrophysiological
properties22 and served to restrict propagation to the
surface from which action potentials were recorded. Hearts were
stained with 100 mL of the voltage-sensitive dye di-4-ANEPPS (15
µmol/L) by direct coronary perfusion for 10 minutes. Beating and perfused hearts were placed in a custom-built imaging chamber. To avoid surface cooling and the formation of intracardiac temperature gradients, the heart was immersed in the coronary effluent, which was maintained at a constant temperature (equal to the perfusion temperature) with a heat exchanger. Gentle pressure was applied to the posterior surface of the heart with a movable piston to stabilize the anterior surface of the ventricle against an imaging window so as to eliminate motion artifacts without altering action potential properties.22 23 Cardiac rhythm was monitored with 3 silver disk electrodes fixed to the chamber in positions corresponding to ECG limb leads I, II, and III. ECG signals were filtered (0.05 to 300 Hz), amplified (x1000), and displayed on a digital oscilloscope. Preparations were stable for at least 3 hours of perfusion.
Optical Mapping System
Previously, we developed an optical action potential mapping
system that is capable of resolving membrane potential changes as small
as 0.5 mV from 128 simultaneous sites across the anterior
epicardial surface of the intact guinea pig ventricle (see References
22 through 2422 23 24 for details). In the present study, an optical
magnification of x1.8 was used, which corresponded to a total mapping
field of 10x10 mm, 0.83-mm interpixel spatial resolution, with
1-ms temporal resolution, permitting detailed and quantitative
analysis of action potential shape and duration. To ensure
consistency and objectivity, depolarization and
repolarization times were determined from each action potential by use
of previously described algorithms.20 22 24
Stimulation Protocol
The ventricular epicardial surface was stimulated at
5 times diastolic threshold current with a Teflon-coated
silver bipolar electrode (1.0-mm interelectrode spacing).
Recordings were made during steady-state (>1 minute) pacing
starting at a CL of 400 ms and then at faster CLs (by 50-ms decrements)
until T-wave alternans was visually observed in at least 1 ECG lead, at
which point CL was shortened by 10-ms intervals. The CL was decreased
until 1-to-1 capture was lost or until ventricular
fibrillation (VF) ensued. Action potential alternans was measured
simultaneously from 128 epicardial sites for 64 consecutive
beats at each CL tested.
Voltage Calibration of Optically Recorded Action
Potentials
The fluorescent signal measured with voltage-sensitive
dyes conveys relative but not absolute transmembrane potential. To
estimate the magnitude of action potential alternans (in millivolts)
from optically recorded action potentials, we developed and
validated a method for calibrating beat-to-beat changes in membrane
potential (
V) from action potential amplitude (APA) measured at a
baseline CL of 400 ms by microelectrode (APAmV)
and optical (APAF) techniques, and from measured
beat-to-beat changes in fluorescence (F) as follows.
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110 mV) at
each recording site, V was estimated from
APAF and F measured optically at each
recording site. The aforementioned calibration technique was validated with floating microelectrode recordings from ventricular myocytes in 2 intact hearts. Action potentials were recorded at a sampling rate of 20 000 Hz from 10 cells corresponding to ventricular sites throughout the optical mapping array. APAs measured with microelectrodes were compared with those measured and calibrated by use of voltage-sensitive dye (ie, calculated in mV).
Measurement of Alternans From Optically Recorded Action
Potentials
Beat-to-beat fluctuations of APA were measured from each
ventricular site by a previously validated spectral
technique,8 13 which was modified for action potential
analysis in this investigation. Briefly, action potentials from
64 consecutive beats were aligned by the stimulus artifact. For every
point along the action potential, a power spectrum was calculated from
a time series representing amplitude fluctuations of that
point over 64 consecutive beats. The resulting spectra were then
averaged over 2 intervals: depolarization (defined from an 8-ms window
centered around the maximum derivative of the action potential
upstroke) and repolarization (defined from the end of the
depolarization interval to the end of phase 3 of the action potential).
Action potential alternans was determined from the noise-corrected
magnitude of the averaged power spectrum registered at a frequency of
0.5 cycles per beat. This technique is capable of distinguishing
alternans-type action potential fluctuations from action potential
fluctuation occurring at other frequencies and from random (ie,
"white") action potential fluctuations.
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Results |
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Estimating Transmembrane Voltage Changes With Voltage-Sensitive Dye
We validated a technique for estimating transmembrane voltage from the fluorescent signal recorded with voltage-sensitive dye. Figure 1
illustrates the close
relationship between APA calculated from optical action potentials
(APAF) and APAmV
recorded from similar sites with a floating microelectrode. As
expected, APA decreased progressively as stimulation rate increased.
The rate of rise of the optically recorded action potential
upstroke (Figure 1, inset) was slower than the upstroke
recorded with the microelectrode because the optical signal is
derived from a small aggregate of cells.23 However, there
was a close linear correlation (P<0.001) between
APAF and APAmV falling near
the line of identity, indicating that the technique used to calibrate
APA from the fluorescent signal provides a reasonable
approximation of the actual change in transmembrane potential.
Therefore, it was valid to compare the magnitude of alternans (in mV)
between cells across the surface of the heart.
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Changes in Membrane Potential Responsible for ECG T-Wave
Alternans
The changes in membrane potential that underlie the development of
ECG T-wave alternans are shown in Figure 2. In this representative
example, the magnitude of alternans measured for each point of the ECG
and the ventricular action potential are compared. At HRs
of 270 and 285 bpm, there was a small peak of alternans during the
upstroke of the action potential that coincided with alternans of the
ECG QRS complex and a larger peak of alternans during phase 3 of the
action potential that coincided with alternans of the ECG T wave.
Alternation in the T wave was caused by alternation in the slope of the
plateau and onset of phase 3 of the action potential. Note that the
amplitude of repolarization alternans of the action potential (eg, 9 mV
at 270 bpm) was more than an order of magnitude larger than the
amplitude of T-wave alternans in the ECG (0.3 mV at 270 bpm).
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The tracings recorded at a pacing CL of 315 ms (Figure 2D
and 2E) illustrate an important point regarding the relationship
between action potential alternans and alternans of the QRS complex
versus the T wave. Note that despite relatively small beat-to-beat
alternation in the timing of the action potential upstroke (5 ms in
Figure 2D) and large alternation in cellular repolarization time
(50 ms), the magnitude of QRS complex alternans is much larger than the
magnitude of T-wave alternans. This paradox is further illustrated in
Figure 2E, in which action potentials are shown from 2
ventricular sites on opposite sides of the mapping array
during ECG alternans. Note that the repolarization gradient between
these sites encompasses the ECG T wave and changes markedly in
amplitude and direction from beat to beat. However, the gradient
produces relatively small T-wave alternans. In contrast, very subtle
propagation alternans (not visibly apparent on the tracing) between
action potentials causes marked QRS complex alternans.
A similar distribution of alternans within the action potential was measured with a floating microelectrode, confirming that the optical recordings did indeed accurately reflect transmembrane potential changes at the level of the single cell. In addition, these results were reproduced after contraction was eliminated with 10 mmol/L diacetyl monoxime, verifying that the changes were not caused by mechanical alternans.
Heart Rate Dependence of Cellular Alternans
Figure 3 illustrates the HR
dependence of action potential alternans measured
simultaneously from 5 representative
epicardial sites. At relatively slow HRs, no alternans was present
in either phase of the action potential. Above a critical threshold HR,
however, alternans was present during cellular repolarization
(Figure 3, solid arrows). Repolarization alternans continued to
increase up to a HR of 315 bpm and then either plateaued or decreased
as HR was further increased. Interestingly, action potential duration
(APD) never fluctuated at other nonalternating frequencies.
Depolarization alternans was also present above a critical
threshold HR (Figure 3), which was significantly greater (by
64±41 bpm, Table) than the HR threshold
for repolarization alternans (ie, repolarization alternans preceded
depolarization alternans). Similar results were observed at a
temperature of 37°C, except that the HR thresholds for depolarization
(TD) and repolarization
(TR) alternans were shifted to higher rates.
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) was larger in magnitude and occurred at
a lower threshold HR (solid arrows) than depolarization alternans
(
). Open arrows indicate critical threshold HR for
depolarization.
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Spatial Heterogeneity of Cellular
Alternans
The characteristics of action potential alternans varied
considerably between cells across the epicardial surface of the heart.
The median and range of TR,
TD, and maximum alternans of cellular
depolarization and repolarization measured from all 128
recording sites are shown in the Table. In all
experiments, TR and TD
varied between cells across the epicardial surface. The maximum
magnitude of action potential alternans also varied substantially (by
as much as 60%) between epicardial cells (Table).
Figure 4 illustrates the spatial
distribution of action potential alternans as a function of HR from a
representative experiment. At a HR of 200 bpm, low
levels of repolarization alternans were present at each
recording site in the absence of any depolarization alternans,
demonstrating again that TR is less than
TD. Although repolarization alternans was
present throughout the mapping field, there was no visible
alternation in the T wave of the ECG. At a HR of 240 bpm, the magnitude
of repolarization alternans increased substantially and was
heterogeneous between cells across the epicardial surface.
At a somewhat faster rate (285 bpm), the pattern of repolarization
alternans changed importantly. Although the HR was faster, the
magnitude of repolarization alternans was markedly reduced across a
linear band (blue contour in Figure 4, right panel) spanning the
epicardial surface. This band was surrounded on either side by cells
exhibiting a relatively large magnitude of repolarization alternans
extending toward the base and apex of the ventricle.
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The mechanisms responsible for producing the band of low alternans were
investigated by analyzing action potentials recorded from sites in
close proximity to the band. Action potentials shown in Figure 5 were recorded from cells located
within 3 mm of the low-alternans band, either toward the base (top
potentials) or apex (bottom potentials) of the ventricle, and from
cells within the band (potentials in center). At the slower HR (285
bpm, Figure 5, left), APDs during each beat either prolonged or
shortened at all sites (ie, concordant alternans). In contrast, at a
critical HR (315 bpm, Figure 5, right), the low-alternans band
was present, as evidenced by the black line on the isoalternans
plot (Figure 5, right), which marks the sites at which the
difference in local repolarization time between 2 consecutive beats was
zero. Action potentials recorded from the most basal site (site A,
Figure 5) alternated in a long-short pattern, whereas the most
apical site (site E, Figure 5) alternated in a short-long
pattern. In other words, adjacent regions of myocardial cells were
alternating with opposite phase, ie, discordant alternans. Therefore,
the band of low alternans could be explained by the discordant
alternation in the action potentials on either side of the band leading
to cancellation of repolarization alternans along the band. Discordant
alternans between cells was consistently oriented in a
base-to-apex direction, which closely follows regional heterogeneities
of membrane kinetics known to exist across the epicardial surface of
guinea pig ventricle.24 Moreover, this pattern of
heterogeneity was largely independent of pacing site,
suggesting that it was caused by heterogeneities of repolarization
properties intrinsic to each cell rather than heterogeneous
propagation delays.
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Effects of Discordant Alternans on the Sequence, Pattern, and
Dispersion of Repolarization
The spatial patterns of depolarization and repolarization during
concordant and discordant alternans are compared in Figure 6. During concordant alternans (Figure 6, left), the pattern and sequence of ventricular
depolarization and repolarization were similar from beat to beat. In
contrast, during discordant alternans, the patterns of repolarization
varied substantially (Figure 6, right), because the direction of
repolarization reversed nearly 180° on consecutive beats.
Furthermore, repolarization was twice as slow during discordant
alternans because of steep gradients of repolarization (ie, crowding of
isochrones) that were not present during concordant alternans
(Figure 6). Discordant alternans–induced gradients of
repolarization were sufficiently large to cause secondary propagation
delays, as conduction velocity near the base of the heart (Figure 6, beat 2) slowed by 44% relative to concordant alternans.
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The importance of discordant alternans in producing spatial
heterogeneity of repolarization is demonstrated
quantitatively in Figure 7. Spatial
dispersion of repolarization was calculated from the variance of the
repolarization times recorded from all 128 recording sites
within the mapping array. Dispersion of repolarization measured on
consecutive beats is plotted as a function of HR. Dispersion of
repolarization was not substantially increased over baseline values
during concordant alternans. In contrast, dispersion of repolarization
increased >13-fold during discordant alternans.
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Role of Discordant Alternans in the Mechanism of Initiation of
VF
Discordant alternans produced a state of marked electrical
instability, because VF was always preceded by discordant alternans and
never by concordant alternans. The mechanism of initiation of VF during
discordant alternans was investigated by mapping propagation and
repolarization in detail as steady-state CL was shortened by 10-ms
decrements. As shown in Figure 8, during
steady-state discordant alternans, the patterns of depolarization were
similar from beat to beat, whereas the patterns of repolarization
changed markedly on alternating beats (Figure 8, bottom).
Although the patterns of repolarization were complex, they were nearly
identical on alternating beats (Figure 8, compare beats 3 and
5). Notice that during beat 5 (ie, when CL was shortened by 10 ms), the
area of most delayed repolarization and steepest repolarization
gradient was in the upper right corner of the mapping array. This
region corresponded to the area in which the depolarizing wave front
blocked on the next beat (beat 6) and propagated around either side of
the line of block (off of the mapping field). However, 90 ms later, the
zone of block regained excitability and the impulse reentered it from
the opposite direction, forming the first spontaneous beat of VF.
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site 2
indicates stimulus
site.
During discordant alternans (Figure 8, beats 1 through 5),
propagation proceeded consistently from the site that is
proximal (site 1) to the site that is distal (site 2) to the stimulus
electrode. Note that there is a considerable difference in the
magnitude and phase of action potential alternans between these sites.
Although the action potentials recorded from site 2 have relatively
small amplitudes on beats 2 and 4, inspection of action potentials at
sites immediately distal to site 2 (eg, site 3) confirmed that these
were indeed propagated and not electrotonic responses (ie, no decrement
in APA). Moreover, if these were nonpropagating (ie, 2:1) responses,
the effective pacing CL for these cells would be 360 ms. At this CL,
APD at site 2 was 218 ms, whereas in Figure 8 (beats 1, 3, and
5), APD is 148 ms, 32% shorter than would be expected had 2:1
conduction been present. After the stimulus CL was shortened by 10
ms (beat 5), the impulse propagated successfully into site 2, because
this beat followed a long diastolic interval providing
sufficient time for the cells of site 2 to regain excitability.
However, as a direct consequence of discordant alternans, the next beat
(beat 6) followed a short diastolic interval at sites 2 and
3 and a long diastolic interval at site 1, resulting in
successful propagation of the impulse through site 1 and failure to
propagate (ie, block) through site 2. Therefore, unidirectional block
was caused by critical repolarization gradients established during
discordant alternans.
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Discussion |
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For more than three quarters of a century, T-wave alternans has been closely associated with susceptibility to ventricular arrhythmias in remarkably broad patient populations both with13 and without5 structural heart disease. Therefore, an understanding of the mechanisms responsible for T-wave alternans may provide important insights into the pathophysiology of sudden cardiac death. Previously, it was not clear whether T-wave alternans is causally linked to the pathogenesis of sudden cardiac death or whether it is simply an epiphenomenon related to another process. This is a critical distinction, particularly because T-wave alternans is now being used increasingly to stratify arrhythmia risk in patients. Therefore, we sought to determine a mechanism by which T-wave alternans may be causally linked to the pathogenesis of reentrant excitation in the ventricle.
Experimental Model of Steady-State T-Wave Alternans
To investigate the time course of membrane potential at many sites
during T-wave alternans, we used a Langendorff-perfused guinea pig
model in which electrical alternans could be reproducibly elicited by
constant-rate pacing. Although these results must be extrapolated
cautiously to patients, T-wave alternans in our experimental model
shared many characteristics of ECG T-wave alternans in patients because
it (1) could occur at the microvolt level, (2) was not evenly
distributed over the T wave but instead was largest in amplitude near
the T-wave peak,13 25 (3) was dependent on
HR,26 and (4) was closely associated with the onset of VF.
Because arrhythmia risk associated with T-wave alternans is in
most instances unrelated to ischemia,13 27 we
purposely avoided an experimental model that required ischemia
to induce alternans.
Our model has several potential limitations. For example, measurements were made in a nonworking heart, whereas mechanical loading can potentially influence electrical alternans via mechanoelectrical feedback mechanisms.7 9 10 17 Also, some evidence suggests that T-wave alternans is dependent on sympathetic stimulation,5 which is absent in isolated heart preparations. However, sympathetic stimulation does not appear to influence the amplitude of T-wave alternans in patients with structural heart disease and ventricular arrhythmias.28 Moreover, when autonomically mediated HR changes are carefully controlled for, sympathetic stimulation can actually reduce alternans.29 Although the present study does not resolve this controversy, our data indicate that sympathetic stimulation is not necessary for the development of T-wave alternans. Finally, our preparation included a thin rim of normal epicardial tissue, which eliminated possible contributions of the His-Purkinje system, the endocardium, and the midmyocardial layers of the ventricle to the generation of T-wave alternans. This was an expected trade-off that ensured that the observed ECG patterns were indeed arising from the epicardial regions that were accessible for mapping. However, the principles set forth by these epicardial mapping studies should apply to any myocardial surface on which spatial heterogeneities of membrane function exist (eg, transmural wall30 ).
Action Potential Alternans in the Intact Heart
Limited information is available on regional cellular changes that
underlie T-wave alternans in the intact heart. Our data indicate that
beat-to-beat alternation of membrane repolarization is a rate-dependent
property of cardiac myocytes (Figures 3, 4, and 5), as postulated earlier by Hoffman and
Suckling.15 Alternans most commonly involved the slope of
the action potential plateau and the onset of final repolarization
(Figure 2). The HR-alternans relation was highly nonlinear, such
that transmembrane potential alternation was provoked only above a
critical threshold HR, and above this threshold the magnitude of
alternation increased markedly (Figure 3). Evidence supporting a
HR threshold for action potential alternans was demonstrated previously
in isolated cat ventricular myocytes.18
However, in isolated cells, repolarization alternans increased
monotonically with HR,18 whereas in the intact heart,
cellular repolarization alternans typically failed to increase or even
decreased at rapid rates (Figure 3). The explanation for this
difference is the development of discordant alternans between cells,
which caused electrotonic attenuation of cellular alternans, especially
along bands of tissue that border neighboring regions of cells whose
repolarization times alternate with the opposite phase (Figures 5 and 6).
Although we did not measure ionic currents, our results are
consistent with the hypothesis that T-wave alternans is caused
by beat-to-beat changes of the membrane ionic and intracellular
processes that determine the time course of
repolarization.15 18 31 Alternation of membrane potential
was provoked above a threshold HR, which most likely corresponds to a
time interval that is shorter than the recovery kinetics of one or more
time-dependent currents.9 31 For example, APD shortening
during alternans (as in Figure 2E, second beat at site AP2)
followed a short diastolic interval and is potentially
attributable to incomplete deactivation of outward potassium current or
lesser activation of inward calcium plateau currents secondary to
reduced action potential upstroke amplitude. It is expected, therefore,
that pathological conditions that impair ion channel function may also
reduce the HR threshold required to elicit T-wave alternans. This may
explain why T-wave alternans was accentuated by hypothermia in this and
other8 9 experimental studies and why T-wave alternans is
observed at relatively slow HRs in patients at risk for sudden cardiac
death6 13 27 but is provoked only by very rapid HRs in
normal hearts.32 Further studies are required to determine
how disease states lower the HR threshold for alternans and thereby
increase vulnerability to arrhythmias.
Our data also suggest that alternation of action potential propagation is secondary to repolarization alternans, because propagation alternans never occurred in the absence of repolarization alternans and because conduction slowing on alternating beats typically followed prolongation of repolarization from the previous beat. Had propagation alternans caused repolarization alternans, the opposite relation between the phases of propagation and repolarization alternans would be expected. The effects of repolarization alternans on conduction were particularly important during discordant alternans (see Mechanism Linking T-Wave Alternans to the Initiation of Reentrant VF).
Cellular Basis for ECG T-Wave Alternans
The results of this study indicate that T-wave alternans arises
from repolarization alternans at the level of the single cell. Although
this is the first study to directly map patterns of cellular
repolarization during T-wave alternans, earlier recordings from
single ventricular sites support our finding that T-wave
alternans is produced by alternations of membrane
repolarization.9 27 Interestingly, a primary role of
repolarization in the mechanisms of T-wave alternans was supported by a
systematic investigation of T-wave alternans in humans13
in which T-wave alternans but not QRS alternans was common in high-risk
arrhythmia patients.
It is important to emphasize that beat-to-beat alternation of
propagation and repolarization are not equally reflected on the surface
ECG. In general, propagation alternans causes accentuated alternation
of the QRS complex, whereas repolarization alternans causes relatively
subtle T-wave alternans. This apparent discrepancy can be explained by
biophysical principles that state that the ECG is generated by spatial
gradients in transmembrane potential, which are larger during the
upstroke of the action potential compared with cellular repolarization,
which is a slower process. Therefore, even subtle alternation of action
potential propagation generates relatively large alternans of the ECG
QRS complex. Conversely, relatively subtle T-wave alternans can be
associated with marked alternation in the timing and amplitude of
cellular repolarization. These data are relevant to recent findings
that microvolt-level T-wave alternans is closely associated with
susceptibility to sudden cardiac death in humans.13
Microvolt-level T-wave alternans was a feature of our experimental
model (see Figure 4, 240 bpm and Figure 2B and 2C) and
was associated with cellular alternans across large regions of the
ventricle (Figure 4, 200 bpm). The ECG manifestation of cellular
alternans is probably attenuated to a greater extent in patients in
whom impedance barriers between the heart and body surface are much
larger than those imposed by the perfusate-filled bath used in
this study. Therefore, even subtle microvolt-level T-wave alternans in
humans are most likely associated with considerable alternations of
repolarization within the heart.
Mechanism Linking T-Wave Alternans to the Initiation of
Reentrant VF
To the best of our knowledge, this is the first study to establish
a mechanism directly linking T-wave alternans to the initiation of
reentry. We found that repolarization alternans at the level of the
single cell triggered a predictable cascade of events leading to VF.
Discordant alternans, which was characterized by
simultaneous prolongation and shortening of repolarization
in different myocardial regions, was central to this mechanism. Recent
data suggest that the phase of APD alternation in a cell (ie,
prolongation versus shortening) is determined by the ionic properties
of the cell and the timing of the stimulus used to induce
alternans.18 We observed extensive inhomogeneities in the
phase and amplitude of alternans between neighboring regions of cells,
suggesting that the ionic currents that determine repolarization differ
substantially between these regions so as to overcome electrotonic
forces that ordinarily act to synchronize repolarization.
Interestingly, the spatial pattern of discordant alternans was not
random. Instead, cells typically alternated with the opposite phase on
the base and apex of the heart (Figures 4 and 6). We
recently found that APD restitution, which is an index of membrane
ionic kinetics, also varies systematically from base to
apex,24 further supporting a role of ion channel
heterogeneity in the development of discordant
alternans. One would predict, therefore, that pathological conditions
that increase spatial heterogeneity of membrane ionic
properties or impair coupling between cells may facilitate the
development of discordant alternans.
Consequently, it is not surprising that Konta et al21
reported a close association between discordant alternans of
extracellular electrograms recorded over ischemic border
zones and the development of VF. However, the mechanisms by which
spatially discordant alternans facilitated the initiation of VF were
not established. Our data indicate that discordant alternans is
responsible for the development of steep spatial gradients (ie,
dispersion) of repolarization of sufficient magnitude to cause
unidirectional block and reentry. In contrast, concordant alternation
between cells never produced substantial gradients of repolarization
(Figures 7 and 8), unidirectional block, or VF. It is
well established that a critical dispersion of repolarization is an
important condition for the development of reentrant
arrhythmias.33 The present study demonstrates
that repolarization alternans is a property that is intrinsic to a cell
and therefore does not require spatial dispersion of repolarization to
develop. However, in the presence of relatively minor heterogeneities
of repolarization properties between cells, concordant alternans can be
transformed into discordant alternans, causing marked dispersions that
form the substrate for VF.
Because discordant alternans and VF were initiated by pacing, it is
important to consider the possibility that elevation of HR alone,
rather than discordant alternans, contributed to the mechanism of
initiation of VF. Our data do not support a major contributory role of
HR, however, because VF occurred only in the presence of discordant and
not concordant cellular alternans, irrespective of HR. Finally, in
these studies, we did not simply identify an association between
discordant alternans and VF but rather were able to directly map the
interaction between repolarization gradients and propagating wave
fronts that cause conduction block and reentry during discordant
alternans (Figure 8).
The mechanisms responsible for initiating discordant alternans are unknown. One can speculate that physiological perturbations that are known to affect repolarization alternans, such as transient ischemia, PVCs, or sympathetic stimulation, may trigger discordant alternans in patients. Further studies aimed at delineating these mechanisms are expected to improve our ability to understand and potentially prevent the complex sequence of events that precipitate sudden cardiac death episodes in patients.
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Acknowledgments |
|---|
This study was supported by National Institutes of Health grant HL-54807, the Medical Research Service of the Department of Veterans Affairs, The Whitaker Foundation, and the American Heart Association. We thank Dr Joseph M. Smith for reviewing the manuscript.
Received April 29, 1998; revision received October 20, 1998; accepted November 3, 1998.
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N. Bursac, F. Aguel, and L. Tung Multiarm spirals in a two-dimensional cardiac substrate PNAS, October 26, 2004; 101(43): 15530 - 15534. [Abstract] [Full Text] [PDF]
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I. R. Efimov, V. P. Nikolski, and G. Salama Optical Imaging of the Heart Circ. Res., July 9, 2004; 95(1): 21 - 33. [Abstract] [Full Text] [PDF]
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E. M. Cherry and F. H. Fenton Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2332 - H2341. [Abstract] [Full Text] [PDF]
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F. Hua, D. C. Johns, and R. F. Gilmour Jr. Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2342 - H2351. [Abstract] [Full Text] [PDF]
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C. Omichi, S. T. Lamp, S.-F. Lin, J. Yang, A. Baher, S. Zhou, M. Attin, M.-H. Lee, H. S. Karagueuzian, B. Kogan, et al. Intracellular Ca dynamics in ventricular fibrillation Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1836 - H1844. [Abstract] [Full Text] [PDF]
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I. Libbus, X. Wan, and D. S. Rosenbaum Electrotonic load triggers remodeling of repolarizing current Ito in ventricle Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1901 - H1909. [Abstract] [Full Text] [PDF]
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E. J. Pruvot, R. P. Katra, D. S. Rosenbaum, and K. R. Laurita Role of Calcium Cycling Versus Restitution in the Mechanism of Repolarization Alternans Circ. Res., April 30, 2004; 94(8): 1083 - 1090. [Abstract] [Full Text] [PDF]
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Z. Qu, H. S. Karagueuzian, A. Garfinkel, and J. N. Weiss Effects of Na+ channel and cell coupling abnormalities on vulnerability to reentry: a simulation study Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1310 - H1321. [Abstract] [Full Text] [PDF]
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M. E. Diaz, S. C. O'Neill, and D. A. Eisner Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans Circ. Res., March 19, 2004; 94(5): 650 - 656. [Abstract] [Full Text] [PDF]
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R. P. Katra, E. Pruvot, and K. R. Laurita Intracellular calcium handling heterogeneities in intact guinea pig hearts Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H648 - H656. [Abstract] [Full Text] [PDF]
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P. Smetana, V. N. Batchvarov, K. Hnatkova, A. J. Camm, and M. Malik Ventricular gradient and nondipolar repolarization components increase at higher heart rate Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H131 - H136. [Abstract] [Full Text] [PDF]
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 B. D. Nearing and R. L. Verrier Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology J Appl Physiol, December 1, 2003; 95(6): 2265 - 2272. [Abstract] [Full Text]
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Y.-W. Qian, R. J. Sung, S.-F. Lin, R. Province, and W. T. Clusin Spatial heterogeneity of action potential alternans during global ischemia in the rabbit heart Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2722 - H2733. [Abstract] [Full Text] [PDF]
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M. L. Walker, X. Wan, G. E. Kirsch, and D. S. Rosenbaum Hysteresis Effect Implicates Calcium Cycling as a Mechanism of Repolarization Alternans Circulation, November 25, 2003; 108(21): 2704 - 2709. [Abstract] [Full Text] [PDF]
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F. G. Akar and D. S. Rosenbaum Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure Circ. Res., October 3, 2003; 93(7): 638 - 645. [Abstract] [Full Text] [PDF]
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S. H. Hohnloser, T. Klingenheben, D. Bloomfield, O. Dabbous, and R. J. Cohen Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2220 - 2224. [Abstract] [Full Text] [PDF]
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K. R. Laurita, R. Katra, B. Wible, X. Wan, and M. H. Koo Transmural Heterogeneity of Calcium Handling in Canine Circ. Res., April 4, 2003; 92(6): 668 - 675. [Abstract] [Full Text] [PDF]
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M. L Walker and D. S Rosenbaum Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death Cardiovasc Res, March 1, 2003; 57(3): 599 - 614. [Abstract] [Full Text] [PDF]
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L. A Blatter, J. Kockskamper, K. A Sheehan, A. V Zima, J. Huser, and S. L Lipsius Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes J. Physiol., January 1, 2003; 546(1): 19 - 31. [Abstract] [Full Text] [PDF]
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J. Kockskamper and L. A Blatter Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes J. Physiol., November 15, 2002; 545(1): 65 - 79. [Abstract] [Full Text] [PDF]
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S. M. Narayan, F. Bode, P. L. Karasik, and M. R. Franz Alternans of Atrial Action Potentials During Atrial Flutter as a Precursor to Atrial Fibrillation Circulation, October 8, 2002; 106(15): 1968 - 1973. [Abstract] [Full Text] [PDF]
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B. Pieske and J. Kockskamper Alternans Goes Subcellular: A "Disease" of the Ryanodine Receptor? Circ. Res., October 4, 2002; 91(7): 553 - 555. [Full Text] [PDF]
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A. A. Armoundas, G. F. Tomaselli, and H. D. Esperer Pathophysiological basis and clinical application of T-wave alternans J. Am. Coll. Cardiol., July 17, 2002; 40(2): 207 - 217. [Abstract] [Full Text] [PDF]
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H. Kitamura, Y. Ohnishi, K. Okajima, A. Ishida, E. Galeano, K. Adachi, and M. Yokoyama Onset heart rate of microvolt-level T-wave alternans provides clinical and prognostic value in nonischemic dilated cardiomyopathy J. Am. Coll. Cardiol., January 16, 2002; 39(2): 295 - 300. [Abstract] [Full Text] [PDF]
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T. Klingenheben, G. Gronefeld, Y.-G. Li, and S. H. Hohnloser Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans: Results of a prospective, double-blind, randomized study J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2013 - 2019. [Abstract] [Full Text] [PDF]
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K. J. Sampson and C. S. Henriquez Simulation and prediction of functional block in the presence of structural and ionic heterogeneity Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2597 - H2603. [Abstract] [Full Text] [PDF]
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F. G. Akar, B. J. Roth, and D. S. Rosenbaum Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H533 - H542. [Abstract] [Full Text] [PDF]
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J. A. Kovach, B. D. Nearing, and R. L. Verrier Angerlike behavioral state potentiates myocardial ischemia-induced T-wave alternans in canines J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1719 - 1725. [Abstract] [Full Text] [PDF]
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K. R. Laurita and A. Singal Mapping action potentials and calcium transients simultaneously from the intact heart Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2053 - H2060. [Abstract] [Full Text] [PDF]
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D. J. Christini, K. M. Stein, S. M. Markowitz, S. Mittal, D. J. Slotwiner, M. A. Scheiner, S. Iwai, and B. B. Lerman Nonlinear-dynamical arrhythmia control in humans PNAS, April 18, 2001; (2001) 91553398. [Abstract] [Full Text]
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F. L Burton and S. M Cobbe Dispersion of ventricular repolarization and refractory period Cardiovasc Res, April 1, 2001; 50(1): 10 - 23. [Full Text] [PDF]
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R. D. Berger Repolarization Alternans : Toward a Unifying Theory of Reentrant Arrhythmia Induction Circ. Res., December 8, 2000; 87(12): 1083 - 1084. [Full Text] [PDF]
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J. N. Weiss, P.-S. Chen, Z. Qu, H. S. Karagueuzian, and A. Garfinkel Ventricular Fibrillation : How Do We Stop the Waves From Breaking? Circ. Res., December 8, 2000; 87(12): 1103 - 1107. [Abstract] [Full Text] [PDF]
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J. M. Pastore and D. S. Rosenbaum Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry Circ. Res., December 8, 2000; 87(12): 1157 - 1163. [Abstract] [Full Text] [PDF]
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M. L. Koller, M. L. Riccio, and R. F. Gilmour Jr Effects of [K+]o on electrical restitution and activation dynamics during ventricular fibrillation Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2665 - H2672. [Abstract] [Full Text] [PDF]
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B.-R. Choi and G. Salama Simultaneous maps of optical action potentials and calcium transients in guinea-pig hearts: mechanisms underlying concordant alternans J. Physiol., November 15, 2000; 529(1): 171 - 188. [Abstract] [Full Text] [PDF]
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K. R. Laurita and D. S. Rosenbaum Interdependence of Modulated Dispersion and Tissue Structure in the Mechanism of Unidirectional Block Circ. Res., November 10, 2000; 87(10): 922 - 928. [Abstract] [Full Text] [PDF]
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Z. Qu, A. Garfinkel, P.-S. Chen, and J. N. Weiss Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue Circulation, October 3, 2000; 102(14): 1664 - 1670. [Abstract] [Full Text] [PDF]
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 P M I Sutton, P Taggart, T Opthof, R Coronel, R Trimlett, W Pugsley, and P Kallis Repolarisation and refractoriness during early ischaemia in humans Heart, October 1, 2000; 84(4): 365 - 369. [Abstract] [Full Text]
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