(Circulation. 1999;100:1887-1893.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Demonstration of the Proarrhythmic Preconditioning of Single Premature Extrastimuli by Use of the Magnitude, Phase, and Distribution of Repolarization Alternans
Presented in part in the Samuel A. Levine Young Investigator Award Competition of the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-M, I-27).
From the Division of Cardiology/Electrophysiology, Washington University School of Medicine, St. Louis, Mo.
Correspondence to Dr Sanjiv M. Narayan, Division of Cardiology/Electrophysiology, Campus Box 8086, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110. E-mail snarayan{at}im.wustl.edu
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Abstract |
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Background—We hypothesized that single premature extrastimuli (S2) insufficient to induce reentry produce proarrhythmic effects (proarrhythmic preconditioning) that are measurable by use of the magnitude, phase, and temporal distribution of repolarization alternans (RPA; alternate-beat fluctuations in ECG repolarization).
Methods and Results—Before programmed electrical stimulation
(PES), surface ECG leads I, aVF, and V1 were recorded
in 30 patients during simultaneous atrial and
ventricular pacing at 500 ms with S2 coupling
intervals (CIs) decreasing from 400 to 240 ms in 20-ms steps. We
determined RPA magnitude (Valt) as the 0.5-cycle/beat peak
after spectral decomposition of consecutive STU intervals over 64 beats
immediately preceding and following each S2, RPA phase
reversals as discontinuities in the even/odd phase of STU alternation,
and RPA distribution as the time point of median RPA magnitude within
repolarization. Eighteen patients were induced into
ventricular tachycardia (VT), whereas 12 were
not. Extrastimuli dynamically modulated each characteristic of RPA.
S2 augmented Valt in inducible (8.2±2.3 versus
6.2±1.6 µV; P=0.003) but not noninducible patients.
S2 reversed RPA phase more in inducible than in
noninducible patients (56.7% versus 45.3%; P=0.02 by
2), particularly when CI was 
300 ms (66.3% versus
46.5%; P=0.006). Finally, S2 redistributed
RPA significantly later within repolarization in inducible patients.
Each effect was more marked for CI 300 ms.
Conclusions—A single S2 increases RPA magnitude, reverses its phase, and redistributes it later in repolarization in patients with the substrates for VT. These effects become more pronounced with shorter coupling intervals. These results suggest that it is possible to track the dynamic proarrhythmic preconditioning of single premature depolarizations.
Key Words: tachyarrhythmias • pacing • computers • waves • depolarizing • death, sudden
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Sudden cardiac death resulting from ventricular tachycardia (VT) or fibrillation (VF)1 occurs with an annual incidence of 1 to 2/1000 in the United States.2 However, the manner in which "experiments of nature" such as premature ventricular depolarizations dynamically modulate electrical instability to facilitate these arrhythmias remains unclear and unmeasured. Although a series of extrastimuli may induce reentrant arrhythmias during programmed electrical stimulation (PES) of the ventricle, the proarrhythmic effects of single premature depolarizations that do not induce echo beats or initiate reentry remain poorly defined and unmeasurable.
We set out to determine whether a single ventricular premature depolarization may alter repolarization dynamics and increase the propensity for ventricular arrhythmias in susceptible individuals (proarrhythmic preconditioning) using repolarization alternans (RPA). RPA measures microvolt-level fluctuations in the ECG STU segment occurring on an alternate-beat basis, reflects spatial3 and temporal4 5 6 dispersion of repolarization, and has been linked with ventricular arrhythmias experimentally7 8 and clinically.7 9 However, work to date has focused on the static relationship between clinical arrhythmic outcome and RPA magnitude at steady-state heart rates.10 11
Three lines of experimental evidence suggest that distinct characteristics of RPA may reflect dynamic changes in myocardial electrical instability. First, ventricular arrhythmias become more likely with increasing magnitude of action potential duration (APD) alternans (in feline myocytes12 and intact guinea pig5 and canine3 13 hearts) and RPA (in hypothermic7 and ischemic8 14 canine hearts). Second, the phase of RPA is not static; phase reversal in the alternation of isolated myocytes12 and opposite phase of alternation between adjacent regions of Langendorff-perfused guinea pig heart15 portend ventricular arrhythmias. Third, we recently reported6 that RPA has a nonuniform temporal distribution within a beat. RPA late in repolarization better reflects reentrant substrates than early RPA, and furthermore, RPA temporally redistributes later with heart rate acceleration.
We therefore hypothesized that the proarrhythmic preconditioning of a single premature depolarization may be reflected by an increased magnitude, reversed phase, and later redistribution of RPA within the STU segment. We further hypothesized that such dynamics should become more marked with increasing stimulus prematurity and in individuals with demonstrable substrates for reentrant arrhythmias. We tested these hypotheses in patients undergoing PES.
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Methods |
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Patient Recruitment and Clinical ECG Collection
Studies were approved by the Human Subjects Committee of the Washington University School of Medicine, and all subjects provided written informed consent. We recruited 30 patients referred for PES for the evaluation of unexplained syncope or VT. A subset of these patients has been studied previously.6 Patients were prepared for PES in the standard fashion, and antiarrhythmic medications were withheld for
2 days. After light sedation with
intravenous midazolam, standard 6F quadripolar catheters
were positioned in the right atrium and right ventricle via transvenous
sheaths as part of the prescribed PES and used for
simultaneous atrial and ventricular pacing.
To provide a uniform heart rate between patients, baseline pacing was
applied at a cycle length of 600 ms for 2 to 5 minutes. Extrastimulus
experiments then commenced. Ninety-nine beats were delivered at a cycle
length of 500 ms, followed by 1 premature extrastimulus
(S2) at varying coupling intervals (CIs), then a
500-ms delay (Figure 1
). The cycle was
repeated with the CI shortening from 400 to 240 ms in progressive 20-ms
steps. S2 were delivered twice at each CI.
Surface ECG leads I, aVF, and V1 were
recorded with a 16-channel analogue amplifier (Bloom & Associates)
with bandpass of 0.04 to 100 Hz, sampled at 1 kHz to 12-bit resolution,
then transferred to a UNIX workstation (Sun Computer) for offline
analysis.
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Spectral Computation of RPA
RPA was analyzed with interactive graphic software
written by the authors in Labview (National Instruments). For each ECG
lead, 64 contiguous-beat sequences avoiding ectopic or fusion complexes
were selected (1) before S2 (ending with the beat
preceding S2) and (2) after
S2 (starting with and including
S2) (Figure 1
). Beats were baseline
corrected, then aligned to their maximal normalized QRS dot-product
with a template beat, and then these 64 aligned beats were used to
calculate a mean QRS complex that served as the template for a second
alignment.16
RPA was computed on arrays of aligned beats from each ECG lead by use
of multidimensional spectral analysis over the STU segment,
which was identified by an investigator who was blinded to
clinical data (Figure 2).7 16 STU series were
represented as 2D repolarization matrices R
(n, s), where n indicates the sequence
beat (0n63) and s the millisecond time sample
within STU. A fast Fourier transform was used to compute power spectra
(power= voltage2) across all beats n
at each successive time sample s (along each vertical arrow
in Figure 2, left).
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Power spectra were summed into a composite in which the magnitude at
0.5 cycle/beat indicates raw alternans, 
T (in
µV2) (Figure 2a). The dimensionless
T-wave alternans ratio (TWAR) represents the difference between
alternans and nonalternating periodicity (spectral noise mean,
µnoise, prospectively defined as the 10
spectral point bandwidth, 0.33 to 0.48 cycle/beat), measured in units
of the SD of noise (
noise) (all in
µV2):
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3
may predict ventricular arrhythmias.9
The mean absolute voltage difference of alternation was also estimated
(Figure 2, left)16 :
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RPA magnitudes were analyzed for each ECG lead and combined into the resultant vector by the Pythagorean theorem. Vector magnitudes were subsequently analyzed because of the spatial nonuniformity of RPA between leads.
Determining the Phase of RPA
RPA phase was determined relative to the position of
S2 in each 64-beat sequence. The voltage
alternation of 1 STU time sample is shown in Figure 3 (top). A premature
S2 may leave the phase either unaltered (Figure 3a) or reversed (Figure 3b) in subsequent beats. Phase
reversal was therefore defined by interrupted RPA
oscillation (Figure 3b) in
post-S2 compared with
pre-S2 sequences in 1 surface ECG lead,
providing that TWAR was >0 in both sequences in that lead.
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Determining the Temporal Distribution of RPA Within
Repolarization
The temporal distribution of RPA within repolarization was
analyzed in pre-S2 and
post-S2 sequences as described
previously.6 Briefly, RPA was reconstructed in the time
domain to represent RPA magnitude for each STU time sample
(Figure 2b). We used the time point of median RPA magnitude (the
abscissa of the center-of-area), x, normalized to STU
duration (d), to indicate RPA distribution as
T=x/d (0<T<1). Figure 2b
illustrates centrally distributed RPA (T 
0.5); earlier or
later distributions would result in T<0.5 and
T>0.5, respectively.
PES Protocol and Outcome Comparisons
PES was performed in standard fashion by pacing at the right
ventricular apex. A train of 8 S1
stimuli were followed progressively by single
(S2), double
(S2S3), or triple
(S2S3S4)
premature extrastimuli as required to induce sustained monomorphic VT.
If unsuccessful, this process was repeated at a second
ventricular site. Each patient (n=30) was considered
inducible or noninducible accordingly. Similarly, patients were
RPA-positive if TWAR was 3 in any of the 3 surface leads I, aVF, or
V1, or RPA-negative if not. These data were
compared prospectively with inducibility at PES.
Statistical Analysis
Continuous data are presented as mean±SD. The 2-tailed
t test was used to compare RPA magnitude and centers-of-area
between groups, with Bonferroni correction applied for multiple
comparisons. The 2 test was applied to
contingency tables of phase reversal. A probability level of 5%
(P<0.05) was considered statistically significant.
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Results |
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Sustained monomorphic VT was induced in 18 patients at the time of PES, whereas 12 patients were noninducible. All inducible patients presented with clinical VT. Of the noninducible patients, 3 presented with VT and the remainder with syncope of uncertain cause. Their demographics are shown in Table 1
. None of our patients exhibited
polymorphic VT or VF, and single extrastimuli did not induce echo
beats or VT in any of them.
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Relationship Between RPA Magnitudes and VT
RPA magnitude was higher in patients with than in those without
VT. In pre-S2 sequences, inducible patients had
mean vector Valt=6.15±1.57 versus 3.98±1.65
µV in noninducible patients (P=0.019 by t
test). In post-S2 sequences, corresponding
magnitudes were Valt=8.22±2.30 versus 3.94±2.18
µV (P=0.003). Similar results were obtained for TWAR
(Figure 4).
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Effect of S2 on RPA Magnitude
In each patient group, TWAR and Valt were
higher in post-S2 than
pre-S2 sequences for pooled CIs (computing the
unweighted arithmetic mean of data after all CIs). However, the
magnitude of post-S2 RPA augmentation was
significant only in inducible patients (Valt
increased from 6.15±1.57 to 8.22±2.30 µV for pooled CIs;
P=0.003) and not in noninducible patients
(Valt=3.98±1.65 versus 3.94±2.18 µV;
P=NS).
Figure 4 (top) shows that TWAR augmentation was especially
marked after S2 with a short CI (300 ms) in
inducible but not in noninducible patients, further widening the
statistical difference between patient groups
(pre-S2 P<0.01,
post-S2 P<0.005). Conversely, longer
S2 CIs (320 ms) augmented TWAR to a lesser
extent and affected both groups similarly (Figure 4, bottom).
Similar results were found for Valt.
RPA Phase Modulation by S2
Phase reversal was significantly more common in inducible patients
(and followed 56.7% or 127 of 224
presentations) than in noninducible patients (45.3% or 81
of 179 presentations; P=0.02 by
2) for pooled CIs (Table 2). The effect of CI was again bimodal,
with short (300 ms) but not longer (320 ms) CIs causing
significantly more phase reversals in inducible than in noninducible
patients (P=0.006; Table 2 and Figure 5). Only sequences lacking ectopy and
other spurious ECG events were analyzed.
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Figure 5 shows that the proportion of S2
presentations causing phase reversal in patients with VT
increased with progressive S2 prematurity,
reaching 83.3% after the shortest CI (240 ms). This trend was not
observed in noninducible patients. Importantly, there was a trend for
inducible patients who showed RPA phase reversal after
S2 CI 240 ms to be more readily inducible on
subsequent PES (requiring a mean of 1.6 extrastimuli) than those
without phase reversals (2.3 extrastimuli, P=0.10 by
t test).
RPA Temporal Distribution After S2
RPA was distributed later within repolarization for inducible than
for noninducible patients (Figure
6). In all
patients, extrastimuli redistributed RPA later within repolarization
for short CIs (300 ms) but not CIs 320 ms. Furthermore, inducible
patients experienced a greater redistribution that further widened the
statistical difference between groups (pre-S2
T=0.574 versus 0.524 [P<0.02] and
post-S2 T=0.616 versus 0.562
[P<0.005] [t test]).
When individual S2 CI was considered, the magnitude of RPA redistribution in inducible patients was significant after S2 CIs of 380 (P=0.016), 320 (P=0.011), 300 (P=0.049), 280 (P=0.014), and 240 ms (P=0.049) (Bonferroni correction applied).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study is the first to demonstrate that single premature ventricular depolarizations that do not induce VT may still produce measurable repolarization effects that reflect an enhanced propensity for ventricular arrhythmias (proarrhythmic preconditioning). Single extrastimuli augment the magnitude, reverse the phase, and cause a later distribution of RPA in inducible patients. These effects become more pronounced with increasing stimulus prematurity (CI
300 ms), and
phase reversal, in particular, correlates with the subsequent ease of
induction of VT. These repolarization dynamics were not observed in
patients without inducible VT.
Pathophysiology Underlying RPA
RPA may arise through 2 distinct mechanisms. In the first,
intrinsic dispersion of refractoriness prevents the complete
depolarization of myocytes with the longest recovery times (or alters
their phase 2 action potential morphology15 ), allowing
depolarization only on alternate cycles. In the second hypothesis,
discordance in the generation of myocardial action
potentials17 causes a secondary dispersion of
repolarization. Extracellular recordings3 18 19 20 21
and voltage-sensitive dye data5 15 suggest that APD
variability is primary. The dispersion of recovery in either case
produces ephemeral conduction barriers15 22 that
predispose to demonstrable wavefront fractionation and reentrant
arrhythmias.23
S2 Augment RPA Magnitude
This report is the first to document the effects of premature
extrastimuli on clinical RPA and their differential effects in subjects
with and without VT. RPA magnitude in inducible patients was augmented
by extrastimuli (Figure 4), consistent with studies of
APD in nonischemic24 and
ischemic3 25 dogs. These effects were bimodal with
respect to CI, and RPA was augmented to a greater extent after CIs
300 ms than after CIs 320 ms (Figure 4). In noninducible
patients, the small magnitude of RPA and its relative insensitivity to
extrastimuli and heart rate6 may reflect different
underlying substrates.
Mechanistically, extrastimuli may augment RPA magnitude either by
modulating repolarization dispersion or by altering depolarization with
secondary repolarization effects. Dispersion of repolarization has been
shown to follow single5 24 26 and double27 28
extrastimuli in several preparations and may represent the
mechanism by which long-short extrastimulus sequences induce reentry.
Although the depolarization sequence may be altered by extrastimuli
(for example, when CI differs from the paced cycle length by 250
ms29 ), the primary contribution of this mechanism to RPA
requires additional study.
Extrastimuli Reverse the Alternating Phase of RPA
This is the first study of RPA phase and its modulation by
extrastimuli in humans, and its results are consistent with
observations of alternans phase reversal and discordance in
experimental preparations. Post-S2 RPA phase
reversals were significantly more common in patients with than without
the substrates for reentry and increased in frequency with
S2 prematurity (Table 2 and Figure 5).
RPA on the surface ECG likely represents a weighted integral of
alternans in competing myocyte subpopulations, each having distinct
magnitude and phase. Phase reversal after appropriately timed
extrastimuli may therefore reflect an altered predominance of 1
subpopulation or direct reversal ("resetting") of myocyte APD
alternans. The range of CIs found to cause RPA phase reversal in the
present study agrees with studies in feline myocytes12
and canine ventricle3 and, in general, may be a function
of cycle length, the CI-to–cycle length relationship, and stimulus
amplitude (in canine myocytes30 ). Our finding that
patients with phase reversal more readily experienced
ventricular arrhythmias agrees with results of
isolated myocyte studies12 and may represent the
onset of discordant alternans: the spatial juxtaposition of
subpopulations alternating with opposite phase. In cellular and
tissue-level studies, discordance may lead to unidirectional conduction
block15 22 and set the stage for reentry. Furthermore,
spontaneous discordant APD alternans has been noted in
quinidine-intoxicated dogs with VT/VF30 and
ischemic canine ventricle preceding the onset of
ventricular arrhythmias.3 31 Notably,
RPA magnitude and phase may be synergistic. Greater alternans
magnitudes are associated with phase reversal of APD alternans at
less-premature CIs in feline myocytes12 and facilitate the
onset of discordant ST-T alternans in dogs.31
A full understanding of the relationship between RPA phase lability and dynamic arrhythmia initiation requires additional study. Although RPA phase reversal was associated with a readier induction of VT, our goal was to study the effects of stimuli insufficient to induce reentry, and we did not examine RPA phase immediately preceding VT. This may explain why even the most premature S2 produced a submaximal (84.3%) incidence of phase reversals. However, these results hint at the exciting future possibility of dynamically tailoring device or pharmacological therapy in response to measured arrhythmic susceptibility.
RPA Redistributes Later Within Repolarization After
Extrastimuli
Extrastimuli caused RPA to redistribute later within
repolarization in inducible patients. The extent of temporal
redistribution was again bimodal for CI and reached significance for
S2 CI 300 ms (Figure 6). Evidence
increasingly supports the notion that the distal T wave reflects a
potentially arrhythmogenic transmural gradient of repolarization in
normal32 and long-QT syndrome
physiology.33 34 This is reflected in the T-wave
peak–to-offset interval,32 by dispersion of the late QT
interval in Langendorff-perfused rabbit heart,35 and by
late RPA in humans.6 Speculatively, a single extrastimulus
may therefore create temporal variability in the trailing edge of
repolarization, enabling an advancing wavefront of activation to
encounter inhomogeneously refractory myocardium
and predisposing to wavefront fractionation and reentry. This
hypothesis requires additional study.
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Study Limitations
We paced the atria and ventricles simultaneously to
minimize R-R (and hence repolarization) variability and to allow
analysis of late repolarization unobscured by superimposed
atrial activity. This method differs from other clinical
studies10 11 and may preclude a direct comparison of RPA
magnitude between studies.
As expected, there was a trend for inducible patients to have worse
cardiac systolic function and a higher incidence of previous
myocardial infarction than noninducible patients (Table 1).
Although 1 measure of RPA has been found to be independent of the
presence of structural heart disease,9 10 data do suggest
that myocyte slippage36 and neurohumoral tone may modulate
repolarization, whereas myocardial stretch may also modulate action
potential morphology.37 Larger studies should therefore
address whether RPA reflects electrical instability independently of
such pathology. Finally, we acknowledge that ours is a small study and
that additional work in larger groups of patients is required to
validate our results.
Conclusions
In patients with the substrates for VT, increasingly premature
single extrastimuli increase the magnitude of RPA, reverse its phase,
and cause it to be distributed later within repolarization. These
results suggest that a single premature extrastimulus that fails to
induce VT may still produce proarrhythmic effects in susceptible
individuals. Measuring such proarrhythmic preconditioning may have
implications for dynamically tailoring therapy to arrhythmic
susceptibility.
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Acknowledgments |
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We are grateful to Drs Brett M. Baker, Gregory W. Botteron, Van H. De Bruyn, Mitchell N. Faddis, Marye J. Gleva, and Patricia A. Guerrero for their help in facilitating data recordings for this study. We also thank Dr Benico Barzilai for his helpful comments on the manuscript.
Received January 29, 1999; revision received June 24, 1999; accepted July 2, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Bayes de Luna A, Coumel P, Leclerq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J. 1989;117:151–159.[Medline] [Order article via Infotrieve]
2. Kligfield P, Levy D, Devereaux RB, Savage DD. Arrhythmias and sudden death in mitral valve prolapse. Am Heart J. 1987;113:1298–1307.[Medline] [Order article via Infotrieve]
3. Hashimoto H, Suzuki K, Nakashima M. Effects of the ventricular premature beat on the alternation of the repolarization phase in ischemic myocardium during acute coronary occlusion in dogs. J Electrocardiol. 1984;17:229–238.[Medline] [Order article via Infotrieve]
4. Adam DR, Smith JM, Akselrod S, Nyberg S, Powell AO, Cohen RJ. Fluctuations in T-wave morphology and susceptibility to ventricular fibrillation. J Electrocardiol. 1984;17:209–218.[Medline] [Order article via Infotrieve]
5.
Laurita KR, Girouard SD, Rosenbaum DS. Modulation of
ventricular repolarization by a premature stimulus: role of
epicardial dispersion of repolarization kinetics demonstrated by
optical mapping of the intact guinea pig heart. Circ Res. 1996;79:493–503.
6. Narayan SM, Smith JM. Differing rate dependence and temporal distribution of repolarization alternans in patients with and without ventricular tachycardia. J Cardiovasc Electrophysiol. 1999;10:61–71.[Medline] [Order article via Infotrieve]
7.
Smith JM, Clancy E, Valeri C, Ruskin J, Cohen R.
Electrical alternans and cardiac electrical instability.
Circulation. 1988;77:110–121.
8.
Nearing BD, Huang AH, Verrier RL. Dynamic tracking of
cardiac vulnerability by complex demodulation of the T-wave.
Science. 1991;252:437–440.
9.
Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin
JN, Cohen RJ. Electrical alternans and vulnerability to
ventricular arrhythmias. N Engl J
Med. 1994;330:235–291.
10. Hohnloser SH, Klingenheben T, Li Y-G, Zabel M, Peetermans J, Cohen RJ. T-wave alternans as a predictor of recurrent ventricular tachyarrhythmias in ICD recipients: prospective comparison with conventional risk markers. J Cardiovasc Electrophysiol. 1998;9:1258–1268.[Medline] [Order article via Infotrieve]
11. Estes NAM, Michaud G, Zipes DP, Elsherif N, Venditti FJ, Rosenbaum DS, Albrecht P, Wang PJ, Cohen RJ. Electrical alternans during rest and exercise as predictors of vulnerability to ventricular arrhythmias. Am J Cardiol. 1997;80:1314–1318.[Medline] [Order article via Infotrieve]
12.
Rubenstein DS, Lipsius SL. Premature beats elicit a
phase reversal of mechanoelectrical alternans in cat
ventricular myocytes: a possible mechanism for reentrant
arrhythmias. Circulation. 1995;91:201–214.
13.
Saitoh H, Bailey JC, Surawicz B. Alternans of action
potential duration after abrupt shortening of cycle length: differences
between dog Purkinje and ventricular muscle fibers.
Circ Res. 1988;62:1027–1040.
14. Green LS, Fuller MP, Lux RL. Three-dimensional distribution of ST-T wave alternans during acute ischemia. J Cardiovasc Electrophysiol. 1997;8:1413–1419.[Medline] [Order article via Infotrieve]
15.
Pastore JM, Girouard SD, Laurita KR, Akar FG, Rosenbaum
DS. Mechanism linking T-wave alternans to the genesis of cardiac
fibrillation. Circulation. 1999;99:1385–1394.
16. Narayan SM, Smith JM. Spectral analysis of periodic fluctuations in ECG repolarization. IEEE Trans Biomed Eng. 1999;46:203–212.[Medline] [Order article via Infotrieve]
17. Hashimoto H, Nakashima M. Effects of calcium antagonists on the alternation of the ST-T complex and associated conduction abnormalities during coronary occlusion in dogs. Br J Pharmacol. 1981;74:371–380.[Medline] [Order article via Infotrieve]
18. Carson DL, Cardinal R, Savard P, Vermeulen M. Characterisation of unipolar waveform alternation in acutely ischaemic porcine myocardium. Cardiovasc Res. 1986;20:521–527.[Medline] [Order article via Infotrieve]
19.
Dilly SG, Lab MJ.
Electrophysiological alternans and restitution
during acute regional ischemia in myocardium of
anesthetized pig. J Physiol (London). 1988;402:315–333.
20.
Hirayama Y, Saitoh H, Atarashi H, Hayakawa H.
Electrical and mechanical alternans in canine myocardium in
vivo: dependence on intracellular calcium cycling.
Circulation. 1993;88:2894–2902.
21. Murphy CF, Horner SM, Dick DJ, Coen B, Lab MJ. Electrical alternans and the onset of rate-induced pulsus alternans during acute regional ischaemia in the anaesthetised pig heart. Cardiovasc Res. 1996;32:138–147.[Medline] [Order article via Infotrieve]
22.
Tachibana H, Kubota I, Yamaki M, Watanabe T, Tomoike H.
Discordant S-T alternans contributes to formation of reentry: a
possible mechanism of reperfusion arrhythmia. Am J
Physiol. 1998;275:H116–H121.
23.
Gotoh M, Uchida R, Mandel WJ, Fishbein MC, Chen P-S,
Karagueuzian HS. Cellular graded responses and a
ventricular vulnerability to reentry by a premature
stimulus in isolated canine ventricle. Circulation. 1997;95:2141–2154.
24.
Saitoh H, Bailey JC, Surawicz B. Action potential
duration in dog Purkinje and ventricular muscle fibers:
further evidence in support of two different mechanisms.
Circulation. 1989;80:1421–1431.
25. Hashimoto H, Asano M, Nakashima M. Alternation in refractoriness and in conduction delay in the ischemic myocardium associated with the alternation in the ST-T complex during acute coronary occlusion in anesthetized dogs. J Electrocardiol. 1986;9;77–84.
26.
Kuo C-S, Munakata K, Reddy CP, Surawicz B.
Characteristics and possible mechanism of ventricular
arrhythmia dependent on the dispersion of action potential
durations. Circulation. 1983;67:1356–1367.
27.
Kuo C-S, Atarashi H, Reddy CP, Surawicz B. Dispersion
of ventricular repolarization and arrhythmia: study
of two consecutive premature complexes. Circulation. 1985;72:370–376.
28. Kobayashi Y, Gotoh M, Mandel WJ, Karagueuzian HS. Increased temporospatial dispersion of repolarization during double premature stimulation in the intact ventricle. Pacing Clin Electrophysiol. 1992;15:2194–2199.[Medline] [Order article via Infotrieve]
29.
Goyal R, Harvey M, Daoud EG, Brinkman K, Knight BP,
Bahu M, Weiss R, Bogun F, Man KC, Strickberger SA, Morady R. Effect of
coupling interval and pacing cycle length on morphology of paced
ventricular complexes: implications for pace mapping.
Circulation. 1996;94:2843–2849.
30.
Karagueuzian HS, Khan SS, Hong K, Kobayashi Y, Denton
T, Mandel WJ, Diamond GA. Action potential duration alternans and
irregular dynamics in quinidine-intoxicated ventricular
muscle cells: implications for ventricular
proarrhythmia. Circulation. 1993;87:1661–1672.
31.
Konta T, Ikeda K, Yamaki M, Nakamura K, Honma K, Kubota
I, Yasui S. Significance of discordant ST alternans in
ventricular fibrillation. Circulation. 1990;82:2185–2189.
32.
Yan G-X, Antzelevitch C. Cellular basis for the normal
T-wave and the electrocardiographic manifestations of the long-QT
syndrome. Circulation. 1998;98:1928–1936.
33.
Shimizu W, Antzelevitch C. Cellular basis for T-wave
alternans. Circulation. 1999;99:1499–1507.
34. Lubinski A, Lewicka-Nowak E, Kempa M, Baczynska AM, Romanowska I, Swiatecka G. New insight into repolarization abnormalities in patients with congenital long QT syndrome: the increased transmural dispersion of repolarization. Pacing Clin Electrophysiol. 1998;21(pt II):172–175.
35. Zabel M, Portnoy S, Franz MR. Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study. J Am Coll Cardiol. 1995;25:746–752.[Abstract]
36.
Zaman AG, Morris JL, Smyllie JH, Cowan JC. Late
potentials and ventricular enlargement after myocardial
infarction. Circulation. 1993;88:905–914.
37. Lab MJ, Dean J. Myocardial mechanics and arrhythmia. J Cardiovasc Pharmacol. 1991;18(suppl 2):S72–S79.
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