(Circulation. 1998;98:1928-1936.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome
From the Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail ca{at}mmrl.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—This study probes the cellular basis for the T wave under baseline and long-QT (LQT) conditions using an arterially perfused canine left ventricular (LV) wedge preparation, which permits direct temporal correlation of cellular transmembrane and ECG events.
Methods and Results—Floating microelectrodes were used to record transmembrane action potentials (APs) simultaneously from epicardial, M-region, and endocardial sites or subendocardial Purkinje fibers. A transmural ECG was recorded concurrently. Under baseline and LQT conditions, repolarization of the epicardial action potential, the earliest to repolarize, coincided with the peak of the T wave; repolarization of the M cells, the last to repolarize, coincided with the end of the T wave. Thus, the action potential duration (APD) of the longest M cells determine the QT interval and the Tpeak–Tend interval serves as an index of transmural dispersion of repolarization. Repolarization of Purkinje fibers outlasted that of the M cell but failed to register on the ECG. The morphology of the T wave appeared to be due to currents flowing down voltage gradients on either side of the M region during phase 2 and phase 3 of the ventricular action potential. The interplay between these opposing forces determined the height of the T wave as well as the degree to which the ascending or descending limb of the T wave was interrupted, giving rise to bifurcated T waves and "apparent T-U complexes" under LQT conditions. Spontaneous and stimulation-induced polymorphic ventricular tachycardia with characteristics of torsade de pointes (TdP) developed in the presence of dl-sotalol.
Conclusions—Our results provide the first direct evidence that opposing voltage gradients between epicardium and the M region and endocardium and the M region contribute prominently to the inscription of the ECG T wave under normal conditions and to the widened or bifurcated T wave and long-QT interval observed under LQT conditions. Our data suggest that the "pathophysiological U" wave observed in acquired or congenital LQTS is more likely to be a second component of an interrupted T wave, and argue for use of the term T2 in place of U to describe this event.
Key Words: cells • electrophysiology • waves • action potentials • electrocardiography • long-QT syndrome
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
It is generally accepted that the QT interval encompasses the time from the earliest activation to the latest repolarization of ventricular myocardium and that the T wave is the result of repolarization gradients within the ventricles of the heart.1 2 Previous studies have described various degrees of heterogeneous repolarization along the endocardial and epicardial surfaces in the heart of several species.3 4 5 6 7 Transmembrane action potentials (APs) recorded from the right ventricle are usually longer than those from the left, and APs from the apical regions are generally longer than those recorded near the base. Such apico-basal repolarization gradients have been proposed to contribute to the electrocardiographic T wave,8 although the magnitude and direction of ventricular gradients within the hearts remain poorly defined. Prominently lacking are data relative to transmural gradients across the ventricular wall. As a consequence, the mechanisms responsible for the T wave under normal as well as pathophysiological conditions are not well understood.
The congenital and acquired long-QT syndromes (LQTS) represent pathophysiological states characterized by the appearance in the ECG of LQT intervals, notched T waves, prominent U waves, and an atypical polymorphic ventricular tachycardia known as torsade de pointes (TdP). Although the ionic bases for the different forms of LQTS are coming into focus,9 10 the cellular basis for the ECG manifestations of the disease remains poorly understood. Recent studies have implicated M cells located in the intramural layers of the ventricular myocardium in the manifestation of these repolarization phenomenon and arrhythmic sequelae.10 11
The present study provides a direct test of the hypothesis that transmural voltage gradients contribute prominently to the T wave and the ECG manifestations of LQTS using the perfused wedge preparation described in the adjoining article.12 A preliminary report appeared in abstract form.13
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Arterially Perfused Wedge of Canine Ventricle
The methods for isolation, perfusion, and recording of transmembrane activity from the arterially perfused canine left ventricular (LV, anterior wall) wedge preparation, as well as the viability and electrical stability of the preparation, are described and discussed in the accompanying article.12
A transmural ECG was recorded using electrodes consisting of AgCl half cells attached to Tyrode's solution–filled tapered polyethylene electrodes, placed in the Tyrode's solution bathing the preparation 1.0 to 1.5 cm from the epicardial and endocardial surfaces, along the same vector as the transmembrane recordings (Epi:"+"pole). The electrical field of the preparation as a whole was measured using this technique. Thus, the ECG registration represents a pseudo-ECG of that part of the LV. To differentiate it from local electrogram activity, we refer to it as an ECG. In one series of experiments, 4 pairs of electrodes were used to simultaneously record ECG signals at 0o, 45o, -45o, and 90o relative to the transmural axis. LV wedges spanning at least 5 cm along the apico-basal axis were also used in this series. The QT interval was defined as the time interval between the initial deflection of the QRS complex and the point at which a tangent drawn to the steepest portion of the terminal part of the T wave crossed the isoelectric line.
APs were simultaneously recorded from the epicardial, M, and endocardial or subendocardial Purkinje sites using 3 separate intracellular floating microelectrodes as described in the accompanying article.12 Impalements were obtained from the cut surface as well as epicardial and endocardial surfaces of the preparation at positions approximating the transmural vector of the ECG recording. In all Figures, graphic correlation of transmembrane and ECG activity was achieved by dropping a dotted line from the point of full repolarization of each AP (APD100–approximated by eye) to the ECG trace.
To ensure that transmembrane activity recorded at the cut surface of the preparation was representative of the activity in the intramural layers, we used unipolar electrodes in some experiments to measure the activation-recovery interval (ARI) in the deeper layers of the wedge. The ARI values were then compared with values for action potential duration (APD) recorded at the surface. Plunge electrodes consisting of silver wire (120 µm diameter), Teflon insulated except at the tip, were introduced to the center of the preparation. Each electrode was referenced to the bath ground (AgCl electrode). Caution was exercised to ensure that the position of the bath ground did not influence the morphology of the unipolar electrogram. Each unipolar recording was differentiated and the ARI approximating the APD at each site was measured as the interval between the time minimum of the first derivative (Vmin) of the QRS deflection and the maximum first derivative (Vmax) of the T wave. ARI was compared with either APD at 90% repolarization (APD90) or the interval between Vmax and Vmin of the differentiated AP trace. Validation of the use of this technique for the approximation of APD at transmural sites within canine ventricular myocardium was recently provided by El-Sherif and coworkers.14
Amplified signals were digitized, stored on magnetic media and WORM-CD, and analyzed using Spike 2 (Cambridge Electronic Design).
Statistics
Statistical analysis of the data was performed using
Student's t test for paired data or 1-Way ANOVA coupled
with Scheffé's test. Data are presented as mean±SD
unless otherwise indicated.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Contribution of Epicardium, M Region, Endocardium, and the Purkinje Network to Repolarization Waves in the ECG
Figure 1
illustrates the temporal
relationship between transmembrane APs simultaneously
recorded from the epicardium, M region, and endocardium or
subendocardial Purkinje and the ECG T wave. Repolarization of the M
cell (deep subendocardium–midmyocardium) is temporally
aligned with the end of the T wave, whereas repolarization of the
epicardial cells is coincident with the peak of the T wave. Similar
results were obtained in 20 of 20 preparations studied. The APD of
endocardial cells was usually intermediate, as in Figure 1A, although
in preparations obtained very close to the septum, repolarization of
endocardium closely approximated the end of the QT interval. This is
most likely due to the fact that in this part of the LV, M cells are
located in the deep subendocardium and exert a strong electrotonic
influence to prolong neighboring endocardial cells.
|
Interestingly, the APD of subendocardial Purkinje fibers was always
longer than that of the M cell, but the delayed repolarization of the
Purkinje system failed to register on the ECG (Figure 1B
). In 14
experiments in which APs from M cells and subendocardial Purkinje
fibers were simultaneously recorded,
APD90 was 260±21 and 299±17 ms in M and
Purkinje, respectively, (P<0.01) at BCL=1000 ms.
These temporal relations between cellular electrical activity and the
QT complex in the ECG remain constant over a wide range of conditions.
In Figure 2, the wedge was perfused with
Tyrode's solution containing different
[K+]o. The changes
observed are very similar to those observed clinically with hypo- and
hyperkalemia. Low
[K+]o (2 mmol/L)
prolonged the QT interval and flattened the T wave, whereas high
[K+]o (6 mmol/L)
abbreviated the QT interval and gave rise to tall upright T waves.
Throughout this protocol, repolarization of epicardium defines the peak
of the T wave and repolarization of the M region defines the end of the
T wave, so that the interval between the peak and the end of the T wave
approximates the transmural dispersion of repolarization (difference in
repolarization times between epicardium and the M region).
|
The temporal association between cellular electrical activity and the
QT interval was also observed with variation of stimulation rate as
illustrated in Figure 3 (n=15).
Rate-dependent changes in the QTpeak and
QTend intervals are closely approximated by the
rate-dependent changes in the APD plus activation time (AT) of
epicardium and of the M cells, respectively. Moreover, rate-dependent
changes in the interval between the start of the QRS and the peak of
the T wave (QTpeak) closely approximate the
rate-dependent changes in the repolarization time of epicardium. A
disproportionate prolongation of the AP in the M region accounts for
the prolongation of the QT interval and the widening of the T wave.
Significant transmural dispersion of repolarization is evident at BCL
=1000 ms and is more accentuated at slower rates.
|
Voltage Gradients at the Level of the Action Potential Plateau
Contribute Prominently to Inscription of the T wave
Although ventricular gradients (generally defined as
transmural gradients in the timing of phase 3) have been the focus in
the past, our data suggest that much of the T wave is inscribed as a
result of voltage gradients present at the level of the plateau
(Figures 4 and 5). This parameter has not
been quantified previously because of the lack of adequate
methodology. To assess the contribution of voltage gradients on
either side of the M region to the registration of the T wave, we
constructed voltage difference plots (eg, Figure 4). APs
simultaneously recorded from endocardial, epicardial,
and M-region sites are shown in the top trace. The middle trace in each
panel displays the ECG recorded across the wedge and the bottom
grouping shows the computed voltage differences between the epicardium
and M-region APs (
VM-Epi) and between the M
region and endocardium responses (VEndo-M). If
these traces are representative of the opposing voltage
gradients on either side of the M region (responsible for inscription
of the T wave), then the weighted sum of the 2 traces should yield a
trace (middle trace in bottom grouping) resembling the ECG, which it
does. A weighting coefficient of 0.7 was applied to
VEndo-M in this and other experiments in
calculating the sum of VM-Epi and
VEndo-M so that they more accurately reflect
opposing currents responsible for the T wave. This coefficient reflects
the ratio of average tissue resistance between Endo-M and M-Epi
regions.12
|
|
Under control conditions, the T wave begins when the plateau of the
epicardial AP separates from that of the M cell (Figure 4A). As
epicardium repolarizes, the voltage gradient between epicardium and the
M region continues to grow, giving rise to the ascending limb of the T
wave. The voltage gradient between the M region and epicardium
(VM-Epi) reaches a peak when the epicardium is
fully repolarized— this marks the peak of the T wave. On the other end
of the ventricular wall, the endocardial plateau deviates
from that of the M cell, generating an opposing voltage gradient
(VEndo-M) that limits the amplitude of the T
wave and contributes to the initial part of the descending limb of the
T wave. The voltage gradient between the endocardium and the M region
reaches a peak when the endocardium is fully repolarized. The gradient
continues to decline as the M cells repolarize. All gradients are
extinguished when the longest M cells are fully repolarized. Full
repolarization of the M region, therefore, marks the end of the T
wave.
Long-QT Intervals, Notched T Waves, and
Pathophysiological U Waves
In isolated tissues, IK blockers
produce a dramatic effect to prolong the APD of the M cell and very
modest effects to prolong the APD of epicardial and endocardial cells.
In the perfused wedge, the prolongation of the M-cell AP acts to
electrotonically prolong epicardium and endocardium more than
they would intrinsically, often leading to a separation of their
repolarization time (depending on their proximity to the M region;
Figure 4B). The separation of epicardial and endocardial repolarization
times often gives rise to a notch in the descending limb of the T wave.
Again, the data suggest that the T wave begins when the plateau of
epicardial AP diverges from that of the M cell. The voltage gradient
between epicardium and the M region (M-Epi) grows progressively as
epicardium repolarizes, giving rise to the ascending limb of the T
wave, which reaches a peak when the epicardium is fully repolarized. On
the other side of the ventricular wall, the divergence of
the endocardial plateau from that of the M cell generates an opposing
voltage gradient (Endo-M) that limits the amplitude of the T wave and
contributes to the initial part of the descending limb of the T wave.
The voltage gradient between the endocardium and the M region reaches a
peak when the endocardium is fully repolarized, creating a notch in the
descending limb. The remainder of the T wave is due to repolarization
of the M cells. It is noteworthy that the
dl-sotalol–induced increase in dispersion of repolarization
across the wall is accompanied by a corresponding increase in the
Tpeak-Tend interval in the
ECG.
Similar relationships were observed in varying degrees in 9 of 10 preparations exposed to either 100 µmol/L dl-sotalol or 5 mmol/L 4-aminopyridine in the presence of normal [K+]o. In 3 of these, interruption of the T wave was barely perceptible; a smooth broad T wave was observed. In 1 of the 10 preparations, exposure to dl-sotalol caused an interruption of the ascending limb of the T wave. Full repolarization of epicardium in this case was coincident with the second component of the T wave. The relations described for this one outstanding case proved to be the rule rather than the exception under conditions of hypokalemia.
In the presence of hypokalemia, IKr block
causes a more pronounced bifurcation of the T wave, as illustrated in
Figure 5. dl-sotalol (100 µmol/L) and hypokalemia
produce a remarkable prolongation of the QT interval and a deeply
notched T wave , a configuration that some authors refer to as T-U
complex. The rate of repolarization of phase 3 of the AP is slowed,
giving rise to small opposing voltage gradients that crossover
producing a low amplitude bifid T wave. Initially the voltage gradient
between the epicardium and M regions (M-Epi) is greater than that
between endocardium and M region (Endo-M). When endocardium pulls away
from the M cell, the opposing gradient (Endo-M) increases, interrupting
the ascending limb of the T wave. Predominance of the M-Epi gradient is
restored when the final segment of the epicardial response undergoes an
accelerated repolarization, thus resuming the ascending limb of the T
wave. Full repolarization of epicardium marks the peak of the T wave.
Repolarization of both endocardium and the M region contribute
importantly to the descending limb.
Are we justified in calling this a U wave? Our data would suggest that we may not be. The apparent T-U complex is in fact a T wave whose ascending limb is interrupted. The forces that give rise to this second component or "pathophysiological U wave" appear no different than those responsible for the T wave.
Figure 6 shows another example of a
preparation exposed to dl-sotalol and severe hypokalemia.
Recordings from epicardium, M, and endocardial regions are
superimposed. It is noteworthy that the T-U complex attending the
premature beat (but not that of the basic beat) conforms with the
classic definition of a U wave, because the T wave returns to the
isoelectric line before the U wave is inscribed, yet clearly it is a
second component of the T wave.
|
Figure 7 graphically illustrates the
result of 20 experiments in which the effects of dl-sotalol
(100 µmol/L), 4-aminopyridine (5 mmol/L;
blocks Ito and
IK), and dl-sotalol (100
µmol/L) + hypokalemia (1.5 mmol/L) were studied. Drug-induced
prolongation of the AP of the M cell is greater than that of the
endocardium or epicardium, although this difference is reduced under
severe hypokalemic conditions (because electrotonic interactions
between these 2 neighboring tissues are enhanced). In contrast, the
effects of both 4-aminopyridine and sotalol to prolong
the AP in epicardium were much smaller than in the M cell region. The
figure also shows that the QT interval is most closely approximated by
the APD90 of cells in the M region, that both
agents act to increase the transmural dispersion of refractoriness in
the presence of normal
[K+]o, and that the
drug-induced increase of transmural dispersion is smaller under severe
hypokalemic conditions.
|
Transmural Versus Apico-Basal or Anterior-Posterior
Repolarization Gradients
Apico-basal and anterior-posterior repolarization gradients are
thought to play a prominent role in the registration of the T
wave.8 15 Little is known about the relative
importance of repolarization gradients perpendicular (transmural)
versus parallel to the surface of the heart.
To assess the contribution of repolarization gradients along these
different vectors, we simultaneously recorded ECG
traces at 0°, 45°, -45°, and 90° relative to the transmural
axis. In the representative example illustrated in
Figure 8, a prominent T wave recorded
along the transmural axis progresses to a flat T wave when the ECG is
recorded at a 90° angle to the transmural axis. In wedge
preparations that spanned at least 5 cm of the apico-basal length of
the LV, T wave amplitude averaged 0.72±0.09 mV along the transmural
vector versus 0.06±0.01 mV along apico-basal vector (n=4;
P<0.01). These findings suggest that inscription of the T
wave is largely the result of voltage gradients along the transmural
axis in this part of the ventricular wall (anterior, mid
apico-basal). Similar experiments will have to be repeated using wedge
preparations obtained from different parts of the heart and with
different stimulation protocols before any definitive conclusions can
be made.
|
Correspondence Between the Electrical Activity of Surface and
Intramural Layers
APs recorded from the cut surface of the wedge can be
influenced by poor coupling of the surface layers to deeper layers or
the juxtaposition of healthy cells to injured cells. When present
(during the healing over process), these influences are obvious based
on AP, conduction, and/or ECG characteristics (eg, poor correspondence
between transmural activation times and the phase of the QRS). These
indications notwithstanding, it is important to assess whether the
electrical heterogeneity recorded at the surface is
representative of the rest of the perfused wedge
preparation. This is particularly significant when attempting to
correlate transmembrane and ECG data. To address this issue, we
monitored the ARI using unipolar plunge electrodes inserted into
regions subtending the area mapped with the transmembrane electrodes.
Figure 9 compares the ARI measurements
made in the intramural layers with APD measurements of the
transmembrane AP recorded at the surface, under control conditions,
and following exposure to 100 µmol/L dl-sotalol to
exaggerate the transmural dispersion of repolarization. The data show
good correspondence between the transmembrane activity recorded at
the cut surface and activation recovery intervals recorded in
subtending intramural sites (Figure 10). Comparable results were obtained
in 2 other experiments. In control, APD/ARI averaged 227±7/230±8 and
282±6/280±6 ms in Epi and M cells, respectively, whereas after
dl-sotalol (100µmol/L), the APD/ARI values averaged
270±9/272±10 and 363±17/359±15 ms in Epi and M cells, respectively
(n=3). A slightly longer ARI than APD in epicardium and a slightly
shorter ARI than APD in the M cells was a consistent finding;
we attribute this to the "wider field of view" of the unipolar
electrode.
|
min of QRS and
|
Torsade de Pointes
The development of a large dispersion of transmural repolarization
as seen in response to IK block would be
expected to provide the substrate for intramural reentry. In previous
studies, we have demonstrated both spontaneous and programmed
stimulation-induced (PES) TdP arrhythmias in the wedge
following exposure to d-sotalol and ATX-II. Figure 10 illustrates
examples of spontaneous and PES-induced TdP in wedge preparations in
response to dl-sotalol (100 µmol/L). In Figure 10A, dl-sotalol increased transmural dispersion of repolarization
to 74 ms and the QT interval to 398 ms. No early afterdepolarization
(EAD), EAD-induced triggered activity, or premature beats induced by
any mechanisms were observed. An extrastimulus introduced to the
epicardial surface at an S1-S2 of 250 ms induces a long episode of
polymorphic ventricular tachycardia in
which the QRS is seen to twist about the isoelectric line, typical of
TdP. The episode self-terminates after 231 s. Programmed
stimulation applied during the predrug control period failed to induce
TdP. TdP was induced with PES in 5 of 8 perfused wedge preparations
pretreated with dl-sotalol. TdP was much more difficult to
induce with S2 applied to endocardium. In Figure 10B, dl-sotalol increased transmural dispersion of repolarization
to 83 ms. A spontaneous premature beat with a coupling interval of 348
ms initiates an episode of TdP that self-terminates after 6.2 s.
The tall, upright and narrow configuration of the QRS of the premature
beat suggests that it originates in the subendocardial Purkinje
system.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Although ECG recordings have been used as important diagnostic tools for more than a century, correspondence between cellular events, especially of intramural structures, and the various components of the surface ECG has not been well established. The cellular bases for the ECG, repolarization waves in particular, have been less than completely understood because earlier studies have not been able to provide simultaneous and direct recordings of transmembrane APs from intramural sites throughout the ventricular wall together with a transmural ECG. Our recently developed arterially perfused canine ventricular wedge preparation provides this capability, permitting a direct temporal correlation of cellular transmembrane and ECG events.
The chief findings of the present study are that the morphology of the electrocardiographic T wave measured across the LV wall appears to be due in large part to currents flowing down voltage gradients present on either side of the M region, during both phase 2 and phase 3 of the ventricular AP. Our data indicate that the interplay between these opposing currents determines the height of the T wave as well as the degree to which either the ascending or descending limb of the T wave is interrupted, leading to a bifurcated or notched appearance. The voltage gradients are the results of a more positive AP plateau (phase 2) in the M region versus epicardium or endocardium and differences in the timing of phase 3 of the AP of the 3 predominant ventricular cell types. Under baseline and LQT conditions, the epicardial response is always the earliest to repolarize and the M-cell AP is the last. Full repolarization of the epicardial AP was always coincident with peak of the T wave and repolarization of the M cells coincided with the end of the T wave. The duration of the M-cell AP was found to determine the duration of the QT interval under a wide variety of conditions in which the QT interval was altered, including changes in pacing rate, prematurity, alterations in [K+]o, and exposure to APD-prolonging drugs. Finally, the Tpeak–Tend interval is shown to provide an index of transmural dispersion of repolarization.
Our demonstration of a correspondence between cellular events and
components of the ECG is based on the assumption that the activity
recorded from surface cells is representative of
cells within the respective layers of the wall throughout the wedge.
Such validation is provided in this study (Figure 9; see
also reference 10). ARI values recorded from
intramural electrograms correspond well to APD values recorded at
the surface, even when heterogeneity is amplified with
sotalol or ATX-II, indicating that the electrical
heterogeneity recorded at the surface of the
perfused wedge is representative of the rest of the
preparation.
Correspondence of Cellular Transmembrane and ECG Activity
Under baseline conditions, the first structure to repolarize is
the last to depolarize. The early repolarization of epicardium provides
for a T wave displaying the same polarity as that of the QRS. The start
of the T wave, often so gradual as to be indeterminate, is caused by
the more rapid rate of decline of the plateau or phase 2 of the
epicardial AP, creating a voltage gradient and electrotonic current
flow across the wall (Figures 4 and 5). The gradient gradually
increases as the epicardial AP continues to repolarize, reaching a
maximum with full repolarization of epicardium; this juncture marks the
peak of the T wave. Divergence of the plateau of the endocardial AP
from that of the M cell occurs soon after that of epicardium, causing a
voltage gradient between endocardium and the M region and thus a
current opposite to that generated by the voltage gradient that
develops between epicardium and the M region. Under normal conditions,
current flow between the M region and epicardium is greater than that
between the M region and endocardium, resulting in the inscription of
the ascending limb of the upright T wave. Once epicardium is fully
repolarized, continued repolarization of endocardium leads to a
progressively larger voltage gradient between endocardium and the M
region, giving rise to the initial descending limb of the upright T
wave. The last cells to repolarize are the M cells, contributing to the
final segment of the T wave. Full repolarization of the M region marks
the end of the T wave. The time interval between the peak and the
end of the T wave therefore represents the maximum difference
in final repolarization time or the dispersion of repolarization across
the ventricular wall.
In the presence of IKr blockers, M cells in
the deep layers of the wedge display the greatest prolongation of APD.
The APD prolongation of the M region is less than that observed in
isolated tissues and cells, and the prolongation of APD observed in
epicardium and endocardium is greater than in isolated tissues and
cells (see companion
article12 ).16 17 18 These
differences are expected and are accounted for by the greater
electrotonic interaction among the 3 cell types when in the intact
wedge. Electrotonic influences are also responsible for the slower
repolarization of the AP, particularly in epicardium and endocardium.
In isolated tissues and cells, phase 3 is invariably steeper than in
the functional syncytium represented by the wedge. Phase 3
is still more gradual in preparations exposed to hypokalemia (Figures 5 and 6). This may be due to (1) a smaller
IKr and IK1 at
the lower [K+]o; (2) more
potent drug-induced inhibition of IKr at
the lower
[K+]o19 ;
and (3) the longer space constant expected at the lower
[K+]o. Our data suggest
that the electrotonic influence of the M cells may be greater on
endocardium than it is on epicardium because of: (1) the closer
proximity of the longest M cells to
endocardium12 ; and (2) the greater tissue
resistivity between the midmyocardium and the
epicardium.12 The considerable electrotonic
interaction between endocardium and the M region becomes apparent when
the endocardium is excised from the wedge; this procedure gives rise to
a much longer M-cell AP.20
In the wedge as in the clinic, IKr blockers
lead to the development of long-QT intervals and either smooth broad T
waves, notched T waves , or pathophysiological T-U
complexes. Our results indicate that a notch on the descending limb of
the T wave results when the current generated as a result of the
voltage gradient between endocardium and the M region changes abruptly
during the descending limb of the T wave; this occurs as endocardium
approaches full repolarization (Figure 4).
A notch on the ascending limb of the T wave occurs when a gradient
develops between endocardium and the M region capable of generating
current sufficient to change the direction of net current flow across
the wall (Figures 5 and 6). This usually occurs under the condition of
hypokalemia where the slope of phase 3 of the AP is greatly reduced.
The ascending limb of the T wave is interrupted until the voltage
gradient between the epicardium and the M region becomes large enough
to overcome the current flowing between endocardium and the M region,
at which point the ascending limb proceeds upward once more. The notch
often gives rise to a bifurcated T wave, the second component of which
is often referred to as a U wave in the literature. Our observations
suggest that the second component is not a U wave but rather the
resumption of an interrupted T wave (Figures 5 through 7). The data
clearly demonstrate that the sources responsible for the second
component of the T wave are no different from those generating the
first component.
These results and interpretations are consistent with those of Lehmann et al,21 who demonstrated the presence of two components of the T wave (T1, T2) together with a U wave in patients with the long-QT syndrome and used these observations to argue against the labeling of T2 as a U wave.
The basis for the U wave has been a subject of debate stemming back to the days of Einthoven, who originally described this ECG deflection and attributed it to late repolarization of a region of ventricular myocardium.22 23 24 25 26 27 28 29 30 31 32 The most popular theory to explain the U wave ascribes it to the delayed repolarization of the His-Purkinje system.29 It has been difficult for us, as for others, to reconcile the small mass of the specialized conduction system with the relatively large U wave deflections reported in the literature, especially in cases of acquired and congenital long-QT syndrome. We therefore suggested that the M cells, more abundant in mass and possessing repolarization characteristics similar to Purkinje, are responsible for the inscription of these pathophysiological U waves.33 Our findings suggest that what many physicians and scientists refer to as U waves under pathophysiological conditions are not U waves but rather second components of the T wave whose descending or ascending limb (especially during hypokalemia) is interrupted. What then is responsible for the normal U wave, the very small distinct deflection following the T wave? The canine perfused wedge preparation does not manifest a U wave under normal conditions. This is not surprising in light of the absence of a U wave in the ECG of most dogs.34 This may be due to a relatively small mass of the conduction system in the dog. We hope to perform a direct test of the His-Purkinje hypothesis previously advanced by Watanabe and coworkers29 in the near future.
Clinical Implications
If the Tpeak to Tend
interval proves to accurately reflect transmural dispersion of
repolarization in the clinic, it may serve as a useful index for the
assessment of arrhythmic risk.35
Our results indicate that IKr block
produces a broad tall T wave with or without a notch on the descending
limb when [K+]o is normal
(Figure 4). Mild hypokalemia can exaggerate dispersion of
repolarization across the ventricular wall, whereas severe
hypokalemia has the opposite effect. Severe hypokalemia reduces the
slope of phase 3 of the AP and increases the space constant, thus
decreasing transmural voltage gradients and currents. As a consequence,
the amplitude of the T wave is low and more likely to be bifurcated.
Although a smaller dispersion of transmural repolarization may reduce
arrhythmic risk, an increased propensity for development of EADs under
these conditions would have the opposite effect.
The appearance of bifurcated or notched T waves of large amplitude clearly denotes the presence of a large transmural dispersion of repolarization and refractoriness. Such ECG manifestation in the acquired or congenital LQTS has been shown to be associated with increased risk21 36 for the development of TdP. In our experimental model, as in the clinical syndromes, marked transmural dispersion of repolarization signified by these ECG changes is associated with the development of TdP. The characteristics of the arrhythmia induced by dl-sotalol are similar to those described for d-sotalol. Although it is beyond the scope of this article to deal with the mechanism underlying TdP, our data in the wedge point to a reentrant mechanism as the basis for maintenance of the arrhythmia and triggered activity as the initiating mechanism.10 11
Limitations of the Study
We would like to stress that the T wave measured in the intact
organism is generated by more than transmural
ventricular gradients. Apico-basal
gradients5 are thought to influence the
morphology of the T wave in the dog, and may do so in the human as
well. The present study indicates that such gradients are not
nearly as accentuated as transmural voltage gradients, but the data
presented do not permit a full assessment of the extent to
which apico-basal or antero-posterior versus transmural gradients
contribute to the ECG. Further studies are clearly needed to address
these points.
|
Acknowledgments |
|---|
This work was supported by grant HL-47678 from the National Institutes of Health and grants from the SADS Foundation and the Sixth and Seventh Manhattan Masonic Districts. It was also supported by the Masons of New York and Florida. We gratefully acknowledge the expert technical assistance of Judy Hefferon, Di Hou, Tengxian Liu, and Robert Goodrow. We are grateful to Dr Wataru Shimizu for conducting the experiments involving recording of multiple ECG signals from the perfused wedge preparation.
Received September 29, 1997; revision received May 26, 1998; accepted June 10, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Hurst JW. Ventricular Electrocardiography. New York: Gower Medical Publishing; 1991:1.2–13.36.
2. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark MA, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115–172.[Medline] [Order article via Infotrieve]
3. Van Hemel NM, Swenne CA, De Bakker JMT, Defauw JAM, Guiraudon GM. Epicardial reflection as a cause of incessant ventricular bigeminy. PACE. 1988;11:1036–1044.
4. Surawicz B. In: Electrophysiologic Basis of ECG and Cardiac Arrhythmias. Malvern, Pa: Williams & Wilkins; 1995.
5. Sicouri S, Fish J, Antzelevitch C. Distribution of M cells in the canine ventricle. J Cardiovasc Electrophysiol. 1994;5:824–837.[Medline] [Order article via Infotrieve]
6. Han J, Millet D, Chizzonitti B, Moe GK. Temporal dispersion of recovery of excitability in atrium and ventricle as a function of heart rate. Am Heart J. 1966;71:481–487.[Medline] [Order article via Infotrieve]
7.
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.
8. Noble D, Cohen IS. The interpretation of the T wave of the electrocardiogram. Cardiovasc Res. 1978;12:13–27.[Medline] [Order article via Infotrieve]
9. Shimizu W, Antzelevitch C. Cellular basis for the electrocardiographic features of the LQT1 form of the long-QT syndrome: effects of ß-adrenergic agonists, antagonists, and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. 1998. In press.
10.
Shimizu W, Antzelevitch C. Sodium channel block with
mexiletine is effective in reducing dispersion of repolarization and
preventing torsade de pointes in LQT2 and LQT3 models of the long-QT
syndrome. Circulation. 1997;96:2038–2047.
11. Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX . Cellular and ionic mechanisms underlying erythromycin-induced long QT and torsade de pointes. J Am Coll Cardiol. 1996;28:1836–1848.[Abstract]
12. Yan GX, Shimizu W, Antzelevitch C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation. 1998; 98:1921–1927.
13. Yan GX, Antzelevitch C. Contribution of M cells to the electrocardiographic U wave: direct evidence from arterially perfused canine left ventricle. PACE. 1995;18:II-933. Abstract.
14.
El-Sherif N, Caref EB, Yin H, Restivo M. The
electrophysiological mechanism of
ventricular arrhythmias in the long-QT syndrome:
tridimensional mapping of activation and recovery patterns. Circ
Res. 1996;79:474–492.
15. Cohen IS, Giles WR, Noble D. Cellular basis for the T wave of the electrocardiogram. Nature. 1976;262:657–661.[Medline] [Order article via Infotrieve]
16. Sicouri S, Antzelevitch C. Afterdepolarizations and triggered activity develop in a select population of cells (M cells) in canine ventricular myocardium: the effects of acetylstrophanthidin and Bay K 8644. PACE. 1991;14:1714–1720.
17. Sicouri S, Antzelevitch C. Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cell (M cells) in the canine heart: quinidine and digitalis. J Cardiovasc Electrophysiol. 1993;4:48–58.[Medline] [Order article via Infotrieve]
18. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: the role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol. 1994;23:259–277.[Abstract]
19.
Yang T, Roden DM. Extracellular potassium modulation of
drug block of IKr. Implications for torsade
de pointes and reverse use-dependence. Circulation. 1996;93:407–411.
20.
Yan GX, Antzelevitch C. Cellular basis for the
electrocardiographic J wave. Circulation. 1996;93:372–379.
21. Lehmann MH, Suzuki F, Fromm BS, Frankovich D, Elko P, Steinman RT, Fresard J, Baga JJ, Taggart RT. T-wave "humps" as a potential electrocardiographic marker of the long QT syndrome. J Am Coll Cardiol. 1994;24:746–754.[Abstract]
22. Einthoven W. The galvanometric registration of the human electrocardiogram, likewise a review of the use of the capillary electrometer in physiology. Pflugers Arch. 1903;99:472–480.
23. Einthoven W. Uber die deutung des electrokardiogramms. Pflugers Arch. 1912;149:65–86.
24. Zuckerman R, Cabrera-Cosio E. La ondu U. Arch Inst Cardiol Mex. 1947;17:521–532.[Medline] [Order article via Infotrieve]
25. Furbetta D, Bufalari A, Santucci F, Solinas P. Abnormality of the U wave and the T-U segment of the electrocardiogram: the syndrome of the papillary muscles. Circulation. 1956;14:1129–1137.[Medline] [Order article via Infotrieve]
26. Nahum LH, Hoff HE. The interpretation of the U wave of the electrocardiogram. Am Heart J. 1939;17:585–598.
27. Lepeschkin E. Genesis of the U wave. Circulation. 1957;15:77–81.[Medline] [Order article via Infotrieve]
28. Hoffman BF, Cranefield PF, Lepeschkin E, Surawicz B, Herrlich HC. Comparison of cardiac monophasic action potentials recorded by intracellular and suction electrodes. Am J Physiol. 1959;196:1297–1301.
29.
Watanabe Y. Purkinje repolarization as a possible cause
of the U wave in the electrocardiogram.
Circulation. 1975;51:1030–1037.
30. Patterson E, Szabo B, Scherlag BJ, Lazzara R. Early and delayed afterdepolarizations associated with cesium chloride-induced arrhythmias in the dog. J Cardiovasc Pharmacol. 1990;15:323–331.[Medline] [Order article via Infotrieve]
31.
Lab MJ. Contraction-excitation feedback in
myocardium: physiologic basis and clinical relevance.
Circ Res. 1982;50:757–766.
32.
Choo MH, Gibson DG. U waves in ventricular
hypertrophy: possible demonstration of mechano-electrical
feedback. Br Heart J. 1986;55:428–433.
33. Antzelevitch C, Nesterenko VV, Yan GX. The role of M cells in acquired long QT syndrome, U waves and torsade de pointes. J Electrocardiol. 1996;28(suppl):131–138.
34. Ettinger SJ, Suter PF. In: Canine Cardiology. 1970: 102–151.
35. Antzelevitch C, Shimizu W, Yan GX, Sicouri S. Cellular basis for QT dispersion. J Electrocardiol. 1998;30(suppl):168–175.
36. Malfatto G, Beria G, Sala S, Bonazzi O, Schwartz PJ. Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol. 1994;23:296–301.This study probes the cellular basis for the T wave under baseline and long- QT (LQT) conditions using an arterially perfused canine ventricular wedge preparation, which permits a direct temporal correlation of cellular transmembrane and ECG events. Our results provide the first direct evidence that opposing voltage gradients between epicardium and the M region and endocardium and the M region are largely responsible for inscription of the ECG T wave under normal conditions and for the widened or bifurcated T wave observed under LQT conditions.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  C. Patel, J. F. Burke, H. Patel, P. Gupta, P. R. Kowey, C. Antzelevitch, and G.-X. Yan Is there a significant transmural gradient in repolarization time in the intact heart?: Cellular Basis of the T Wave: A Century of Controversy Circ Arrhythmia Electrophysiol, February 1, 2009; 2(1): 80 - 88. [Full Text] [PDF]
|
|
|
|
|
|
T. Opthof, R. Coronel, and M. J. Janse Is there a significant transmural gradient in repolarization time in the intact heart?: Repolarization Gradients in the Intact Heart Circ Arrhythmia Electrophysiol, February 1, 2009; 2(1): 89 - 96. [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Zhu, C. Patel, S. Martin, X. Quan, Y. Wu, J. F. Burke, M. Chernick, P. R. Kowey, and G.-X. Yan Ventricular transmural repolarization sequence: its relationship with ventricular relaxation and role in ventricular diastolic function Eur. Heart J., February 1, 2009; 30(3): 372 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Taggart, V. N. Batchvarov, P. Sutton, G. Young, S. Young, and D. Patterson Repolarization Changes Induced by Mental Stress in Normal Subjects and Patients with Coronary Artery Disease: Effect of Nitroglycerine Psychosom Med, January 1, 2009; 71(1): 23 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. V. Hume-Smith, S. Sanatani, J. Lim, A. Chau, and S. D. Whyte The Effect of Propofol Concentration on Dispersion of Myocardial Repolarization in Children Anesth. Analg., September 1, 2008; 107(3): 806 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Moss and I. Goldenberg Importance of Knowing the Genotype and the Specific Mutation When Managing Patients With Long-QT Syndrome Circ Arrhythmia Electrophysiol, August 1, 2008; 1(3): 219 - 226. [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. del Rio, T. A. Dawson, B. D. Clymer, D. J. Paterson, and G. E. Billman Effects of acute vagal nerve stimulation on the early passive electrical changes induced by myocardial ischaemia in dogs: heart rate-mediated attenuation Exp Physiol, August 1, 2008; 93(8): 931 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. H. Medei, J. H.M. Nascimento, R. C. Pedrosa, L. Barcellos, M. O. Masuda, S. Sicouri, M. V. Elizari, and A. C. Campos de Carvalho Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration Europace, July 1, 2008; 10(7): 868 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Due-Andersen, T. Hoi-Hansen, C. E. Larroude, N. V. Olsen, J. K. Kanters, F. Boomsma, U. Pedersen-Bjergaard, and B. Thorsteinsson Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity Europace, July 1, 2008; 10(7): 860 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Due-Andersen, T. Hoi-Hansen, N. V. Olsen, C. E. Larroude, J. K. Kanters, F. Boomsma, U. Pedersen-Bjergaard, and B. Thorsteinsson Cardiac repolarization during hypoglycaemia and hypoxaemia in healthy males: impact of renin-angiotensin system activity Europace, February 1, 2008; 10(2): 219 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Notomi, Z. B. Popovic, H. Yamada, D. W. Wallick, M. G. Martin, S. J. Oryszak, T. Shiota, N. L. Greenberg, and J. D. Thomas Ventricular untwisting: a temporal link between left ventricular relaxation and suction Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H505 - H513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Weiss, D. U.J. Keller, G. Seemann, and O. Dossel The influence of fibre orientation, extracted from different segments of the human left ventricle, on the activation and repolarization sequence: a simulation study Europace, November 1, 2007; 9(suppl_6): vi96 - vi104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Gallacher, A. Van de Water, H. van der Linde, A. N. Hermans, H. R. Lu, R. Towart, and P. G.A. Volders In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome Cardiovasc Res, November 1, 2007; 76(2): 247 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2024 - H2038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fanoe, C. Hvidt, P. Ege, and G. B. Jensen Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen Heart, September 1, 2007; 93(9): 1051 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes Europace, September 1, 2007; 9(suppl_4): iv4 - iv15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ahmad and P. Dorian Drug-induced QT prolongation and proarrhythmia: an inevitable link? Europace, September 1, 2007; 9(suppl_4): iv16 - iv22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Shantsila, T. Watson, and G. Y. Lip Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias Europace, September 1, 2007; 9(suppl_4): iv37 - iv44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Akar, R. D. Nass, S. Hahn, E. Cingolani, M. Shah, G. G. Hesketh, D. DiSilvestre, R. S. Tunin, D. A. Kass, and G. F. Tomaselli Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1223 - H1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Morita, D. P. Zipes, S. T. Morita, and J. Wu Mechanism of U wave and polymorphic ventricular tachycardia in a canine tissue model of Andersen-Tawil syndrome Cardiovasc Res, August 1, 2007; 75(3): 510 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Iacoviello, C. Forleo, P. Guida, R. Romito, A. Sorgente, S. Sorrentino, S. Catucci, F. Mastropasqua, and M. Pitzalis Ventricular Repolarization Dynamicity Provides Independent Prognostic Information Toward Major Arrhythmic Events in Patients With Idiopathic Dilated Cardiomyopathy J. Am. Coll. Cardiol., July 17, 2007; 50(3): 225 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Jeyaraj, L. D. Wilson, J. Zhong, C. Flask, J. E. Saffitz, I. Deschenes, X. Yu, and D. S. Rosenbaum Mechanoelectrical Feedback as Novel Mechanism of Cardiac Electrical Remodeling Circulation, June 26, 2007; 115(25): 3145 - 3155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Hansen, S.-P. Olesen, and M. Grunnet Pharmacological Activation of Rapid Delayed Rectifier Potassium Current Suppresses Bradycardia-Induced Triggered Activity in the Isolated Guinea Pig Heart J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 996 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Huffaker, J. N. Weiss, and B. Kogan Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3089 - H3102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Poelzing and R. Veeraraghavan Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3043 - H3051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Morita, D. P. Zipes, H. Morita, and J. Wu Analysis of action potentials in the canine ventricular septum: No phenotypic expression of M cells Cardiovasc Res, April 1, 2007; 74(1): 96 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Whyte, S. Sanatani, J. Lim, and P. D. Booker A Comparison of the Effect on Dispersion of Repolarization of Age-Adjusted MAC Values of Sevoflurane in Children Anesth. Analg., February 1, 2007; 104(2): 277 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bai, X. Y. Yang, Y. Song, L. Lin, J. G. Lu, C. K. Ching, J. Pu, R. Kam, L. F. Hsu, C. T. Zhang, et al. Impact of left ventricular epicardial and biventricular pacing on ventricular repolarization in normal-heart individuals and patients with congestive heart failure. Europace, November 1, 2006; 8(11): 1002 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Viitasalo, L. Oikarinen, H. Swan, H. Vaananen, J. Jarvenpaa, H. Hietanen, J. Karjalainen, and L. Toivonen Effects of Beta-Blocker Therapy on Ventricular Repolarization Documented by 24-h Electrocardiography in Patients With Type 1 Long-QT Syndrome J. Am. Coll. Cardiol., August 15, 2006; 48(4): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Santangelo, E. Ammendola, V. Russo, C. Cavallaro, F. Vecchione, S. Garofalo, A. D'Onofrio, and R. Calabro Influence of biventricular pacing on myocardial dispersion of repolarization in dilated cardiomyopathy patients Europace, July 1, 2006; 8(7): 502 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chalil, Z. R. Yousef, S. A. Muyhaldeen, R. E. A. Smith, P. Jordan, C. R. Gibbs, and F. Leyva Pacing-Induced Increase in QT Dispersion Predicts Sudden Cardiac Death Following Cardiac Resynchronization Therapy J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2486 - 2492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Castro Hevia, C. Antzelevitch, F. Tornes Barzaga, M. Dorantes Sanchez, F. Dorticos Balea, R. Zayas Molina, M. A. Quinones Perez, and Y. Fayad Rodriguez Tpeak-Tend and Tpeak-Tend Dispersion as Risk Factors for Ventricular Tachycardia/Ventricular Fibrillation in Patients With the Brugada Syndrome J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1828 - 1834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Fish, D. R. Welchons, Y.-S. Kim, S.-H. Lee, W.-K. Ho, and C. Antzelevitch Dimethyl Lithospermate B, an Extract of Danshen, Suppresses Arrhythmogenesis Associated With the Brugada Syndrome Circulation, March 21, 2006; 113(11): 1393 - 1400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ueda, D. P. Zipes, and J. Wu Coronary occlusion and reperfusion promote early afterdepolarizations and ventricular tachycardia in a canine tissue model of type 3 long QT syndrome Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H607 - H612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P. Sengupta, B. K. Khandheria, J. Korinek, J. Wang, A. Jahangir, J. B. Seward, and M. Belohlavek Apex-to-Base Dispersion in Regional Timing of Left Ventricular Shortening and Lengthening J. Am. Coll. Cardiol., January 3, 2006; 47(1): 163 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Viitasalo, L. Oikarinen, H. Swan, K. A. Glatter, H. Vaananen, H. Fodstad, N. Chiamvimonvat, K. Kontula, L. Toivonen, and M. M. Scheinman Ratio of Late to Early T-Wave Peak Amplitude in 24-h Electrocardiographic Recordings as Indicator of Symptom History in Patients With Long-QT Syndrome Types 1 and 2 J. Am. Coll. Cardiol., January 3, 2006; 47(1): 112 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Fish, J. Brugada, and C. Antzelevitch Potential Proarrhythmic Effects of Biventricular Pacing J. Am. Coll. Cardiol., December 20, 2005; 46(12): 2340 - 2347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Viitasalo, L. Oikarinen, H. Swan, K. A. Glatter, H. Vaananen, H. Fodstad, N. Chiamvimonvat, K. Kontula, L. Toivonen, and M. M. Scheinman Ratio of Late to Early T-Wave Peak Amplitude in 24-h Electrocardiographic Recordings as Indicator of Symptom History in Patients With Long-QT Syndrome Types 1 and 2 J. Am. Coll. Cardiol., December 13, 2005; (2005) j.jacc.2005.07.068v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Yue, M. R. Franz, P. R. Roberts, and J. M. Morgan Global Endocardial Electrical Restitution in Human Right and Left Ventricles Determined by Noncontact Mapping J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1067 - 1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Janse, E. A. Sosunov, R. Coronel, T. Opthof, E. P. Anyukhovsky, J. M.T. de Bakker, A. N. Plotnikov, I. N. Shlapakova, P. Danilo Jr, J. G.P. Tijssen, et al. Repolarization Gradients in the Canine Left Ventricle Before and After Induction of Short-Term Cardiac Memory Circulation, September 20, 2005; 112(12): 1711 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Kowey and G.-X. Yan Making a Silk Purse Out of a Sow's Ear J. Am. Coll. Cardiol., August 16, 2005; 46(4): 688 - 689. [Full Text] [PDF]
|
|
|
|
|
|
W. Shimizu The long QT syndrome: Therapeutic implications of a genetic diagnosis Cardiovasc Res, August 15, 2005; 67(3): 347 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Ritsema van Eck, J. A. Kors, and G. van Herpen The U wave in the electrocardiogram: A solution for a 100-year-old riddle Cardiovasc Res, August 1, 2005; 67(2): 256 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Taggart, P. Sutton, C. Redfern, V. N. Batchvarov, K. Hnatkova, M. Malik, U. James, and A. Joseph The Effect of Mental Stress on the Non-Dipolar Components of the T Wave: Modulation by Hypnosis Psychosom Med, May 1, 2005; 67(3): 376 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pathak, D. Curnier, J. Fourcade, J. Roncalli, P. K. Stein, P. Hermant, M. Bousquet, P. Massabuau, J.-M. Senard, J.-L. Montastruc, et al. QT dynamicity: a prognostic factor for sudden cardiac death in chronic heart failure Eur J Heart Fail, March 2, 2005; 7(2): 269 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Clancy and R. S. Kass Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+ and K+ Channels Physiol Rev, January 1, 2005; 85(1): 33 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Cardiac repolarization. The long and short of it Europace, January 1, 2005; 7(s2): S3 - S9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Weiss, G. Seemann, F. B. Sachse, and O. Dössel Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall Europace, January 1, 2005; 7(s2): S105 - S117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Whyte, P. D. Booker, and D. G. Buckley The Effects of Propofol and Sevoflurane on the QT Interval and Transmural Dispersion of Repolarization in Children Anesth. Analg., January 1, 2005; 100(1): 71 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ueda, D. P. Zipes, and J. Wu Functional and transmural modulation of M cell behavior in canine ventricular wall Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2569 - H2575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashikaga, J. H. Omens, N. B. Ingels Jr., and J. W. Covell Transmural mechanics at left ventricular epicardial pacing site Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2401 - H2407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Fish, J. M. Di Diego, V. Nesterenko, and C. Antzelevitch Epicardial Activation of Left Ventricular Wall Prolongs QT Interval and Transmural Dispersion of Repolarization: Implications for Biventricular Pacing Circulation, May 4, 2004; 109(17): 2136 - 2142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E Conrath, R. Wilders, R. Coronel, J. M.T de Bakker, P. Taggart, J. R de Groot, and T. Opthof Intercellular coupling through gap junctions masks M cells in the human heart Cardiovasc Res, May 1, 2004; 62(2): 407 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Oikarinen, M. S. Nieminen, M. Viitasalo, L. Toivonen, S. Jern, B. Dahlof, R. B. Devereux, P. M. Okin, and for the LIFE Study Investigators QRS Duration and QT Interval Predict Mortality in Hypertensive Patients With Left Ventricular Hypertrophy: The Losartan Intervention for Endpoint Reduction in Hypertension Study Hypertension, May 1, 2004; 43(5): 1029 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gaita, C. Giustetto, F. Bianchi, R. Schimpf, M. Haissaguerre, L. Calo, R. Brugada, C. Antzelevitch, M. Borggrefe, and C. Wolpert Short QT syndrome: pharmacological treatment J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1494 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch, L. Belardinelli, L. Wu, H. Fraser, A. C. Zygmunt, A. Burashnikov, J. M. Di Diego, J. M. Fish, J. M. Cordeiro, R. J. Goodrow Jr, et al. Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S65 - S83. [Abstract] [PDF]
|
|
|
|
|
|
H. Ashikaga, J. C. Criscione, J. H. Omens, J. W. Covell, and N. B. Ingels Jr. Transmural left ventricular mechanics underlying torsional recoil during relaxation Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H640 - H647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
M. N. Obreztchikova, E. A. Sosunov, E. P. Anyukhovsky, N. S. Moise, R. B. Robinson, and M. R. Rosen Heterogeneous Ventricular Repolarization Provides a Substrate for Arrhythmias in a German Shepherd Model of Spontaneous Arrhythmic Death Circulation, September 16, 2003; 108(11): 1389 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Di Diego, L. Belardinelli, and C. Antzelevitch Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation Circulation, August 26, 2003; 108(8): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Yan, R. S. Lankipalli, J. F. Burke, S. Musco, and P. R. Kowey Ventricular repolarization components on the electrocardiogram: Cellular basis and clinical significance J. Am. Coll. Cardiol., August 6, 2003; 42(3): 401 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. X. Roithinger, T. Berger, F. Hintringer, C. Butter, M. Schlegl, G.-X. Yan, P. R. Kowey, C. Droogan, R. S. Lankipalli, C. Antzelevitch, et al. Effect of Epicardial or Biventricular Pacing to Prolong QT Interval and Increase Transmural Dispersion of Repolarization * Effect of Epicardial or Biventricular Pacing to Prolong QT Interval and Increase Transmural Dispersion of Repolarization * Response Circulation, July 29, 2003; 108 (4): e27 - e28. [Full Text] [PDF]
|
|
|
|
|
|
C. Swerdlow, K. Shivkumar, and J. Zhang Determination of the Upper Limit of Vulnerability Using Implantable Cardioverter-Defibrillator Electrograms Circulation, June 24, 2003; 107(24): 3028 - 3033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T.C.E. Robinson, N. D. Harris, R. H. Ireland, S. Lee, C. Newman, and S. R. Heller Mechanisms of Abnormal Cardiac Repolarization During Insulin-Induced Hypoglycemia Diabetes, June 1, 2003; 52(6): 1469 - 1474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Smetana, V. Batchvarov, K. Hnatkova, A John Camm, and M. Malik Sex differences in the rate dependence of the T wave descending limb Cardiovasc Res, June 1, 2003; 58(3): 549 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Takenaka, T. Ai, W. Shimizu, A. Kobori, T. Ninomiya, H. Otani, T. Kubota, H. Takaki, S. Kamakura, and M. Horie Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome Circulation, February 18, 2003; 107(6): 838 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Medina-Ravell, R. S. Lankipalli, G.-X. Yan, C. Antzelevitch, N. A. Medina-Malpica, O. A. Medina-Malpica, C. Droogan, and P. R. Kowey Effect of Epicardial or Biventricular Pacing to Prolong QT Interval and Increase Transmural Dispersion of Repolarization: Does Resynchronization Therapy Pose a Risk for Patients Predisposed to Long QT or Torsade de Pointes? Circulation, February 11, 2003; 107(5): 740 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nemec, J. B. Hejlik, W.-K. Shen, and M. J. Ackerman Catecholamine-Induced T-Wave Lability in Congenital Long QT Syndrome: A Novel Phenomenon Associated With Syncope and Cardiac Arrest Mayo Clin. Proc., January 1, 2003; 78(1): 40 - 50. [Abstract] [PDF]
|
|
|
|
|
|
M. Viitasalo, L. Oikarinen, H. Swan, H. Vaananen, K. Glatter, P. J. Laitinen, K. Kontula, H. V. Barron, L. Toivonen, and M. M. Scheinman Ambulatory Electrocardiographic Evidence of Transmural Dispersion of Repolarization in Patients With Long-QT Syndrome Type 1 and 2 Circulation, November 5, 2002; 106(19): 2473 - 2478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Di Diego, J. M. Cordeiro, R. J. Goodrow, J. M. Fish, A. C. Zygmunt, G. J. Perez, F. S. Scornik, and C. Antzelevitch Ionic and Cellular Basis for the Predominance of the Brugada Syndrome Phenotype in Males Circulation, October 8, 2002; 106(15): 2004 - 2011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Pietila, H. Fodstad, E. Niskasaari, P.a. J. Laitinen, H. Swan, M. Savolainen, Y. A. Kesaniemi, K. Kontula, and H. V. Huikuri association between HERG K897T polymorphism and QT interval in middle-aged finnish women J. Am. Coll. Cardiol., August 7, 2002; 40(3): 511 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Sympathetic modulation of the long QT syndrome Eur. Heart J., August 2, 2002; 23(16): 1246 - 1252. [PDF]
|
|
|
|
|
|
W. Shimizu, Y. Tanabe, T. Aiba, M. Inagaki, T. Kurita, K. Suyama, N. Nagaya, A. Taguchi, N. Aihara, K. Sunagawa, et al. Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the lqt1 and lqt2 forms of congenital long qt syndrome J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1984 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gima and Y. Rudy Ionic Current Basis of Electrocardiographic Waveforms: A Model Study Circ. Res., May 3, 2002; 90(8): 889 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Noble Modeling the Heart--from Genes to Cells to the Whole Organ Science, March 1, 2002; 295(5560): 1678 - 1682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wu, J. Wu, and D. P. Zipes Early Afterdepolarizations, U Waves, and Torsades de Pointes Circulation, February 12, 2002; 105(6): 675 - 676. [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Yan, S. J. Rials, Y. Wu, T. Liu, X. Xu, R. A. Marinchak, and P. R. Kowey Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1968 - H1975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. di Bernardo, A. Murray, A. A.M. Wilde, and D. M. Roden T-Wave Shape in Clinical Research Response Circulation, October 9, 2001; 104 (15): e80 - e80. [Full Text] [PDF]
|
|
|
|
|
|
J. E. Burnes, R. N. Ghanem, A. L. Waldo, and Y. Rudy Imaging Dispersion of Myocardial Repolarization, I: Comparison of Body-Surface and Epicardial Measures Circulation, September 11, 2001; 104(11): 1299 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Johansson and L. Carlsson Female Gender Does Not Influence the Magnitude of Ibutilide-Induced Repolarization Delay and Incidence of Torsades de Pointes in an In Vivo Rabbit Model of the Acquired Long QT Syndrome Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2001; 6(3): 247 - 254. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch Heterogeneity of cellular repolarization in LQTS: the role of M cells Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K2 - K16. [Abstract] [PDF]
|
|
|
|
|
|
A. C. Zygmunt, G. T. Eddlestone, G. P. Thomas, V. V. Nesterenko, and C. Antzelevitch Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H689 - H697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Yan, Y. Wu, T. Liu, J. Wang, R. A. Marinchak, and P. R. Kowey Phase 2 Early Afterdepolarization as a Trigger of Polymorphic Ventricular Tachycardia in Acquired Long-QT Syndrome : Direct Evidence From Intracellular Recordings in the Intact Left Ventricular Wall Circulation, June 12, 2001; 103(23): 2851 - 2856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Transmural dispersion of repolarization and the T wave Cardiovasc Res, June 1, 2001; 50(3): 426 - 431. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rosati, Z. Pan, S. Lypen, H.-S. Wang, I. Cohen, J. E Dixon, and D. McKinnon Regulation of KChIP2 potassium channel {beta} subunit gene expression underlies the gradient of transient outward current in canine and human ventricle J. Physiol., May 15, 2001; 533(1): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tanabe, M. Inagaki, T. Kurita, N. Nagaya, A. Taguchi, K. Suyama, N. Aihara, S. Kamakura, K. Sunagawa, K. Nakamura, et al. Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome J. Am. Coll. Cardiol., March 1, 2001; 37(3): 911 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Lupoglazoff, I. Denjoy, M. Berthet, N. Neyroud, L. Demay, P. Richard, B. Hainque, G. Vaksmann, D. Klug, A. Leenhardt, et al. Notched T Waves on Holter Recordings Enhance Detection of Patients With LQT2 (HERG) Mutations Circulation, February 27, 2001; 103(8): 1095 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Glatter, Y. Yang, K. Chatterjee, G. Modin, J. Cheng, S. Kayser, and M. M. Scheinman Chemical Cardioversion of Atrial Fibrillation or Flutter With Ibutilide in Patients Receiving Amiodarone Therapy Circulation, January 16, 2001; 103(2): 253 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. M. Wilde and D. M. Roden Predicting the Long-QT Genotype From Clinical Data : From Sense to Science Circulation, December 5, 2000; 102(23): 2796 - 2798. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||