(Circulation. 1999;99:1499-1507.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Cellular and Ionic Basis for T-Wave Alternans Under Long-QT Conditions
Presented in part at the 19th Scientific Sessions of NASPE, San Diego, Calif, May 6, 1998, and published as an abstract (PACE. 1998;21:856).
From Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501-1787. E-mail ca{at}mmrl.edu
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Abstract |
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Background—T-wave alternans (TWA), an ECG phenomenon characterized by beat-to-beat alternation of the morphology, amplitude, and/or polarity of the T wave, is commonly observed in the acquired and congenital long-QT syndromes (LQTS). This study examines the cellular and ionic basis for TWA induced by rapid pacing under conditions mimicking the LQT3 form of the congenital LQTS in an arterially perfused canine left ventricular wedge preparation.
Methods and Results—Transmembrane action potentials from epicardial, M, and endocardial cells and 6 to 8 intramural unipolar electrograms were simultaneously recorded together with a transmural ECG and isometric tension development. In the presence of sea anemone toxin (ATX-II; 20 nmol/L), an increase in pacing rate (from a cycle length [CL] of 500 to 400 to 250 ms) produced a wide spectrum of T-wave and mechanical alternans. Acceleration to CLs of 400 to 300 ms produced mild to moderate TWA principally due to beat-to-beat alternation of repolarization of cells in the M region. Transmural dispersion of repolarization during alternans was exaggerated during alternate beats. Acceleration to CLs of 300 to 250 ms caused more pronounced beat-to-beat alternation of action potential duration (APD) of the M cell, resulting in a reversal of repolarization sequence across the ventricular wall, leading to alternation in the polarity of the T wave. The peak of the negative T waves coincided with repolarization of the M region, whereas the end of the negative T wave coincided with the repolarization of epicardium. In almost all cases, electrical alternans was concordant with mechanical alternans. Torsade de pointes occurred after an abrupt acceleration of CL, which was associated with marked TWA. Both ryanodine and low [Ca2+]o completely suppressed alternans of the T wave, APD, and contraction, suggesting a critical role for intracellular Ca2+ cycling in the maintenance of TWA.
Conclusions—Our results suggest that TWA observed at rapid rates under long-QT conditions is largely the result of alternation of the M-cell APD, leading to exaggeration of transmural dispersion of repolarization during alternate beats, and thus the potential for development of torsade de pointes. Our data also suggest that unlike transient forms of TWA that damp out quickly and depend on electrical restitution factors, the steady-state electrical and mechanical alternans demonstrated in this study appears to be largely the result of beat-to-beat alternans of [Ca2+]i.
Key Words: torsade de pointes • waves • action potentials • long-QT syndrome
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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T-wave alternans (TWA), an ECG phenomenon characterized by beat-to-beat alternation of the morphology, amplitude, and/or polarity of the T wave, is often associated with the acquired and congenital long-QT syndromes (LQTS). It is an important prognostic indicator in that it is commonly observed just preceding episodes of torsade de pointes.1 2 3 Although beat-to-beat alternation of repolarization somewhere in the heart is presumed to underlie TWA, the precise cellular and ionic basis has not been elucidated. The present study uses an arterially perfused canine left ventricular wedge preparation4 5 6 7 8 to assess the cellular and subcellular mechanisms of TWA observed under long-QT conditions.
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Methods |
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Arterially Perfused Wedge of Canine Left Ventricle
Mongrel dogs weighing 20 to 25 kg were anticoagulated with heparin and anesthetized with pentobarbital (30 to 35 mg/kg IV). The chest was opened with a left thoracotomy, and the heart was excised and placed in a cardioplegic solution consisting of cold (4°C) or room temperature Tyrode's solution containing 8.5 mmol/L [K+]o. Transmural wedges with dimensions of
2x1.5x0.9 cm to 3x2x1.5 cm were
dissected from the left ventricular anterior wall. The
tissue was cannulated through a small (diameter 100 µm)
native branch of the left descending coronary artery and
perfused with cardioplegic solution. Unperfused tissue, readily
identified by its maintained red appearance (erythrocytes not washed
away) was carefully removed with a razor blade. The preparation was
then placed in a small tissue bath and arterially perfused
with Tyrode's solution of the following composition (mmol/L): 129
NaCl, 4 KCl, 0.9 NaH2PO4,
20 NaHCO3, 1.8 CaCl2, 0.5
MgSO4, and 5.5 glucose, buffered with 95%
O2 and 5% CO2 (37±1°C).
The perfusate was delivered to the artery by a roller pump
(Cole Parmer Instrument Co). Perfusion pressure was monitored with a
pressure transducer (World Precision Instruments, Inc) and maintained
between 40 and 50 mm Hg by adjustment of the perfusion flow
rate. The preparations remained immersed in the arterial
perfusate, which was allowed to rise to a level 2 to 3 mm
above the tissue surface when possible. To facilitate impalement with
the floating microelectrode, in some experiments the bath solution was
brought to a level just shy of the top of the wedge and the chamber was
covered to the extent possible to avoid a temperature gradient between
the top and lower segments of the preparation. Preparations displaying
significant ST-segment elevation or depression were excluded from the
study.
Recording of Transmural ECG and Transmembrane Action
Potentials
The ventricular wedges were allowed to equilibrate
until electrically stable (usually 1 hour) and stimulated with bipolar
silver electrodes insulated except at the tips and applied to the
endocardial surface.
A transmural ECG was recorded with the use of 3 mol/L KCl-Agar
electrodes (1.1 mm inner diameter). The electrodes were placed in
the Tyrode's solution, bathing the preparation 1.0 to 1.5 cm from the
epicardial and endocardial surfaces of the preparation, along the same
vector as the transmembrane recordings (Epi: "+" pole)
(Figure 1
). The electrical field of the
preparation as a whole was measured with the use of this technique.
Thus the electrocardiographic registration represents a
pseudo-ECG of that part of the left ventricle. To differentiate it from
local electrogram activity, we refer to it as an ECG in the remainder
of the text.
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Transmembrane action potentials were simultaneously
recorded from the epicardial, M, and endocardial sites with the use
of 3 to 4 separate intracellular floating microelectrodes (DC
resistance: 10 to 20 M
, 2.7 mol/L KCl). Epicardial and endocardial
action potentials (APs) were recorded from the epicardial and the
endocardial surfaces of the preparations at positions approximating the
transmural axis of the ECG recording. M-cell APs were
recorded at the site along the same axis at which APD was longest,
usually in the deep subendocardium (Figure 1
).
APD was measured at 90% repolarization (APD90). Activation time (AT) was measured as the interval between the stimulus artifact and the upstroke of the AP. Transmural dispersion of repolarization (TDR) was defined as the difference between the longest and the shortest repolarization time (AT+APD90) of transmembrane APs recorded across the wall. The QT interval was defined as the time between QRS onset and the point at which the final downslope of the T wave crossed the baseline. 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) or from the time maximum of the first derivative (Vmax) of the T wave of the unipolar electrograms (shortest in Epi/Endo and longest in the M region) to the ECG trace.
Recordings of Unipolar Electrograms
Six to 8 unipolar electrodes were used to measure the
activation-recovery interval (ARI) in the deeper layers of the wedge
(Figure 1). Unipolar electrodes consisting of silver wire
(120 µm diameter), Teflon insulated except at the tip, were
introduced halfway into the wedge from the cut transmural surface so
that the extracellular recording sites subtended those of the
transmembrane recordings. Each electrode was referenced to the
bath ground (silver chloride 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 at each site was measured as the
interval between the time minimum of the first derivative
(Vmin) of the QRS deflection and the
Vmax of the T wave. AT was measured as the
interval between the stimulus artifact and the
Vmin of the QRS. Validation of the use of this
technique for the approximation of APD at transmural sites within
canine ventricular myocardium was provided in
previous studies with the use of the perfused wedge
preparations.5 8 as well as in vivo studies by El-Sherif
and coworkers.9 The viability and electrical stability of
the wedge preparations have been detailed
elsewhere.4 5 6 7 8 10
Recordings of Isometric Contractility
In some preparations, isometric contractile force was
simultaneously recorded together with transmembrane,
intramural, and ECG activity (Figure 1). One end of the wedge
preparation was fixed to the bath with stainless steel pins; the other
end was attached to a Grass force-displacement transducer (Grass
Instruments, Astro-Med, Inc) to record isometric contractile
force.
All amplified signals were digitized, stored on magnetic media and WORM-CD, and analyzed with the use of Spike 2 (Cambridge Electronic Design, Cambridge, UK-CED).
Study Protocols
Sea anemone toxin (ATX-II; 20 nmol/L) was used to augment the
late sodium current (INa) and produce long-QT
conditions similar to those caused by the defect in SCN5A,
which is responsible for the LQT3 syndrome. The validity of such
pharmacological models as surrogates for the congenital syndromes was
previously demonstrated in myocyte,11
wedge,5 and in vivo studies.9
T-wave alternans was induced by reducing the pacing cycle length (CL) from 2000 to 1000, 800, 500, 400, 350, 300, and 250 ms. In some cases, CL was decreased from 500 to 400, 350, 300, and 250 ms (20 to 30 seconds at each CL).
To assess the role of acceleration-induced Ca2+ loading on TWA, we blocked Ca2+ release from the sarcoplasmic reticulum (SR) by using ryanodine (1 µmol/L) (n=6). In another 6 preparations, extracellular Ca2+ was reduced to 50 µmol/L to deplete SR calcium.
Control measurements were generally obtained after 1 hour of equilibration. The ATX-II data were collected for a period of up to 1 hour starting 1 hour after addition of the drug. Ryanodine and low [Ca2+]o data were recorded after 10 minutes of exposure to the intervention.
Statistics
Statistical analysis of the data was performed with the
use of a Student's t test for paired data or ANOVA coupled
with Scheffé's test, as appropriate. Data are expressed as
mean±SD values, except for those shown in the figures, which are
expressed as mean±SEM values. Significance was defined as a value
of P<0.05.
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Results |
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Correspondence Among Transmural ECG, Transmembrane AP, and Intramural Unipolar Electrograms
Figure 2
illustrates the
correspondence among the transmembrane, unipolar, and ECG
recordings in the absence and the presence of ATX-II. In both
cases, the peak of the T wave in the ECG is coincident with the
repolarization of epicardial AP as well as the
Vmax of the epicardial electrogram, whereas the
end of the T wave is coincident with the repolarization of the M cell
AP (deep subendocardium, M2) as well as the Vmax
of the M2 electrogram. Repolarization of the endocardial AP was
intermediate between that of the M cell and epicardial cell. Thus TDR
across the ventricular wall was defined as the difference
in repolarization time between the M cell that had the longest APD and
epicardial cell. ATX-II (20 nmol/L) markedly prolonged the
APD90 and ARI of the 3 cell types and the QT
interval (307±9 to 551±38 ms; n=12; P<0.0005) and
increased TDR (48±6 to 158±21 ms; n=12; P<0.0005) because
of the much greater prolongation of APD90 and ARI
in the M region (APD90 278±7 to 520±40 ms;
n=12; P<0.0005) than those of epicardium
(APD90 221±6 to 352±32 ms; n=12;
P<0.0005) (Figure 2B).
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T-Wave Alternans During Rapid Pacing
Figure 3 illustrates the TWA induced
by an abrupt acceleration of pacing rate. TWA usually was not observed
under control conditions (Figure 3A) but could be easily induced
after 20 nmol/L ATX-II (Figure 3B). TWA was subtle at a CL of
400 ms and became progressively more prominent with acceleration to
briefer CLs (350 and 300 ms). At a CL of 250 ms, TWA consisted of
beat-to-beat changes in the polarity of the T wave. In most
preparations, subtle alternans of the T-wave amplitude was observed at
CLs of 400 to 300 ms, and marked alternans including alternans of
T-wave polarity occurred at CLs of 300 to 250 ms.
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Figure 4 illustrates the cellular basis
for alternans in the amplitude of the T wave. The T-wave amplitude and
QT interval differed in the successive beats principally because of
beat-to-beat alternation of APD90 and ARI of
cells in the M region. In contrast, epicardial cells showed very little
beat-to-beat change of APD90 and ARI. The extent
to which endocardium contributes is difficult to discern because this
tissue is in close electrical contact with the M region. Because
repolarization of the M cell with the longest
APD90 (M2 in this preparation) marks the end of
the T wave, the QT (QTend) interval alternates beat to beat, whereas
the QTpeak interval showed very little beat-to-beat change as the
result of small change of APD90 and ARI of
epicardium. AT of each electrogram and of each AP was constant in each
successive beat.
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Figure 5 illustrates the cellular basis
for alternans in the polarity of the T wave. The magnitude of the
beat-to-beat alternation of APD90 and ARI in the
M region is much more pronounced than that of the epicardial and
endocardial cells. Transmural repolarization was as previously
described (epicardium was the first to repolarize and the M region was
the last) when the T wave was positive (first and third beats in Figure 5). When in alternate beats repolarization gradients reversed
(the M region repolarized first and epicardium last), the T wave became
negative (second beat in Figure 5). In all cases, repolarization
of the endocardial cells was intermediate between that of the M and
epicardial cells. AT remained constant in successive beats.
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Figure 6 shows composite data of
beat-to-beat change in the QT interval, APD90 of
the 3 cell types, and TDR evaluated for 3 successive beats under
steady-state conditions at CLs of 350 and 250 ms. At both CLs,
beat-to-beat alternation of the APD90 was more
pronounced in the M cells than in epicardial and endocardial cells,
resulting in a significant beat-to-beat change in the QT interval and
TDR. At a CL of 250 ms, the APD90 of the second
beat (N+1) is shorter in the M cells than in the epicardial and
endocardial cells, creating a negative TDR (Figure 6B). It is
noteworthy that the magnitude of the maximal TDR is not reduced, and in
some cases increased, at the shorter CL of 250 ms, even though the QT
interval and APD90 of the 3 cell type abbreviate
(Figures 4, 5, 6A, and 6B).
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Effects of Ryanodine and Low Extracellular Ca2+ on
T-Wave Alternans
Ryanodine (1 µmol/L) slightly abbreviated the
APD90 of the 3 cell types as well as the QT
interval (P=NS) and did not alter TDR at a basic CL (BCL) of
2000 ms in the continued presence of 20 nmol/L ATX-II (Table 1). Low extracellular
Ca2+ (50 µmol/L) further prolonged the
APD90 and the QT interval (P<0.0005)
but did not change TDR at a BCL of 2000 ms in the presence of ATX-II
(Table 2).
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Both ryanodine and low
[Ca2+]o in the continued
presence of ATX-II completely suppressed pacing-induced TWA. Figure 7 illustrates the effects of ryanodine
and low [Ca2+]o to
suppress the beat-to-beat alternation of transmembrane and ECG
activity. As in Figure 5, alternating negative T waves in the
presence of ATX-II alone are the result of early repolarization of the
M region and late repolarization of epicardium (Figures 7A and 7C). Ryanodine and low
[Ca2+]o totally suppress
the beat-to-beat alternation of APD90, QT
interval, and TDR (Figures 7B and 7D). It is noteworthy that the
magnitude of the maximal TDR is reduced after ryanodine or low
[Ca2+]o. Composite data
from 3 successive beats recorded under steady-state conditions
(CL=250 ms) are shown in Figures 6C and 6D. The maximal TDR is
reduced after either ryanodine or low
[Ca2+]o.
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Induction of Torsade de Pointes
Torsade de pointes was observed during rapid pacing in 3 out of 12
preparations in the presence of ATX-II alone. Torsade de pointes was
induced by an abrupt acceleration of pacing CL to 250 ms, which was
associated with marked TWA (Figure 8A).
Figure 8B shows the initiation of torsade de pointes during
simultaneous recordings of 6 unipolar electrograms
from endocardial, M, and epicardial regions and a transmural ECG.
Unipolar electrograms in the M region (M1, M2, and M3) display marked
alternation of ARI. Torsade de pointes was induced after a third paced
(captured) beat (P3) whose propagation was markedly delayed or blocked
in the M region (between M1 and M2), presumably setting the stage for
reentry. In contrast, torsade de pointes was never observed at
relatively short CLs, causing only subtle or no TWA in the presence of
ATX-II. Torsade de pointes was never observed in control or after
ryanodine or low [Ca2+]o
in the presence of ATX-II.
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Correlation Between Electrical and Mechanical Alternans
To further evaluate the role of intracellular
Ca2+ loading in TWA, we correlated electrical
alternans with the mechanical alternans measured by using isometric
tension techniques. Under control conditions, neither electrical (T
wave and APD) nor mechanical alternans were observed at any pacing CL
(Figure 9A). In the presence of ATX-II,
TWA mainly caused by beat-to-beat alternation of the M cell APD was
always accompanied by a mechanical alternans (Figure 9B). In
most preparations (>90%), the longer AP was associated with a larger
contraction, whereas the subsequent shorter AP coincided with the
smaller contraction (concordant alternans) (Figure 9B, 10A, and 10C). Both ryanodine and low
[Ca2+]o completely
suppressed the beat-to-beat alternation of contraction as well as that
of the T wave, QT interval, and APD (Figures 10B and 10D).
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Discussion |
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Cellular Basis for T-Wave Alternans
T-wave alternans is a well-known ECG phenomenon often associated with the development of cardiac arrhythmias,12 13 particularly in the setting of the acquired and congenital LQTS.1 2 3 14 In tissue and single-cell studies, alternans of APD is a well-recognized event that usually occurs during rapid rates of stimulation or after an abrupt abbreviation of CL.15 16 17 18 19 20 Although linked to spatial (transmural, interventricular) and temporal (beat-to-beat) heterogeneity of repolarization, the precise cellular mechanism underlying TWA is not known. The present study uses the arterially perfused wedge preparation to probe the relation between transmembrane AP activity (or intramural ARI) and transmural ECG activity during TWA induced under long-QT conditions.4 5 6 7 8 The data indicate that TWA occurring in the presence of ATX-II is in large part secondary to beat-to-beat alternation of the repolarization of cells in the M region, consistent with the findings of Chinushi and coworkers.21 Smaller alternation of the APD of epicardium and endocardium results in dynamic modulation of the transmural voltage gradients that contribute to inscription of the T wave. It is noteworthy that in most preparations, small beat-to-beat alternation of APD in the M region precedes visually detectable TWA in the ECG (data not shown). Recent studies have reported that microvolt TWA, detected by digital signal-processing techniques, can serve as a noninvasive marker of vulnerability to ventricular arrhythmias.12 13 22 Our data demonstrating beat-to-beat undulation of transmural dispersion of repolarization attending TWA support the prognostic value of this parameter.
The data also elucidate the cellular basis for the negative T wave commonly observed during marked TWA. The M-cell AP is the last to repolarize in beats manifesting a positive T wave. Voltage gradients between M and epicardium contribute to the positive excursion of the T wave, whereas the gradient between M and endocardium limit the magnitude of the T wave and contribute to its descending limb.8 This situation is reversed in beats that manifest a negative T wave. The M cell is now the first to repolarize and the voltage gradients between M and epicardium and endocardium and M are reversed, leading to inscription of a negative T wave.
Role of T-Wave Alternans in Development of Torsade de
Pointes
Torsade de pointes is an atypical polymorphic
ventricular tachycardia most often associated
with QT prolongation in both congenital and acquired LQTS. Although the
precise mechanism of torsade de pointes has not been established,
recent in vivo studies,9 23 perfused wedge
studies,4 5 6 and clinical observations made with
monophasic AP recordings24 25 have
presented evidence in support of the hypothesis that an early
afterdepolarization–induced, triggered response initiates
torsade de pointes but that the arrhythmia is maintained by a
reentrant mechanism. The present study demonstrates that maximal
TDR increases during marked T-wave alternans when compared with that
observed in the presence of ryanodine, low
[Ca2+]o, or at longer CLs
at which TWA is subtle or absent. Of note, acceleration-induced TDR is
amplified despite an abbreviation of the average QT interval and
APD90. The large fluctuations of TDR and M-cell
APD are more pronounced during the first few beats after an increase in
pacing rate, consistent with the findings of Verduyn et
al.23 Indeed, abrupt acceleration of rate induces episodes
of torsade de pointes, usually after the first or third beat at the
abbreviated CL, since TDR attending these beats is most pronounced
(Figure 8). Torsade de pointes could only be induced at the
shorter CL (250 ms), which was associated with marked TWA in the
presence of ATX-II, but was never observed at any pacing CL yielding
subtle or no TWA. These results suggest that the exaggerated TDR
attending marked TWA leads to a wider than usual vulnerable window,
during which programmed stimulation or pacing can precipitate a
reentrant arrhythmia such as torsade de pointes. In the absence
of alternans, the vulnerable window is too small to induce torsade de
pointes. Previous studies with the wedge have shown that at relatively
slow rates, extrastimulation-induced torsade de pointes is a function
of TDR, which determines the temporal width of the vulnerable
window.5 With abbreviation of CL from 2000 to 350 ms, the
vulnerable window is expected to narrow progressively, making torsade
de pointes more difficult or noninducible. Further abbreviation of the
CL (250 ms) restores the ability of the preparation to develop torsade
de pointes in response to programmed stimulation by virtue of the fact
that TDR and the vulnerable window are amplified in alternate beats
during the period of TWA.
Ionic Basis for T-Wave and Mechanical Alternans
Sundry mechanisms have been proposed to explain the ionic basis
for TWA, including beat-to-beat changes in intracellular levels of
Ca2+, IK,
K+ accumulation in the extracellular clefts, and
Na+/Ca2+ exchange
current.15 16 17 18 19 20 26 There is growing evidence that
electrical alternans of the AP is intimately coupled to mechanical
alternans and that intracellular Ca2+ released
from the SR plays a pivotal role in the maintenance of
both.27 The simultaneous elimination of both
electrical and mechanical alternans after block of the SR with
ryanodine and depletion of SR calcium with low
[Ca2+]o (Figures 6, 7, and 10) provides further support for the hypothesis that
that beat-to-beat changes in the level of
[Ca2+]i modulate the
repolarizing currents in the heart and thus contribute to TWA.
Sustained TWA was never observed without mechanical alternans, and when
they occurred, the two were almost always concordant (ie, the longer
M-cell AP was associated with the larger contraction) (Figures 9 and 10). The time course of repolarization of the M cells differs from
that of epicardium and endocardium, causing a small dispersion of
repolarization and refractoriness across the ventricular
wall in control and a much larger TDR under long-QT
conditions.28 A weaker, slowly activating delayed
rectifier potassium current (IKs)29
and larger late INa30 contribute to the
longer APD of the M cell in the dog. The weaker net outward current
active during the plateau phase also contributes to the greater
response of M cells to agents that prolong APD, such as an ATX-II, and
is likely to be responsible for the greater sensitivity of the M cell
to fluctuation in
[Ca2+]i.
The available data suggest that electrical alternans in some cases is coupled to mechanical alternans and that Ca2+ release from the SR plays a pivotal role in the maintenance of both. Mechanical alternans is thought to occur when the next paced beat encroaches on the time required for reuptake of calcium into the network SR and transport to the junctional SR for rerelease.31 Thus mechanical alternans is induced when the pacing CL is briefer than the interval required for calcium release, reuptake, and transport to the junctional SR. Sustained TWA occurs only when the pacing rate is rapid enough to cause mechanical alternans.
How is mechanical alternans related to electrical alternans? If mechanical alternans is secondary to alternans in the availability of SR calcium ready for release, then it must also reflect alternation in [Ca2+]i. Relatively high [Ca2+]i can augment outward IKs, outward calcium-activated chloride current (ICl(Ca)), and inward electrogenic Na+/Ca2+ exchange current (INa-Ca). In concordant alternans, it seems reasonable to speculate that the larger contraction is accompanied by the larger increase in [Ca2+]i, which in turn augments the 3 currents discussed above. Predominance of INa-Ca over IKs and ICl(Ca) would reduce net repolarizing current and prolong the M-cell AP. The smaller rise in [Ca2+]i attending the next beat would activate less INa-Ca, resulting in less inward current to maintain the plateau and a briefer APD. This scenario would be more likely to occur in M cells, in which IKs is intrinsically small. Discordant alternans would be expected when calcium-induced augmentation of outward current predominates. The larger [Ca2+]i would be expected to increase outward IKs and/or ICl(Ca) more than inward INa-Ca, thus abbreviating APD. The small rise in [Ca2+]i attending the next beat would be expected to activate less IKs and/or ICl(Ca), resulting in a more prolonged APD. Although these hypotheses remain to be more fully evaluated, they are consistent with recent work demonstrating conversion of concordant alternans to discordant alternans in isolated feline myocytes by lowering the temperature of the superfusate.20 Because the temperature coefficient (Q10) of INa-Ca is much larger than that of the ionic currents, the contribution of INa-Ca is deemphasized.
We think it important to point out that the mechanism of sustained (steady-state) TWA observed in this study may be different from the transient TWA and APD prolongation observed during and/or immediately after pacing or at slower rates. Transient T-wave changes and APD prolongation during and/or immediately after an increase in rate is likely due to a transient increase of INa-Ca secondary to intracellular Ca2+ loading32 as well as to other restitution factors. Larger fluctuations of TDR and M-cell APD are generally seen in our study during the first few beats after an increase in pacing rate, congruent to the findings of Verduyn et al.23 Thus electrical alternans secondary to restitution parameters quickly damps, whereas that secondary to alternation of [Ca2+]i is generally sustained at fast rates.
Limitations of the Study
Our interpretations of the data are based on the assumption that
the activity recorded from the cut surface of the perfused wedge
preparation is representative of cells within the
respective layers of the wall throughout the wedge. Such validation was
provided in 2 previous studies with the perfused wedge
preparation6 8 as well as in the present study.
The extent to which ATX-II-induced augmentation of INa mimics the SCN5A defect responsible for the LQT3 syndrome is difficult to measure. Slowed or incomplete inactivation of INa by whatever means33 leads to a large late INa during the plateau phase and a prolonged APD. ATX-II similarly exerts its action to prolong APD by augmenting late INa. Previous studies have demonstrated the ability of the pharmacological model to closely mimic features of LQT3, including a prolonged QT interval, late-appearing T waves, a steep QT-rate relation, induction of torsade de pointes, and a high sensitivity to Na+ channel blockers.5 9 21 We believe that these qualitative similarities validate the ATX-II model as a surrogate for LQT3.
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Acknowledgments |
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This study was supported by grant HL-47678 from the National Heart, Lung, and Blood Institute (C.A.) and grants from Medtronic Japan (W.S.), the American Heart Association (W.S.), and NYS and Florida Grand Lodges F&AM. We gratefully acknowledge the expert technical assistance of Judy Hefferon, Di Hou, and Robert Goodrow. We are grateful to Dr J.M. Di Diego for assistance with the experimental protocols involving recordings of unipolar electrograms and contractile force.
Received August 14, 1998; revision received October 30, 1998; accepted November 5, 1998.
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References |
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