(Circulation. 1998;98:2314-2322.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome
Effects of ß-Adrenergic Agonists and Antagonists and Sodium Channel Blockers on Transmural Dispersion of Repolarization and Torsade de Pointes
From the 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—This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by ß-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome.
Methods and Results—A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific IKs blocker, dose-dependently (1 to 100 µmol/L) prolonged the QT interval and action potential duration (APD90) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 µmol/L abbreviated the APD90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the IKs blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 µmol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 µmol/L abbreviated the APD90 of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP.
Conclusions—This experimental model of LQT1 indicates that a deficiency of IKs alone does not induce TdP but that the addition of ß-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual IKs in epicardial and endocardial cells but not in M cells, in which IKs is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of ß-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.
Key Words: long-QT syndrome • arrhythmia • KvLQT1 • chromanol 293b • isoproterenol
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The long-QT syndrome (LQTS) is characterized by the appearance of long QT intervals in the ECG and atypical polymorphic ventricular tachycardia that can lead to sudden cardiac death.1 2 3 4 5 6 It has long been appreciated that some forms of congenital and acquired LQTS are exquisitely sensitive to the activity of the sympathetic branch of the autonomic nervous system. An imbalance of sympathetic inputs to the heart was at one time thought to underlie congenital LQTS.1 6 Recent studies have shown that congenital LQTS is a primary electrical disease caused by mutations in specific ion channel genes.7
Genetic linkage analysis has identified 4 forms of congenital
LQTS caused by mutations in ion channel genes located on chromosomes 3,
7, 11, and 21.8 9 10 11 Chromosome 3–linked LQT3 is
associated with a mutation in SCN5A, a gene that encodes for
the 
-subunit of the sodium channel in heart,8
whereas chromosome 7–linked LQT2 is associated with a mutation in
HERG, a gene that encodes for the channel that carries the
rapidly activating delayed rectifier potassium current
(IKr).12 Chromosome
11–linked LQT1 is associated with a mutation in KvLQT1 that
encodes for the slowly activating delayed rectifier potassium current
(IKs),13 14 and
chromosome 21–linked LQT5 is caused by a mutation in KCNE1
(minK), whose product coassembles with that of
KvLQT1 to form the IKs
channel.11 13 14
In the clinic, Moss and coworkers15 reported that patients with these ion channel defects often display different phenotypic T wave patterns in the ECG. LQT3 patients show distinctive late-appearing T waves, whereas LQT1 or LQT2 patients display broad-based, prolonged T waves or low-amplitude T waves, respectively.
Among the 3 forms of congenital LQTS, cardiac events (cardiac arrhythmias and sudden cardiac death) are more likely to be associated with adrenergic factors (defined as either physical or emotional stress) in the LQT1 syndrome than in either the LQT2 or LQT3 syndrome.16 Moreover, ß-blockers were reported to reduce cardiac events dramatically in LQT1 patients.17 The mechanisms responsible for these actions of the ß-adrenergic system remain largely unknown.
Using an arterially perfused left ventricular wedge preparation, we recently developed models of LQT2 and LQT3 and showed that sodium channel block with mexiletine is effective in decreasing transmural dispersion of repolarization (TDR) and in suppressing TdP in both.18
In the present study, we use this preparation to develop an experimental model of LQT1 in which we (1) elucidate the cellular basis of catecholamine-induced phenotypic appearance of broad-based T wave, increased TDR, and TdP and (2) examine the effects of rapid pacing as well as of ß-adrenergic and sodium channel blockers to abbreviate the QT interval, diminish TDR, and prevent TdP.
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Methods |
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Arterially Perfused Wedge of Canine Left Ventricle
Dogs weighing 20 to 25 kg were anticoagulated with heparin and anesthetized with pentobarbital 30 to 35 mg/kg IV. The chest was opened via 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 to 3x2x1.5 cm were dissected from
the left ventricle. The tissue was cannulated via a small (diameter,
100 µm) native branch of left anterior 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): NaCl 129, KCl 4,
NaH2PO4 0.9,
NaHCO3 20, CaCl2 1.8,
MgSO4 0.5, and glucose 5.5, 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 microelectrodes, 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 so as to avoid a temperature gradient
between the top and lower segments of the wedge.
Recordings of a 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 3 mol/L KCl-agar electrodes (ID, 1.1 mm). The electrodes were 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 (epicardial, positive pole). The electrical field of the preparation as a whole was measured by this technique. Thus, the ECG 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 text.
Transmembrane action potentials (APs) were recorded
simultaneously from the epicardial, M, and endocardial
sites with 3 or 4 separate intracellular floating microelectrodes (DC
resistance, 10 to 20 M
; 2.7 mol/L KCl). Epicardial and endocardial
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 from the
site along the same axis at which AP duration (APD) was longest.
Amplified signals were digitized, stored on magnetic media and WORM-CD, and analyzed with Spike 2 (Cambridge Electronic Design).
Study Protocols
The IKs blocker chromanol 293B 1 to
100 µmol/L was used to create a model that mimics the defect in
KvLQT1, which results in a reduced
IKs, believed to underlie the congenital
LQT1 syndrome. Isoproterenol 10 to 100 nmol/L was used to mimic
increased ß-adrenergic tone. The effects of ß-adrenergic blockade
were evaluated with propranolol 0.1, 0.3, 1, and 3
µmol/L and those of sodium channel blocker with mexiletine 2, 5, 10,
and 20 µmol/L.
Control measurements were generally obtained after 1 hour of equilibration. The chromanol 293B data were collected for a period of up to 30 minutes starting 30 minutes after addition of the drug. Isoproterenol data in the absence and presence of chromanol 293B were collected within 10 minutes after addition of isoproterenol. Mexiletine and propranolol data were recorded after 30 minutes of exposure to each concentration of drug.
APD was measured at 90% repolarization (APD90). TDR was defined as the difference between the longest and the shortest repolarization times (activation time+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 line of maximal 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 the AP (APD100, approximated by eye) to the ECG trace.
The development of spontaneous and programmed electrical stimulation (PES)–induced polymorphic ventricular tachycardia displaying characteristics of TdP was assessed in the presence of chromanol 293B 30 µmol/L or isoproterenol 10 to 100 nmol/L alone and after the combination of chromanol 293B and isoproterenol 50 to 100 nmol/L. PES-induced arrhythmias were evaluated with a single extrastimulus applied to the epicardium.
Statistics
Statistical analysis of the data was performed with 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.
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Results |
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Dose-Dependent Effect of Chromanol 293B on QT Interval, APD, and TDR
Figure 1A
illustrates the
dose-dependent effect of chromanol 293B on transmembrane and ECG
activity. Chromanol 293B, in concentrations 
10 µmol/L,
significantly prolonged the QT interval and APD90
of the 3 cell types (Figure 1B). However, because the prolongation of
APD90 of the 3 cell types was
homogeneous, chromanol 293B did not widen the T wave or
significantly increase TDR (Figure 1C).
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), APD90 in M (B, 
), endocardial (B, 
), and
epicardial (B, 
) cells. TDR time (RT) (C,
Rate Dependence of QT Interval, APD, and Dispersion of
Repolarization
The rate-dependent changes in the QT interval were closely
approximated by changes in the repolarization time of the M cell both
under control conditions and after chromanol 293B, as illustrated in
Figures 2 and 3. Chromanol 293B 30 µmol/L
produced a steepening of the APD-rate relations and a significant
prolongation of APD90 and of the QT interval at
all rates studied (Figures 2B, 3A, 3B, and 3C). TDR did not change
significantly at any rate (Figures 2B and 3D) because of the effect of
chromanol 293B to prolong the APD90 of the 3 cell
types homogeneously.
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Influence of Isoproterenol on Phenotypic ECG Pattern, Transmembrane
APD, TDR, and TdP
Figure 4 shows transmembrane
activity recorded simultaneously from endocardial, M,
and epicardial regions together with a transmural ECG in the absence
and presence of chromanol 293B 30 µmol/L and in the presence of
isoproterenol 100 nmol/L and chromanol 293B (basic cycle length
[BCL], 2000 ms). In all cases, the peak of the T wave in the ECG was
coincident with the repolarization of the epicardial cell, whereas the
end of the T wave was coincident with the repolarization of the M
region (deep subendocardium). 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 the repolarization time between the M cell (longest AP) and
epicardial cell (shortest AP). Once again, 30 µmol/L of
chromanol 293B prolonged the APD of the 3 cell types and the QT
interval, but it neither increased TDR nor widened the T wave (Figure 4B). Isoproterenol 10 to 100 nmol/L in the continued presence of
chromanol 293B 30 µmol/L abbreviated the APD of epicardial and
endocardial cells but not that of the M cell, resulting in a widening
of the T wave and in a very significant increase in TDR, as commonly
seen in LQT1 patients (Figure 4C). The data presented are those
collected at the point of maximum TDR during the first 10 minutes of
exposure to isoproterenol. In many preparations, the APD in the M
region prolonged soon after addition of isoproterenol and then
abbreviated, whereas the APD of epicardium displayed a constant
abbreviation. Maximum TDR usually occurred within 2 to 5 minutes. It is
noteworthy that the prolongation of the M-cell APD was attended by a
prolongation of the QT interval during the early phase of exposure to
isoproterenol.
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Composite data of the influence of isoproterenol 50 to 100 nmol/L in
the presence of 30 µmol/L chromanol 293B on the QT interval,
APD90 of M and epicardial cells, and TDR are
shown in Figure 5. Chromanol 293B
significantly prolonged the QT interval, from 314±9 to 383±23 ms
(n=8; P<0.0005) at a BCL of 2000 ms. The change in QT
interval was paralleled by an increase in
APD90 of the M cell (286±10 to 354±24 ms; n=8;
P<0.0005). Chromanol 293B homogeneously
prolonged the APD90 of the M cell and the
epicardial cell (234±14 to 298±22 ms; n=8; P<0.0005),
resulting in no significant increase of TDR (43±6 to 47±7 ms; n=8).
Isoproterenol in the continued presence of chromanol 293B significantly
shortened the APD90 of the epicardial cell
(267±15 ms; n=8; P<0.05 versus 293B) but not that of the M
cell (350±19 ms; n=8) (Figure 5A), resulting in a significant increase
of the TDR (75±9 ms; n=8; P<0.0005 versus 293B) (Figure 5B).
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P<0.05,
In 4 preparations, we examined the influence of isoproterenol 10, 50, and 100 nmol/L on transmembrane and ECG activity. Isoproterenol homogeneously abbreviated the APD90 of the 3 cell types in a dose-dependent manner, thus abbreviating the QT interval with no major changes in TDR or width of the T wave.
In the presence of both isoproterenol and chromanol 293B, spontaneous
TdP was observed in 2 of 8 preparations (Figure 6A), and PES-induced TdP was reproducibly
produced in 4 of 8 preparations (Figure 6B). In contrast, neither
spontaneous nor PES-induced TdP was observed under control conditions
or in the presence of chromanol 293B or isoproterenol alone.
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Dose-Dependent Effect of Propranolol on QT Interval,
APD, and TDR
Table 1 summarizes the effects of
propranolol on QT interval, APD90,
and TDR in the continued presence of chromanol 293B 30 µmol/L at
a BCL of 2000 ms (n=6). Chromanol 293B produced a
homogeneous prolongation of the QT interval and of
APD90. In the continued presence of chromanol
293B, 0.1 to 1 µmol/L of propranolol exerted no
significant effect, whereas the highest concentration (3 µmol/L)
significantly abbreviated the APD90 of the M
cell, probably because of its effect to block the late sodium current
(INa), which is intrinsically larger in the
M cell than in the epicardial cell.
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Effect of Propranolol on Repolarization Changes and TdP
Induced by Isoproterenol
Figure 7 illustrates the effect of
propranolol 1 µmol/L to inhibit the influence of
isoproterenol in a wedge preparation pretreated with chromanol 293B
30 µmol/L. Therapeutic concentrations of propranolol
(0.5 to 1 µmol/L), which block ß-adrenergic receptors in the
heart with little or no block of INa,
completely prevented the influence of isoproterenol to increase TDR
(Figures 7C and 7D).
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The average data of 6 experiments are shown in Figure 8. Propranolol 1
µmol/L in the continued presence of chromanol 293B 30 µmol/L
completely suppressed the influence of isoproterenol to shorten the
APD90 of the epicardial cell and to increase TDR
(see Figures 4C
, 5A, and 5B). Moreover, therapeutic concentrations of
propranolol (0.5 to 1 µmol/L) totally suppressed the
spontaneous as well as PES-induced TdP produced in the presence of
isoproterenol and chromanol 293B.
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Dose-Dependent Effect of Mexiletine on QT Interval, APD, and
TDR
Table 2 summarizes the effects of
mexiletine on QT interval, APD90, and TDR in the
continued presence of chromanol 293B 30 µmol/L (BCL, 2000 ms;
n=6). In the continued presence of chromanol 293B, 2 to 20
µmol/L of mexiletine dose-dependently abbreviated the QT interval and
APD90 of M cells more than those of epicardial
cells, thus reducing TDR. Mexiletine 20 µmol/L reversed 70% of
the effect of chromanol 293B to prolong the APD90
of the M cell and the QT interval but only 45% of the effect of
chromanol 293B to prolong the epicardial AP.
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Effect of Mexiletine on Repolarization Changes and TdP Induced
by Isoproterenol
Figure 9 illustrates the effect of
mexiletine 20 µmol/L to inhibit the influence of isoproterenol
on transmembrane and ECG activity in the continued presence of
chromanol 293B 30 µmol/L. Mexiletine 10 to 20 µmol/L
decreased TDR in the presence of chromanol 293B and prevented the
influence of isoproterenol to increase TDR (Figures 9C and 9D).
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Composite data of 6 experiments are shown in Figure 10. Mexiletine 20 µmol/L in the
continued presence of chromanol 293B 30 µmol/L abbreviated the M
cell AP more than that of the epicardial cell, resulting in a
significant decrease of TDR. In the continued presence of mexiletine,
isoproterenol 50 to 100 nmol/L slightly abbreviated the
APD90 of the epicardial cell but not that of the
M cell, resulting in a slight but statistically insignificant increase
in TDR.
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In concentrations of 10 to 20 µmol/L, mexiletine totally suppressed the spontaneous as well as PES-induced TdP provoked with isoproterenol.
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Discussion |
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Catecholamine-Induced Broad-Based Long-QT and Increased Dispersion of Repolarization
Sympathetic stimulation or the administration of exogenous catecholamines is known to produce paradoxical QT prolongation and TdP, often associated with syncope or sudden cardiac death in patients with congenital LQTS.1 2 3 4 5 6 Cardiac arrhythmias and sudden death are more often associated with adrenergic factors, defined as physical and emotional stress, in patients with the LQT1 syndrome than in those with either the LQT2 or LQT3 syndrome.16 A mutation in KvLQT1, which coassembles with the product of KCNE1 to form the IKs channel, has recently been shown to be responsible for the LQT1 syndrome.13 14 ß-Adrenergic stimulation is known to increase ionic current through L-type calcium channels (ICa), IKs, and chloride channels [ICl(Ca) and ICl-cAMP].19 20 A net increase of outward repolarizing current, due to a greater increase of IKs and ICl versus ICa, is usually encountered in response to adrenergic stimulation, and this is thought to underlie abbreviation of APD and QT interval under normal conditions. A smaller increase in IKs (especially in the M region) could offset this balance and account for failure of adrenergic stimulation to abbreviate APD and QT interval in LQT1 patients.7 18 21 22
Our findings indicate that chromanol 293B, a relatively specific IKs blocker,23 homogeneously prolongs the APD90 of the 3 ventricular cell types, thus increasing the QT interval with little or no change in the width of the T wave or TDR. This response is different from that observed with all other APD-prolonging agents. Agents that block IKr, augment ICa, or slow the inactivation of INa all produce a dramatic prolongation of the M-cell APD but a much more modest prolongation of the APD of epicardium and endocardium, presumably because of the presence of a strong net repolarizing current (strong IKs and weak late INa) in the latter and weak net repolarizing current (weak IKs and strong late INa) in the former. The homogeneous response to chromanol 293B is best explained by the presence of unequal levels of IKs in the 3 cell types. Because epicardial and endocardial cells have a larger IKs than M cells, the same percentage inhibition of IKs in the 3 cell types would be expected to decrease total repolarizing current more in the epicardial and endocardial cells than the M cell, resulting in a greater prolongation of the APD of epicardial and endocardial cells. However, the smaller intrinsic repolarizing current of the M cell provides for a greater input (membrane) resistance during phases 2 and 3 of the AP. As a consequence, a smaller absolute decrease in IKs can cause an APD prolongation in M cells comparable to that seen in epicardial and endocardial cells. Consistent with this reasoning, on a percentage basis, 293B-induced APD prolongation in epicardium and endocardium is greater than in the M cell.
In the continued presence of chromanol 293B, ß-adrenergic stimulation with isoproterenol abbreviates the APD90 of epicardial and endocardial cells but not that of the M cell, resulting in an accentuated TDR and a broad-based T wave, consistent with the phenotypic appearance of the ECG in patients afflicted with the LQT1 syndrome.15 The differential response to isoproterenol is probably the result of intrinsic differences in IKs among the 3 cell types. A large augmentation of residual IKs would be expected in epicardial and endocardial cells but not in M cells, in which IKs is intrinsically weak. The weaker endocardial response is most likely due to the strong electrotonic influence of the M cells, which reside in the deep subendocardium in this part of the left ventricular wall. When studied as isolated strips, epicardial and endocardial APs prolonged by chromanol 293B display a marked abbreviation in response to isoproterenol, whereas the M-cell preparations usually exhibit a prolongation of APD within the first few seconds of exposure to isoproterenol (unpublished data).
Our data indicate the lack of an arrhythmogenic substrate when IKs is diminished in the absence of ß-adrenergic influence. Because sympathetic tone is always present under normal physiological conditions, decreased levels of IKs may be arrhythmogenic under conditions in which the sympathetic system has not been pharmacologically or surgically disabled. The concordance of our results in the wedge with the phenotypic ECG and pharmacological manifestations of LQT1 observed in patients suggests that chromanol 293B is a reasonable surrogate for the LQT1 syndrome.
Catecholamine-Induced TdP
TdP is an atypical polymorphic ventricular
tachycardia most often associated with QT prolongation in
both the congenital and acquired forms of LQTS. Although the precise
mechanism of TdP has not been established, several
experimental24 and clinical observations using
monophasic AP recordings25 26 suggest a
role for early afterdepolarization (EAD)–induced triggered activity in
the genesis of TdP. Recent in vivo studies from El-Sherif et
al27 28 and perfused-wedge studies from our
group21 present evidence in support of the
hypothesis that an EAD-induced triggered response initiates TdP but
that the arrhythmia is maintained by a reentrant mechanism. Our
data, showing induction of TdP only in the presence of chromanol 293B
and isoproterenol under conditions in which TDR is increased, provide
further support for reentry as the basis for the maintenance of
TdP. Conversely, several experimental studies have suggested that
inward current through ICa
channels29 or through sodium-calcium
exchange30 contributes to development of EADs.
These mechanisms are thought to contribute to the effect of
ß-adrenergic agonists to induce EADs and triggered activity in M
cells and Purkinje fibers, in which repolarizing currents are reduced.
Thus, sympathetic stimulation may create the substrate for EAD-induced
triggered activity as well as the substrate for reentry in the LQT1
syndrome.
Effect of Rapid Pacing on QT Interval, APD, and TDR
The present study shows a reduction of TDR as a function of
rate and a steeper APD-rate relation for APD90
and QT interval under LQT1 conditions compared with control. Unlike
IKr block, whose APD-prolonging effects are
abolished at fast rates, IKs block with
293B prolongs APD90 and QT even at BCLs as short
as 300 ms (Figures 2 and 3). The protective effect of pacing in LQTS
has been documented in other experimental models as well as in the
clinic.18 31 32
Effect of Propranolol on Repolarization and
TdP
ß-Blockers are widely reported to reduce the incidence of
syncope and sudden death in patients with congenital
LQTS.4 Consistent with reports of a high
sensitivity of patients with the LQT1 syndrome to adrenergic
stimulation, greater than those with either LQT2 or LQT3
syndrome,16 ß-blockers have been shown to
reduce cardiac events very effectively in LQT1
patients.17 Priori et al33
reported that in patients with the Romano-Ward form of LQTS, cardiac
events were reduced more in patients in whom ß-blockers caused a
large decrease in corrected QT (QTc) dispersion. In contrast, other
clinical studies have shown that ß-blockers modified neither QTc
interval nor QTc dispersion as measured with a 12-lead
ECG34 or an 87-lead body surface mapping system
in the LQTS patients.35 Our finding of little or
no effect of therapeutic levels of propranolol (0.1 to
1 µmol/L) on the APD90 of the M cell in
either the presence or absence of isoproterenol is in agreement with
the latter observations. Nevertheless, the effects of isoproterenol to
increase TDR and to produce spontaneous as well as PES-induced TdP were
completely inhibited by propranolol in therapeutic
concentrations. Our data point to a diminution of TDR during normal
sympathetic tone or prevention of an augmentation in TDR in response to
strong sympathetic stimulation as the basis for the antiarrhythmic
effectiveness of propranolol. TDR under these conditions is
measured by the difference in repolarization time of the epicardial and
M regions; the interval between the peak and end of the T wave has been
shown to provide an ECG index of this
parameter.18 36 37 This index may
prove useful in discerning between the actions of
propranolol to reduce TDR already augmented by normal
sympathetic tone or its actions to prevent accentuation of TDR after a
strong sympathetic discharge.
Effect of Mexiletine on Repolarization and TdP
Recent preliminary clinical studies suggested that sodium channel
block with mexiletine is more effective in abbreviating the QT interval
in LQT3 patients (those manifesting the sodium channel defect) than in
either LQT1 or LQT2 patients (those with the
IK defect).31 38 A
significant mexiletine-induced abbreviation of QT was observed in
<10% of LQT1 patients.38 However, studies using
the arterially perfused wedge have shown that although
mexiletine is more effective in abbreviating the QT interval in the
LQT3 than in the LQT2 model, the sodium channel blocker reduces TDR and
prevents the development of TdP equally in the 2
models.18 The present study of the LQT1 model
shows the effect of mexiletine to reduce the QT interval and TDR in the
absence of isoproterenol and to reduce the action of isoproterenol to
accentuate TDR and induce TdP. Our results suggest that sodium channel
block with mexiletine in combination with ß-blockade warrants further
consideration as a therapeutic approach in the treatment of the LQT1
syndrome.
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 that used the perfused-wedge
preparation.18 37
The extent to which chromanol 293B–induced inhibition of IKs mimics the KvLQT1 defect responsible for the LQT1 syndrome is difficult to quantify, because the current density of IKs is intrinsically heterogeneous in the 3 cell types. Our data demonstrate the ability of the model to closely mimic the ECG and pharmacological features of the LQT1 syndrome, including a prolonged QT interval, broad-based T waves, a moderately steep QT-rate relation, and exceptional sensitivity to ß-adrenergic influences. We believe that these qualitative similarities validate chromanol 293B as a surrogate for LQT1.
Our LQT1 model is less than physiological with respect to the manner in which sympathetic influences are examined. An imbalance between left and right stellate inputs to the heart was first suggested to underlie LQTS in 1975.1 The sympathetic-imbalance hypothesis as a primary cause lost ground when genetic linkage analysis uncovered 4 gene mutations responsible for ion channel defects. The role of the sympathetic system remained largely unexplained. The present study advances our understanding of the action of ß-adrenergic influences to amplify transmural dispersion of repolarization. However, perfusion of the wedge preparations with isoproterenol causes homogeneous stimulation of ß1-receptors only and does not take into account differences in the distribution of left and right sympathetic stellate inputs to the heart or the possibility that a pathophysiological sympathetic imbalance may further amplify transmural and interventricular dispersion of repolarization. This disclaimer notwithstanding, the available data suggest the hypothesis that differences in the distribution and characteristics of M cells in right versus left ventricle coupled with physiological differences in right versus left sympathetic innervation of the heart can explain the preeminent role of the left stellate in LQTS. This hypothesis remains to be tested.
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Acknowledgments |
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This study was supported by grant HL-47678 from the National Institutes of Health and grants from Medtronic Japan and the Sixth, Seventh, and Eighth Manhattan Masonic Districts and New York State and Florida Grand Lodges of Free and Accepted Masons. Dr Shimizu was a finalist in the Young Investigator Award Competition of the American College of Cardiology on the basis of this work (47th Annual Scientific Sessions, Atlanta, Ga, March 30, 1998). Chromanol 293B was generously donated by Hoechst. We gratefully acknowledge the expert technical assistance of Judy Hefferon and Di Hou. We are grateful to Brandon McMahon, a participant in our summer fellowship program, for his help with some of the experiments.
Received December 1, 1997; revision received June 23, 1998; accepted June 23, 1998.
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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]
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C. Chiello Tracy, C. Cabo, J. Coromilas, J. Kurokawa, R. S. Kass, and A. L. Wit Electrophysiological consequences of human IKs channel expression in adult murine heart Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H168 - H175. [Abstract] [Full Text] [PDF]
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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]
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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]
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C. Antzelevitch Sympathetic modulation of the long QT syndrome Eur. Heart J., August 2, 2002; 23(16): 1246 - 1252. [PDF]
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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]
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T. Noda, H. Takaki, T. Kurita, K. Suyama, N. Nagaya, A. Taguchi, N. Aihara, S. Kamakura, K. Sunagawa, K. Nakamura, et al. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome Eur. Heart J., June 2, 2002; 23(12): 975 - 983. [Abstract] [Full Text] [PDF]
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T. Nagatomo, C. T. January, B. Ye, H. Abe, Y. Nakashima, and J. C. Makielski Rate-dependent QT shortening mechanism for the LQT3 {Delta}KPQ mutant Cardiovasc Res, June 1, 2002; 54(3): 624 - 629. [Abstract] [Full Text] [PDF]
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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]
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D. Escande Inhibition of repolarizing ionic currents by drugs Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K17 - K22. [Abstract] [PDF]
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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]
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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]
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C. Antzelevitch Transmural dispersion of repolarization and the T wave Cardiovasc Res, June 1, 2001; 50(3): 426 - 431. [Full Text] [PDF]
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P. Chevalier, C. Rodriguez, L. Bontemps, M. Miquel, G. Kirkorian, R. Rousson, F. Potet, J.-J. Schott, I. Baro, and P. Touboul Non-invasive testing of acquired long QT syndrome: Evidence for multiple arrhythmogenic substrates Cardiovasc Res, May 1, 2001; 50(2): 386 - 398. [Abstract] [Full Text] [PDF]
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P.-S. Chen, L. S Chen, J.-M. Cao, B. Sharifi, H. S Karagueuzian, and M. C Fishbein Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 409 - 416. [Abstract] [Full Text] [PDF]
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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]
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W. Han, Z. Wang, and S. Nattel Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1075 - H1080. [Abstract] [Full Text] [PDF]
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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]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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C.-M. Chang, T.-J. Wu, S. Zhou, R. N. Doshi, M.-H. Lee, T. Ohara, M. C. Fishbein, H. S. Karagueuzian, P.-S. Chen, and L. S. Chen Nerve Sprouting and Sympathetic Hyperinnervation in a Canine Model of Atrial Fibrillation Produced by Prolonged Right Atrial Pacing Circulation, January 2, 2001; 103(1): 22 - 25. [Abstract] [Full Text] [PDF]
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P. J. Schwartz, S. G. Priori, C. Spazzolini, A. J. Moss, G. M. Vincent, C. Napolitano, I. Denjoy, P. Guicheney, G. Breithardt, M. T. Keating, et al. Genotype-Phenotype Correlation in the Long-QT Syndrome : Gene-Specific Triggers for Life-Threatening Arrhythmias Circulation, January 2, 2001; 103(1): 89 - 95. [Abstract] [Full Text] [PDF]
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S. G. Priori, R. Bloise, and L. Crotti The long QT syndrome Europace, January 1, 2001; 3(1): 16 - 27. [PDF]
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L. Zhang, K. W. Timothy, G. M. Vincent, M. H. Lehmann, J. Fox, L. C. Giuli, J. Shen, I. Splawski, S. G. Priori, S. J. Compton, et al. Spectrum of ST-T-Wave Patterns and Repolarization Parameters in Congenital Long-QT Syndrome : ECG Findings Identify Genotypes Circulation, December 5, 2000; 102(23): 2849 - 2855. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Electrical Heterogeneity, Cardiac Arrhythmias, and the Sodium Channel Circ. Res., November 24, 2000; 87(11): 964 - 965. [Full Text] [PDF]
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J. Merot, V. Probst, M. Debailleul, U. Gerlach, N. S. Moise, H. Le Marec, and F. Charpentier Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: abnormal response to potassium channel blockers J. Am. Coll. Cardiol., September 1, 2000; 36(3): 939 - 947. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Effects of a K+ Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome Circulation, August 8, 2000; 102(6): 706 - 712. [Abstract] [Full Text] [PDF]
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W Haverkamp, G Breithardt, A.J Camm, M.J Janse, M.R Rosen, C Antzelevitch, D Escande, M Franz, M Malik, A Moss, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology Eur. Heart J., August 1, 2000; 21(15): 1216 - 1231. [PDF]
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W. Haverkamp, G. Breithardt, A.J. Camm, M. J Janse, M. R Rosen, C. Antzelevitch, D. Escande, M. Franz, M. Malik, A. Moss, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications: Report on a Policy Conference of the European Society of Cardiology Cardiovasc Res, August 1, 2000; 47(2): 219 - 233. [Full Text] [PDF]
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C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]
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P. G.A. Volders, M. A. Vos, B. Szabo, K. R. Sipido, S.H.M. de Groot, A. P.M. Gorgels, H. J.J. Wellens, and R. Lazzara Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts Cardiovasc Res, June 1, 2000; 46(3): 376 - 392. [Full Text] [PDF]
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P. C. Viswanathan and Y. Rudy Cellular Arrhythmogenic Effects of Congenital and Acquired Long-QT Syndrome in the Heterogeneous Myocardium Circulation, March 14, 2000; 101(10): 1192 - 1198. [Abstract] [Full Text] [PDF]
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L. C. Baker, B. London, B.-R. Choi, G. Koren, and G. Salama Enhanced Dispersion of Repolarization and Refractoriness in Transgenic Mouse Hearts Promotes Reentrant Ventricular Tachycardia Circ. Res., March 3, 2000; 86(4): 396 - 407. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome J. Am. Coll. Cardiol., March 1, 2000; 35(3): 778 - 786. [Abstract] [Full Text] [PDF]
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A. Varro, B. Balati, N. Iost, J. Takacs, L. Virag, D. A Lathrop, L. Csaba, L. Talosi, and J. G. Papp The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization J. Physiol., February 15, 2000; 523(1): 67 - 81. [Abstract] [Full Text] [PDF]
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P. G. A. Volders, K. R. Sipido, M. A. Vos, R. L. H. M. G. Spatjens, J. D. M. Leunissen, E. Carmeliet, and H. J. J. Wellens Downregulation of Delayed Rectifier K+ Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes Circulation, December 14, 1999; 100(24): 2455 - 2461. [Abstract] [Full Text] [PDF]
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A. Bauer, R. Becker, K. D. Freigang, J. C. Senges, F. Voss, A. Hansen, M. Muller, H. J. Lang, U. Gerlach, A. Busch, et al. Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New IKs-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart Circulation, November 23, 1999; 100(21): 2184 - 2190. [Abstract] [Full Text] [PDF]
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J. J. Lynch Jr, M. S. Houle, G. L. Stump, A. A. Wallace, D. B. Gilberto, H. Jahansouz, G. R. Smith, A. J. Tebben, N. J. Liverton, H. G. Selnick, et al. Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current, IKs, in Canine Models of Malignant Ischemic Ventricular Arrhythmia Circulation, November 2, 1999; 100(18): 1917 - 1922. [Abstract] [Full Text] [PDF]
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N. S. Moise, C. Antzelevitch, and W. Shimizu As Americans, We Should Get This Right • Response Circulation, September 28, 1999; 100(13): 1462 - 1462. [Full Text] [PDF]
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Gene-specific lethality of arrhythmic events in the long QT syndrome? A message from the International Registry Eur. Heart J., August 2, 1999; 20(16): 1137 - 1139. [PDF]
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A. Busjahn, H. Knoblauch, H.-D. Faulhaber, T. Boeckel, M. Rosenthal, R. Uhlmann, M. Hoehe, H. Schuster, and F. C. Luft QT Interval Is Linked to 2 Long-QT Syndrome Loci in Normal Subjects Circulation, June 22, 1999; 99(24): 3161 - 3164. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Cellular and Ionic Basis for T-Wave Alternans Under Long-QT Conditions Circulation, March 23, 1999; 99(11): 1499 - 1507. [Abstract] [Full Text] [PDF]
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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]
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