(Circulation. 2000;101:1192.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Cellular Arrhythmogenic Effects of Congenital and Acquired Long-QT Syndrome in the Heterogeneous Myocardium
From the Cardiac Bioelectricity Research and Training Center, Department of Physiology and Biophysics (P.C.V., Y.R.), and the Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio.
Correspondence to Yoram Rudy, PhD, Cardiac Bioelectricity Research and Training Center, 505 Wickenden Bldg, Case Western Reserve University, Cleveland, OH 44106-7207. E-mail yxr{at}po.cwru.edu
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Abstract |
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Background—Certain alterations by mutations or drugs of the potassium currents IKs and IKr and the sodium current INa give rise to several types of the long-QT syndrome. IKs is heterogeneously distributed across the ventricular wall.
Methods and Results—We investigated the effects of reducing IKs or IKr or enhancing late INa (to simulate the 3 forms of long-QT syndrome) on action potential duration (APD) in the context of IKs heterogeneity. We introduced IKs heterogeneity in the Luo-Rudy dynamic cell model to simulate epicardial, endocardial, and midmyocardial (M) cells. Results demonstrated higher susceptibility of M cells to the development of arrhythmogenic early afterdepolarizations (EADs) in isolated cells and poorly coupled tissue. An important observation is that IKr block or late INa acts to increase APD differences between the cell types, whereas IKs block minimizes such differences. Also, for normal transverse coupling, EADs develop in the endocardial region rather than in the M region as the result of strong electrotonic interaction.
Conclusions—IKs heterogeneity and intercellular coupling strongly influence EAD development during interventions or disorders that prolong APD. M cells in isolation or in poorly coupled tissue are more susceptible to EAD development than epicardial or endocardial cells. In well-coupled myocardium, EAD formation in the subendocardium can be the source of focal arrhythmias or provide the trigger for reentrant excitation. The efficacy of IKs block in minimizing APD dispersion could have important implications for antiarrhythmic therapy.
Key Words: action potentials • cells • long-QT syndrome • arrhythmia
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Introduction |
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Asubpopulation of cells (midmyocardial [M] cells) has been described1 2 in the ventricular wall. These cells display a longer action potential duration (APD) and a steeper dependence of APD on rate than epicardial or endocardial cells. M cells display greater responsiveness to interventions that prolong APD (eg, agents with class III antiarrhythmic action) and a higher susceptibility to the development of arrhythmogenic early afterdepolarizations (EADs).3 These properties suggest that M cells play an important role in arrhythmias associated with abnormal repolarization such as the congenital or acquired long-QT syndrome (LQTS). We recently showed that differences in IKs:IKr density ratios result in heterogeneity of the repolarization properties of cells.4 A smaller density of IKs results in longer APD and its greater prolongation with slowing of rate, an experimentally observed behavior typical of M cells.5
The density of functional channels can be altered by disease, as occurs in the congenital LQTS, in which mutations in the genes that encode IKs (KvLQT1 or MinK) or IKr (HERG) act through a dominant negative mechanism to cause a loss of function of IKs (LQT1) or IKr (LQT2), thereby slowing action potential repolarization. LQT3 involves mutations in the SCN5A gene that cause incomplete inactivation of INa and a persistent inward current that prolongs APD. Prolonged repolarization also can be acquired. Methanesulfonanilides (E-4031) block IKr and chromanol 293B blocks IKs, whereas the neurotoxin anthopleurin A slows INa inactivation, resulting in a sustained inward current during the action potential (AP) plateau. All these interventions prolong APD.
The different IKs:IKr density ratios in different cell types and the fact that these currents are affected in the LQTS and by antiarrhythmic agents necessitates characterization of the cellular responses to such pathologies and interventions. In this study we used theoretical models of isolated cells and multicellular fibers to investigate the effects of heterogeneities of IKs on steady-state APD and EAD formation during prolonged repolarization caused by the different LQTS types or antiarrhythmic agents that block IKr or IKs.
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Methods |
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The theoretical Luo-Rudy model of a mammalian ventricular action potential provides the basis for the simulations in this study (Figure 1
). The
action potential is numerically reconstructed from ionic processes that
are formulated on the basis of experimental data obtained mostly from
the guinea pig. The model also accounts for processes that regulate
dynamic concentration changes of Na+,
K+, and Ca2+. References 6
and 76 7 provide a detailed description of the cell model and a list of
equations governing its behavior. The 3 different cell types
(epicardial, midmyocardial, and endocardial) are formulated by altering
IKs density while keeping
IKr density constant.4
Heterogeneity of IKs
density is introduced by altering its maximum conductance,
ks.
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Acquired and Congenital Long-QT Syndrome
Evidence suggests that congenital long-QT syndromes (LQTS)
LQT1 and LQT2 involve reduction in the density of functional
IKs or IKr
channels, respectively, through a dominant negative mechanism.
Acquired LQTS results from drugs that prolong action potential
duration (APD) by blocking IKs or
IKr. In our studies we reduced the maximum
conductance of IKs or
IKr to represent the effects of the
congenital or acquired LQTS. We simulated LQT3 by altering the
steady-state inactivation of the h (fast) and j (slow) inactivation
gates of INa.8 This results in a
persistent late current that is 0.2% of peak
INa during a voltage clamp protocol (step
from -120 to -30 mV). The overall behavior of the current is in good
agreement with whole cell recordings of mutant
INa channels.9 10 11
Protocols
Cells were paced for 5 minutes at each cycle length (CL) to
reach steady state. The effects of drugs were simulated by reducing
IKs or IKr at
steady state. Results are reported for CL=300 ms (rapid pacing) and
CL=2000 ms (slow pacing). These CLs are in the range of clinically
observed heart rates. APD was measured from stimulus onset to 90%
repolarization (APD90). Simulations were
performed for 37°C.
1D Fiber
The theoretical fiber12 (Figure 1B
) is
composed of 190 Luo-Rudy cells. It contains an endocardial region
(cells 1 to 80), M-cell region (81 to 110), and epicardial region (111
to 190). Gap-junction conductance (gj) is
homogeneous throughout the fiber and for different
simulations varies from 2.5 µS (normal longitudinal coupling) to
0.025 µS (poor coupling). A stimulus is applied to cell 1 to simulate
normal endocardial to epicardial activation. Pacing studies were
conducted by stimulating cell 1 at CL=300 ms (3.3 Hz) or 2000 ms (0.5
Hz) for 90 seconds.
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Results |
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Reduction of IKr or Presence of Late INa Enhances APD Differences Between Isolated Cells of the Different Types. Reduction of IKs Eliminates Such Differences
Figure 2
shows the effects of
IKs or IKr
block, simulating the effects of congenital or acquired LQT1 and LQT2,
respectively, on APD during rapid pacing.
IKr block prolongs M-cell APD more than
that of epicardial or endocardial cells. In contrast,
IKs block has a smaller effect on the M
cell than on the other cell types. At a cycle length (CL)=300 ms, 100%
IKr block prolongs APD by 20%, 36%, and
25% in epicardial cells, M cells, and endocardial cells, respectively,
whereas 100% IKs block prolongs the
respective APDs by 43%, 26%, and 37%. Figure 3 shows the effect of persistent
INa on APD of the 3 cell types at CL=300
ms. Late INa prolongs APD of the M cell
much more than that of the other cell types. APD prolongation is 17%,
35%, and 22% in epicardial cells, M cells, and endocardial cells,
respectively. An important observation from Figures 2 and 3 is that IKr block and late
INa act to increase APD differences between
the cell types. In contrast, IKs block acts
to reduce such APD differences. Figure 4
shows APDs from the 3 cell types during different interventions
(complete IKs block, complete
IKr block, and in presence of late
INa) at CL=300 ms.
IKs block decreases 
APD
(APDM-APDEpi), whereas
IKr block or presence of late
INa increases APD. In the absence of
intervention, APD=27 ms. IKr block or
late INa increases APD to 53 or 55 ms,
respectively; IKs block reduces APD to
17 ms.
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Figure 5 shows the effect of 50%
IKr or IKs
block and Figure 6 shows the effect of
late INa on APD during slow pacing (CL=2000
ms). A 50% IKr block causes EAD
development in the M cell only, whereas 50%
IKs block fails to produce EADs even in
these cells. A higher degree of IKs block
results in EAD development in all 3 cell types (data not shown). The
degree of IKs block required to develop
EADs in endocardial cells, M cells, and epicardial cells is 85%, 64%,
and 90%, respectively. Late INa also
results in EADs in the M cell but not in other cell types. These
results demonstrate the higher susceptibility of M cells to the
development of arrhythmogenic EADs as a consequence of processes
(congenital or interventional) that reduce
IKr or IKs or
enhance late INa.
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Effect of Gap-Junction Coupling on APD and Development of
EADs
In the previous section we focused on the effects of
IKs and IKr
reduction and of late INa on APD and the
development of EADs in isolated cells. In the intact heart, cells are
coupled through gap junctions and are subject to electrotonic
interactions. In this section, we study the effects of intercellular
coupling on the development of EADs during simulated LQTS.
Figure 7 shows APs (aligned for
comparison) from the middle of each region of the multicellular fiber
for CL=300 ms and gap-junctional conductance
gj=0.43 µS (corresponding to velocity of 30
cm/s, typical of transmural propagation transverse to fibers). During
control conditions, M-cell APD is longest (panel A), and the difference
in APD between M and epi cells
(APD=APDM-APDEpi) is
20 ms. APD at CL=2000 ms is 30 ms (not shown). This suggests that
baseline level of APD differences exists in the normal
myocardium. On block of IKs
(panel B), APD differences are greatly reduced. For 100%
IKs block, APD decreases to 6 ms. In
contrast, complete IKr block (panel C) or
late INa (panel D) increases APD from 20
to 32 or 33 ms, respectively. This behavior is similar to that observed
in isolated cells (Figure 6) in which
IKr block and late
INa enhanced the differences of APD between
cell types, whereas IKs block eliminated
it.
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Figure 8 shows APD along the
multicellular fiber for longitudinal coupling (panel A,
gj=2.5 µS, conduction velocity of 56 cm/s) and
for transverse coupling as in Figure 7 (panel B,
gj=0.43 µS). A 100%
IKr block or late
INa increases APD in the M region
preferentially, thereby increasing APD differences between M and
epicardial or endocardial cells (compared with control). A 100%
IKs block, on the other hand, decreases APD
differences between M cells and other cell types.
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The above studies were conducted at a short CL of 300 ms. At this rate,
APDs were significantly shorter than during slower pacing. At this fast
rate, EADs did not develop during complete block of either
IKr or IKs even
during extreme gap-junctional uncoupling. Figure 9 shows APs of the middle cell from each
region of the fiber for CL=2000 ms with gap-junctional coupling of 0.43
µS (panel A) or 0.025 µS (corresponding to a slow velocity of 3.5
cm/s, observed during pathological conditions such as infarction). For
the normal transverse coupling (gj=0.43 µS),
85% reduction of IKs results in the
appearance of an EAD in the endocardial cell and not in the M cell, in
contrast to the single cell behavior in which EADs developed in the M
cell (Figure 5 and 6 and corresponding text). However, a
similar degree of IKs block on the
background of pathologically reduced intercellular coupling resulted in
the development of EADs in the M region (Figure 9B) similar to
the isolated cell behavior. We also conducted simulations in which the
pacing stimulus was applied epicardially or in the M region (not
shown). In all cases, EADs develop in the endocardial region for 85%
IKs block when intercellular coupling is
normal. This phenomenon highlights the importance of electrotonic
influences in modulating the behavior of different cell types. During
normal coupling, the epicardial region acts as a sink for axial current
from the M region because of its shorter APD and earlier repolarization
than that of the other regions. Note the existence of a large potential
gradient between cells in the M and epicardial regions during the
plateau and phase 3 of the AP (Figure 9A). This causes
shortening of M-cell APD as axial current is lost to the epicardial
region. Shortening of the APD prevents EAD development in the M
region.
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Discussion |
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We have demonstrated4 that changes in IKs:IKr density ratios can explain heterogeneity of the repolarization properties of cells in the ventricular myocardium. Consistent with the experimentally observed behavior,1 2 simulated M cells could be distinguished from epicardial and endocardial cells by their longer APD and greater APD prolongation with slowing of stimulation rate. In this study, we have investigated the rate-dependent effects of reduced IKr or IKs or the presence of late INa to mimic the 3 forms of the LQTS and to simulate the effects of drugs with class III antiarrhythmic action. Effects on APD and the development of EADs were considered in isolated cells and in a multicellular fiber with varying degrees of gap-junctional coupling. Important findings of this study include the following: (1) At fast pacing, IKr block and late INa prolong APD of isolated M cells more than that of isolated epicardial or endocardial cells. In contrast, IKs block prolongs APD of M cells less than that of the other cell types. (2) Greater prolongation of M-cell APD by IKr block or late INa augments APD differences between the different cell types. In contrast, smaller prolongation of M-cell APD by IKs block acts to minimize such APD differences. (3) At slow pacing, M cells are highly susceptible to the development of plateau EADs upon IKr block or presence of late INa. A higher degree of IKs block is necessary for EAD development in the M cells. (4) When cells are electrotonically coupled through gap junctions, IKr block or late INa enhances APD dispersion along the fiber during rapid pacing. In contrast, IKs block reduces APD dispersion, similar to the behavior observed in isolated cells. (5) At slow pacing and when cells are well coupled, IKs block results in the appearance of EADs in the endocardial region. However, in the presence of reduced coupling, EADs develop in the M region.
Heterogeneity of APD and the resulting dispersion of
repolarization provide a substrate for unidirectional block and
reentry. This study demonstrates that at rapid rates,
IKr block or late
INa enhances APD differences between
different cell types not only in isolated cells (Figure 6) but
also in the multicellular tissue (Figures 7 and 8). This
is due to the greater effect of these interventions in prolonging the
APD of M cells than epicardial or endocardial cells.
IKr block or late
INa prolongs APD of the M cell most because
of its smaller total repolarizing current (caused by a smaller
IKs). Both these interventions have a
similar effect on M cells because these currents are uniformly
distributed in all cell types. In contrast,
IKs block prolongs the APD of M cells less
than that of epicardial or endocardial cells because of the smaller
density of IKs in the M cells. This
theoretical observation is consistent with experimental
observations by Shimizu and Antzelevitch,13 who
showed that the percentage of APD prolongation in epicardium or
endocardium is greater than in the M cell upon application of chromanol
293B, a selective IKs blocker. This tends
to minimize APD differences between the 3 cell types. It is therefore
observed that IKr block or late
INa increases APD differences and
dispersion, thereby creating a substrate for the development of
unidirectional block and reentry, whereas
IKs block tends to minimize APD differences
and eliminate dispersion.
During slow pacing, IKr or IKs block and late INa result in preferential EAD development in isolated M cells similar to experimental observations. A 50% IKr block was sufficient to cause EADs in the M cell, whereas EADs did not develop in epicardial or endocardial cells, even for complete IKr block. A higher percentage of IKs block (64%) was necessary to cause EADs in the M cell. In a multicellular fiber, EADs developed in the M region under conditions of reduced gap-junctional coupling. For example, when gj=0.025 µS, EADs developed in the M region, which in turn prolonged APD and greatly enhanced APD dispersion. The higher likelihood of EADs in the M region suggests that M cells could become a source of triggered activity and focal arrhythmias3 when gap-junctional coupling is reduced. On the background of enhanced APD dispersion caused by greater APD prolongation in the M region, such EADs can provide the triggering event for the development of reentry.
Surprisingly, when cells are well coupled (gj=0.43 µS), endocardial cells are more susceptible to APD prolongation and EAD development than M cells, which suggests their involvement in EAD-related arrhythmias. This behavior is consistent with experimental findings demonstrating that focal activity (possibly caused by EADs) in the subendocardium generates the initial beat of polymorphic tachycardias in the LQTS14 or in ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy.15 Purkinje fibers are also known to be highly susceptible to interventions that prolong APD. It is possible that EADs generated in Purkinje fibers play an important role in these arrhythmias. The results of this study demonstrate the possibility that EADs in endocardial cells can also provide the trigger for ventricular arrhythmias associated with abnormal repolarization.
An important mechanistic observation is that in all cases (single cell or multicellular fiber), EAD depolarization is due to recovery from inactivation and reactivation of the L-type calcium channel current, ICa(L), as we have shown previously.16 Prolongation of the AP to provide sufficient time for ICa(L) recovery is achieved in a nonspecific manner. In LQT1 and LQT2 it is achieved by reduction of outward repolarizing currents IKs or IKr, respectively. In LQT3 it is achieved by an increase of an inward depolarizing current, late INa. In a related study8 we showed that pause-induced EADs in the 3 types of LQTS also involve recovery and reactivation of ICa(L) during a prolonged AP plateau. These observations suggest a universal mechanism for EAD formation at plateau potentials, namely ICa(L) reactivation, whereas prolongation of the plateau that is necessary for ICa(L) recovery does not involve a specific mechanism, and its underlying ionic current is different in the different types of LQTS.
Conclusions and Implications for Antiarrhythmic Therapy
Electrophysiological
heterogeneity is an important property of the
myocardium that must be considered in the determination of
arrhythmogenic mechanisms and the administration of antiarrhythmic drug
therapy. Results from the multicellular fiber suggest that APD
dispersion in the myocardium is greatly influenced by the
degree of gap-junctional coupling and the type of intervention that
prolongs APD. Substantial APD differences can exist in the
myocardium when intercellular coupling is reduced, even in
the absence of ion channel modification by drugs or disease.
Conversely, the higher susceptibility of M cells to pathologies and
interventions that prolong APD suggests that large APD dispersions can
arise even in the normally coupled myocardium. A
combination of reduced cellular coupling and enhanced cellular
heterogeneity can result in extreme levels of APD
dispersion, setting the stage for unidirectional block and reentry.
Such a situation can arise when an antiarrhythmic drug that prolongs
APD is administered in an aging or infarcted heart in which
intercellular coupling is reduced. Studies (for review see Reference
1717 ) have shown that antiarrhythmic drugs could become proarrhythmic
when the substrate is altered by ischemia or infarction.
Similar changes can occur during
electrophysiological remodeling caused by
various pathologies (eg, hypertrophic or dilated
cardiomyopathy) or as a result of the fast rates
associated with the arrhythmia itself (as can occur during
atrial flutter and fibrillation).18 Our results show that
drugs that prolong APD by blocking IKr
aggravate APD dispersion in the presence of reduced cellular coupling.
Recent studies19 20 showed changes in the
distribution and concentration of the gap-junctional protein connexin
43 during acute ischemia and infarction. It is likely that
heterogeneity of gap junction distribution acts
synergistically with ion channel heterogeneity to
aggravate APD dispersion and EAD formation during administration of
drugs that prolong APD or in the presence of disease that prolongs
repolarization (eg, LQTS). A striking result of our simulations is that
IKs block minimized APD dispersion even in
the presence of reduced cellular coupling. This is a very important
observation because it could be a beneficial antiarrhythmic property
that is not shared by drugs that block
IKr.
Limitations of the Study
The role of gap-junctional coupling in APD
heterogeneity and EAD formation during prolonged
repolarization was studied in a 1D fiber. This is a simplified model
that allowed us to investigate this phenomenon at the cellular and
ionic channel levels. Moreover, propagation that can be simulated in a
1-D model occurs frequently in the 3D heart when broad-plane waves are
generated. Importantly, this is the situation during normal sinus
rhythm in which planar waves created by the Purkinje network propagate
from endocardium to epicardium. A similar situation occurs in the wedge
preparation used extensively21 to study myocardial
heterogeneity. It should be emphasized that local
dispersion on a cellular scale is involved in the generation of
unidirectional block and reentry. Even in the presence of complex 3D
global wave fronts, local excitation can be 1D in nature. This is
particularly true in the presence of pathological structural
complexities such as narrow fibers connecting islands of surviving
tissue in an infarct.
Clinically, LQT3 is usually associated with arrhythmias occurring at slow heart rates (during sleep), whereas arrhythmias in LQT1 often occur during exercise and/or excitement.22 It is likely that these different scenarios reflect different levels of sympathetic activity. A possible explanation for this behavior is that in LQT3, prolongation of APD is greater at slow rates, when the mutant late INa is opposed by a smaller repolarizing current as the result of greater deactivation of IKs between APs. In the case of LQT1, the mutation results in reduced IKs. Sympathetic activity augments both IKs and ICa(L), in addition to other effects on calcium cycling, INa and the Na/K pump. The net effect on APD depends on the balance between IKs reduction by the mutation and the enhancement of IKs and ICa(L) by ß-adrenergic stimulation. This effect is likely to be nonuniform because of the heterogeneous distribution of IKs in the myocardium, thereby increasing dispersion of repolarization and enhancing arrhythmogenesis. The multifactorial cellular effects of ß-adrenergic stimulation can be simulated in the Luo-Rudy model.16 Their interactions with the different types of LQTS are complex and require extensive simulation protocols that are outside the scope of this study.
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Acknowledgments |
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This study was supported by National Institutes of Health–National Heart, Lung, and Blood Institute grants R01-HL-49054 and R37-HL-33343 (to Dr Rudy) and by a Development Award from the Whitaker Foundation.
Received June 14, 1999; revision received September 2, 1999; accepted September 23, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle: the M cell. Circ Res. 1991;68:1729–1741.
2. Drouin E, Charpentier F, Gauthier C, Laurent K, Le Marec H. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells. J Am Coll Cardiol. 1995;26:185–192.[Abstract]
3. Sicouri S, Antzelevitch C. Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cells (M cells) in the canine heart: quinidine and digitalis. J Cardiovasc Electrophysiol. 1993;4:48–58.[Medline] [Order article via Infotrieve]
4.
Viswanathan PC, Shaw RM, Rudy Y. Effects of
IKr and IKs
heterogeneity on action potential duration and its
rate-dependence: a simulation study. Circulation. 1999;99:2466–2474.
5.
Liu DW, Antzelevitch C. Characteristics of the delayed
rectifier current (IKr and
IKs) in canine ventricular
epicardial, midmyocardial and endocardial myocytes: a weaker
IKs contributes to the longer action potential of
the M cell. Circ Res. 1995;76:351–365.
6.
Luo CH, Rudy Y. A dynamic model of the cardiac
ventricular action potential, I: simulations of ionic
currents and concentration changes. Circ Res. 1994;74:1071–1096.
7.
Zeng J, Laurita KR, Rosenbaum DS, Rudy Y. Two
components of the delayed rectifier K+ current in
ventricular myocytes of the guinea pig type: theoretical
formulation and their role in repolarization. Circ Res. 1995;77:140–152.
8.
Viswanathan PC, Rudy Y. Pause induced early
afterdepolarizations in the long QT syndrome: a simulation study.
Cardiovasc Res. 1999;42:530–542.
9. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376:683–685.[Medline] [Order article via Infotrieve]
10. Chandra R, Starmer F, Grant AO. Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells. Am J Physiol. 1998;274:H1643–H1654.
11. Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature. 1999;400:566–569.[Medline] [Order article via Infotrieve]
12.
Shaw RM, Rudy Y. Ionic mechanisms of propagation in
cardiac tissue: roles of the sodium and L-type calcium currents during
reduced excitability and decreased gap junction coupling. Circ
Res. 1997;81:727–741.
13.
Shimizu W, Antzelevitch C. 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. Circulation. 1998;98:2314–2322.
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.
Pogwizd SM, McKenzie JP, Cain ME. Mechanisms underlying
spontaneous and induced ventricular arrhythmias in
patients with idiopathic dilated cardiomyopathy.
Circulation. 1998;98:2404–2414.
16. Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J. 1995;68:949–964.[Medline] [Order article via Infotrieve]
17.
Zipes DP, Wellens HJJ. Sudden cardiac death.
Circulation.. 1998;98:2334–2351. Review (no abstract
available).
18.
Tieleman RG, Van Gelder IC, Crijns HJ, De Kam PJ, Van
Der Berg MP, Haaksma J, Van Der Woude HJ, Allessie MA. Early
recurrences of atrial fibrillation after electrical
cardioversion: a result of fibrillation-induced electrical remodeling
of the atria? J Am Coll Cardiol. 1998;31:167–173.
19. Huang XD, Sandusky GE, Zipes DP. Heterogeneous loss of connexin43 protein in ischemic dog hearts. J Cardiovasc Electrophysiol. 1999;10:79–91.[Medline] [Order article via Infotrieve]
20.
Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed
connexin43 gap junction distribution correlates with the location of
reentrant circuits in the epicardial border zone of healing canine
infarcts that cause ventricular tachycardia.
Circulation. 1997;95:988–996.
21.
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.
22.
Priori SG, Barhanin J, Hauer RNW, Haverkamp W, Jongsma
HJ, Kleber AG, McKenna WJ, Roden DM, Rudy Y, Schwartz K, Schwartz PJ,
Towbin JA, Wilde AAM. Genetic and molecular basis of cardiac
arrhythmias: impact on clinical management parts I and II.
Circulation. 1999;99:518–528. Review.
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 K. Liu, T. Yang, P. C. Viswanathan, and D. M. Roden New Mechanism Contributing to Drug-Induced Arrhythmia: Rescue of a Misprocessed LQT3 Mutant Circulation, November 22, 2005; 112(21): 3239 - 3246. [Abstract] [Full Text] [PDF]
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 D. E. Gutstein, S. B. Danik, S. Lewitton, D. France, F. Liu, F. L. Chen, J. Zhang, N. Ghodsi, G. E. Morley, and G. I. Fishman Focal gap junction uncoupling and spontaneous ventricular ectopy Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1091 - H1098. [Abstract] [Full Text] [PDF]
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D. Xing, A. L. Kjolbye, J. S. Petersen, and J. B. Martins Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H511 - H516. [Abstract] [Full Text] [PDF]
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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]
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 D. Stilli, R. Berni, L. Bocchi, M. Zaniboni, F. Cacciani, A. Sgoifo, and E. Musso Vulnerability to ventricular arrhthmias and heterogeneity of action potential duration in normal rats Exp Physiol, July 1, 2004; 89(4): 387 - 396. [Abstract] [Full Text] [PDF]
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 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]
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 P. D. Booker, S. D. Whyte, and E. J. Ladusans Long QT syndrome and anaesthesia Br. J. Anaesth., March 1, 2003; 90(3): 349 - 366. [Abstract] [Full Text] [PDF]
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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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K. H. W. J. Ten Tusscher and A. V. Panfilov Reentry in heterogeneous cardiac tissue described by the Luo-Rudy ventricular action potential model Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H542 - H548. [Abstract] [Full Text] [PDF]
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X. Xu, J. J. Salata, J. Wang, Y. Wu, G.-X. Yan, T. Liu, R. A. Marinchak, and P. R. Kowey Increasing IKs corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H664 - H670. [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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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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R. N. Ghanem, J. E. Burnes, A. L. Waldo, and Y. Rudy Imaging Dispersion of Myocardial Repolarization, II: Noninvasive Reconstruction of Epicardial Measures Circulation, September 11, 2001; 104(11): 1306 - 1312. [Abstract] [Full Text] [PDF]
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 Y. Rudy Multiple interactions determine cellular electrical processes in the multicellular tissue Cardiovasc Res, July 1, 2001; 51(1): 1 - 3. [Full Text] [PDF]
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C. E. Clancy and Y. Rudy Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 301 - 313. [Abstract] [Full Text] [PDF]
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 U. C. Hoppe, E. Marban, and D. C. Johns Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1 PNAS, April 24, 2001; 98(9): 5335 - 5340. [Abstract] [Full Text] [PDF]
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L. M. Hondeghem, L. Carlsson, and G. Duker Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic Circulation, April 17, 2001; 103(15): 2004 - 2013. [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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D. E. Gutstein, G. E. Morley, H. Tamaddon, D. Vaidya, M. D. Schneider, J. Chen, K. R. Chien, H. Stuhlmann, and G. I. Fishman Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 Circ. Res., February 16, 2001; 88(3): 333 - 339. [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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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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