(Circulation. 2000;102:584.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel 
-Subunit
A Computational Analysis
From the Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY, and the Heiden Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel (J.B.). Drs Wehrens, Abriel, and Cabo contributed equally to this work.
Correspondence to R.S. Kass, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032. E-mail rsk20{at}columbia.edu
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Abstract |
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Background—D1790G, a mutation of SCN5A, the gene that encodes the human Na+ channel
-subunit, is linked to 1 form of the congenital long-QT
syndrome (LQT-3). In contrast to other LQT-3–linked
SCN5A mutations, D1790G does not promote sustained
Na+ channel activity but instead alters the kinetics and
voltage-dependence of the inactivated state. Methods and Results—We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na+ channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na+ channel activity prolong APs in a steeply heart rate–dependent manner not directly due to changes in Na+ entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents.
Conclusions—We conclude that the D1790G mutation of the
Na+ channel -subunit can prolong the cardiac
ventricular AP despite the absence of mutation-induced
sustained Na+ channel current. This prolongation is
calcium-dependent, is enhanced at slow heart rates, and at sufficiently
slow heart rate triggers arrhythmogenic early afterdepolarizations.
Key Words: sodium • calcium • arrhythmia • torsad de pointes • action potentials
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The congenital long-QT syndrome (LQTS) is an inherited cardiac disorder that is defined in part by prolonged ventricular repolarization, an association with recurrent syncope, a propensity to polymorphous ventricular tachycardia (torsade de pointes), and sudden death.1 2 Multiple genes that encode ion channel subunits have now been shown to be linked to LQTS,3 and in most cases, the functional properties of the mutant gene products are consistent with the disease phenotype, ie, increase of inward or decrease of outward plateau current.4 5
LQT-3 is linked to the gene encoding the -subunit of the cardiac
voltage-gated sodium channel (SCN5A on chromosome
3).6 Functional analysis of initially
reported SCN5A mutations revealed mutant
Na+ channels that fail to inactivate
completely on prolonged depolarization7 8 and produce
a small but functionally important enhancement of inward plateau
current sufficient to delay repolarization and increase vulnerability
of the heart to arrhythmias.9 All subsequently
reported LQT-3 mutations with the exception of D1790G (DG) promote
sustained Na+ current and are expected to prolong
repolarization through this common mechanism.9 10 11 12 13 14
The purpose of the present study was to use a computational approach to determine whether or not the biophysical properties of DG mutant Na+ channels might affect the cellular action potential (AP) through mechanisms other than a direct contribution to maintained Na+ channel plateau current. We modeled the cardiac ventricular AP using parameters and techniques described by Luo and Rudy15 as our control and modified only the properties of the voltage-gated Na+ channel according to our patch-clamp analysis of DG channels. Our results indicate that the DG mutation can prolong AP duration (APD) despite the absence of mutation-induced inward Na+ channel current during the plateau phase. Instead, the mutation indirectly affects other electrogenic pathways, which have a common interdependence on altered cellular calcium homeostasis. The computations predict DG mutation–induced AP prolongation, which is heart rate–dependent and driven by subsequent changes in the intracellular calcium transient. These results are important not only for the novel fundamental insight into the mechanistic basis of inherited arrhythmias but also because they suggest novel targets (ie, calcium-handling proteins) as therapeutic agents.
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Methods |
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Computer-Generated AP Reconstruction
The AP was calculated by solving the differential equation Iion=-Cm(dVm/dt), where Iion is the total transmembrane ionic current (µA/cm2), Cm is the specific capacitance of the membrane (1 µF/cm2), and Vm is the transmembrane potential (mV). All ionic currents were formulated according to the Luo-Rudy model15 of a ventricular AP, except that the sodium current was formulated to reproduce our patch-clamp experiments in HEK 293 cells. The differential equation was solved numerically with a discretization time step of 10 µs.
Experimental parameters used in the model were determined from experimental data for voltage-dependence of steady-state activation and inactivation and the kinetics of the onset and recovery from inactivation. Parameters for Boltzmann relationships and time constants were extracted as previously described.16 Rate constants were adjusted with temperature, assuming Q10 factors (the factor is usually between 2 and 3 for rate constants between different states in ionic channels).
To simulate wild-type (WT) channels, we used
m
=1/{1+exp[-(Vm+32.5)/9]}
and
h=1/{1+exp[(Vm+57.87)/7]}.
To simulate DG channels,
m=1/{1+exp[-(Vm+29)/10.5]}
and
h=1/{1+exp[(Vm+74.3)/6.5]}
were used. In the DG channels, the time constants of onset of
inactivation (
h) and the slow inactivation
gate (j) were half of those used in the WT
channels. The maximum sodium conductance was 27
mS/cm2. In all simulations, the maximum
conductance of the slow component of the delayed rectifier potassium
current, IKs, was reduced by 40% to
uncover AP differences between cells with WT and DG channels. These APs
thus simulate endocardial or M-cell activity.5 17 18 19 20
APs were initiated by intracellular 0.5-ms current pulses (100
µA/cm2). Initial conditions were established by
stimulating cells with WT and DG channels once per second for a
3-minute period. Then, cells were stimulated 20 times at a constant
cycle length. Cycle lengths between 500 and 4000 ms were used.
Expression of Recombinant Na+ Channels
Na+ channels were expressed in HEK 293
cells as previously described.11 Transfections were
carried out with equal amounts of Na+ channel
-subunit cDNA (WT or DG, respectively), with
hß1- and/or hß2-subunit
cDNA subcloned individually into the pcDNA3 (Invitrogen) vector (total
cDNA 2.5 µg). Control experiments (data not shown) indicated no
significant differences in channel activity for these subunit
combinations.
Electrophysiology
Membrane currents were measured with whole-cell patch-clamp
procedures21 with Axopatch 200B amplifiers (Axon
Instruments) as previously described.11 Unless noted
otherwise, recordings were made at room temperature (22°C)
with previously published solutions.11 Data acquisition
and analysis were carried out with pClamp7 (Axon Instruments),
Excel (Microsoft), and Origin (Microcal Software). Steady-state
inactivation was determined after application of 500-ms conditioning
pulses applied once every 2 seconds. Recovery from inactivation was
measured in paired pulse experiments, with a test pulse applied at
variable times after a 100-ms conditioning pulse to -10 mV.
Holding potentials were -80 mV.
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Results |
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Biophysical Properties of DG Mutant Channels: Computational Parameter Set
Figure 1
shows families of
experimental records of WT and DG mutant channels expressed in HEK
293 cells as well as analysis of the experimentally determined
voltage-dependence of the time constants of the onset of inactivation.
As illustrated in Figure 1A, we compared experimental
recordings of WT and DG channels at 22°C (top) and 29°C
(bottom). Clearly, increasing temperature speeds the kinetics of both
WT and DG mutant channels, as expected,22 but it neither
changes the relationship between WT and DG mutant channel time
constants nor promotes DG-induced sustained inward current. Figure 1B summarizes time constants obtained by fitting experimental
records with functions containing 1 exponential component. Although
in a limited number of experiments, we previously reported no effect of
the DG mutation on the kinetics of the onset of inactivation, in a more
complete analysis we have found that, in fact, this mutation
speeds the onset of inactivation (Figure 1) and slightly alters
the voltage-dependence of activation (Figure 3). Using these
data, we extrapolated the temperature coefficient
(Q10) of 2.1 for inactivation kinetics for both
WT and DG mutant channels to compute the effects of the mutation on APs
at physiological temperatures.
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) and DG (•) channels.
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Figure 2 shows the simulated changes in
Na+ channel currents and the time constants of
the onset of inactivation generated by the computer-based model. As is
the case for the experimental data, the simulated currents reflect the
speeding of the onset of inactivation as a function of membrane
potential but do not exhibit enhanced sustained current.
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Figure 3
illustrates experimental and
computational data showing the effects of the DG mutation on the
voltage-dependence of steady-state inactivation and activation and on
the time course of recovery from the inactivated state. The
mutation causes a marked negative shift of the voltage-dependence of
inactivation with relatively minor changes in the voltage-dependence of
activation, as we previously reported.11 The mutation also
causes a small but significant speeding of the recovery process. The
results obtained in experiments (A) were incorporated into the
simulated channels (B).
Simulation of Cellular Electrical Activity: AP Prolongation That Is
Heart Rate–Dependent
Figure 4 shows the consequences of
these mutation-induced changes in channel properties on cellular
electrical activity that is predicted by the computer-generated model.
At a basic cycle length (BCL) of 1000 ms, there is little effect of the
DG mutation despite a significant APD prolongation. At a BCL of 3000
ms, however, it causes dramatic APD prolongation, which results in the
generation of early afterdepolarizations (EADs). The results of similar
calculations repeated over a series of BCLs are summarized in Figure 5, in which APD is plotted versus BCL for
both WT and DG channels. The expression of mutant DG channels markedly
alters this relationship. Figure 5 shows that even at moderately
long BCLs (1000 to 2000 ms), the DG mutation prolongs APs compared with
cells expressing WT channels. This effect becomes very pronounced (note
change in vertical scale) as heart rate slows further, and at a BCL of
3000 ms, as illustrated above, the mutation-induced action prolongation
is sufficient to induce EADs (arrow). Similarly, the DG mutation
induces EADs after pauses in AP activity (Figure 6).
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Ionic Basis of DG Cellular Phenotype: A Role for
[Ca2+]i
Figures 7 and 8 show the effects of the DG mutation on
several key ionic pathways underlying the computed APs. These
computations reflect steady-state conditions during a BCL of 3000 ms,
but the patterns revealed are the same as those that occur in
DG-induced pause-dependent AP prolongation (data not shown). Figure 7 focuses on computed Na+ channel currents
and illustrates current during the AP plateau (A) as well as, on an
expanded time scale, during the upstroke (B). As predicted by the
voltage-clamp data, the DG mutation does not promote sustained inward
Na+ current that would account for AP
prolongation (A, lower row). In fact, the computations show that the
overall effect of this mutation is to reduce the contribution of
Na+ channel activity to the initial upstroke and
overshoot (arrow) of the AP.
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Figure 8 illustrates DG mutation–induced changes in other
pathways that occur during the duration of the AP. The computations
reveal an increase in Ca2+ influx through L-type
Ca2+ channels, an increase in the magnitude of
the transient change in
[Ca2+]i, changes in
Na+/Ca2+ exchange current,
and an initial reduction followed by prolonged activation of the slowly
activating K+ channel current,
IKs. The mechanisms underlying these
changes are discussed below.
DG-Induced Changes in [Ca2+]i Determine
Frequency-Dependent ADP Prolongation
Perhaps the most prominent feature of the DG cellular
phenotype predicted from these computations is the marked
dependence of APD on heart rate (Figure 5). Figure 9 shows marked DG mutation–induced
changes in the calcium transient that are steeply frequency-dependent.
At low stimulation frequencies (long BCLs), the calcium transient in
cells expressing DG Na+ channels is increased in
both amplitude and duration. At faster heart rates (BCLs on the order
of 1000 ms), there is little difference between calcium transients of
WT and DG-expressing cells (A). The computations thus suggest a complex
calcium-dependent pathway regulating APD that becomes altered, as
described above, by DG-induced changes in calcium entry. Because the
effects of these changes on the calcium transient are predicted to be
steeply frequency-dependent, the calculations suggest a strong
interdependence on the filling and subsequent emptying of intracellular
calcium stores in this process.
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Discussion |
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Sustained Na+ Channel Current Is Not Necessary to Prolong the Ventricular AP
The major finding reported in this study is the fact that biophysical properties of DG mutant Na+ channel
-subunits prolong computer-simulated ventricular APs,
even though this mutation does not promote sustained
Na+ channel current during the AP plateau phase.
This study thus extends our understanding of the molecular basis of the
disease phenotype, the prolonged QT intervals, and confirms the
importance of computational studies in bridging information relating
functional changes in individual ion channel subunits to predictions of
cellular and even system phenotypes.
The plateau phase of the cardiac ventricular AP is
maintained by a delicate balance between inward and outward movement of
ions, and even very small changes in ionic currents during the plateau
are expected to have marked effects on APD.4 23 The
functional properties of channels encoded by DG mutant -subunits
have defied interpretation within a framework that requires direct
mutation-dependent increase in Na+ channel
current during the AP plateau, because this mutation does not promote
sustained Na+ channel activity in the face of
cellular depolarization.11 Instead, the most prominent
characteristics of DG channels are a negative shift in channel
availability as a function of membrane potential and a speeding of the
kinetics of the onset of inactivation. However, our computations reveal
the importance of these biophysical changes in channel properties to
events that determine the duration of the AP and show that events that
occur during the initial 5 ms of the AP can have profound effects on
electrical activity that occurs during the following several hundred
milliseconds.
DG-Induced Decrease in Na+ Channel Activity Leads to an
Increase in the [Ca2+]i Transient
Figures 7, 8, and 9 provide insight into the
mechanism(s) by which the DG mutation delays AP repolarization. Because
of the changes in Na+ channel kinetics, fewer
channels are available for activation at the cellular resting
potential, and once opened, these channels inactivate
faster than WT channels. This results in a reduced
Na+ channel current, slower upstroke, and more
importantly, a less positive overshoot of the AP (Figure 7, arrow). The change in dV/dt and overshoot occurs during the very early
stages of ventricular depolarization, as seen in Figure 8, and in turn causes an increase of Ca2+
entry via L-type Ca2+ channels during this
crucial period of electrical activity. The primary mechanism underlying
this effect is not a change in gating parameters for
Ca2+ channel activation and inactivation,
but the effect of the DG mutation on the AP overshoot and subsequent
change in the driving force for Ca2+ entry via
L-type Ca2+ channels (not illustrated). With this
alteration in Ca2+ entry, the model predicts that
the subsequent Ca2+ transient will be altered in
both time and magnitude, and as a result, all
[Ca2+]i-dependent
processes will subsequently be altered (Figure 8). Two important
ionic pathways, the
Na+/Ca2+
exchanger24 and the slowly activating delayed
K+ channel current,
IKs,25 are affected
(Figure 8). The result is a net increase of inward plateau
current and corresponding increase in APD. The fundamental difference
between the generation of the cellular phenotype in the case of
the DG mutation compared with previously described LQT-3 mutations is
that the increase of inward current does not come from a direct
contribution of altered Na+ channel activity but
rather from other pathways.
The computations also reveal a critical role of
IKs in the DG-induced cellular
phenotype (Figure 8) as a result of the reduction in
this current that occurs as a consequence of mutation-induced changes
in Vm. Thus, although the disease-linked mutation
is in the SCN5A gene, the cellular phenotype is due
in part to changes in activity of channels encoded by LQT-1– and
LQT-5–linked genes.26 27
Relationship Between Cellular and Clinical Phenotypes
The work presented here is the result of incorporation of
biophysical properties of human WT and DG mutant
Na+ channels expressed in a mammalian cell line
into a computational model that integrates experimental data obtained
from a variety of cell types and species.15 Extrapolation
of these results to a precise understanding of human pathophysiology is
not possible and goes beyond the scope of this study. Qualitative, but
not quantitative, conclusions may be drawn from this work.
Nevertheless, comparison to appropriate clinical parameters
that have been measured for carriers of the DG mutation is important,
and in fact, a stringent test of the validity of the methodology.
The model suggests that under steady-state pacing conditions, the Na+ current is smaller in myocytes expressing DG mutant channels next to WT channels. This will most likely lead to a reduced rate of rise of the AP upstroke (dV/dt) as predicted for the cellular model, and this, in turn, would be expected to be reflected in a widening of the QRS complex on the ECG of mutation carriers. Indeed, DG carriers tend to have wider QRS complexes than control patients.28 The computational work clearly indicates that for this mutation, bradycardia will potentiate APD prolongation. It is interesting to note that heart rates of DG carriers have been found to be slower than those of noncarriers.10 In fact, in several members of the DG family that have been studied, sinus slowing and even arrest may have been as significant as APD prolongation. This raises the interesting and important question as to a causal relationship between pacing and the DG mutation, a question that certainly is beyond the scope of the present study.
Role of Ito in Modulating the Effect of
the DG Mutation on APD
In the computations that we have carried out and reported, we have
not included a contribution of the transient outward current
(Ito). We did, however, test for its
effects in calculations, which we have not illustrated. We find, as
might be expected, that if expressed at sufficiently high levels, this
current will tend to offset the effects of the DG mutation and modify
its influence on APD. Thus, cells expressing
Ito at the highest densities (epicardial
cells) would be expected to have substantially shorter APDs than cells
in which Ito is expressed at the lowest
densities (endocardial cells), because the additional contribution of
DG mutant channels would then follow the same anatomic
pattern.20 This pattern of channel expression would
thus be expected to favor enhanced T-wave dispersion,19
which, interestingly, is what is observed in carriers of the DG
mutation.28 Heterogeneity in the
expression of ion channel genes, no doubt, remains an important area of
investigation that will be needed to provide a causal link between
expression of specific gene mutations and generation of the systemic
disease phenotype.
Novel Therapeutic Strategies for LQT-3
Our analysis has revealed that beat-dependent changes in
intracellular calcium that occur as a consequence of the DG LQT-3
mutation should be considered major factors in generating the disease
phenotype (delayed ventricular repolarization) in
carriers of this gene defect. This work therefore strongly suggests
that a therapeutic strategy that includes inhibition of L-type calcium
channel activity may be beneficial for carriers of the DG gene
defect.
In summary, our computations show that the biophysical properties of DG mutant channels are sufficient to account for a cellular phenotype consistent with LQT-3: prolongation of the ventricular AP. This occurs despite the absence of mutation-induced sustained Na+ current. This finding not only is a necessary step in understanding the molecular basis of QT prolongation in carriers of the DG mutation but also raises the possibility that previously overlooked functional properties of other LQT-3 SCN5A mutations may also contribute to the disease phenotype and may require further investigation. Furthermore, our work suggests that novel therapeutic strategies may include modulation of calcium as well as sodium channel activity.
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Acknowledgments |
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This work was supported by US Public Health Service grant R01-HL-568105-02 (Dr Kass). Dr Abriel was supported the Swiss National Foundation for Fellowships in Medicine and Biology, Mr Wehrens by the Dutch foundation De Drie Lichten, and Dr Cabo in part by a research grant of the Whitaker Foundation.
Received December 31, 1999; revision received March 4, 2000; accepted March 8, 2000.
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 B. Ye, C. R. Valdivia, M. J. Ackerman, and J. C. Makielski A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation Physiol Genomics, February 6, 2003; 12(3): 187 - 193. [Abstract] [Full Text] [PDF]
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C.-j. Liu, S. D. Dib-Hajj, M. Renganathan, T. R. Cummins, and S. G. Waxman Modulation of the Cardiac Sodium Channel Nav1.5 by Fibroblast Growth Factor Homologous Factor 1B J. Biol. Chem., January 3, 2003; 278(2): 1029 - 1036. [Abstract] [Full Text] [PDF]
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E. Moric, E. Herbert, M. Trusz-Gluza, A. Filipecki, U. Mazurek, and T. Wilczok The implications of genetic mutations in the sodium channel gene (SCN5A) Europace, January 1, 2003; 5(4): 325 - 334. [Abstract] [Full Text] [PDF]
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 X. H.T. Wehrens, M. A. Vos, P. A. Doevendans, and H. J.J. Wellens Novel Insights in the Congenital Long QT Syndrome Ann Intern Med, December 17, 2002; 137(12): 981 - 992. [Abstract] [Full Text] [PDF]
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D. Noble Unraveling the genetics and mechanisms of cardiac arrhythmia PNAS, April 30, 2002; 99(9): 5755 - 5756. [Full Text] [PDF]
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G. A. Papadatos, P. M. R. Wallerstein, C. E. G. Head, R. Ratcliff, P. A. Brady, K. Benndorf, R. C. Saumarez, A. E. O. Trezise, C. L.-H. Huang, J. I. Vandenberg, et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a PNAS, April 18, 2002; (2002) 82121299. [Abstract] [Full Text] [PDF]
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J. W. Cormier, I. Rivolta, M. Tateyama, A.-S. Yang, and R. S. Kass Secondary Structure of the Human Cardiac Na+ Channel C Terminus. EVIDENCE FOR A ROLE OF HELICAL STRUCTURES IN MODULATION OF CHANNEL INACTIVATION J. Biol. Chem., March 8, 2002; 277(11): 9233 - 9241. [Abstract] [Full Text] [PDF]
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 X.H.T. WEHRENS and A.R. MARKS Myocardial Disease in Failing Hearts: Defective Excitation-Contraction Coupling Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 533 - 542. [Abstract] [PDF]
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 H. Wedekind, J. P.P. Smits, E. Schulze-Bahr, R. Arnold, M. W. Veldkamp, T. Bajanowski, M. Borggrefe, B. Brinkmann, I. Warnecke, H. Funke, et al. De Novo Mutation in the SCN5A Gene Associated With Early Onset of Sudden Infant Death Circulation, September 4, 2001; 104(10): 1158 - 1164. [Abstract] [Full Text] [PDF]
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P. C. Viswanathan, C. R. Bezzina, A. L. George Jr., D. M. Roden, A. A.M. Wilde, and J. R. Balser Gating-Dependent Mechanisms for Flecainide Action in SCN5A-Linked Arrhythmia Syndromes Circulation, September 4, 2001; 104(10): 1200 - 1205. [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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H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]
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C. A. Ufret-Vincenty, D. J. Baro, W. J. Lederer, H. A. Rockman, L. E. Quinones, and L. F. Santana Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure J. Biol. Chem., July 20, 2001; 276(30): 28197 - 28203. [Abstract] [Full Text] [PDF]
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I. Rivolta, H. Abriel, M. Tateyama, H. Liu, M. Memmi, P. Vardas, C. Napolitano, S. G. Priori, and R. S. Kass Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes J. Biol. Chem., August 10, 2001; 276(33): 30623 - 30630. [Abstract] [Full Text] [PDF]
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G. A. Papadatos, P. M. R. Wallerstein, C. E. G. Head, R. Ratcliff, P. A. Brady, K. Benndorf, R. C. Saumarez, A. E. O. Trezise, C. L.-H. Huang, J. I. Vandenberg, et al. From the Cover: Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a PNAS, April 30, 2002; 99(9): 6210 - 6215. [Abstract] [Full Text] [PDF]
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M. Mantegazza, F. H. Yu, W. A. Catterall, and T. Scheuer Role of the C-terminal domain in inactivation of brain and cardiac sodium channels PNAS, December 18, 2001; 98(26): 15348 - 15353. [Abstract] [Full Text] [PDF]
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 H. Abriel, C. Cabo, X. H. T. Wehrens, I. Rivolta, H. K. Motoike, M. Memmi, C. Napolitano, S. G. Priori, and R. S. Kass Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel Circ. Res., April 13, 2001; 88(7): 740 - 745. [Abstract] [Full Text] [PDF]
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C. E. Clancy and Y. Rudy Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Circulation, March 12, 2002; 105(10): 1208 - 1213. [Abstract] [Full Text] [PDF]
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