© 1999 American Heart Association, Inc.
Cellular Biology |
Ionic Mechanisms Responsible for the Electrocardiographic Phenotype of the Brugada Syndrome Are Temperature Dependent
From the Departments of Molecular Biology and Experimental Cardiology (R.D., D.M.V., V.V.N., C.A.), Masonic Medical Research Laboratory, Utica, NY; Departments of Pediatrics (J.A.T., M.V.) and Medicine (R.B.), Baylor College of Medicine, Houston, Texas; Cardiovascular Center (P.B.), OLV Hospital, Aalst, Belgium; and Cardiovascular Institute (J.B.), Hospital Clinic, University of Barcelona, Barcelona, Spain.
Correspondence to Dr Robert Dumaine, Department Molecular Biology, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail rdumaine{at}mmrl.edu
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Abstract—The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the
subunit of the cardiac sodium channel. When heterologously
expressed in frog oocytes,
electrophysiological data recorded from
the Thr1620Met missense mutant failed to adequately explain the
electrocardiographic phenotype. Therefore, we sought to further
characterize the electrophysiology of this mutant. We hypothesized that
at more physiological temperatures, the missense
mutation may change the gating of the sodium channel such that the net
outward current is dramatically augmented during the early phases of
the right ventricular action potential. In the present
study, we test this hypothesis by expressing Thr1620Met in a mammalian
cell line, using the patch-clamp technique to study the currents at
32°C. Our results indicate that Thr1620Met current decay kinetics are
faster when compared with the wild type at 32°C. Recovery from
inactivation was slower for Thr1620Met at 32°C, and steady-state
activation was significantly shifted. Our findings explain the features
of the ECG of Brugada patients, illustrate for the first time a cardiac
sodium channel mutation of which the arrhythmogenicity is revealed only
at temperatures approaching the physiological
range, and suggest that some patients may be more at risk during
febrile states.
Key Words: Brugada syndrome • Na+ channel • temperature
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) developing in patients with structurally normal hearts accounts for 5% to 12% of the >300 000 sudden deaths of Americans each year.1 2 Approximately half of these are attributed to the Brugada syndrome, a familial disease electrocardiographically characterized by a downsloping ST-segment elevation terminating in a negative T wave in the right precordial leads, an apparent right bundle branch block,3 4 and rapid polymorphic VT capable of degenerating to VF.5 6 Slightly prolonged H-V intervals are observed in 60% of patients7 with Brugada syndrome.
Chen et al8 recently uncovered the first gene defects linked to the Brugada syndrome, identifying different mutations in SCN5A, the cardiac sodium channel gene, in each of the 3 families studied. A frameshift mutation resulted in an in-frame stop codon in the pore region of domain III in one family. Because the syndrome has an autosomal dominant pattern of inheritance, the frameshift mutation is likely to result in a decrease in the number of functional channels, which can explain the clinical manifestation of the syndrome.3 4 Missense mutations involving a double substitution of arginine at position 1232 by a tryptophan (Arg1232Trp) and the threonine at position 1620 by a methionine (Thr1620Met) were also found. Heterologous expression of these mutant channels in Xenopus oocytes revealed that the Thr1620Met mutation shifts steady-state inactivation of the channels toward more positive potentials and accelerates reactivation, whereas Arg1232Trp did not produce these effects and is thought to be a rare polymorphism. The electrophysiological profile reported for this mutant at room temperature does not adequately explain the ECG signature of the Brugada syndrome, however. We hypothesized that, at more physiological temperatures, the missense mutation may accelerate the decay of the sodium current, thus leaving the large transient outward current normally present in right ventricular epicardium unopposed. To test this hypothesis, we studied the kinetics of the current at 32°C using the patch-clamp technique.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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The coding sequence of hH1a wild type (WT) was cloned in the pGEM-3 (Promega) expression vector,8 9 and the Thr1620Met mutation was produced by site-directed mutagenesis as previously described.10 11 The clones were then cut out of pGEM-3 by restriction digest and ligated in pcDNA3.1 (Invitrogen) for expression in mammalian cells. Cells were transfected using the Ca2+ phosphate precipitation method, as previously described.12 The cells were grown in a polylysine-coated 35-mm culture dish and placed in a heating chamber for electrophysiological measurements (Medical Systems). For patch-clamp experiments, the bath solution contained (in mmol/L) KCl 2, NaCl 150, CaCl2 1.5, MgCl2 1, glucose 10, and tetraethylammonium 5, at pH 7.2 (NaOH). The pipette solution contained (in mmol/L) NaCl 35, HEPES 10, EGTA 10, and CsF 105, at pH 7.4 (CsOH) and 309 mosm (sucrose). Micropipettes were drawn from Corning 7052 glass tubing, and microelectrode resistance varied between 0.8 and 1.4 m
when measured in the
extracellular solution. Capacitance and series resistances were
adjusted to obtain minimal contribution of the capacitive transients. A
70% to 80% compensation of the series resistance was usually achieved
without ringing. Currents were recorded with an Axopatch 200A
amplifier (Axon Instruments) and digitally stored on the hard disk of
an IBM-compatible computer. Analysis was done with the Axon
PCLAMP V.7 suite of software (Axon Instruments). Where indicated, the
fit to a Boltzmann distribution function was obtained by fitting the
data to
1/[1+e(Vm–V0.5)/k],
where Vm represents the membrane
potential, V0.5 the midpoint of activation,
and k the slope factor. The temperature sensitivity
coefficient Q10 was obtained by the
expression ln(Q10)=
10/
Txln(
I/F),
where T, I, and F
represent the temperature and the time constant values at the
initial and final temperatures, respectively. Statistical significance
was determined using ANOVA or paired Student t test.
Cardiac Action Potential (AP) Modeling
We simulated endocardial, left ventricular
epicardial, and right ventricular epicardial APs using a
modified version of the Luo-Rudy 2 (phase 2) model.13 14
To obtain realistic APs of the right epicardium, we made the following
minor changes:
(1) The model of the transient inward potassium current was incorporated into the Luo-Rudy 2 model (see Appendix for the model expressions). Activation of this current is relatively fast, with time to peak of 1.7 ms at +10 mV; the steady-state activation curve is sigmoid, with V1/2=-4 mV (3 activation gates) and a slope of 11.5 mV. The inactivation time constant is 10 ms over the voltage range above -20 mV (threshold=-30 mV), and the reactivation time constant is 67 ms at -80 mV (but 450 ms at -50 mV). Maximal conductance of Ito (GIto) was set to 0 for endocardial AP, 0.5 for left ventricular epicardial AP, and 1.1 for right ventricular epicardial AP.
(2) The maximal conductance of ICaL was decreased by 20% to 50% in epicardial models to obtain realistic durations of simulated APs.
(3) To reproduce faster current decay for Thr1620Met mutant as compared
with the WT sodium channel, we multiplied both rate constants for
inactivation gate h (h and
ßh) by a factor of 2, which leaves steady-state
inactivation characteristics unchanged. The faster inactivation of
INa resulted in a 32% smaller peak current
during upstroke of AP.
Parameters of the model assume that the APs are simulated at the normal body temperature of 37°C. The effects of a faster rate of INa decay were tested using a simple cable model (1-cm cable, 0.01-cm space steps) to account for the significant electrotonic load on the upstroke of the AP during propagation. Only APs simulated in the center of the cable are shown in this article.
The differential equations were solved numerically using the
second-order Runge-Kutta method for time derivatives (time steps of
10 µs) and the Crank-Nicholson method (the average of the second
central difference at time t and at time
t+t) for space derivatives (space steps of 0.1
cm).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Recordings of macroscopic sodium currents at physiological temperatures are technically challenging. To avoid changes in the kinetics of the current or its voltage relationship due to modified solutions and to minimize errors due to uncompensated series resistance, the experiments used for the statistical analysis were done at 22°C and 32°C. We then routinely tested at higher temperatures, on cells transfected with lower amounts of cDNA and expressing low amplitude currents, the predictions from the experiments at lower temperature. Figure 1
shows whole-cell currents recorded
2 days posttransfection using low-resistance patch-clamp electrodes
(0.6 to 1.0 M). The current waveforms and current-voltage relations
(IVRs) were similar in WT (n=5) and Thr1620Met (n=4) at 22°C. At
32°C, the activation and the decay of INa
was faster for Thr1620Met (Figure 1A) resulting in a steeper IVR
(Figure 1B) and a peak of IVR 10 mV more positive when compared
with WT (n=6). In the experiments shown, the voltage errors due to
uncompensated series resistance at 32°C were 0.4 and 0.9 mV for WT
and Thr1620Met, respectively, as estimated from the capacitive
artifacts.
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)
and Thr1620Met mutants (•) at 22°C and 32°C (
and 
) from 4
to 6 different cells at each temperature (see text).
To elucidate the basis for the shift of IVR, we examined the
temperature dependence of steady-state activation and inactivation
(Figure 2). At 22°C, we observed no
significant difference between the mid-activation potential for WT
(-43.9±0.8 mV) and Thr1620Met (-39±4 mV) (Boltzmann function fit,
Figure 2A). At 32°C, steady-state activation for Thr1620Met
was significantly shifted toward more positive potentials when compared
with WT (P<0.001), with mid-potential values of -38.8±0.4
mV and -49.5±0.4 mV, respectively, and was less sensitive than WT to
changes of membrane potential with slope factors (k) of
5.4±0.4 mV and 6.8±0.4 mV, respectively (P<0.05).
Steady-state inactivation protocols (Figure 2B) revealed no
significant differences between WT and Thr1620Met at 22°C and
32°C with half-inactivation voltages, as follows: -91.5±0.1 mV and
-91.9±0.2 mV (22°C) and -87.1±0.2 mV and -86±0.2 mV (32°C)
for WT and Thr1620Met, respectively (Figure 2C).
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We next looked for changes in the current kinetics of
INa (Figure 3) in a range of potentials encompassing
the plateau of the AP and fitted the decay of the current to a sum of 2
exponentials. The fast component accounted for 87±3% and 83±5% (WT)
and 88±4% and 90±3% (Thr1620Met) of the total amplitude of the
current at 22°C and 32°C, respectively. The time constant of the
fast component () of the current decay was similar for WT and
Thr1620Met at 22°C between-50 and 20 mV, but significantly faster
for Thr1620Met at 32°C (Figure 3B). At a potential of 10 mV,
INa fully inactivated 4 ms
sooner in Thr1620Met than in WT (Figure 3A).
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To predict the changes in the decay of the sodium current in more
physiological conditions, we did a set of
experiments at temperatures between 35°C and 42°C and a holding
potential of -80 mV. In this set of experiments, the amount of cDNA
used for transfection was reduced by 75%, yielding currents with
maximal amplitudes between 1 and 2 nA, filtering of the signal was
decreased to 10 kHz, and acquisition was increased to 50 kHz to
minimize aliasing caused by bandwidth limitations. Figure 4 shows that the decay of the Thr1620Met
current is more rapid than WT in physiological
conditions, as predicted by the experiments at 32°C. We found
Q10 values of 1.2 and 2.3 for WT and Thr1620Met,
respectively, for the current decay at 0 mV.
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We measured the rate of recovery of INa by
varying the interpulse interval of twin pulses to 0 mV from a holding
potential of -110 mV (Figure 5).
At 22°C, recovery was slightly faster for Thr1620Met (=23.1±0.4
and 17.4±0.2 ms for WT and Thr1620Met, respectively). At 32°C,
was much slower for Thr1620Met when compared with WT. A double
exponential fit to the data yielded time constants of 1.1±0.1 (84%)
and 3.7±0.6 (16%), 4.8±0.3 (90%), and 48±5 (10%) ms for WT and
Thr1620Met, respectively. The data of Chen et al8
showed a convergence of recovery kinetics at -110 mV. Our data
suggested that this convergence does not exist at 32°C. We therefore
checked to see whether a slowing of recovery at -80 mV could be
observed at 37°C in 3 cells. Figure 6
shows that recovery of WT current was 93% complete after 60 ms. By
contrast, Thr1620Met currents were slower to recover, as expected from
the measurements at 32°C, with still 95% of channels available after
100 ms.
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To gain more insight into the arrhythmogenic effects of a faster
decay of the sodium current (INa), we
simulated APs from the endocardium, epicardium of the left ventricle,
and epicardium of the right ventricle, which is known to exhibit a
prominent transient outward current Ito in
several species including human.15 In our simulation
(Figure 7), the faster inactivation of
INa increased the net outward current and
lowered the voltage level at the end of phase 1 (Figure 7B and 7C, notches) with little effect on the configuration of the other
phases of the endocardial and left epicardial APs. In the right
ventricular epicardium, however, the acceleration of the
INa decay brings this voltage below the
calcium current (ICaL) threshold, thus
eliminating the dome and triggering all-or-none repolarization (Figure 7C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Our data suggest that the threonine at position 1620 in the coding sequence of SCN5A is an important determinant of the temperature sensitivity of the human cardiac sodium channel. During excitation, the inward sodium current is opposed by the transient outward Ito. As INa decays, the relative contribution of Ito to the net current gradually increases and creates a notch resulting in the spike-and-dome morphology of the right epicardial AP plateau.16 17 18 19 At 32°C, the missense mutation Thr1620Met leads to faster decay and slower reactivation of the current. The more rapid decay of INa would be expected to leave Ito unopposed, thus accentuating phase 1 of the AP. The outward shift of current flowing during phase 1 can lead to loss of the AP dome (plateau) as a result of an all-or-none repolarization at the end of phase 1. This phenomenon is observed in cells and tissues displaying a prominent Ito, such as right ventricular epicardium, but not those exhibiting a small Ito, such as ventricular endocardium. Our AP simulation confirmed this mechanism. Loss of the dome in right ventricular epicardium but not in endocardium creates a transmural voltage gradient that may serve as a basis for the ST-segment elevation observed clinically and for aberrations in the J wave of the ECG. The resulting transepicardial and transmural dispersion of repolarization can also give rise to phase 2 reentrant extrasystoles capable of precipitating a rapid polymorphic VT/VF, the reentrant arrhythmias responsible for sudden death in the Brugada syndrome.3 4 20 21 22
Our simulation also led to another interesting prediction. Because we wanted to alter the model minimally, we only increased the inactivation rate of INa with no modifications of the activation kinetics. This resulted in a 32% decrease in the amplitude of the peak sodium current. We initially expected this decrease to reduce the upstroke velocity of the AP and the activation of Ito and, ultimately, limit the AP plateau depression. Our simulation suggests that the amplitude of Ito is not very sensitive to small variation in the AP upstroke rate. Therefore, reduction of INa density or acceleration of the inactivation is likely to be very effective in modulating phase 1 by leaving the fully activated Ito unopposed.
We observed a 10-mV shift in steady-state activation. Our measurements of the maximal current are accurate within 1 mV of the voltage imposed in the range 6 to 9 nA at 32°C. Therefore, the voltage shift cannot be attributed to uncompensated series resistance. Clinically, this10-mV positive shift of steady-state activation would be expected to raise the activation threshold and thus lead to a mild slowing of conduction. This change in excitability may be responsible for the small H-V interval prolongation and right bundle branch block observed in many patients with the Brugada syndrome.5 6 7
WT and Thr1620Met channels displayed similar steady-state inactivation curves at all temperatures studied. This finding contrasts with the results of Chen et al,8 possibly because of differences in expression systems (Xenopus oocytes versus HEK cells) and/or specific protocols. It is noteworthy that whole-cell measurements of INa produce a time-dependent shift of the steady-state inactivation parameters,23 which is not observed with the agar cushioned 2-electrode voltage-clamp technique applied on frog oocytes. We routinely checked for time-dependent shifts in the midpotential of steady-state inactivation (V0.5) and obtained rates of -0.42±0.05 mV/min (n=3) and -0.27±0.02 mV/min (n=4) for WT and Thr1620Met, respectively, at 32°C and -0.13±0.08 mV/min (n=3) and -0.11±0.15 mV/min (n=3), respectively, at room temperature. The rates were more rapid during the first 8 to 10 minutes and then remained stable below 0.05 mV/min in all the experiments. Most of the data were obtained after 20 minutes in whole-cell configuration. Therefore, our measurements of V0.5 are off by 6 to 8 and 2 to 3 mV at 32°C and room temperature, respectively, when compared with the initial midpotential. This may have contributed to the disparate results of the 2 studies.
Our data demonstrate a faster decay of the sodium channel but slower recovery from inactivation for the Thr1620Met mutant at physiological temperature(s). Therefore, the channels are likely to spend more time in the inactivated states, suggesting that the mutation has a stabilizing effect on inactivation of the channel. This is opposite to the effects of mutations observed in the LQT3 form of long QT syndrome,24 in which a late sodium current is amplified because of destabilized (less absorbent) inactivated states.10 25 26 Given the location of the Thr1620Met mutation in a region strongly involved in the activation-inactivation coupling,27 28 29 30 31 we speculate that the effects may be the result of changes in activation and/or deactivation altering this coupling. The exact mechanism for the acceleration of the current decay remains to be established by an in-depth biophysical study of the single-channel behavior of the Thr1620Met mutant.
To our knowledge, this is the first report of a cardiac sodium channel mutation involved in a genetic disease that reveals its arrhythmogenic potential primarily at temperatures approaching the physiological range. The results suggest caution in the interpretation of data obtained from heterologous expression systems at room temperature.
On the basis of our Q10 measurements, the decay of the Thr1620Met current is 2.4, 3, and 3.4 times faster than WT at 37°C, 39°C, and 40°C, respectively. Furthermore, Li et al15 showed that the inactivation kinetics of Ito was 2 times faster at 36°C than at room temperature. The speeding of the inactivation of Ito at a higher temperature therefore cannot fully compensate for the influence of INa on the balance of currents during the early phase 1 repolarization. These results suggest that the increased temperature sensitivity of the Thr1620Met current decay may predispose some Brugada patients to arrhythmias during a febrile state (fever).
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Acknowledgments |
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This work was supported by grants from National Institutes of Health HL-59449 to R.D. and HL-47678 to C.A. The authors wish to thank Dr Yue Sheng Wu for his expert handling of the cell transfection procedures, M. Todd Richards for part of the cloning work, and J. Hefferon for artwork.
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Appendix 1 |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Model of the Transient Outward Current, Ito
Ito=GItoxz3xyxR(V)x(V-EK), where EK is the reversal potential for potassium ions
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z and ßz, voltage-dependent opening and
closing rate constants of activation gate (msec-1);
y and ßy, voltage-dependent opening and
closing rate constants of inactivation gate (msec-1). Received May 27, 1999; accepted August 20, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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M. Bebarova, T. O'Hara, J. L. M. C. Geelen, R. J. Jongbloed, C. Timmermans, Y. H. Arens, L.-M. Rodriguez, Y. Rudy, and P. G. A. Volders Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H48 - H58. [Abstract] [Full Text] [PDF]
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S. Petitprez, T. Jespersen, E. Pruvot, D. I. Keller, C. Corbaz, J. Schlapfer, H. Abriel, and J. P. Kucera Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome Cardiovasc Res, June 1, 2008; 78(3): 494 - 504. [Abstract] [Full Text] [PDF]
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C. Sims, S. Reisenweber, P. C. Viswanathan, B.-R. Choi, W. H. Walker, and G. Salama Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2 Circ. Res., May 9, 2008; 102(9): e86 - e100. [Abstract] [Full Text] [PDF]
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G. M. Faber and Y. Rudy Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: A simulation study of cellular mechanism Cardiovasc Res, July 1, 2007; 75(1): 79 - 88. [Abstract] [Full Text] [PDF]
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V. Probst, I. Denjoy, P. G. Meregalli, J.-C. Amirault, F. Sacher, J. Mansourati, D. Babuty, E. Villain, J. Victor, J.-J. Schott, et al. Clinical Aspects and Prognosis of Brugada Syndrome in Children Circulation, April 17, 2007; 115(15): 2042 - 2048. [Abstract] [Full Text] [PDF]
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D. W. Wang, R. R. Desai, L. Crotti, M. Arnestad, R. Insolia, M. Pedrazzini, C. Ferrandi, A. Vege, T. Rognum, P. J. Schwartz, et al. Cardiac Sodium Channel Dysfunction in Sudden Infant Death Syndrome Circulation, January 23, 2007; 115(3): 368 - 376. [Abstract] [Full Text] [PDF]
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S. Vecchietti, E. Grandi, S. Severi, I. Rivolta, C. Napolitano, S. G. Priori, and S. Cavalcanti In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H56 - H65. [Abstract] [Full Text] [PDF]
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Z.-S. Zhang, J. Tranquillo, V. Neplioueva, N. Bursac, and A. O. Grant Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H399 - H407. [Abstract] [Full Text] [PDF]
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B.-H. Tan, C. R. Valdivia, C. Song, and J. C. Makielski Partial expression defect for the SCN5A missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1822 - H1828. [Abstract] [Full Text] [PDF]
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B. Sassone, S. Sacca, and M. Donateo Paradoxical effect of ajmaline in a patient with Brugada syndrome. Europace, April 1, 2006; 8(4): 251 - 254. [Abstract] [Full Text] [PDF]
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R. F. Wiegerinck, A. O. Verkerk, C. N. Belterman, T. A.B. van Veen, A. Baartscheer, T. Opthof, R. Wilders, J. M.T. de Bakker, and R. Coronel Larger Cell Size in Rabbits With Heart Failure Increases Myocardial Conduction Velocity and QRS Duration Circulation, February 14, 2006; 113(6): 806 - 813. [Abstract] [Full Text] [PDF]
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G. Berecki, J. G. Zegers, Z. A. Bhuiyan, A. O. Verkerk, R. Wilders, and A. C. G. van Ginneken Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique J. Physiol., January 15, 2006; 570(2): 237 - 250. [Abstract] [Full Text] [PDF]
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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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P. G. Meregalli, A. A.M. Wilde, and H. L. Tan Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res, August 15, 2005; 67(3): 367 - 378. [Abstract] [Full Text] [PDF]
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D. I. Keller, J.-S. Rougier, J. P. Kucera, N. Benammar, V. Fressart, P. Guicheney, A. Madle, M. Fromer, J. Schlapfer, and H. Abriel Brugada syndrome and fever: Genetic and molecular characterization of patients carrying SCN5A mutations Cardiovasc Res, August 15, 2005; 67(3): 510 - 519. [Abstract] [Full Text] [PDF]
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P. Brugada, R. Brugada, J. Brugada, S. G. Priori, C. Napolitano, P. Brugada, R. Brugada, J. Brugada, S. G. Priori, and C. Napolitano Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation, July 12, 2005; 112(2): 279 - 292. [Full Text] [PDF]
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T. Chen, M. Inoue, and M. F. Sheets Reduced voltage dependence of inactivation in the SCN5A sodium channel mutation delF1617 Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2666 - H2676. [Abstract] [Full Text] [PDF]
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X. Sun and H.-S. Wang Role of the transient outward current (Ito) in shaping canine ventricular action potential - a dynamic clamp study J. Physiol., April 15, 2005; 564(2): 411 - 419. [Abstract] [Full Text] [PDF]
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C. Antzelevitch, P. Brugada, M. Borggrefe, J. Brugada, R. Brugada, D. Corrado, I. Gussak, H. LeMarec, K. Nademanee, A. R. Perez Riera, et al. Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association Circulation, February 8, 2005; 111(5): 659 - 670. [Abstract] [Full Text] [PDF]
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T. Aiba, W. Shimizu, M. Inagaki, T. Noda, S. Miyoshi, W.-G. Ding, D. P. Zankov, F. Toyoda, H. Matsuura, M. Horie, et al. Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil J. Am. Coll. Cardiol., January 18, 2005; 45(2): 300 - 307. [Abstract] [Full Text] [PDF]
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L. Livshitz, K. Decker, G. Faber, T. O'Hara, J. Silva, Y. Rudy, K. H. W. J. ten Tusscher, D. Noble, P. J. Noble, and A. V. Panfilov Comments on "A model for human ventricular tissue" Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H453 - H453. [Abstract] [Full Text] [PDF]
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V. Haufe, J.M. Cordeiro, T. Zimmer, Y.S. Wu, S. Schiccitano, K. Benndorf, and R. Dumaine Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles Cardiovasc Res, January 1, 2005; 65(1): 117 - 127. [Abstract] [Full Text] [PDF]
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R. L. Winslow and J. L. Greenstein The Ongoing Journey to Understand Heart Function Through Integrative Modeling Circ. Res., December 10, 2004; 95(12): 1135 - 1136. [Full Text] [PDF]
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T. J. Hund and Y. Rudy Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model Circulation, November 16, 2004; 110(20): 3168 - 3174. [Abstract] [Full Text] [PDF]
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J. Satin, I. Kehat, O. Caspi, I. Huber, G. Arbel, I. Itzhaki, J. Magyar, E. A. Schroder, I. Perlman, and L. Gepstein Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes J. Physiol., September 1, 2004; 559(2): 479 - 496. [Abstract] [Full Text] [PDF]
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B. J. Maron, B. R. Chaitman, M. J. Ackerman, A. Bayes de Luna, D. Corrado, J. E. Crosson, B. J. Deal, D. J. Driscoll, N.A. M. Estes III, C. G. S. Araujo, et al. Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases Circulation, June 8, 2004; 109(22): 2807 - 2816. [Abstract] [Full Text] [PDF]
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S. G. Priori Inherited Arrhythmogenic Diseases: The Complexity Beyond Monogenic Disorders Circ. Res., February 6, 2004; 94(2): 140 - 145. [Abstract] [Full Text] [PDF]
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C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada, J. A. Towbin, and K. Nademanee Brugada syndrome: 1992-2002: A historical perspective J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1665 - 1671. [Abstract] [Full Text] [PDF]
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S. Miyoshi, H. Mitamura, K. Fujikura, Y. Fukuda, K. Tanimoto, Y. Hagiwara, M. Ita, and S. Ogawa A mathematical model of phase 2 reentry: role of L-type Ca current Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1285 - H1294. [Abstract] [Full Text] [PDF]
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H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde Genetic control of sodium channel function Cardiovasc Res, March 15, 2003; 57(4): 961 - 973. [Abstract] [Full Text] [PDF]
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N. Patruno, D. Pontillo, A. Achilli, G. Ruggeri, and G. Critelli Electrocardiographic pattern of Brugada syndrome disclosed by a febrile illness: clinical and therapeutic implications Europace, January 1, 2003; 5(3): 251 - 255. [Abstract] [Full Text] [PDF]
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M. H. Dinckal, V. Davutoglu, I. Akdemir, S. Soydinc, A. Kirilmaz, and M. Aksoy Incessant monomorphic ventricular tachycardia during febrile illness in a patient with Brugada syndrome: fatal electrical storm Europace, January 1, 2003; 5(3): 257 - 261. [Abstract] [Full Text] [PDF]
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C. Cabo and P. A. Boyden Electrical remodeling of the epicardial border zone in the canine infarcted heart: a computational analysis Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H372 - H384. [Abstract] [Full Text] [PDF]
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C.F. Starmer, T. J. Colatsky, and A. O. Grant What happens when cardiac Na channels lose their function? 1 - Numerical studies of the vulnerable period in tissue expressing mutant channels Cardiovasc Res, January 1, 2003; 57(1): 82 - 91. [Abstract] [Full Text] [PDF]
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C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada, W. Shimizu, I. Gussak, and A.R. Perez Riera Brugada Syndrome: A Decade of Progress Circ. Res., December 13, 2002; 91(12): 1114 - 1118. [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. R Bezzina and H. L Tan Pharmacological rescue of mutant ion channels Cardiovasc Res, August 1, 2002; 55(2): 229 - 232. [Full Text] [PDF]
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C. Antzelevitch Late potentials and the Brugada syndrome J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1996 - 1999. [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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J. R. Balser Inherited sodium channelopathies: models for acquired arrhythmias? Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1175 - H1180. [Full Text] [PDF]
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D. W. Wang, P. C. Viswanathan, J. R. Balser, A. L. George Jr, and D. W. Benson Clinical, Genetic, and Biophysical Characterization of SCN5A Mutations Associated With Atrioventricular Conduction Block Circulation, January 22, 2002; 105(3): 341 - 346. [Abstract] [Full Text] [PDF]
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J. Brugada, R. Brugada, C. Antzelevitch, J. Towbin, K. Nademanee, and P. Brugada Long-Term Follow-Up of Individuals With the Electrocardiographic Pattern of Right Bundle-Branch Block and ST-Segment Elevation in Precordial Leads V1 to V3 Circulation, January 1, 2002; 105(1): 73 - 78. [Abstract] [Full Text] [PDF]
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R. Brugada and R. Roberts Brugada Syndrome: Why Are There Multiple Answers to a Simple Question? Circulation, December 18, 2001; 104(25): 3017 - 3019. [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 Antzelevitch The Brugada syndrome: diagnostic criteria and cellular mechanisms Eur. Heart J., March 1, 2001; 22(5): 356 - 363. [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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X. Wan, S. Chen, A. Sadeghpour, Q. Wang, and G. E. Kirsch Accelerated inactivation in a mutant Na+ channel associated with idiopathic ventricular fibrillation Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H354 - H360. [Abstract] [Full Text] [PDF]
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J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]
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D. W. Wang, N. Makita, A. Kitabatake, J. R. Balser, and A. L. George Jr Enhanced Na+ Channel Intermediate Inactivation in Brugada Syndrome Circ. Res., October 13, 2000; 87 (8): e37 - e43. [Abstract] [Full Text] [PDF]
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M. W. Veldkamp, P. C. Viswanathan, C. Bezzina, A. Baartscheer, A. A. M. Wilde, and J. R. Balser Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na+ Channel Circ. Res., May 12, 2000; 86 (9): e91 - e97. [Abstract] [Full Text] [PDF]
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A. A.M. Wilde and M. W. Veldkamp What we can learn from individual resuscitated patients Cardiovasc Res, April 1, 2000; 46(1): 14 - 16. [Full Text] [PDF]
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I. Deschenes, G. Baroudi, M. Berthet, I. Barde, T. Chalvidan, I. Denjoy, P. Guicheney, and M. Chahine Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes Cardiovasc Res, April 1, 2000; 46(1): 55 - 65. [Abstract] [Full Text] [PDF]
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J. R. Balser Sodium "Channelopathies" and Sudden Death : Must You Be So Sensitive? Circ. Res., October 29, 1999; 85(9): 872 - 874. [Full Text] [PDF]
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G. Baroudi, S. Acharfi, C. Larouche, and M. Chahine Expression and Intracellular Localization of an SCN5A Double Mutant R1232W/T1620M Implicated in Brugada Syndrome Circ. Res., January 11, 2002; 90 (1): e11 - e16. [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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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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