Published online before print April 3, 2003, doi: 10.1161/01.RES.0000069689.09869.A8
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© 2003 American Heart Association, Inc.
Clinical Research |
Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families
From the Experimental and Molecular Cardiology Group (M.W.V., A.B., C.R.B., A.A.M.W.) and the Departments of Physiology (R.W., J.G.Z.) and Clinical Genetics (C.R.B.), Academic Medical Center, University of Amsterdam, The Netherlands.
Correspondence to Dr M.W. Veldkamp, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Room M0-053, Meibergdreef 9, 1105 AZ Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail m.w.veldkamp{at}amc.uva.nl
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Abstract |
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One variant of the long-QT syndrome (LQT3) is caused by mutations in the human cardiac sodium channel gene. In addition to the characteristic QT prolongation, LQT3 carriers regularly present with bradycardia and sinus pauses. Therefore, we studied the effect of the 1795insD Na+ channel mutation on sinoatrial (SA) pacemaking. The 1795insD channel was previously characterized by the presence of a persistent inward current (Ipst) at -20 mV and a negative shift in voltage dependence of inactivation. In the present study, we first additionally characterized Ipst over the complete voltage range of the SA node action potential (AP) by measuring whole-cell Na+ currents (INa) in HEK-293 cells expressing either wild-type or 1795insD channels. Ipst for 1795insD channels varied between 0.8±0.2% and 1.9±0.8% of peak INa. Activity of 1795insD channels during SA node pacemaking was confirmed by AP clamp experiments. Next, Ipst and the negative shift were implemented into SA node AP models. The -10-mV shift decreased sinus rate by decreasing diastolic depolarization rate, whereas Ipst decreased sinus rate by AP prolongation, despite a concomitant increase in diastolic depolarization rate. In combination, moderate Ipst (1% to 2%) and the shift reduced sinus rate by
10%. An additional increase in Ipst could result in plateau oscillations and failure to repolarize completely. Thus, Na+ channel mutations displaying an Ipst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SA node cells to repolarize under conditions of extra net inward current.
Key Words: long-QT syndrome • ion channels • sinoatrial node • electrophysiology • sudden death
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Introduction |
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The inherited long-QT syndrome is a familial rhythm disorder typically characterized by prolongation of the QT-interval on the ECG and life-threatening cardiac arrhythmias.1,2 One form of the familial long-QT syndrome (LQT3) is caused by mutations in the gene encoding the cardiac sodium channel (SCN5A).3 To date, the biophysical properties of the mutant sodium channels have been assessed for at least 21 of the distinct genetic mutations in SCN5A that have been linked to LQT3 (see online Table 1, available in the online data supplement at http://www.circresaha.org). In most of these mutations, incomplete or slowed channel inactivation induces a small persistent sodium inward current (Ipst) during prolonged depolarization (see online Table 1). This small Ipst at plateau potentials is sufficient to delay repolarization of the action potential and underlies the QT-prolongation on the ECG.
Previous research has focused on the correlation between altered Na+ channel kinetics and ventricular action potential prolongation, because the latter renders the heart vulnerable to tachyarrhythmias, especially Torsade de Pointes. In addition to the characteristic QT-prolongation, however, bradycardia and sinus pauses have also been associated with the LQT3 phenotype, indicating a role for the sodium channel in sinoatrial pacemaking in humans.4 This was at least reported for carriers of the 
KPQ,5 D1790G,6 E1784K,7 1795insD,8,9 and K150010 mutations. Because QT-prolongation is most pronounced at lower heart rates, whereas virtually absent at high heart rates,11 bradycardia represents an important indirect factor in predisposition to lethal arrhythmias in LQT3 families. However, bradycardia may also be the direct cause of sudden death, as was diagnosed for 1 member of the D1790G family who died of sinus arrest (J. Benhorin, MD, written communication, 2001)12 and, as we suspected, for members of the 1795insD family.9 The latter family with a high incidence of nocturnal sudden death was previously characterized by bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, and generalized conduction abnormalities.9 The mechanism underlying LQT3-associated bradycardia has not been unraveled yet. Thus, the aim of the present study was to investigate whether each of the altered biophysical properties of the mutant 1795insD Na+ channel (and other mutant channels; see the online data supplement), ie, incomplete inactivation and a negative shift in voltage-dependence of inactivation, can give rise to bradycardia and sinus pauses.
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Materials and Methods |
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Transfection
Mutant (1795insD) SCN5A cDNA was prepared in the pCGI vector for bicistronic expression of mutant channel and green fluorescent protein, as described previously.13 To express mutant or wild-type hH1, HEK-293 cells were cotransfected with 2 µg of Na+ channel
-subunit cDNA and 2 µg hß1-subunit cDNA (kindly provided by J.R. Balser, Vanderbilt University, Nashville, Tenn) using lipofectamine (Gibco BRL, Life Technologies). Transfected HEK-293 cells were cultured in MEM (Earle’s salts and L-glutamine) supplemented with nonessential amino acid solution, 10% FBS, 100 IU/mL penicillin, and 100 µg/mL streptomycin in a 5% CO2 incubator at 37°C for 1 to 2 days. Only cells exhibiting green fluorescence were selected for electrophysiological experiments.
Electrophysiology
Sodium currents were measured in the whole-cell configuration of the patch-clamp technique using an Axopatch 200B amplifier (Axon Instruments) and the following solutions (in mmol/L): bath (external) solution: NaCl 140, KCl 4.7, CaCl2 1.8, MgCl2 2.0, NaHCO3 4.3, Na2HPO4 1.4, glucose 11, and HEPES 16.8, pH adjusted to 7.4 (NaOH); and pipette (internal) solution: CsF 100, CsCl 40, EGTA 10, NaCl 10, MgCl2 1.2, and HEPES 10, pH adjusted to 7.3 (NaOH). Patch electrodes were pulled from borosilicate glass and had a tip resistance of 2 to 3 M
when filled with pipette solution. Series resistance was compensated for 75% to 80%. Sodium currents were recorded at room temperature (21°C). Persistent inward Na+ current was determined from the tetrodotoxin (TTX)-sensitive current by taking the average current amplitude over the last 50 ms of the 300-ms depolarizing step, relative to the holding current at -120 mV. TTX-sensitive currents were obtained by subtracting a trace recorded in the presence of 30 µmol/L TTX (Alomone Labs) from a trace recorded earlier in the absence of TTX. Experiments were excluded from analysis when the holding current at -120 mV was more negative than -300 pA or when a >80-pA shift was observed during wash-in of TTX. Whole-cell currents were filtered at 5 kHz and digitized at 30 kHz.
Computer Simulations
The effects of changes in INa were tested in computer simulations using our previously published mathematical model of a rabbit SA nodal cell,14 either with our original INa equations or those by Luo and Rudy.15 To account for recent experimental data showing a INa peak amplitude of 20 to 100 pA/pF in voltage-clamp,16 the maximum INa conductance of the original model was increased to 1.25 nS/pF, yielding a peak amplitude of 31 or 44 pA/pF (original and Luo-Rudy INa equations, respectively). In the thus-modified model, the steady-state inactivation curve (h
versus Vm) was either shifted by 0 (control) or -10 mV (mutant INa; see Figure 2A of Reference 13). Also, a persistent component of INa was introduced by defining a fraction of Na+ channels that do not inactivate, ie, channels that are controlled by the activation variable m but not by the inactivation variable h. This fraction was 0% in control and 1% to 3% in the mutant case. We carried out similar simulations with the peripheral SA nodal cell model by Zhang et al,17 which allows modulation of intrinsic rate by simulated application of acetylcholine.18 All simulations were run for a sufficiently long time to reach steady-state behavior.
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Results |
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1795insD Persistent Inward Current
Recently, we reported that the persistent inward current (Ipst) through 1795insD Na+ channels was 1.4% of the peak current at a potential of -20 mV.13 In the present study, we measured TTX-sensitive currents during 300-ms depolarizations to various potentials between -120 and 0 mV (Figure 1) to establish their amplitudes also at other voltages within the range of the sinus node action potential. Figure 1A shows whole-cell currents recorded during depolarizations to -40 mV from HEK-293 cells cotransfected with hß1 plus wild-type (left) or 1795insD (right) cDNA during control and in presence of 30 µmol/L TTX. Examination of the TTX-sensitive currents at high gain (insets) revealed a small residual current in cells expressing 1795insD Na+ channels but not in cells expressing wild-type channels. At -40 mV, the magnitude of this Ipst was 0.04±0.14% (mean±SEM, n=7) and 1.05±0.26% (n=6) of the peak current (Ipeak) for wild-type and 1795insD channels, respectively, whereas Ipeak was -5.9±0.6 and -6.8±1.2 nA, respectively. Figure 1B shows the average current-voltage (I-V) relation of Ipst for both channel types. The shape of the 1795insD persistent I-V relation was similar to that of 1795insD peak INa (not shown), with an activation threshold of -60 mV and a maximum amplitude near -25 mV. At voltages between -60 and 0 mV, Ipst varied between 0.8±0.2% and 1.9±0.8% of Ipeak (Figure 1C).
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Subsequently, we carried out action potential clamp experiments to test to what extent (mutant) Na+ channels are actually active during SA nodal automaticity. A run of typical SA node action potentials, previously recorded from a single rabbit SA nodal cell, was applied as voltage clamp command potential to HEK-293 cells expressing either wild-type or 1795insD channels. This command potential (Figure 2A) was given an offset to compensate for differences in the voltage of half-maximal (in)activation between INa in rabbit SA node cells19,20 (and cell models14,17) and hH1 INa expressed in HEK-293 cells.13 Figures 2B and 2C show typical recordings of wild-type and 1795insD TTX-sensitive currents, respectively, from cells with similar INa peak amplitude in voltage clamp. For wild-type channels, practically no inward current deflections were observed during the SA nodal AP (Figure 2B). In case of 1795insD channels, however, the upstroke of the AP generated a small and fast inward peak Na+ current, whereas the repolarization phase was accompanied by a small and slow transient increase in inward Na+ current (Figure 2C). Similar results were obtained in another 6 HEK-293 cells expressing wild-type (n=3) or 1795insD (n=3) channels. These data confirm that mutant Na+ channels can be activated during the SA nodal action potential.
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Effects on SA Nodal Action Potential
To establish how the altered inactivation properties of the 1795insD Na+ channel mutant affect sinus node cellular electrical activity, Ipst and the previously reported negative shift in steady-state inactivation8,13 were implemented in a rabbit SA node action potential model.14 The shift in steady-state inactivation was set at -10 mV, and Ipst was varied between 0% and 2%.
Figure 3 shows the computed effects of the altered channel properties on SA nodal pacemaking. Because of the moderately negative maximal diastolic potential (MDP) of the SA node model cell (Figure 3A, top), the far majority of Na+ channels is normally inactivated. Only during the diastolic depolarization phase between -60 and -40 mV (Figure 3A, middle), the voltage range where activation and inactivation relationships overlap, some minor Na+ channel activity is present. During this phase, Na+ channels generate a small inward current, thus contributing to diastolic depolarization. A -10-mV shift in steady-state inactivation per se, which reduces the overlap, renders the AP shape unaltered (Figure 3A, top, dashed line) but decreases diastolic depolarization rate (DDR), thereby increasing cycle length (CL). This effect results from a reduced Na+ current during diastolic depolarization (Figure 3A, middle) and the consequent reduction in net inward membrane current (Figure 3A, bottom).
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Figure 3B shows the effects of 1% to 2% Ipst per se. The presence of 1% Ipst (Figure 3B, dashed lines) becomes manifest as an extra inward sodium current during the AP and during the (final phase of) diastolic depolarization (Figure 3B, middle). Consequently, the net outward membrane current during the AP is reduced, whereas the net inward membrane current during (the final phase of) diastolic depolarization and the upstroke of the AP is slightly increased (Figure 3B, bottom). These changes result in a prolongation of the AP and a slight increase in DDR, respectively (Figure 3B, top). The latter can be appreciated from Figure 3C, where the same data are plotted on an expanded time scale and are aligned at the beginning of the diastolic depolarization phase at -60 mV. Because the AP prolongation dominates, the overall effect is an increase in CL. With 2% Ipst, these effects were similar but more pronounced (Figures 3B and 3C, dotted lines).
Figure 3D shows the aggregate effect of the shift in inactivation and Ipst. The main difference between the aggregate effect compared with Ipst alone is a decreased instead of increased sodium inward current during diastolic depolarization (Figure 3D, middle). Consequently, the increase in DDR as observed for Ipst alone is no longer present, so that the increase in CL is more pronounced (Figure 3D, top).
Figure 4 summarizes the above results. For convenience, CL was transposed to sinus rate (SR). The main conclusion is that the -10-mV shift and Ipst both induce a slowing of SR, both individually and in combination. The negative shift alone gave rise to a 3% decrease in SR from 158 to 153 bpm (Figure 4A). The presence of 1% or 2% Ipst alone reduced SR by 3% and 9% to 153 and 144 bpm, respectively (Figure 4B). In combination with the shift in inactivation, SR decreased by 6% and 11%, respectively (Figure 4C). The mechanism underlying this change in SR is different for both conditions, as can be appreciated from the changes in action potential parameters. In case of the -10-mV shift, the decrease in SR is entirely attributable to a decrease in DDR, which is reduced from 92 to 84 mV/sec (Figure 4A). The effect of the 1% or 2% Ipst is less straightforward (Figure 4B). On the one hand, there is an increase in action potential duration (APD100), eg, from 168 to 225 ms at 2% Ipst, which tends to decrease SR. On the other hand, there is an increase in DDR, eg, from 92 to 97 mV/sec at 2% Ipst, which tends to increase SR. However, the increasing effect of increased DDR on SR is by far outweighed by the decreasing effect of increased APD100.
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max, maximal upstroke velocity.Because several studies report Ipst values of 4% to 6% (see online Table 1), we extended our experiments by examining the effects of Ipst >2%, both alone and in combination with the -10-mV shift. Increasing Ipst to 3% (Figure 5A) critically disturbed the balance between inward and outward currents, resulting in oscillations at plateau potentials and failure to repolarize to MDP.
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Taking into consideration that 1795insD carriers have 1 normal and 1 mutant allele, we repeated the above computations under conditions of 50% wild-type and 50% 1795insD channels. In case of 1% to 2% Ipst, the effects on SA node AP parameters were similar but less pronounced compared with 100% mutant channels (not shown). At 3% Ipst, the plateau oscillations were no longer observed (Figure 5B). These oscillations and failure to repolarize occurred on increasing Ipst to 5% to 6% (not shown).
Next, to investigate to what extent our simulation results depend on the particular INa equations or AP model used, we carried out simulations with our model with the original INa equations replaced with those by Luo and Rudy15 and the peripheral SA nodal cell model by Zhang et al.17 As in our initial simulations (Figures 3 through 5), the negative shift decreased DDR, whereas Ipst prolonged APD (not shown), both causing an increase in CL. However, the effects on CL were more pronounced, both with INa composed of 100% mutant channels (Figure 6A) and with INa composed of 50% mutant and 50% WT channels (Figure 6B). In the latter case, for example, the -10-mV shift and 2% Ipst increased CL by 4.6, 8.2, and 16.3% for our model (open bars), our model with Luo-Rudy INa (gray bars), and the model by Zhang et al (solid bars), respectively. The larger effects on CL can be readily explained by the larger INa under control conditions: INa peak amplitude in voltage clamp is 31, 44, and 258 pA/pF, respectively. In all models, the phenomenon of plateau oscillations and failure to repolarize was observed (crosses in Figures 6A and 6B).
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, Plateau oscillations and failure to repolarize completely. Note differences in ordinate scales.Finally, to investigate to what extent our simulation results depend on the intrinsic rate of the (rabbit) AP model, we carried out additional simulations with the peripheral SA nodal cell model by Zhang and colleagues17,18 (50% mutant and 50% wild-type channels). This model allows for physiological control of intrinsic rate by application of acetylcholine (ACh), which, in a concentration-dependent manner, depresses the L-type calcium current, shifts the activation curve of the hyperpolarization-activated current If, and activates the ACh-induced potassium current IK,ACh.18 Figure 7 shows the computed effects of Ipst and the -10-mV shift on SA nodal pacemaking in the Zhang et al model in the absence (left) and presence (right) of 100 nmol/L ACh. Application of ACh slightly shortened APD and markedly decreased DDR, resulting in an increase in intrinsic cycle length (Figure 7A). As in our previous simulations, the negative shift affects DDR by reducing net inward current during the final phase of repolarization. Because this net inward current is already small in the presence of ACh, as apparent from the reduced DDR (Figure 7A, right), the net effect on CL is larger than in the absence of ACh (Figure 7B). As before, Ipst modulates CL by reducing net outward current during the action potential plateau. In the presence of ACh, the increase in CL is slightly smaller than in the absence of ACh (Figures 7C through 7E). In combination, the effects of the negative shift and Ipst are again almost additive (Figures 7F through 7H). When normalized to intrinsic cycle length, the effects of the shift on CL are more prominent in presence of ACh than in absence thereof, whereas the effects of Ipst are less prominent (Figure 6B, solid bars, and Figure 6C). Because intrinsic cycle length increases with increasing concentrations of ACh,18 Figure 6C also shows that the combined effect of the negative shift and Ipst on the percent decrease in sinus rate (or percent increase in CL) is more pronounced at lower intrinsic sinus rate. In other words, our simulations predict that the bradycardic effect of the 1795insD mutation is more pronounced at low sinus rate, which is in agreement with clinical observations (see Table 2 of Reference 9).
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Discussion |
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Mechanism of Sinus Rate Reduction
In the present study, we describe the effects of the biophysical properties of 1795insD mutant Na+ channels on sinoatrial node electrical activity using rabbit SA node action potential models (and action potential clamp experiments). Our main finding is that the most prominent characteristics of 1795insD mutant Na+ channels—the presence of a persistent inward current and a negative shift in voltage-dependence of inactivation—cause a reduction in sinus rate, both separately and in combination. Our study provides insight into the mechanism by which slowing of sinus rate is being effected.
In the computational model, the contribution of wild-type Na+ channels to SA node automaticity is limited to the diastolic depolarization phase. Because of the moderately negative MDP (near -60 mV) of central SA node cells, most Na+ channels reside in the inactivated state and are not available for activation. In fact, Na+ channel activity is only present in the voltage range of the Na+ window current, where activation and inactivation relationships overlap. Consequently, Na+ channels generate a small inward current at voltages between -60 and -40 mV, thus normally contributing only to diastolic depolarization. Action potential clamp experiments in HEK-293 cells expressing wild-type channels confirmed that little inward current was present during the entire SA nodal AP. Unfortunately, technical limitations (current noise, possible minor offset in zero-current level) prevent detection of current as small as the wild-type sodium current that would flow during diastolic depolarization, as predicted by the SA node AP model (0.06 pA/pF; Figure 3A, middle, solid line).
The negative shift in voltage dependence of inactivation of the 1795insD mutant Na+ channel narrows the voltage range of Na+ window current and thus reduces Na+ inward current during the diastolic depolarization phase. This results in a slowing of diastolic depolarization, thereby increasing the duration of this phase and reducing sinus rate.
A different mechanism underlies the reduction in sinus rate resulting from the presence of persistent inward current. Because of the incomplete channel inactivation at prolonged depolarizations, a small number of (noninactivated) channels remains available for activation, and consequently, Na+ channel openings are present and persist at a very low probability over the entire voltage range of activation. First, this results in extra inward Na+ current during the final phase of diastolic depolarization, increasing diastolic depolarization rate. Second, this results in extra inward Na+ current during the upstroke of the AP, slightly increasing upstroke velocity. Finally and most importantly, this results in extra inward Na+ current during the plateau phase, thereby increasing APD. The overall effect is a slowing of sinus rate, indicating that the effect of increased APD by far outweighs the effect of increased DDR.
When persistent current and a shift in inactivation are combined, the extra net inward Na+ currents during the upstroke and the plateau of the AP are maintained but inward Na+ current during diastolic depolarization is reduced. In effect, this produces an extra reduction in sinus rate, because the negative shift in inactivation cancels out the increase in DDR induced by Ipst without affecting the Ipst-induced increase in APD. In line with the model calculations of Figure 3D, mutant channels in action potential clamp experiments indeed displayed a small, but substantial, inward sodium current during the upstroke and the plateau phase of the SA node AP.
During the plateau and diastolic depolarization phase, membrane resistance is relatively high. Therefore, small changes in current are sufficient to induce considerable changes in the time course of these phases of the action potential. The computational model predicts that the delicate balance of inward and outward currents during the plateau phase gets seriously disturbed when persistent current is increased to >2% (in case of 100% mutant channels). Beyond this critical level, extra net inward current results in oscillating behavior and failure to repolarize. With 50% mutant and 50% wild-type channels, all of the above described effects were qualitatively the same but less pronounced. For example, oscillating behavior and failure to repolarize occurred at 5% to 6% Ipst.
Sodium Current in Mammalian Sinoatrial Node
In the last 2 decades, a large body of information on the ionic mechanism underlying mammalian cardiac pacemaker activity has been obtained from animal experiments.16,21 The importance of Na+ channels in SA nodal pacemaking used to be debated, because INa was assumed to be small or absent in SA nodal cells.19,21 However, an increasing number of studies now report the presence of INa in adult SA nodal cells, up to densities of 100 pA/pF in the more peripheral cells.16 Moreover, experiments with the specific Na+ channel blocker TTX in rabbit SA node preparations clearly show a reduction in beating rate in the presence of the drug, providing evidence that INa actually contributes to SA node electrical activity.19,20,22–25 Also, the recent observations that mice heterozygous for knock-in KPQ-deletion (SCN5A/+) frequently exhibit sinus pauses and bradycardia26 additionally support a role for INa in SA node pacemaking in mammalian species.
The goal of this study was to unravel the mechanism by which sodium channel mutations, in particular the 1795insD mutation, may cause sinus bradycardia and the occurrence of sinus pauses in LQT3 patients. The relevance of the results presented here strongly depends on whether Na+ channels are actually present in human SA node cells. Because human SA node preparations are not available for in vitro experiments, little is known on the various ionic currents present and their relative contribution to pacemaking. However, there are strong indications that Na+ channels also play a role in sinus node automaticity in humans. Several descriptions of plant poisoning involve toxins (grayanotoxins, veratrum alkaloids, and aconitine) that affect the cardiac sodium channel and have an effect on heart rate.25,27 Interestingly, these toxins all induce a persistent inward current by inhibition of inactivation and cause significant bradycardia, among other symptoms. Also, the observation that flecainide, a sodium channel blocker that preferentially inhibits Na+ persistent inward current,28 increased heart rate in D1790G mutation carriers6 may provide additional evidence in favor of a role of Na+ channels in human SA node automaticity.
Comparison With Clinical Features
Apart from the 3 mutations for which sinus bradycardia was observed in presence of drugs (see Table 1 in the online data supplement), there are 5 LQT3 families for which sinus bradycardia and the occurrence of sinus pauses or arrest were explicitly described. In carriers of the KPQ5 and the K150010 mutation, mean heart rate (HR) was reduced by 17% to 19%5 and sinus pauses and arrest were observed.10 In carriers of the 1795insD mutation, mean HR was reduced by 9% and lowest mean HR by 13%.9 In one patient, long asystolic episodes up to 9 seconds were monitored. In carriers of the D1790G mutation, mean HR was also reduced by 9%, and 3 cases with sinus arrest were reported.6 In the E1784K family, sinus bradycardia was present in 3 carriers and occasional sinus pauses in 1 of them.7 Notably, all mutant Na+ channels associated with the above families displayed both a persistent inward current and a negative shift in inactivation.7,8,10,13,29–31 The various computer simulations performed all predict—independent of the particular SA node model, INa equations, and intrinsic cycle length—that this combination reduces sinus rate by increasing APD and slowing DDR. There are, however, quantitative differences. For example, with a shift of -10 mV and a Ipst of 2%, the reduction in SR varied between 4.4% and 22% in case of 50% mutant and 50% wild-type channels (Figures 6B and 6C). The model values for SR reduction compare well with those reported for the respective families. The computer simulations also predict that SA node cells start to oscillate at plateau potentials and fail to repolarize if Ipst is increased above a critical level. This phenomenon may represent the cellular correlate to sinus pauses or arrest. It suggests that intrinsic or extrinsic factors generating little additional net inward current during the plateau phase, either by decreasing outward current or increasing inward current, can induce the transition from relative bradycardia into sinus node dysfunction.
Summary
In summary, bradycardia presents an important factor in the genesis of lethal arrhythmias in LQT3 families. The far majority of LQT3 sodium channel mutations cause a persistent inward current. In about half of these mutations, this persistent current is accompanied by a negative shift in steady-state inactivation. We show that both a persistent inward current and a negative shift in inactivation slow sinus rate and do so through different mechanisms. In combination, the persistent current and the shift reduce sinus rate to a greater extent than each separately, their effects being almost additive. We conclude that LQT3 sodium channel mutations giving rise to a persistent inward current not only underlie QT-prolongation but also sinus bradycardia and sinus pauses. Moreover, in families with LQT3 sodium channel mutations in which the persistent current is accompanied by a negative shift in inactivation, sinus bradycardia is aggravated.
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Acknowledgments |
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This research was supported by grants from the Netherlands Organization for Scientific Research (ZonMW 902-16-193) and the Netherlands Heart Foundation (NHS 200.059).
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Footnotes |
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*Both authors contributed equally to this study.
Received April 12, 2002; revision received March 21, 2003; accepted March 21, 2003.
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References |
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