Published online before print December 2, 2008, doi: 10.1161/CIRCEP.108.788349
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Original Articles |
Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel
From the Department of Medicine (D.W.W., A.L.G.), Vanderbilt University, Nashville, Tenn; Section of Cardiology (L.C., P.J.S.), Department of Lung, Blood and Heart, University of Pavia; Department of Cardiology (L.C., P.J.S.) and Molecular Cardiology Laboratory (L.C., M.P., P.J.S.), IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy; Division of Cardiology (W.S.), Department of Internal Medicine, Department of Pediatric Cardiology (K.K., A.M.), Department of Perinatology (T.I.), National Cardiovascular Center, Osaka, Japan; Department of Cardiology (F.C., P.D.F.), Ospedali Riuniti, Bergamo, Italy; Department of Pharmacology (A.L.G.), Vanderbilt University, Nashville, Tenn.
Correspondence to Alfred L. George Jr, MD, Division of Genetic Medicine, 529 Light Hall, Vanderbilt University, Nashville TN 37232-0275. E-mail al.george{at}vanderbilt.edu
Received April 24, 2008; accepted September 15, 2008.
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Abstract |
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Background— Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity.
Methods and Results— Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by 
10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block (5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant.
Conclusions— Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting.
Key Words: antiarrhythmia agents • arrhythmia • death, sudden • heart arrest • ion channels
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Introduction |
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Sudden unexplained death attributable to cardiac arrhythmia may occur at any age. When death occurs during infancy for no apparent reason, a diagnosis of the sudden infant death syndrome (SIDS) may be appropriate.1,2 Recent evidence suggests that 9% to 10% of SIDS victims carry germ line mutations in arrhythmia susceptibility genes such as those associated with the congenital long-QT syndrome (LQTS).3 Anecdotally, ventricular arrhythmias occurring during the perinatal or neonatal periods are associated with a poor prognosis and a low survival rate.4–7 Whether cardiac arrhythmia susceptibility presenting in early life represents a biologically distinct disease is an unanswered question.
Clinical Perspective see p 370
Mutations in SCN5A encoding the cardiac voltage-gated sodium channel NaV1.5 have been associated with a spectrum of increased sudden death risk extending from fetal life to adulthood. Recurrent third trimester fetal loss has been observed in the setting of occult SCN5A mutations.8 In older children and adults with LQTS of known genotype, only 10% carry mutations in SCN5A,9–11 but the proportion of SCN5A mutations among SIDS victims with an LQTS gene defect approaches 50%.3 Further, among older children and adults with LQTS those individuals harboring SCN5A mutations exhibit a greater likelihood of severe symptoms including sudden death when compared with the majority of individuals who carry mutations in 2 potassium channel genes (KCNQ1, KCNH2).9,11 The higher proportion of SCN5A mutations among SIDS victims with known genotype when compared with older LQTS subjects might be explained by negative selection for more deleterious alleles. Support for this hypothesis requires evidence that mutations with greater functional consequences are responsible for severe and earlier onset arrhythmia syndromes.
Here, we present an extensive characterization of a novel SCN5A mutation that occurred de novo in unrelated and ethnically distinct newborns. In mutation carriers, life-threatening ventricular arrhythmias occurred within hours of birth. The mutation caused a profound degree of sodium channel dysfunction that was more severe than that observed for any previous SCN5A variant. Despite the extreme nature of the mutation and the associated dire clinical scenario, the subjects survived owing to prompt therapeutic interventions including treatment with the combination of mexiletine and propranolol, 2 drugs that exhibited enhanced and additive activity against the mutant allele. These observations illustrate the role of severe sodium channel mutations in a malignant perinatal variant of LQTS and successful use of combination pharmacotherapy to prevent perinatal mortality in this setting.
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Methods |
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Molecular Genetics
Informed consent for performing genetic studies was obtained using methods approved by the Ethics Review Board of IRCCS Fondazione Policlinico San Matteo (Pavia, Italy) or by the Institutional Research Board and Ethics Committee and the Committee on Genetic Analysis and Gene Therapy of the National Cardiovascular Center (Suita, Japan). Genomic DNA was isolated from whole blood and coding exons of SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2 were screened for genetic variants using previously described methods.12,13
Mutagenesis and Heterologous Expression of Na Channels
Mutations were engineered in a human heart sodium channel (NaV1.5) cDNA (hH1) using recombinant polymerase chain reaction. Final constructs were assembled in the mammalian expression plasmid pRc/CMV-hH1 and then sequenced to verify creation of the mutation and to exclude polymerase errors. Cells (tsA201) were transiently transfected with pRc/CMV-hH1 or mutants using FuGene6 (Roche Diagnostics) combined with a bicistronic plasmid (pEGFP-IRES-hβ1) encoding enhanced green fluorescent protein and the human β1 subunit (hβ1) under the control of the cytomegalovirus immediate early promoter. Additional methods are provided in an online supplement.
Statement of Responsibility
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Malignant Perinatal Arrhythmia Associated With a Novel SCN5A Mutation
We identified a novel SCN5A mutation in 2 unrelated newborns that experienced life-threatening perinatal ventricular arrhythmias. The first subject was an Italian male delivered by emergency C-section at 32-weeks gestation for abnormal fetal heart rhythm. Initially, he appeared healthy (APGAR score 8) but then, within hours of his birth, developed polymorphic ventricular tachycardia with periods of bradycardia and frequent premature ventricular beats. Initial treatments with intravenous magnesium and isoproterenol were not effective, but administration of intravenous lidocaine suppressed ventricular arrhythmias and restored sinus rhythm revealing a prolonged QTc interval (520 ms). Empirical treatment with propranolol (1.3 mg/kg/d) and mexiletine (11 mg/kg/d) controlled arrhythmias and normalized the QTc (410 ms) (Figure 1A). One month after discharge, the infant survived an episode of ventricular fibrillation. Ventricular arrhythmia was further controlled by rapid pacing (120 bpm) with increased dosages of propranolol (3 mg/kg/d) and mexiletine (16 mg/kg/d). During the following 12 months, the child exhibited no further ventricular arrhythmias but required recurrent hospitalizations for paroxysmal atrial flutter that was eventually controlled by ablation. The child has survived beyond the age of 26 months without further ventricular or atrial arrhythmias.
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The second proband was a Japanese male delivered by emergency C-section at 34-weeks gestation because of ventricular arrhythmia (torsade de pointes, TdP) documented in utero by magnetocardiography. Initial APGAR scores were 8 and 9, but his QTc interval was 567 ms and he had multiple episodes of TdP. Intravenous injection (3 mg/kg) followed by continuous infusion of mexiletine abolished TdP. He was discharged on oral mexiletine (20 mg/kg/d) but was readmitted for treatment of recurrent TdP approximately 2 months later (QTc=590 ms). Continuous infusion of mexiletine combined with oral mexiletine (serum drug concentration: 1.3 to 1.4 µg/mL) considerably abbreviated the QTc (462 to 499 ms) but did not completely suppress episodes of TdP. The addition of continuous infusion propranolol (0.5 mg/kg/d, serum drug concentration: 18.4 to 25.1 ng/mL) further shortened QTc (395 to 424 ms) and fully suppressed ventricular arrhythmias. Finally, combination therapy with oral mexiletine and oral propranolol was effective in suppressing ventricular arrhythmias through age 8 months (Figure 1A).
A novel SCN5A missense mutation (G1631D) was discovered in both probands (Figure 1B). Family histories were negative for arrhythmia syndromes. The results of ECG testing were normal for both sets of parents, and they were mutation negative. Paternity testing demonstrated that the mutation was de novo in both cases. No other mutations were identified in SCN5A, KCNQ1, KCNH2, KCNE1, or KCNE2 in either proband.
Profound Dysfunction of G1631D Channels
The mutation results in substitution of a highly conserved glycine residue with a negatively charged glutamic acid in the S4 segment of domain 4 (D4/S4; Figure 1C). This residue is 100% conserved in all known voltage-gated sodium channel sequences from several diverse phyla. This structural domain in sodium channels participates as a component of the voltage-sensor important for activation and inactivation.14,15 Introduction of a negatively charged side group into this domain was predicted to have a significant functional effect. To test this hypothesis, we engineered G1631D in recombinant human NaV1.5 for heterologous expression and then performed electrophysiological studies.
Figure 2 illustrates the general functional properties of wild-type (WT) and mutant NaV1.5 channels expressed heterologously in human tsA201 cells. Representative whole-cell current tracings demonstrate that the mutant exhibits a profound level of dysfunction characterized by substantial delays in activation and inactivation. Overall current density was similar between cells expressing WT or mutant channels but there was a positive shift in the peak current-voltage (I-V) relationship for the mutant (Figure 2C). Mutant channels exhibited increased steady-state persistent current measured 200 ms after the peak transient current (Figure 2D; persistent current as % of peak current: WT, 0.31±0.04%, n=8; G1631D, 1.63±0.31%, n=9; P<0.001). Although increased persistent current is characteristic of SCN5A mutations associated with LQTS,16,17 no previously characterized mutation had such a profound inactivation defect.
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Figure 3 illustrates quantitative assessments of activation and inactivation. Mutant channels exhibited a global slowing of activation across the range of tested potentials as assessed by time to peak current (Figure 3A). Similarly, G1631D exhibited a profound slowing of inactivation as illustrated by the voltage dependence of inactivation time constants (Figure 3B). The degree of slowing of inactivation was approximately 10-fold compared with WT. The mutant also exhibited significant depolarizing shifts in the voltage dependence of activation (+12 mV) and steady-state inactivation (+14 mV; Figure 3C and 3D; supplemental Table I, available online). These asymmetrical depolarizing shifts in activation and steady-state inactivation predict an increased window current defined as the overlap of these 2 curves (see Supplemental Figure I).
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In Figure 4A, the time course of recovery from inactivation after a 100-ms conditioning pulse illustrates that the mutant has profound slowing of recovery. This difference was explained by a larger slow component of recovery from inactivation as determined by double exponential fitting (see Supplemental Table I). For WT channels, the majority of recovery occurs with a time constant of approximately 10 ms. By contrast for G1631D channels, the predominant fraction of channels recover from inactivation with a time constant of approximately 100 ms. The marked slowing of recovery from inactivation exhibited by G1631D correlated with a greater loss of channel availability during repetitive membrane depolarizations at frequencies exceeding 1 Hz (Figure 4B).
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These profound gating abnormalities were correlated with aberrant single-channel events. Figure 5 illustrates representative single-channel recordings from cells expressing WT or mutant channels. Wild-type channels exhibited brief and transient openings clustered at the onset of the test depolarization. By contrast, the mutant exhibited a marked increase in probability of late reopenings and occasional prolonged openings (asterisk). Single-channel conductance levels were similar for WT (24pS) and G1631D (25pS), but mutant channels exhibited significantly longer latency to first opening (WT: 0.59±0.03 ms; G1631D: 1.15±0.03 ms; n=3; P<0.001), increased mean open time (WT: 0.34±0.09 ms; G1631D: 0.98±0.03 ms; n=3; P=0.029), and increased NPo (WT: 0.14±0.02; G1631D: 0.22±0.03; n=3; P=0.042) when assessed at a test pulse of –20 mV. Ensemble averaged currents derived from single-channel records closely resemble those obtained from whole-cell recordings. These findings collectively indicate that G1631D causes a fundamental defect in channel activation and inactivation associated with dramatic clinical consequences.
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Enhanced Mexiletine Sensitivity of G1631D Channels
Despite the profound nature of the sodium channel dysfunction caused by G1631D, both probands survived likely because of prompt intervention including pharmacological treatments. We compared the effect of mexiletine on WT and mutant channels. Figure 6A illustrates the responses of WT and G1631D to repetitive membrane depolarizations delivered at a frequency of 1 Hz in the presence of mexiletine (100 µmol/L). Both channels exhibited an initial drop in channel availability followed by further use-dependent loss of activity, but the effect is substantially greater for G1631D suggesting that the mutant has enhanced mexiletine sensitivity. Concentration-response relationships for tonic (Figure 6B) and use-dependent (Figure 6C) mexiletine block of WT and G1631D supported this hypothesis. Mexiletine block of WT channels exhibited EC50 values of 120.9 µmol/L and 50.9 µmol/L for tonic and use-dependent block, respectively. By contrast, G1631D was 1.8-fold and 2.8-fold more sensitive to tonic (EC50 66.7 µmol/L) and use-dependent (EC50 18.3 µmol/L) mexiletine block, respectively. Further, mexiletine induced a hyperpolarizing shift in steady-state inactivation of mutant channels such that this property became more similar to WT channels (G1631D V
: no drug, –74.8±1.1 mV, n=16; 3 µmol/L mexiletine, –85.5±1.3 mV, n=9; P<0.001). By contrast, the same drug concentration has no significant effect on steady-state inactivation of WT channels (WT V: no drug, –89.3±1.1 mV, n=16; 3 µmol/L mexiletine, –86.6±3.2 mV, n=6; NS). Mexiletine also had moderate effects on the kinetics of G1631D inactivation (Figure 6B and 6C), illustrated by significant reductions in the time constants for inactivation, and significantly reduced the level of persistent current (no drug: 1.63±0.31%, n=9; 10 µmol/L mexiletine, 0.54±0.06%, n=8; P=0.0098).
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1=7.7±0.7 ms, Propranolol Block of WT and G1631D Channels
We also considered the role of propranolol in modulating mutant sodium channel behavior. Propranolol is a widely used β-adrenergic receptor antagonist, but early studies indicated that this drug also exhibits antiarrhythmic (membrane stabilizing) properties at high serum concentrations possibly from effects on voltage-gated sodium channels.18,19 Figure 7A illustrates that both WT and G1631D channels are blocked by 3 µmol/L propranolol during repetitive stimulation (1 Hz). Mutant channels exhibited a greater degree of steady-state block than WT channels under these conditions. Concentration-response curves demonstrated that propranolol exerts greater tonic (Figure 7B) and use-dependent (Figure 7C) block of G1631D than that of WT channels. Propranolol use-dependent block was enhanced 5-fold by the mutation (EC50: WT, 3.0 µmol/L; G1631D, 0.6 µmol/L). The effect of propranolol, a racemic mixture, was not likely mediated through endogenous β-adrenergic receptors in the heterologous cell system because we observed similar blocking potency for R-(+)-propranolol, which has no receptor antagonist properties (see supplemental Figure II). Propranolol at a concentration similar to that observed in the Japanese proband (0.1 µmol/L) normalized steady-state inactivation of mutant channels (G1631D V
: no drug, –74.8±1.1 mV, n=16; propranolol, –84.5±1.7 mV, n=10; P<0.001) but had no effect on steady-state inactivation of WT channels (WT V: no drug, –89.3±1.1 mV, n=16; propranolol, –88.8±0.9 mV, n=5; NS). Propranolol did not affect the kinetics of inactivation for WT or mutant channels (Figure 7B and 7C) or the level of persistent current observed for G1631D (no drug: 1.63±0.31, n=9; 1 µmol/L propranolol, 1.44±0.29, n=9; NS).
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Because both probands responded clinically to the combination of mexiletine and propranolol, we tested the effects of both drugs together on G1631D channels. To closely simulate the clinical conditions, we tested use-dependent block at 2 Hz, which was the approximate resting heart rate of the Japanese proband and the frequency of cardiac pacing in the Italian child. The combination of mexiletine (10 µmol/L) and propranolol (0.3 µmol/L) caused a substantial loss of channel availability during a 2-Hz pulse train (Figure 8) when compared with the drug-free condition. The level of channel inhibition observed for the combination of mexiletine and propranolol was greater than either drug applied alone indicating additive effects.
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Discussion |
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During late fetal development through shortly after birth, there is a vulnerable period when death occurs at a rate of 6 to 12 per 1000 live births per year,20 and congenital arrhythmia susceptibility may be a significant contributor to this problem.21,22 Life-threatening cardiac arrhythmias during infancy and the perinatal period may go unnoticed owing to the lack of routine use of electrocardiographic monitoring of the fetus and newborn. Studies of 2 large series of autopsied SIDS victims demonstrated that up to 10% of SIDS cases may represent genetic disorders of congenital arrhythmia susceptibility such as the LQTS,3,23 short-QT syndrome,24,25 and catecholaminergic polymorphic ventricular tachycardia.26 Understanding the genetic risks for perinatal mortality should promote efforts to identify and treat at-risk newborns.
Malignant Perinatal Variant of LQTS
The profoundly dysfunctional SCN5A mutation, G1631D, produced a clinical entity distinct from typical LQTS (LQT3 subtype). Clinically, subjects with typical LQTS first develop symptoms (syncope, cardiac arrest, and sudden death) during late childhood, adolescence, or early adulthood.9,27 Many mutation carriers may in fact be asymptomatic. The 2 probands we described seem to be affected by a very severe and life-threatening process.
At the molecular level, most SCN5A mutations associated with LQTS cause a subtle gain-of-function defect characterized by increased persistent current.16,17 The markedly abnormal channel function we observed for G1631D including a 10-fold slowing of inactivation, substantial shifts in voltage dependence of activation and inactivation along with greatly impaired recovery from inactivation represent distinct molecular defects that distinguish this mutation from typical LQT3 alleles. Other SCN5A alleles may similarly predispose to early onset and severe perinatal arrhythmia syndromes,4,5,28,29 but the functional aberrations associated with most of these reported alleles resemble mutations found in older individuals.
Negative Selection Against SCN5A Mutations
Mutations in SCN5A are represented disproportionately among SIDS victims who carry occult congenital arrhythmia susceptibility gene mutations when compared with older LQTS subjects. The lower proportion of SCN5A mutations among older children and young adults with LQTS when compared with the higher proportion in SIDS victims may be the result of negative selection against mutations in the sodium channel gene. Negative selection would cause an ascertainment bias for genotypes in living individuals in whom survival is favored when carrying mutations having less severe physiological consequences. In the case of SCN5A-G1631D, we assumed that without immediate treatment, this mutation would have been lethal. However, survival after successful treatment confounds the argument for negative selection.
Congenital arrhythmia susceptibility occurring in the perinatal and neonatal periods caused by SCN5A mutations appears biologically distinct from LQTS in older subjects. Carriers of certain SCN5A mutations may present with earlier onset and severe congenital arrhythmia syndromes. An illustration of this idea is recurrent third-trimester fetal loss attributable to inheritance of an SCN5A mutation (R1623Q) from a mother who was mosaic for this deleterious allele.8 The R1623Q mutation, which affects a conserved residue in the D4/S4 segment nearby the location of G1631D, was originally identified in a Japanese child with a severe clinical presentation of LQTS,30 and the molecular defect associated with this allele compromised inactivation to a greater extent than typical LQT3 mutations.31 Our observations regarding the severity of biophysical defects associated with G1631D also support the idea that earlier onset cardiac symptoms may sometimes correlate with a severe molecular phenotype.
Genotype-Specific Pharmacological Treatment
The clinical consequences of G1631D were perinatal arrhythmias successfully managed in part by pharmacotherapy with the combination of mexiletine and propranolol. Mexiletine as well as other sodium channel blockers have been proposed as gene-specific therapeutic agents in LQT3.32–34 In vitro studies have demonstrated the capability of these drugs to selectively suppress increased persistent current conducted by mutant channels29,35 and to normalize ventricular repolarization in animal models.36,37 One study suggested that certain biophysical properties of mutant NaV1.5 channels may be predictive of mexiletine responsiveness. Specifically, Ruan et al38 found that among 4 distinct SCN5A mutations, clinical benefit from mexiletine treatment was observed only in subjects carrying mutations that caused a hyperpolarizing shift in steady-state inactivation and this correlated with in vitro effects of the drug. However, this observation cannot be extrapolated to all SCN5A mutations as evidenced by the favorable response of G1631D to mexiletine both clinically and experimentally despite a depolarizing shift in steady-state inactivation (Figure 3). Similarly, another recently reported SCN5A mutation (F1473C) was also associated with a favorable clinical response to high-dose mexiletine despite having depolarized steady-state inactivation.29 Additional factors besides those emphasized by Ruan et al38 are likely to determine the clinical efficacy of mexiletine.
By contrast, use of β-blockers in the setting of SCN5A mutations has less certain benefits. Three studies have reported that β-blockers are generally less efficacious in LQT3 subjects, but the specific drug used varies considerably.9,39,40 For example, in the report by Priori et al40 the specific β-blocker was known in 69% of cases, and this was either propranolol or nadolol. As we have demonstrated in this study, propranolol may offer specific advantages in treating certain SCN5A mutations because of apparent local anesthetic-like properties of the drug.18,19 By contrast, we recently determined that nadolol has no activity against sodium channels (Wang DW, unpublished observations, 2007). The role of propranolol in treating individuals with SCN5A mutations warrants further study.
Combination pharmacotherapy in the 2 probands with G1631D may have uniquely contributed to their survival. In the Japanese newborn, mexiletine alone was not adequate to control ventricular arrhythmia despite shortening of the QT interval. The addition of propranolol to the treatment regimen conferred better arrhythmia control and survival. In the Italian proband, the coadministration of mexiletine with propranolol was efficacious, but this subject was also treated with ventricular pacing. Our study demonstrated additive effects of the 2 drugs at a pulsing frequency of 2 Hz (Figure 8). This observation suggested that a combination of mexiletine with propranolol in the setting of modest tachycardia were protective of ventricular arrhythmia caused by G1631D. We explain this effect by a combination of the intrinsic activity-dependent loss of channel availability observed for G1631D (Figure 4B) with the use-dependent drug effects.
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Acknowledgments |
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The authors thank Thomas H. Rhodes for providing technical support and Shuji Hashimoto in the Laboratory of Clinical Physiology, National Cardiovascular Center, for technical assistance for MCG recordings.
Sources of Funding
This work was supported by a grant from the NIH (HL083374). Dr Shimizu was supported by a health sciences research grant (H18—Research on Human Genome—002) from the Ministry of Health, Labor, and Welfare, Japan.
Disclosures
None.
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The online-only Data Supplement is available at http://circep.ahajournals.org/cgi/content/full/1/5/378/DC1.
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