(Circulation. 2000;101:1698.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Flecainide in Patients With New SCN5A Mutation
Mutation-Specific Therapy for Long-QT Syndrome?
From the Department of Cardiology (J.B., R.T., I.W., A.M.), Bikur Cholim Hospital, and the Department of Genetics (M.G., B.K.), the Hebrew University, Jerusalem, Israel; and the Department of Pharmacology (R.S.K.), Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to J. Benhorin, MD, The Heiden Department of Cardiology, Bikur Cholim Hospital, PO Box 492, Jerusalem 91004, Israel. E-mail benhorin{at}md2.huji.ac.il
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Abstract |
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Background—Mutations in the cardiac sodium channel gene (SCN5A) can cause one variant of the congenital long-QT syndrome. The effects of some of these mutations on the
-subunit channel properties can be blocked by
type Ib antiarrhythmic drugs. Recently, we have described a new
SCN5A mutation (D1790G) that affects the
channel properties in a manner suggesting that sodium blockers of the
Ib type will be ineffective in carriers of this mutation. Hence, the
ECG effects of flecainide-acetate, a type Ic sodium blocker, were
evaluated in carriers of this mutation. Methods and Results—Eight asymptomatic mutation carriers and 5 control subjects were studied. Intravenous lidocaine was tested first in only 2 mutation carriers and had no significant effect on any ECG parameter. Flecainide significantly shortened all heart rate–corrected repolarization duration parameters only in carriers and not in control subjects: QTc shortened by 9.5% (from 517±45 to 468±36 ms, P=0.011), and the S-offset to T-onset interval shortened by 64.7% (from 187±88 to 66±50 ms, P=0.0092). Flecainide also normalized the marked baseline repolarization dispersion in most mutation carriers. These effects among carriers were maintained during long-term (9 to 17 months) outpatient flecainide therapy with no adverse effects.
Conclusions—This report is the first to describe SCN5A mutation carriers who significantly responded to flecainide therapy yet did not respond to lidocaine. These results have important implications for long-QT allele–specific therapeutic strategies.
Key Words: long-QT syndrome • genetics • sodium (ion) channels
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Introduction |
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The long-QT (LQT) syndrome is an inherited cardiac disorder associated with prolonged ventricular repolarization and a propensity for recurrent syncope and sudden cardiac death caused by malignant ventricular arrhythmias.1 2 Initial linkage studies have demonstrated genetic heterogeneity in this disorder3 4 whereas currently, LQT has been linked to at least 5 chromosomal loci: 11p15.5 (LQT-1), 7q35-36 (LQT-2), 3p21-24 (LQT-3), 4q25-27 (LQT-4), and 21q22.1-22.2 (LQT-5), with several mutations reported for all loci except LQT-4.5 6 7 8 9 10 11 12 13 The SCN5A gene, which in its mutant forms causes LQT-3, encodes the
-subunit of the human cardiac sodium
channel.14 15 16 Three SCN5A mutations have
been reported to cause LQT syndrome in several North American and
European families8 9 : a 9 base-pair deletion
(
-KPQ) and 2 missense mutations (R1644H and
N1325S). An additional sporadic SCN5A mutation
(R1623Q) has been identified in
Japan.17
These mutations of the SCN5A gene prolong repolarization by
promoting sodium entry into myocardial cells during the plateau phase
of the action potential.18 19 Hence, it has been
hypothesized that sodium cannel blockers might shorten
ventricular repolarization in LQT-3. Such an effect was
demonstrated by Schwartz et al,20 who reported shortening
of the QT interval in 7 -KPQ mutation carriers by administration of
oral mexiletine. Rosero et al21 reported QT interval
shortening in 2 carriers of the -KPQ mutation by short-term
administration of intravenous lidocaine and long-term
tocainide therapy. A functional study of the -KPQ mutation
subsequently demonstrated that lidocaine can inhibit the plateau-phase
sodium current leak.22 Recently, we have described a large
LQT-3–affected kindred with a new SCN5A mutation:
D1790G.23 Further functional cellular
studies of the D1790G mutation have suggested that type Ib
sodium blockers might be ineffective in carriers of this
mutation.24 Thus, the purpose of this study was to
evaluate the effects of short-term and long-term oral
flecainide-acetate therapy (type Ic sodium blocker) in carriers of this
mutation.
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Methods |
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Patient Population
The study population consisted of 8 medication-free asymptomatic carriers of the D1790G SCN5A mutation (4 female subjects) and 5 control subjects (3 female subjects). All carriers were members of a single, large, Jewish, LQT-3–affected family that has been previously described in detail.3 25 LQT-related sudden death has been diagnosed in 5 family members (1 documented, 2 highly probable, and 2 probable).
Currently, the D1790G mutation has been identified in 26 family members (8 of whom participated in this study) and has been excluded in 49. All currently living family members except 1 are asymptomatic. All control subjects were patients who were followed in an outpatient clinic after a single, remote, self-terminated bout of paroxysmal atrial fibrillation that was treated with oral flecainide-acetate. The study was approved by the Institutional and the Israeli Ministry of Health Human Subjects Review Boards, and all subjects provided informed consent for the study that was conducted in the Heiden Department of Cardiology at Bikur Cholim Hospital, Jerusalem.
Study Protocol
All drug trials among mutation carriers were performed
in-hospital over a period of 8 days. Intravenous lidocaine
was tested first in only 2 mutation carriers; oral flecainide-acetate
was tested then in all 8 carriers and the 5 control subjects. Lidocaine
was given as an intravenous bolus at a dose of 1 mg/kg,
followed by an infusion at a rate of 3 mg/min for 2 hours. Twelve-lead
ECG recordings were recorded every 15 minutes for 6 hours,
starting 2 hours before and ending 2 hours after lidocaine
administration. Twenty-four hours after lidocaine administration, all
carriers were first studied in a drug-free state for 24 hours by
multiple 12-lead ECG recordings and a 24-hour Holter
recording (Burdick Inc, digital recorder).
Twelve-lead ECG recordings were repeated every 6 hours during the whole hospitalization period at prespecified hours to get a representative sample of the measured repolarization parameters that accounts for possible circadian changes. Oral flecainide-acetate (75 to 150 mg) was administered twice daily after the first drug-free 24 hours for 6 consecutive days. On the sixth day, a 24-hour Holter recording was repeated. All carriers were discharged while receiving flecainide therapy (75 to 100 mg twice daily) and were followed in the outpatient clinic every 4 weeks for 9 to 17 months. All control subjects were started on flecainide-acetate therapy (100 to 150 mg twice daily) in the outpatient clinic on an ambulatory basis while having at least 6 baseline ECG recordings showing sinus rhythm in a drug-free state before the initiation of the study. Multiple 12-lead ECGs were recorded over several weeks among control subjects both before and after flecainide therapy. Control subjects did not receive any additional drugs except aspirin or coumarin. All control subjects were kept on flecainide therapy for 9 to 17 months with good clinical response. Flecainide plasma levels (therapeutic range 200 to 1000 ng/mL) were determined 3 to 6 hours after the last dose by a fluorescence polarization immunoassay (TDx Flecainide Assay System, Abbott Laboratories) in all carriers and control subjects after 6 to 7 days of flecainide oral therapy, while receiving a stable dose.
ECG Parameters
ECG parameters were manually measured on 4 to 5 ECG
recordings per patient for each off-drug period (second 24
hours for carriers, 1 to 5 weeks before flecainide therapy for control
subjects) and on-drug period (sixth day on therapy for carriers, 1 to 5
weeks on therapy for control subjects). Averages of off-drug and
on-drug values were then compared by use of a 2-sided, paired
t test. ECG parameters included the following
intervals: R-R, PR, QRS, QT, QTa, SoTon, and
SoTof. All were measured in limb lead II (lead III in patients with
dextrocardia) on 3 consecutive beats and averaged. Repolarization
parameters (QT, QTa, SoTon, SoTof)
were corrected for heart rate by the use of Bazett’s formula. Holter
recordings were analyzed for ventricular
ectopic activity and for mean heart rate, its standard deviation, and
its 24-hour distribution.
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Results |
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Baseline Clinical Characteristics
Familial relations among the studied carriers and other features of their families are described in Figure 1
. All control subjects had normal left
ventricular function and a history of paroxysmal atrial
fibrillation: 2 had mild hypertension, 2 had mitral valve disease, and
1 had ischemic heart disease. Carriers were significantly
younger than control subjects (32±12 vs 64±11 years, respectively,
P=0.0013).
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Lidocaine Effects
Lidocaine effects were first tested in only 2 carriers (Table 1). There was no
significant effect of lidocaine on any of the measured ECG
parameters, including all those related to repolarization
duration (QT, Q onset to T-wave offset; QTa, Q
onset to T-wave apex; SoTon, S offset to T-wave onset; SoTof, S offset
to T-wave offset; subscript c as in SoTonc and
SoTofc denotes heart rate correction according to
Bazett).
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Baseline ECG Characteristics
Most baseline ECG characteristics differed between carriers and
control subjects (Table 2). QRS duration
and the PR interval were significantly more prolonged among carriers
than among control subjects. QTc and all other
repolarization duration parameters were significantly more
prolonged (P<0.01) as well among carriers than among
control subjects, except for SoTonc (borderline
statistical significance).
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Flecainide Effects
The average daily flecainide dose was higher in control subjects
than in carriers (260±55 vs 188±23 mg, respectively), as were their
corresponding flecainide plasma levels (806±110 vs 491±164 ng/mL,
respectively, P=0.002).
A representative example of a 12-lead ECG pair
(baseline vs flecainide) in mutation carrier No. 5 is presented
in Figure 2. As can be noted, flecainide
induced some increase in heart rate, a marked shortening of
repolarization duration, a normalization of most baseline T-wave
abnormalities, and a prominent decline in T-wave amplitude in most
leads. Figure 3 depicts an example of the
marked repolarization heterogeneity at baseline and its
normalization with flecainide: The marked dispersion of repolarization
duration as well as that of T-wave morphology and amplitude at baseline
all normalized with flecainide, along with some increase in heart rate.
Individual responses among all carriers and control subjects are
depicted in Figure 4.
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) and control subjects (n=5, 
).
A summary of flecainide effects on ECG parameters of
interest among control subjects and carriers (pooled results) is
provided in Table 3 and Table 4, respectively. Flecainide significantly
prolonged the QRS, PR, QT, QTc, and
QTa-c intervals, whereas it had no significant
effects on R-R and all other heart rate–corrected repolarization
parameters among control subjects (Table 3).
However, among carriers, flecainide caused a decrease in R-R interval
(P=0.015), a significant PR and QRS interval prolongation,
and a significant shortening (P<0.03) of all repolarization
duration parameters (Table 4):
QTc decreased from 517±45 to 468±36 ms,
respectively (a 49-ms [9.5%] decrease), and the
QTa-c decreased by 49 ms (10.8%).
SoTonc, and SoTofc, both of
which do not contain the QRS interval, decreased by 64.7%, and 16.5%,
respectively. A graphic presentation of flecainide effects
on heart rate–corrected repolarization parameters among
carriers and control subjects is depicted in Figure 5.
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Flecainide effects on all measured ECG parameters did not
significantly change during long-term (9 to 17 months) follow-up in
carriers and control subjects. Twenty-four–hour Holter monitoring
before and after flecainide administration was performed only among
carriers. Preflecainide and postflecainide recordings did not
reveal any ventricular ectopic activity in all carriers.
Holter recordings were suitable for heart rate analysis
in only 5 of 8 carriers (Table 5).
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Flecainide induced a significant decrease in mean R-R interval only in
3 carriers. Figure 6 depicts the R-R
interval histograms (baseline vs flecainide) in mutation carrier No. 7.
As can be noted, flecainide induced a marked shift to the left of the
R-R histogram that corresponds to increased heart rate, mainly by
eliminating its right-sided tail.
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Discussion |
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The main findings of this study indicate that short-term and long-term flecainide therapy induced significant shortening of repolarization among LQT-3–affected patients who are carriers of the D1790G mutation. It is also the first report of SCN5A mutation carriers who did not exhibit repolarization shortening with intravenous lidocaine.
Functional Cellular Studies of SCN5A
Mutations
Previously studied SCN5A LQT-3 mutations have been
shown to encode voltage-gated -subunit sodium channels that fail to
completely inactivate during prolonged
depolarizations.17 18 19 22 25 Hence, it was predicted
and then verified in clinical20 21 as well as
cellular17 18 19 22 26 27 studies that type Ib sodium
blockers such as lidocaine can normalize the defective channel
properties caused by these previously reported mutations. However, the
functional consequences of the D1790G LQT-3 mutation were
somewhat different. There was little effect on the biophysical
properties of monomeric -subunits of the sodium channel, whereas a
significant effect was observed in heteromeric channels formed by
coexpression of -subunits and ß1-subunits:
It did not promote a detectable sustained inward sodium current but
rather caused a negative shift in steady-state
inactivation.24 Therefore, it was predicted that
carriers of the D1790G mutation will not respond to
lidocaine, as do carriers of other SCN5A mutations. The lack
of response to lidocaine in 2 carriers in the present study was
therefore not surprising. However, in view of the fact that the
findings of the functional cellular study of the D1790G
mutation24 do not fully explain the phenotype
(prolonged QT) in carriers of this mutation, further characterization
of this mutation in cellular models, preferably with flecainide, are
needed.
Specific ECG Effects of Flecainide Among Mutation Carriers
At baseline, carriers had, as expected, significantly more
prolonged heart rate–corrected repolarization duration
parameters than did control subjects. However, they also
had significantly more prolonged PR and QRS intervals, though still
within normal limits. Thus, despite the fact that the functional
cellular study of the D1790G mutation was conducted with
holding potentials of near -90 mV,24 this mutation
probably does have some effect on channel availability in
ventricular cells (that have similar resting potentials).
Flecainide-induced shortening of repolarization duration
parameters among carriers was most pronounced in terms of
the SoTon interval (64.7% reduction, P=0.0092). The fact
that QTc significantly shortened among carriers
but "only" by 9.5%, whereas it became more prolonged among control
subjects, is related to the flecainide-induced QRS prolongation that
was observed among both carriers and control subjects. In fact, the
heart rate–corrected S offset to T offset
(SoTofc) interval, which excludes the QRS, did
shorten with flecainide by 16.5% (P=0.045) only among
carriers. Corrective effects of flecainide on repolarization appeared
to be more prominent among carriers with more pronounced
QTc prolongation at baseline (Figure 4
).
This trend might be related to the effects of modifier genes (undefined
yet) or to possible flecainide effects on ionic channels other than
SCN5A. Flecainide-induced normalization effects on the
marked dispersion of repolarization among carriers in this study were
most pronounced (Figure 3). These effects were not
systematically quantified because of the complexity of the baseline
repolarization dispersion observed: dispersion of duration, amplitude,
and morphology, all of which tended to normalize with flecainide. The
mild effect of flecainide on heart rate in some carriers provides, for
the first time, some evidence that could indirectly explain the
propensity of sinus bradycardia in some variants of LQT syndrome,
especially LQT-3. This might be related to the fact that mutated sodium
channels could be functionally active in the sinus node or nearby
cells. Because sinus node cells are chronically depolarized in
comparison to ventricular cells that are fully polarized,
sinus node cells may be more susceptible to a mutation-induced decrease
in sodium channel availability. This may cause slowing of heart rate,
which is a central phenotypic feature of several LQT variants.
Interestingly, several family members of the mutation carriers reported
in this study do have a relatively slow heart rate, including 3 cases
with documented sinus arrest.
Possible Mechanisms of Flecainide Effects Among Mutation
Carriers
Flecainide, as other type Ic agents, dissociates (unblocks)
relatively slowly after it binds primarily to activated sodium
channels28 and is capable of producing strong
use-dependent block of sodium channels.29 Several previous
studies by Antzelevitch et al30 31 have demonstrated that
epicardial, endocardial, and M cells are
electrophysiologically
heterogeneous, whereas the effects of sodium channel
blockade are heterogeneous across different myocardial
layers.32 Flecainide has been shown to cause either
prolongation or marked abbreviation of action potential duration in
epicardial cells but only a slight prolongation or abbreviation in
endocardial cells in a canine cellular model.33 This
differential effect on action potential duration was more pronounced at
faster stimulation rates. Therefore, one can hypothesize that the
electrophysiological derangement in
D1790G mutation carriers differentially affects different
myocardial layers, depending on the functional distribution of
-subunits and ß1-subunits of the mutated
sodium channel in these layers. The differential effects of flecainide
might be "reciprocal" to the effects of the D1790G
mutation, thereby allowing the drug effects demonstrated among carriers
in this study. In addition, because the transient outward current
(Ito) has been shown to be expressed
differentially across the myocardial wall30 and
flecainide has been shown to block channels encoded by the Kv4.2
-subunit, a major molecular determinant of
Ito,34 it is possible
that Ito block contributed to the
therapeutic effects of flecainide demonstrated in this study. The exact
mechanism by which flecainide exerts its functionally corrective
effects on D1790G-mutated channels is not clear currently
and probably will be better defined by further functional cellular
studies with flecainide in mutant cells carrying the D1790G
and other LQT-3–related SCN5A mutations.
Study Limitations
Flecainide effects were studied among a limited number of
carriers and control subjects. However, the observed effects were
significantly different between carriers and control subjects. All
control subjects had paroxysmal atrial fibrillation; however, none had
other concomitant disorders such as the sick sinus syndrome that might
be familial. Control subjects were significantly older than mutation
carriers, yet this imbalance is overweighed by the fact that none had
baseline conduction abnormalities that might be age related.
Clinical Implications
The results of the present study indicate that flecainide
significantly shortened repolarization among D1790G mutation
carriers and not among control subjects. Flecainide also had corrective
effects on repolarization dispersion and some mild effects on heart
rate, all of which were maintained during long-term therapy without
adverse effects. These salutary effects are encouraging, yet whether
they can be associated with symptomatic and prognostic
improvement among carriers must await further larger-scale controlled
clinical trials. The fact that this is the first report to describe
SCN5A mutation carriers who did not respond to
intravenous lidocaine yet significantly responded to oral
flecainide therapy indicates a possible by-mutation
heterogeneity that might exist in LQT-3. However, just
recently, after the completion of this study, flecainide effects
similar to those we describe here have been observed in 4 LQT-3
patients who are carriers of the -KPQ mutation (A.J. Moss, personal
communication). Therefore, further studies that will assess the effects
of flecainide in LQT-3–affected patients who are carriers of other
SCN5A mutations are needed to finally determine whether the
flecainide effects demonstrated in this study are mutation specific or
gene specific. The results of such studies together with the results of
this study will have important implications for strategies to treat LQT
with a gene-specific approach. We do not recommend the use of
flecainide in the Brugada syndrome,35 which has been
associated with other SCN5A mutations that cause a loss of
function as opposed to a gain of function caused by most LQT-3–related
SCN5A mutations.
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Acknowledgments |
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This study was supported in part by National Institutes of Health grant 5R01-HL-33843.
Received April 28, 1999; revision received October 8, 1999; accepted October 21, 1999.
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J.-F. Desaphy, A. D. E. Luca, M. P. Didonna, A. L. George Jr, and D. C. Camerino Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state-dependent block J. Physiol., January 15, 2004; 554(2): 321 - 334. [Abstract] [Full Text] [PDF]
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M. W. Veldkamp, R. Wilders, A. Baartscheer, J. G. Zegers, C. R. Bezzina, and A. A.M. Wilde Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families Circ. Res., May 16, 2003; 92(9): 976 - 983. [Abstract] [Full Text] [PDF]
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P. E. Light, C. H.R. Wallace, and J. R.B. Dyck Constitutively Active Adenosine Monophosphate-Activated Protein Kinase Regulates Voltage-Gated Sodium Channels in Ventricular Myocytes Circulation, April 22, 2003; 107(15): 1962 - 1965. [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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H. Liu, M. Tateyama, C. E. Clancy, H. Abriel, and R. S. Kass Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide: Evidence from the Analysis of Disease-linked Mutations J. Gen. Physiol., June 24, 2002; 120(1): 39 - 51. [Abstract] [Full Text] [PDF]
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S. G. Priori, C. Napolitano, P. J. Schwartz, R. Bloise, L. Crotti, and E. Ronchetti The Elusive Link Between LQT3 and Brugada Syndrome : The Role of Flecainide Challenge Circulation, August 29, 2000; 102(9): 945 - 947. [Abstract] [Full Text] [PDF]
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H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]
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X. H. T. Wehrens, H. Abriel, C. Cabo, J. Benhorin, and R. S. Kass Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel {alpha}-Subunit : A Computational Analysis Circulation, August 1, 2000; 102(5): 584 - 590. [Abstract] [Full Text] [PDF]
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