Download New Mutations in the KVLQT1 Potassium Channel That Cause Long

New Mutations in the KVLQT1 Potassium Channel That
Cause Long-QT Syndrome
Hua Li, PhD; Qiuyun Chen, PhD; Arthur J. Moss, MD; Jennifer Robinson, MS; Veronica Goytia, BS;
James C. Perry, MD; G. Michael Vincent, MD; Silvia G. Priori, MD; Michael H. Lehmann, MD;
Susan W. Denfield, MD; Desmond Duff, MD; Stephen Kaine, MD; Wataru Shimizu, MD;
Peter J. Schwartz, MD; Qing Wang, PhD; Jeffrey A. Towbin, MD
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Background—Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise
healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35–36 (LQT2), 3p21–24
(LQT3), and 4q25–27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium
channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A).
Methods and Results—After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP)
and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members
of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense
mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in
affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively
spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single
base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein.
Conclusions—We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause
the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and
character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act
through a loss-of-function mechanism or a dominant-negative mechanism. (Circulation. 1998;97:1264-1269.)
Key Words: arrhythmias n long-QT syndrome n potassium n death, sudden n KVLQT1
S
udden death from cardiac arrhythmias is thought to
account for 11% of all natural deaths.1,2 LQTS is an
inherited cardiac disorder that causes syncope, seizures, and
sudden death, usually in young and otherwise healthy individuals.3– 8 In many cases, the first symptom is sudden death.
Individuals with LQTS usually have prolongation of the QT
interval on electrocardiograms, an indication of abnormal
repolarization.5,9,10 The clinical features of LQTS result from
episodic ventricular tachyarrhythmias, specifically torsade de
pointes and ventricular fibrillation.9 –11
Inherited LQTS can result from at least five different
genes. Four genes were mapped to chromosome 11p15.5
(LQT1),12,13 7q35–36 (LQT2),14 3p21–24 (LQT3),14 and
4q25–27 (LQT4).15 Several other families with autosomal
dominant LQTS are not linked to any known LQTS loci
(unpublished data), indicating that additional LQTS locus
heterogeneity exists. Three LQTS genes (LQT1, LQT2, and
LQT3) were identified either by the candidate gene approach
or positional cloning. These include the cardiac potassium
channel genes KVLQT1 (LQT1),16 HERG (LQT2),17 and the
cardiac sodium channel gene SCN5A (LQT3).18,19 In addition,
mutations in KVLQT1 were shown to result in both RomanoWard syndrome (heterozygous mutations) and Jervell and
Lange-Nielsen syndrome (homozygous mutations).16,20 Wang
et al16 identified 11 different types of KVLQT1 mutations (one
3-bp deletion and 10 missense mutations) in 16 LQTS
families with Romano-Ward syndrome and, more recently,
Neyroud et al20 identified a homozygous insertion-deletion
mutation in Jervell and Lange-Nielsen syndrome.16 Here, we
report identification of new KVLQT1 mutations in affected
members of seven families with Romano-Ward syndrome.
We identified two identical missense mutations (one in a
Received June 5, 1997; revision received December 4, 1997; accepted December 5, 1997.
From Lillie Frank Abercrombie Section of Cardiology, Department of Pediatrics (H.L, Q.C., V.G., S.W.D., Q.W., J.A.T.), and Department of Molecular
and Human Genetics (J.A.T.), Baylor College of Medicine, Houston, Tex; Children’s Hospital and Health Center, San Diego, Calif (J.C.P.); Department
of Medicine, University of Rochester Medical Center, Rochester, NY (A.J.M., J.R.); Department of Medicine, LDS Hospital and University of Utah
School of Medicine, Salt Lake City (G.M.V.); Department of Cardiology, University of Pavia and Policlinico S. Matteo, IFCCS, Pavia, Italy (S.G.P.,
P.J.S.); Arrhythmia Center, Sinai Hospital, Wayne State University School of Medicine, Detroit, Mich (M.H.L.); Pediatric Cardiology, Our Lady’s
Hospital for Sick Children, Dublin, Ireland (D.D.); Pediatric Cardiology, Children’s Mercy Hospital, Kansas City, Mo (S.K.); and National Cardiovascular
Center, Osaka, Japan (W.S.).
Guest editor for this article was D. Woodrow Benson, MD, Seidman Laboratory, Boston, Mass.
Correspondence to Jeffrey A. Towbin, MD, Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030.
E-mail [email protected]
© 1998 American Heart Association, Inc.
1264
Li et al
LQTS
PCR
QTc
SSCP
April 7, 1998
1265
Selected Abbreviations and Acronyms
5 long-QT syndrome
5 polymerase chain reaction
5 QT interval on ECG corrected for heart rate
5 single-strand conformation polymorphism
white kindred and the other in a Japanese family), four
identical splicing mutations, and a 3-bp deletion that truncates
the KVLQT1 channel; the latter mutation arose de novo.
Methods
Identification of LQTS Patients
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LQTS patients were identified throughout North America, Europe,
and Asia, with the majority of patients being identified from the
International LQTS Registry established by the National Institutes of
Health at the University of Rochester, NY. Informed consent was
obtained from participants in 115 families in accordance with
standards established by local institutional review boards. For each
individual, historical data (the presence of syncope, the number of
syncopal episodes, the presence of seizures, the age of onset of
symptoms, and the occurrence of sudden death) and the length of the
QTc21 were obtained. Phenotypic criteria used were as follows: (1)
Individuals without any symptoms and with a QTc of #0.41 second
were classified as unaffected, (2) symptomatic individuals with a
QTc of $0.45 second and asymptomatic individuals with a QTc of
$0.47 seconds were considered affected, and (3) symptomatic
individuals with a QTc of #0.44 second and asymptomatic individuals with a QTc between 0.41 and 0.47 second were classified as
uncertain.12,14,16,18
Genomic DNA Samples and Linkage Analysis
Genomic DNA was prepared from peripheral blood lymphocytes or
cell lines derived from Epstein-Barr virus–transformed lymphocytes
by standard procedures.22
Genotypic analysis for paternity evaluation was performed with 15
short-tandem-repeat polymorphisms that were previously mapped to
15 different chromosomes (Genome Data Base). Amplification of
each short tandem repeat was carried out as previously described.14,16
SSCP Analysis
SSCP and DNA sequence analyses were used to screen for KVLQT1
mutations with DNA samples from 115 LQTS families. The partial
genomic structure of KVLQT1 was previously determined.16 Primers
(intronic sequences) that can PCR-amplify exons encoding transmembrane domains S2-S6 were defined previously from the partial
genomic structure and used in this study for SSCP analysis.16 PCR
was carried out in a 10-mL volume containing 50 ng genomic DNA,
0.52 mmol/L of each primer, 75 mmol/L of each dNTP, 1 mCi
[a-32P]dCTP, 0.24 mmol/L spermidine, 1.5 mmol/L MgCl2,
10 mmol/L Tris (pH 8.3), 50 mmol/L KCl, and 1 U Taq DNA
polymerase (Promega and Gibco-BRL). PCR amplification was
carried out in a Perkin-Elmer System 9600 thermocycler using the
following profile: 1 cycle of denaturation at 94°C for 5 minutes; 5
cycles at 94°C for 20 seconds, 64°C for 20 seconds, 72°C for 30
seconds; and 25 cycles of 94°C for 20 seconds, 62°C for 20 seconds,
72°C for 30 seconds; followed by a 5-minute extension at 72°C.
Amplified samples were diluted fivefold with 50 mL of formamide
buffer (95% formamide, 10 mmol/L EDTA, 0.1% bromphenol blue,
0.1% xylene cyanol) and 50 mL of 0.1% SDS/10 mmol/L EDTA.
The mixture was denatured at 94°C for 5 minutes, then cooled
rapidly on ice and held for 5 minutes. For each sample, 3 to 5 mL was
loaded onto 10% nondenaturing polyacrylamide gels (acrylamide to
bisacrylamide ratio550:1) and run at 8 W overnight at room
temperature. Gels were dried on Schleicher and Schuell filter paper
and exposed to x-ray film.
Figure 1. KVLQT1 splicing mutation cosegregating with LQT in
families F1002, F1003, F1004, and F1005. Pedigree structures
are shown. Individuals with characteristic features of LQT,
including prolongation of QT interval on ECG and history of syncope or aborted sudden death are indicated by solid circles
(females) or squares (males). Unaffected individuals are indicated by open symbols, and individuals with an equivocal phenotype by hatched symbols. Deceased individuals are indicated
by a slash. Results of SSCP analyses are shown below each
pedigree. Aberrant SSCP conformers are indicated by arrows.
Sequence analyses of normal (left) and aberrant (right) conformers revealed that all four families had an identical change, a G
to A substitution (SP/A249/g-a). This mutation occurs in splicedonor sequence of exon in S6 domain. PCR primers 9 and 10 in
Wang et al16 were used: 9, CCCCAGGACCCCAGCTGTCCAA;
and 10, AGGCTGACCACTGTCCCTCT.
DNA Sequencing
Both normal and aberrant SSCP bands were cut out of the gel and
rehydrated in 100 mL water for 30 minutes at 65°C. Ten microliters
of the eluted DNA was reamplified with the original PCR primers in
a total volume of 100 mL. Amplified products were purified through
2% low-melting agarose. These products were sequenced directly
with an ABI Sequencer or subcloned into PBluescript-SK(1) (Stratagene) by use of the T-vector method as described,23 and several
colonies were sequenced by the dideoxy chain termination method
with Sequenase Version 2.0 (United States Biochemicals, Inc).
Results
KVLQT1 Splicing Mutations Associated With
LQTS in Four Families
Aberrant SSCP conformers were identified in affected members of four families (F1002, F1003, F1004, and F1005; Fig
1); these SSCP anomalies were not observed in DNA samples
from unaffected members of these families (Fig 1) or from
more than 150 control subjects (data not shown). The pattern
of aberrant banding appeared to be similar in all four LQTS
families (Fig 1). Sequence analysis of the aberrant bands
revealed the presence of an identical splicing mutation, a
G-to-A substitution, in all four families. This substitution
occurs at the third position of codon A249 (SP/A249/g-a) and
1266
New KVLQT1 Mutations in Long-QT Syndrome
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Figure 2. KVLQT1 missense mutation identified in F1006 and
F1007. Results of SSCP analyses are shown below each pedigree, with aberrant SSCP conformer indicated by arrow.
Sequence analyses of normal (left) and aberrant (right) conformers reveal a C to T substitution at codon 246. This mutation
causes substitution of an alanine residue by a valine (A246V).
F1006 is a Japanese family and F1007 a white family. Same
mutation was previously reported in six other families.16,25 PCR
primers 9 and 10 in Wang et al16 were used (see Fig 1).
disrupts the splice-donor sequence within the S6 transmembrane domain. The fact that the same substitution cosegregated with the disease status in four unrelated LQTS families
(one Italian, one Irish, and two American) strongly suggests
this variant to be a mutation.
KVLQT1 Missense Mutations Associated With
LQTS in Two Families
SSCP analysis with a pair of primers in the S6 domain
revealed aberrant bands in affected members of families
F1006 and F1007 (Fig 2). These abnormal SSCP bands were
not seen in DNA samples from unaffected members of these
families (Fig 2) or from more than 150 control individuals
(data not shown). DNA sequence analysis of the normal and
aberrant conformers revealed that both F1006 and F1007 had
an identical missense mutation, a single base substitution (C to
T) (Fig 2). This mutation results in substitution of an alanine by
a valine at position 246 (A246V) within transmembrane domain
S6 (Fig 2C).
Figure 3. De novo mutation of KVLQT1 identified in sporadic
case of LQT. Pedigree structure of F1008 is shown. Results of
SSCP analyses are shown below pedigree. Aberrant conformer
is indicated by arrow. DNA sequence analysis identified a 3-bp
deletion (SP/V212/Dggt) spanning an exon-intron boundary in
pore region. This mutation results in a frame shift in KVLQT1
cDNA sequence, leading to a nonfunctional protein. Genotypic
analysis of this kindred using more than 15 polymorphic markers confirmed maternity and paternity. QTc intervals for proband,
proband’s father, and proband’s mother are 0.50, 0.39, and
0.36 second, respectively. PCR primers 7 and 8 in Wang et al16
were used: 7, TCCTGGAGCCCGAACTGTGTGT; and 8,
AGGCTGACCACTGTCCCTCT.
abnormal SSCP band identified a 3-bp deletion (SP/V212/
DGGT) spanning an exon-intron boundary in the pore region.
This deletion results in a frame shift and alters splicing,
leading to the truncation of the KVLQT1 protein. Genotypic
analysis of this family using more than 15 polymorphic
markers confirmed paternity.
Phenotype-Genotype Correlation
De Novo Intragenic Deletion of KVLQT1 in a
Sporadic Case of LQTS
Despite the genotypic differences found in these seven
families, the phenotype was fairly similar in all affected
individuals (Table 1). In six of seven families, the QTc was
.0.500 second; the seventh family had QTc measured in the
range of 0.490 to 0.493. In addition, six of seven families
were symptomatic, with episodes of syncope. Only the family
in which the QTc was ,0.500 second was without symptoms
(Table 1). T-wave alternans, ventricular tachycardia, and
torsade de pointes were uncommon; only one family had
evidence of T-wave alternans, and two families were noted to
have episodes of torsade de pointes (Table 1).
SSCP analysis with a pair of primers within the pore region
of KVLQT1 identified an aberrant conformer in an affected
individual in F1008 (Fig 3). This SSCP anomaly was not
observed in DNA samples from either parent, from the
patient’s unaffected brother (Fig 3), or from more than 150
control subjects (data not shown). Direct sequencing of the
The potassium channel gene KVLQT1 was initially identified
by positional cloning,16 and 11 different types of missense
mutations of KVLQT1 were identified in 16 LQTS families16
in the original report (Table 2). Later, Tanaka et al24 reported
Discussion
Li et al
TABLE 1.
April 7, 1998
1267
Phenotype-Genotype Correlation
Family
No.
Affected
F1002
7
SP/A249/g-a
0.510 (0.505–0.515)
F1003
6
SP/A249/g-a
0.537 (0.500–0.613)
No
Syncope
No
No
F1004
1
SP/A249/g-a
0.493
No
No
No
No
F1005
2
SP/A249/g-a
0.520 (0.510–0.530)
No
Syncope
No
No
F1006
9
A246V
0.550 (0.500–0.570)
No
Syncope
No
Yes; n52
F1007
2
A246V
0.623
Yes
Syncope
TdP
Yes; n51
F1008
4
SP/V212/DGGT
0.502 (0.500–0.505)
No
Syncope
No
No
Mutation
QTc Average, s
(Range)
T-Wave
Alternans
No
Symptoms
VT/TdP
Syncope
TdP
SCD
No
QTc indicates corrected QT interval for heart rate by Bazzett’s formula: QT =R2R ; VT, ventricular tachycardia; TdP, torsade
de pointes; and SCD, sudden cardiac death.
four missense mutations, and Russell et al25 reported two
additional missense mutations in three LQTS families, including a previously reported mutation, A246V (previously
named A212V) (Table 2). In this report, we found the same
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TABLE 2.
A246V mutation in affected members of two more LQTS
families, including one Japanese family (Table 2 and Fig 4).
To date, of 30 families with KVLQT1 mutations, alanine at
position 246 was mutated 10 times (33%) (Table 2). The
Summary of KVLQT1 Mutations
Nucleotide Change
Coding Effect
Mutation
Denotation (Old)
Region
Mutation Denotation
(New)*
Reference
DTCG
Missense
F38W/G39D
S2
F72W/G73D
Wang et al16
GCC to CCC
Missense
A49P
S2-S3
A83P
Wang et al16
GCC to ACC
Missense
A49T
S2-S3
A83T
Tanaka et al24
GGG to AGG
Missense
G60R
S2-S3
G94R
Wang et al16
CGG to CAG
Missense
R61Q
S2-S3
R95Q
Wang et al16
GTG to ATG
Missense
V125M
S4-S5
V159M
Wang et al16
CTC to TTC
Missense
L144F
S5
L178F
Wang et al16
GGG to AGG
Missense
G177R
Pore
G211R
Wang et al16
DGGT
Deletion
Pore
SP/V212(DGGT)
This study
ACC to ATC
Missense
T1831
Pore
T2171
Wang et al16
ATC to ATG
Missense
I184M
Pore
I218M
Tanaka et al24
GGC to AGC
Missense
G185S
Pore
G219S
Russel et al25
GGC to AGC
Missense
G185S
Pore
G219S
Russel et al25
GGG to AGG
Missense
G196R
S6
G230R
Tanaka et al24
GCG to GAG
Missense
A212E
S6
A246E
Wang et al26
GCG to GAG
Missense
A212E
S6
A246E
Wang et al16
GCG to GTG
Missense
A212V
S6
A246V
Wang et al16
GCG to GTG
Missense
A212V
S6
A246V
Wang et al16
GCG to GTG
Missense
A212V
S6
A246V
Wang et al16
GCG to GTG
Missense
A212V
S6
A246V
Wang et al16
GCT to GTG
Missense
A212V
S6
A246V
Russel et al25
GCT to GTG
Missense
A212V
S6
A246V
This study
GCT to GTG
Missense
A212V
S6
A246V
This study
GCG to GCA
Splicing
S6
SP/A249(g-a)
This study
GCG to GCA
Splicing
S6
SP/A249(g-a)
This study
GCG to GCA
Splicing
S6
SP/A249(g-a)
This study
GCG to GCA
Splicing
S6
SP/A249(g-a)
This study
GGG to GAG
Missense
G216E
S6
G250E
Wang et al16
GGG to CCG
Missense
R237P
S6
R271P
Tanaka et al24
CAGTACT to GTTGAGAT
Deletion and Insertion
C-terminal
G415 Y416 S417 Q418 G419
to
V415 E46 I417 A418 G419 X522
Neyroud et al20
*The previously reported KVLQT1 sequence by Wang et al16 lacked 34 amino acids at the N-terminal end, which has been cloned recently.32 The
new mutation denotation system is based on the complete amino acid sequence of KVLQT1.
1268
New KVLQT1 Mutations in Long-QT Syndrome
Figure 4. Model for KVLQT1 potassium channel and location of
LQT mutations. Channel consists of six putative membrane-embedded homologous domains (S1 to S6).
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frequent occurrence of A246 mutations and its presence in
both white and Japanese populations indicate that the alanine
residue at position 246 is a mutational hot spot in KVLQT1.
An identical splicing mutation was identified in affected
members of four unrelated families (one Italian, one Irish,
and two American); no unaffected individuals from these
families or from more than 150 normal control subjects
demonstrate the splicing mutation. In addition, the mutation
occurs in a highly conserved region of the gene. Together,
these data strongly suggest that the splicing change we
identified is the disease-causing mutation. We also identified
a 3-bp deletion that arose de novo. The 3-bp deletion,
spanning an exon-intron boundary in the pore region, not only
alters splicing but also leads to a 1-bp deletion in the coding
region, causing a frame shift and truncation of the KVLQT1
protein. These data strongly support the notion that mutations
in KVLQT1 cause the chromosome 11–linked LQTS.
Since the original identification of genes for chromosome
3–linked LQTS (SCN5A) and chromosome 7–linked LQTS
(HERG), electrophysiological studies have established that
the molecular mechanism for chromosome 3–linked LQTS is
the presence of a late phase of inactivation-resistant sodium
current in the plateau phase of the action potential (a
gain-of-function mechanism),26,27 whereas HERG mutations
cause the loss of IKr potassium current28,29 through dominantnegative mechanisms or loss-of-function mechanisms.30 Molecular mechanisms of KVLQT1 mutations are currently
unknown. Analysis of the predicted amino acid sequence of
KVLQT1 suggests that it encodes a potassium channel subunit.16 Recent electrophysiological characterization of the
KVLQT1 protein in various heterologous systems has confirmed that KVLQT1 is a voltage-gated potassium channel
protein.31,32 When coexpressed with minK, KVLQTI forms the
slowly activating potassium current (IKs) in cardiac myocytes.31,32 A combination of normal and mutant KVLQT1
subunits could therefore form abnormal IKs channels. Thus,
LQTS-associated mutations of KVLQT1 could act through a
dominant-negative mechanism. The type and location of
KVLQT1 mutations described here are consistent with this
hypothesis. The missense mutation, A246V, was identified in
two families and affects the S6 domain. Two mutations lead
to premature termination and truncated proteins (one splicing
mutation identified in four unrelated families and one 3-bp
deletion that arose de novo). In the first case, the S6 domain
and the carboxyl end of the protein are truncated, leaving
intact the amino end of the protein and S1 domain to the pore.
In the second case, a frame shift and altered splicing cause
truncation of the protein in the pore. Alternatively, the latter
two mutations could act through a loss-of-function mechanism. In general, these patients had moderate symptomatology, with relatively frequent episodes of syncope and long
QTc intervals (.0.500 second). It is unclear whether mutations in certain regions of the KVLQT1 gene will cause more
malignant disease than mutations in other regions of the gene.
Electrophysiological characterization of KVLQT1 mutations
will shed light on the molecular mechanisms of these mutations and possibly allow for predictions of clinical outcome.
Neyroud et al20 demonstrated a homozygous insertiondeletion mutation in the 39 end of KVLQT1 leading to Jervell
and Lange-Nielsen syndrome, which includes LQT and
deafness. They show that the hearing abnormality occurs in
three individuals because of the loss of function of the
channel, which is the result of mutation on both alleles (ie,
homozygous mutation). When a heterozygous mutation occurs, no matter at which end of the gene, it appears that
Romano-Ward syndrome (ie, no deafness) results. Despite
the possibility that heterozygous mutations in KVLQT1 act in
a dominant-negative mechanism, some functional KVLQT1
potassium channels exist in the stria vascularis of the inner
ear. Therefore, deafness is averted.
Identification of SCN5A and HERG as LQTS genes has led
to potential new rational gene-specific therapy to prevent
life-threatening arrhythmias. Mexiletine, a sodium channel
blocking agent, has been shown to markedly shorten the QTc
of chromosome 3–linked LQTS patients and to have only a
modest effect on chromosomes 7–and 11–linked LQTS patients.33 By contrast, raising the serum potassium concentration was shown to be effective in shortening the QTc interval
for patients with chromosome 7–linked LQTS; however, no
corresponding data have yet been reported for chromosomes
3–and 11–linked patients.34 No effective treatment for patients with chromosome 11–linked LQTS is currently known.
Studies with various interventions, for example, potassium
channel opening agents,35 are needed to identify therapeutic
strategies aimed at reducing the risk of life-threatening
arrhythmias in patients with KVLQT1 mutations.
Acknowledgments
This work was supported by the Abercrombie Cardiology Fund,
Texas Children’s Hospital (Dr Wang), NIH grants R01-HL-33843
and R01-HL-51618 (Dr Moss), and The Texas Children’s Hospital
Foundation Endowed Chair in Pediatric Cardiac Research (Dr
Towbin). Dr Wang is also a Visiting Professor of the China National
Rice Research Institute.
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Circulation. 1998;97:1264-1269
doi: 10.1161/01.CIR.97.13.1264
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