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Teaching Rounds in Cardiac Electrophysiology
Congenital Sick Sinus Syndrome With Atrial Inexcitability
and Coronary Sinus Flutter
Niraj Varma, MA, DM, FRCP; Ray Helms, MD; D. Woodrow Benson, MD; Thriveni Sanagala, MD
C
ongenital sick sinus syndrome has been described sporadically. The syndrome may comprise various components of sinus bradycardia, atrial fibrillation, and right atrial
inexcitability.1–7 In the current case, detailed electrophysiological evaluation was undertaken with electroanatomic mapping of the right atrium and coronary sinus (CS) and of
associated supraventricular arrhythmias.
a maximum of 131 beats/min and always remained regular.
Baseline atrial activity (if any) was not interpretable because
of exercise artifact. Isolated premature ventricular contractions were observed during exercise. A 24-hour Holter
monitor showed regular rhythm (mean heart rate, 47 beats/
min; range, 35–95 beats/min; maximum R-R interval, 1.8 s)
with 56 ventricular bigeminal cycles. The only symptom
during recording periods was an abnormal lateral chest
sensation that corresponded with heart rates between 30 and
40 beats/min. The patient underwent an external cardioversion without appreciable change in heart rate (44 beats/min),
although electrocardiographic intervals between QRS-T complexes became completely isoelectric for several minutes
before small-amplitude deflections resumed (Figure 1B).
At electrophysiology study, the first electrode catheter was
placed in the CS and demonstrated regular, rapid atrial
activity at a cycle length of 274 ms, suggestive of atrial flutter
(Figure 3A). In striking contrast, a subsequently placed
duodecapolar electrode catheter sited conventionally to map
the right atrial free wall and cavotricuspid annulus recorded
no electric activity, despite excellent tissue contact. This
remained unchanged by deflecting the catheter around the
right atrium to include posterior locations or by varying its
vertical tilt. Point-by-point electroanatomical mapping
(CARTO) confirmed absolute lack of recordable electrograms in the free wall (Figure 4A through 4C). Low-voltage
activity was observed in the septum at and above the ostium
of the CS. Normal CS electrograms were recorded in the body
of the CS but diminished distally. Exploration of the anticipated region of the sinus node (filter settings, 0.05–500 Hz)
revealed slow (⬍30 beats/min) electric activity in a discrete
location without corresponding local atrial depolarization
(Figure 4D).
Atrial flutter was mapped to a region of the proximal CS
and its roof. Fractionated local electrograms were recorded at
its junction with the inferior midseptum. Flutter was not pace
terminable. Radiofrequency energy applied to the proximal
CS slowed tachycardia and rendered it pace terminable. On
termination, the His bundle escape rhythm was clear (Figure
3C). The His-ventricular interval (50 ms) was normal. An
irregular, dissociated slow atrial escape emerged from the
distal CS. No AV or VA conduction was observed with CS or
Case
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A 37-year-old asymptomatic male physician from Mexico
without any previous medical problems was referred after
routine physical examination for evaluation of atrial fibrillation with a slow ventricular rate. Arrhythmia duration was
unknown. He stated that bradycardia had been consistently
noted on previous clinical examinations and had been attributed to competitive long-distance running since childhood.
Heart rates in the “40s” had been noted since age 10 to 11
years when he had been informed of a “heart murmur.”
Subsequent echocardiographic examination had been normal.
The patient denied any family history of sudden death or
arrhythmias. He had no siblings and no children. His prior
records (and those of his parents) were unavailable.
Physical examination was normal except for a regular
bradycardia of 45 beats/min. Twelve-lead ECG showed fixed
R-R intervals. No clear P-wave activity was identified.
However, there was small-amplitude baseline electric activity
of debatable origin, interpreted variously by experienced
electrocardiographers as standstill, artifact, or atrial fibrillation waves (Figure 1A). A transthoracic echocardiogram
showed normal ventricular volume and function (left ventricular end-diastolic diameter, 52 mm; left ventricle end-systolic
diameter, 34 mm) and mild tricuspid regurgitation with
estimated pulmonary artery systolic pressure of 40 mm Hg.
Both atria were severely enlarged (left atrial volume index, 58
mL; right atrial area, 41 cm2). Doppler echocardiographic
examination of both tricuspid and mitral atrioventricular
(AV) inflow showed complete absence of A waves, indicating lack of left and right atrial contractile activity (Figure 2).
A transesophageal echocardiogram did not reveal any evidence of an intracardiac shunt. A Bruce protocol exercise
treadmill test was stopped at 10 minutes and 26 s because of
patient shortness of breath. Heart rate accelerated gradually to
Received May 10, 2011; accepted July 19, 2011.
From the Loyola University Medical Center, Maywood, IL (N.V., R.H., T.S.), and Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati,
OH (W.B.).
Correspondence to Niraj Varma, MA, DM, FRCP, J2–2 Cardiac Electrophysiology, Cleveland Clinic, Cleveland, Ohio 44195. E-mail [email protected]
(Circ Arrhythm Electrophysiol. 2011;4:e52-e58.)
© 2011 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
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DOI: 10.1161/CIRCEP.111.964213
Varma et al
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Figure 1. A, The 12-lead ECG demonstrates a
fixed R-R interval at 45 beats/min with regular
(⬇260 ms) low-amplitude deflections (flutter
waves) from the isoelectric baseline consistent
with either artifact or atrial activity. B, Immediately
after electric cardioversion there is a regular narrow complex rhythm at 42 beats/min with a completely isoelectric baseline (left). Ten minutes later
(right), the escape rhythm has increased to 46
beats/min with accompanying, but dissociated
regular baseline undulations (arrows) suggestive of
atrial activity (cycle length, 360 ms). These narrow,
small-amplitude deflections are of similar morphology but are slower than those observed in A.
(ECG amplitudes as seen on the left and right
gained equivalently.) These findings suggest that
the presenting rhythm (A) was an atrial flutter
causing small-amplitude P waves and was briefly
cardioverted to atrial standstill (B, left) followed by
recurrence at a slower rate (B, right). No sinus P
waves were observed. C, A follow-up 12-lead ECG
showed prolonged repolarization (QT interval, 600
ms). The T wave is bifid, and this morphology is
observed in almost all leads. (The second lesser
amplitude component is unlikely to be a U wave,
which usually is observed in a few leads [typically
V2 and V3] and defined as a secondary deflection
following T-wave return to the isoelectric baseline.8) This repolarization abnormality was intermittently observed.
ventricular pacing. The junctional rhythm was remarkably
responsive to isoproterenol, increasing to 130 beats/min at a
dose of 1 ␮g/kg per minute, and easily suppressible by
ventricular pacing, which resulted in offset pauses of up to
4 s. Attempts at right atrial stimulation were unsuccessful,
despite using high outputs (20 mA and 9-ms pulse widths) at
various sites. Inexcitability of this chamber was absolute.
More aggressive ablation attempts were not made in the
junction of CS roof and midseptal area to avoid potential
injury to junctional activity, that is, the source of this patient’s
intrinsic rhythm. Fibrillatory activity spontaneously occurred in
the CS (Figure 3D).
Ventricular effective refractory periods were normal. A
single-chamber permanent pacemaker was recommended and
implanted, and anticoagulation with warfarin initiated.
Twelve-lead ECGs during follow-up showed variability.
Asymptomatic corrected QT interval prolongation was intermittently observed (Figure 1).8
Genomic DNA was isolated from blood, and polymerase
chain reaction was used to amplify the coding region and
flanking intronic sequence of SCN5A as previously described.9 Sequencing reactions were performed in the presence of fluorescent-labeled dideoxynucleotides and additional primer for exon-specific sequencing in both sense and
antisense direction on isolated polymerase chain reaction
product. SCN5A was evaluated as a candidate gene, and
mutations were sought using direct, bidirectional sequencing
of the coding region. Sequence analysis revealed a heterozygous change of adenine to guanine (A1673G), resulting in an
amino acid change from histidine to arginine (H558R) at
codon 558, a common SCN5A polymorphism.10
Discussion
A spectrum of asymptomatic electrophysiological abnormalities of sinus node, atrial excitability, and ventricular repolarization was observed in the current case. These features are
consistent with the syndrome of congenital absence of the
sinus node that has been sporadically reported over several
decades. Abnormalities may extend beyond the sinus node
mechanism and incorporate various additional elements of
atrial refractoriness, flutter, or fibrillation-like supraventricular activity; familial carriage; and sudden death.1–7 There also
may be an association with cardiomyopathy.11–13 To our
knowledge, the current case is the first detailed electrophysiological assessment of this condition.
The occurrence of sinus node dysfunction and atrial arrhythmias in young patients is puzzling. In adults, the
combination is well described and may represent effects of
aging and comorbidities, such as hypertension, coronary
artery disease, and LA fibrotic disease. In young patients,
prior structural heart disease or surgery may predispose
similarly. In contrast, the current case describes isolated sick
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Figure 2. Transthoracic echocardiographic examination of the tricuspid (left) and mitral valve (right). The top shows Doppler echocardiography of mitral and tricuspid inflow. Normally during diastole, an E wave representing early diastolic filling is followed by an A wave
of late diastolic filling propelled by atrial contraction. In this case, the E wave is present, but the A wave is absent, indicating an
absence of both left and right atrial contraction. The bottom shows pulsed tissue Doppler echocardiography of mitral and tricuspid
annuli. E⬘, representing early diastolic recoil, is observed in both tricuspid and mitral annuli. E⬘ velocities are normal, consistent with
normal diastolic relaxation. However, A⬘ velocities are absent, confirming lack of both left and right atrial contractile activity.
sinus syndrome. This rare condition also has sometimes been
associated with difficulty in atrial pacing. Pathological data
are scant. In one case, open chest device implant (for sudden
death) permitted direct visualization. Atria, which had been
inexcitable and devoid of electrogram activity during prior
EP study, appeared glistening white, compatible with complete fibrotic replacement (P. Tchou, MD, personal communication, July 2011). Histology may reveal myocardial fibrillar disarray, degeneration, and interstitial fibrosis. In 2
patients with congenital sinus node disease who died suddenly, atrophy, degeneration, and isolation of the sinus node
with fatty metamorphosis of the atrial preferential fibers that
approach the sinoatrial node was noted. More recently,
several genetic lesions have been described in association
with this syndrome.14
In the current case, isolated sinus node activity was
detected during endocardial mapping (Figure 4D). In normal
patients, electrode catheter recording in the sinus node region
demonstrates cyclic activity with slowly rising low-amplitude
deflections.15,16 These endocardial extracellular recordings,
similar to those recorded experimentally with intracellular
electrodes, are consistent with sinus node depolarizations.
Normally, each is followed closely by the higher-frequency
larger-amplitude deflection of local atrial depolarization.
When absent (eg, in second-degree sinoatrial block), the
smooth descending contour of the sinus node electrogram
may be revealed.15 In the current case, the recording of
periodic electrograms indicated the presence of sinus node
pacemaking activity, although this was very slow; however,
these were never accompanied by atrial depolarization, indicating permanent sinoatrial conduction block.
Electric activity was conspicuously lacking throughout the
right atrial body. The chamber did not depolarize in response
to CS electric activity (fibrillation, flutter, ectopic rhythm, or
pacing) and remained inexcitable during direct high-current
stimulation. Electric inexcitability was accompanied by mechanical standstill. Right atrial electric abnormality has been
described previously in conjunction with congenital sick
sinus syndrome, manifesting with prolonged effective refractory periods or more severely with complete inexcitability,
and likely underlies the inability to find a suitable atrial
electrode position during attempted permanent pacing. This
range of abnormality may represent a natural history, that is,
earlier subtle electrophysiological abnormalities progressing
to complete inexcitability by young adulthood. Mapping in
the current case demonstrated that inexcitability was not a
regional phenomenon but extended throughout the chamber.
This supports a primary electric abnormality and not the
consequence of a secondary process (eg, postsurgery) when
regions of preserved function mingle with scarred and fibrotic
tissues.
The left atrium was likely affected similarly to the right
atrium for the following reasons. Normally, the CS musculature is electrically connected to both the right and left atria.
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Figure 3. Recordings of surface leads and intracardiac electrograms from electrode catheters (A through D, reading counterclockwise).
A, A duodecapolar electrode catheter encircling the right atrial free wall revealed no electric activity at maximum gain. However, regular
electrograms (cycle length, 274 ms) were recorded from the coronary sinus (proximal electrodes at the ostium). Ventricular activity
(cycle length, 1215 ms) was regular but dissociated from the flutter recorded in the coronary sinus. B After pace termination of atrial
flutter, regular QRS activity is seen to be due to a junctional escape rhythm (966 ms). The His-ventricular interval and QRS duration are
normal. Coronary sinus depolarization is regular (1078 ms) but dissociated (ie, there is AV block). The right atrium remained electrically
silent during recording and inexcitable during maximal output pacing at several sites (not shown). C, His bundle pacing results in conduction to the ventricles with a narrow QRS complex. The coronary sinus rhythm continues independently, indicating absent ventriculoatrial conduction. D, At a later time point of the study, after burst pacing, there is irregular rapid activity recorded in the coronary
sinus suggestive of fibrillation, without right atrial depolarization.
Electrograms recorded from the proximal CS represent composite effects of depolarization both of the left atrium, a
rounded, low-frequency potential, and of the CS musculature,
characterized by a sharp potential.17 However, in the current
case, electrograms inscribed in this region were characteristic
of CS musculature only and lacked the low-amplitude farfield components of left atrial activity seen normally. Surface
ECG inscription of atrial activation, normally dominated by
depolarization of the comparatively massive left atrium,18 is
distorted and diminished by scar replacement.19 Here, the
failure of CS rhythms (flutter or ectopic rhythm) or pacing to
inscribe significant surface P waves supported left atrial
electric abnormality. Echocardiographically, the right and left
atria were affected similarly (ie, demonstrated enlargement
and mechanical standstill) (Figure 2). Increased left atrial
pressure has been noted on invasive hemodynamic measurements in a prior study.1 These observations indicate that
inexcitability and standstill are likely common to both atrial
chambers in this syndrome, although definitive demonstration
would require direct left atrial mapping. This form of atrial
pathology may increase propensity to thrombus formation,
similarly to fibrillating atria, even without conventional
CHADS (congestive heart failure, hypertension, age ⱖ75
years, diabetes mellitus, and prior stroke) risk factors.20
Atrial fibrillation has been associated with congenital sick
sinus syndrome.2 The presence of atrial inexcitability would
appear to be incompatible with (and indeed preclude) the
coexistence of fibrillatory effect. In some instances, atrial
standstill may be misinterpreted as fibrillation on a surface
ECG. Some previous reports attributed the source of flutter
and fibrillation-like phenomena to the tricuspid valve4 or
within the His bundle1 to explain how part of the atrium can
be in atrial flutter despite electric standstill elsewhere in the
same chamber. The current case with detailed mapping may
reconcile these findings. The CS acted as a distinct nonatrial
source of supraventricular arrhythmias. The CS is intimately
connected with both atria but derives separate embryologically origins from the left sinus horn and contains myocardial
fibers.17,21 The muscular sleeve is known to participate in
flutter circuits and in the maintenance of atrial fibrillation
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Figure 4. Electroanatomic mapping of the right atrium and CS (A through D, reading counterclockwise). A through C, Bipolar chamber
mapping was performed using a CARTO 3D electroanatomical mapping system. Areas are color-coded according to electrogram voltage recorded (red, ⬍0.10 mV [scar]; violet, ⬎0.5 mV [normal]; intermediate colors, 0.1 to 0.5 mV [representing transitional zones]). Dots
signify recording points (silver, areas mapped for sinus node activity; orange, sites recording His bundle depolarization; red, ablation
lesion locations). A, RAO projection. B, Left posterior oblique (135°) projection. Electrograms with voltage in the transitional range were
observed over the midseptum at the margins of the CS. Ablation lesion locations are marked in the low midseptal region. C, LAO projection showing the CS extending to its junction with the great cardiac vein and His bundle inscription. CS voltages are normal. D, The
anticipated zone of the sinus node in the superior vena cava-right atrial junction was explored using unipolar map settings (0.05–500
Hz) marked by silver dots in A through C. Electric recording at the superior vena cava-right atrial junction (marked by arrow in A) shows
cyclic electric activity (⬇3000 ms), suggesting sinus node electrograms (marked by arrows in D) (see Discussion). Concurrent CS recordings display rapid supraventricular arrhythmia. CS indicates coronary sinus; LAO, left anterior oblique; RAO, right anterior oblique.
through its left atrial connections. Elimination of the latter
may be an objective during atrial fibrillation ablation.22,23 In
the present case, the CS was anatomically and electrically
normal but electrically “isolated” because atrial connections,
if existent, led to an inert chamber. This supports the notion
that the muscular CS per se can contain flutter circuits and
sustain fibrillatory activity without any atrial contribution,
despite its lesser muscular bulk. These may explain the
diminutive surface ECG inscription of “flutter waves” and the
response to cardioversion (Figure 1). These sustained arrhythmias may be triggered by ectopic activity from cells with
pacemaker activity in the CS and vein of Marshall.24,25 The
terminal portion of the muscular CS connects with the right
atrium21 and produces fibers extending anterosuperiorly into
the interatrial septum close to the AV node.22,24 It is possible
that these extensions, interlacing with inexcitable tissues,
were responsible for some degree of voltage preservation
observed inferior to the point of inscription of the His
electrogram (Figure 4).
Normally, the AV node receives left- as well as right-sided
inputs. The observation that CS pacing normally results in
shorter AH intervals compared with right atrial pacing may
signify that the CS has a preferential input bypassing a
section of the AV node.26 –28 However, in the current case,
there was no AV conduction associated with CS rhythm
(Figure 3B), indicating that the CS did not maintain an
independent direct AV nodal connection.17 An AV nodal
escape rhythm is characteristic of this condition (Online
Mendelian Inheritance of Man database [OMIM] 163800).29
The current patient had a robust escape and remained asymptomatic until incidental discovery. However, an association
with syncope and sudden death indicates that the syndrome
may not always be benign.1,11,30 This could result from
inconsistencies in the junctional escape rhythm responsible
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for sustaining ventricular activity. In the current case, intermittent ventricular repolarization abnormalities indicated extension of electric pathology beyond atrial tissue, possibly
predisposing to ventricular arrhythmias, and this may be an
additional cause of syncope and sudden death in this
condition.
One or more underlying ion channel defects likely explain
this condition, with familial clustering and effects spanning
the entire cardiac electric cycle from sinus node depolarization to ventricular repolarization.2,7,14,29 –31 Mutations in the
gene for the cardiac Na⫹ channel (SCN5A)32–35 have been
implicated, although sinus pacemaker activity does not require Na⫹ channel activity. One explanation proposed for this
is a failure of conduction of impulses from the sinus node to
the adjacent atrial myocardium rather than an electric lesion
of the sinus node itself. The current case is the first in our
knowledge to directly test and provide support for this
hypothesis because sinus node electrograms could be recorded in isolation without evidence of local atrial depolarization (Figure 4D). Nevertheless, sinus node activity was slow.
Therefore, we cannot assert that sinus node function was
normal but disguised by atrial inexcitability. The findings
also may indicate the balance of dynamic processes affecting
both the sinus node and atrial excitability. Thus, carriers of
recessive SCNA5 mutations may demonstrate initial sinus
bradycardia but atrial inexcitability later in life.32 An inherent
disorder of the sinus node is supported by the observation that
sinus bradycardia is frequently found in carriers of dominant
long-QT 3 mutations.14 Other genes also may play a role (eg,
HCN4 in idiopathic sinoatrial node disease36) and in individuals with the combination of long QT, ventricular
tachycardia, and sinoatrial node disease.37 Mutations in a
Ca2⫹-handling gene (calsequestrin gene, CASQ2) that lead to
autosomal recessive catecholaminergic polymorphic ventricular tachycardia also are associated with sinoatrial node
dysfunction,37 and some patients have revealed a right bundle
branch block with a Brugada-like ST-segment elevation. The
phenomenon of atrial standstill may be accompanied by
connexin40 abnormalities.34,38 Multiple clinical arrhythmia
phenotypes (sinus node dysfunction, atrial fibrillation, ventricular arrhythmias) suggest involvement of complex molecular phenotypes in each individual cardiac cell type, and these
require further elucidation.
In conclusion, this congenital electric disorder was dominated by atrial inexcitability with ensuing loss of electric
connectivity to adjoining structures (ie, the sinus and AV
nodes and CS) and was not merely an isolated disorder of
sinus pacemaker cells. Although historically described as
congenital sick sinus syndrome, this term may be a misnomer
because it incompletely describes frequently accompanying
electric abnormalities in the ventricular myocardium and
conduction system in addition to genetic ablation of atrial
excitability.
Disclosures
None.
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KEY WORDS: congenital 䡲 sick sinus syndrome 䡲 atrial flutter
fibrillation 䡲 long-QT syndrome 䡲 mapping 䡲 coronary sinus
standstill
䡲
䡲
atrial
atrial
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EDITOR’S PERSPECTIVE
In this segment of Teaching Rounds in Cardiac Electrophysiology, Varma et al present and discuss an interesting patient
with an electrically silent right atrium but with supraventricular arrhythmia rising within the coronary sinus. There are
several teaching points of value that are highlighted by this case and discussion for the interventional electrophysiologist.
Intraatrial segmentation and dissociation. As we perform increasingly complex ablation procedures in patients with prior
maze procedure, multiple atriotomies, congenital heart disease, and so forth, we now appreciate that the atria cannot always
be considered as 1 electrically continuous complete structure. Patients may have 2 different rhythms (sinus and atrial
fibrillation, atrial flutter, and atrial fibrillation) in the right and left atria. When the atria are truly dissociated from each
other, each chamber’s arrhythmia can be addressed independently. More complex scenarios occur when the 2 atria are not
electrically disparate structures; rather, varying degrees of entrance and exit block between them are present. In such cases,
mapping of the arrhythmia (flutter in the right atrium when there is variable conduction into the right atrium from rapid
tachycardia in the left atrium) is necessary. The more rapid or disorganized arrhythmia will need to be terminated with
pacing or cardioversion and then the slower arrhythmia induced in the chamber of origin mapped and ablated.
The coronary sinus as a distinct chamber. Electrophysiologists now accept that the coronary sinus represents a fifth cardiac
chamber with its own atrial myocardium and venular tissue. This chamber may show in patients an independent arrhythmia
or serve as a conduit between the atria for large loops of interatrial reentrant tachycardia as highlighted in this present case.
The arrhythmia may be contained within this cardiac chamber in exceptional cases.
What will be our reference point? In addition to difficulty with simply mapping 1 chamber’s arrhythmia when another
chamber or segmented portion of the atrium has another arrhythmia, picking the reference electrogram to create an
activation map can be challenging. For example, in a patient with congenital heart disease, prior atriotomy, and a
right-sided maze procedure, it is not uncommon to find an isolated portion of atrium on the free wall with a cycle length
of activation different from a flutter in the remaining right atrium or left atrium. If the same reference for mapping is used,
then taking activation points in the isolated chamber will create a meaningless map that cannot be used to define the circuit
or ablation targets in either of these portions of the atrium. The electrophysiologist will need to create separate maps, each
with its own reference point located within the portion of the atrium being mapped.
The case presentation by Varma et al brings to light the importance of appreciating varying arrhythmias in separate portions
of the atrium in an exceptional situation—a patient with a sodium channel mutation affecting sinus node function and atrial
conduction. These findings, however, bring into focus critical issues in terms of mapping and understanding multiple
arrhythmias when occurring simultaneously but in isolated (partially or completely) portions of the atria and coronary
sinus.
Congenital Sick Sinus Syndrome With Atrial Inexcitability and Coronary Sinus Flutter
Niraj Varma, Ray Helms, D. Woodrow Benson and Thriveni Sanagala
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Circ Arrhythm Electrophysiol. 2011;4:e52-e58
doi: 10.1161/CIRCEP.111.964213
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