fragmented qrs complex in adult patients with ebstein’s...

DOI: 10.1161/CIRCEP.113.000636

1

Fragmented QRS Complex in Adult Patients with Ebstein’s Anomaly and Its Association with Arrhythmic Risk and the Severity of the Anomaly

Running title: Park et al.; Fragmented QRS in Ebstein’s Anomaly

Seung-Jung Park, MD, PhD1; Seungmin Chung, MD1; Young Geun On, MD, PhD1;

June Soo Kim, MD, PhD1; Ji-Hyuk Yang, MD, PhD2; Tae-Gook Jun, MD, PhD2;

Shin Yi Jang, RN, PhD1; Ok Jung Lee, MD3; Jinyoung Song, MD, PhD3;

I-Seok Kang, MD3; June Huh, MD, PhD3

Department of 1Medicine, 2Thoracic and Cardiovascular Surgery, and 3Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence:

June Huh, MD, PhD

Associate Professor

Grown-Up Congenital Heart Disease Clinic,

Department of Pediatrics, Cardiac and Vascular Center,

Samsung Medical Center, Sungkyunkwan University School of Medicine,

50 Irwon-dong, Gangnam-gu

Seoul 135-710

Korea

Tel: +82-2-3410-3526

Fax: +82-2-3410-0043

E-mail: [email protected]

Journal Subject Code: [171] Electrocardiology

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DOI: 10.1161/CIRCEP.113.000636

2

Abstract:

Background - Fragmented QRS complex (fQRS) on 12-lead ECG, a marker of myocardial scar,

is a predictor of arrhythmic events in patients with ischemic and non-ischemic cardiomyopathy.

We investigated whether the presence of fQRS is associated with the severity of the anomaly and

with increased arrhythmic events in adult patients with Ebstein’s anomaly (EA).

Methods and Results - In 51 consecutive adult EA patients (median age, 37 years; 18 males), the

severity index of EA calculated from echocardiographic data and clinical arrhythmic events were

analyzed. The extent of fQRS in each patient was measured by counting the number of ECG

leads showing fQRS. There were 35 (68.6%) patients with fQRS (fQRS group) and 16 (31.4%)

patients without fQRS (non-fQRS group). fQRS was observed more frequently in the inferior

(n=26) and precordial (n=25) leads versus the lateral leads (n=5). The patients in the fQRS group

had a worse functional class, greater cardiothoracic ratios, more severe tricuspid regurgitation,

larger atrialized right ventricular (aRV) areas, higher EA severity scores, and more frequent

arrhythmic events compared to those in the non-fQRS group. The aRV area showed a positive

correlation with the fQRS extent (r=0.51, P<0.001). In multivariable Cox regression models, the

presence of fQRS was independently associated with arrhythmic events (P=0.036).

Conclusions - Fragmented QRS on 12-lead ECG was associated with larger aRV area and an

increased risk of arrhythmic events in adult patients with EA.

Key words: ECG, Ebstein's anomaly, adult congenital heart disease, arrhythmia, fragmented QRS complex

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DOI: 10.1161/CIRCEP.113.000636

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Ebstein’s anomaly (EA) is a congenital malformation of the tricuspid valve (TV) and the right

ventricle (RV). The most prominent morphological feature of EA is the varying degree of apical

displacement of the TV into the RV, dividing the RV into a proximal chamber of “atrialized RV

(aRV)” and distal portion of “functional RV”. This abnormality often causes tricuspid

regurgitation (TR), progressive dilatation and dysfunction of the right atrium (RA) and RV.1

Therefore, the most common clinical presentations in adolescents and adults with this

malformation are arrhythmic events and right-sided heart failure.2-5 Moreover, these

complications are expected to become more frequent with the improvement in long-term survival

of patients5,6 However, there have been very few studies investigating the risk factors for

arrhythmic complications, especially in adults with EA.

Fragmented QRS complexes (fQRS) on 12-lead ECG, which represent conduction delay

caused by myocardial scar, have been identified as a predictor of arrhythmic events in patients

with ischemic or non-ischemic heart disease7,8 Recently, the fQRS found in adults with repaired

tetralogy of Fallot (TOF) was reported to represent more extensive RV scarring and dilatation.9

In this study, we evaluated whether the presence of fQRS reflects a greater risk of

arrhythmic events and more severe abnormalities of the right-sided chambers in adult patients

with EA.

Methods

Patient Population

Fifty-one adult patients (>18 years old) diagnosed consecutively with EA at the Samsung

Medical Center from November 1994 to April 2011 were enrolled for the present study. EA was

diagnosed by echocardiography when the apical displacement of the septal leaflet of the TV

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relative to the insertion of the anterior leaflet of the mitral valve was measured at least 20 mm or

8 mm/m2 body surface area (BSA). Patients with failed ablation of accessory pathways (AP),

paced ventricular rhythms, and a previous cardiac surgery were excluded because these

conditions could affect the QRS morphology. Demographic, electrocardiographic, and

echocardiographic data were analyzed retrospectively. The study protocol was approved by our

institutional review board, and the requirement for written informed consent was waived.

Definition of fQRS and Measurement of ECG Parameters

Standard 12-lead ECGs were obtained with an optimal low-pass filter setting (filter range 0.15 to

100 Hz, alternating current filter 60 Hz, 25 mm/s, 10mm/mV; GE Marquette, Milwaukee, WI,

USA). To assess the correlation between fQRS and the severity of the structural abnormality in

EA, we analyzed the index electrocardiogram recorded closest in time to the echocardiographic

examination performed during the first visit to our institute. The time interval between

electrocardiographic and echocardiographic study ranged from 0 to 105 days (median 1 day).

QRS complexes were defined t ') or notch on the

R/S waves were present in narrow QRS complexes (<120ms), or when >2 notches on the R/S

waves were noted in wide QRS complexes ( .7-9 This fragmentation should be observed

in at least two contiguous leads representing anterior (V1–V5), inferior (II, III, aVF), or lateral (I,

aVL, V6) myocardial segments (Figure 1). The extent of the fQRS in each patient was estimated

by counting the number of ECG leads showing fQRS.9 In the presence of delta-waves in the

QRS complex, electrocardiograms obtained after accessory pathway (AP) ablation were used

because pre-excitation of the ventricle through the AP could alter the QRS morphology,

mimicking fQRS. All ECG tracings were analyzed by two independent cardiologists who were

blinded to clinical outcome data. There was a 97% and 95% intra- and interobserver agreement

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for the presence of fQRS, respectively. Electrocardiographic parameters such as

PR/QRS/corrected QT/corrected JT intervals and QRS/QT/JT dispersion were also measured

manually.

Echocardiographic Parameters and Severity Grading of Ebstein’s Anomaly

Comprehensive transthoracic echocardiography was performed using 2.5 to 4 MHz transducers

(Vivid 7, GE Medical System, Milwaukee, WI or Acuson 512, Siemens Medical Solution,

Mountain View, CA, USA). Maximal apical displacement of the TV was measured from the

hinge point of TV septal leaflet to the insertion point of the MV anterior leaflet. The severity

index of EA was estimated using the Great Ormond Street Score (GOSE), an echocardiographic

method described previously.10 The GOSE was calculated as the ratio of the combined area of

the RA and aRV divided by the combined area of the RV proper, left atrium (LA), and left

ventricle (LV) in a four-chamber view at the end of diastole (Figure 2). Four grades of increasing

severity were defined: grade 1, ratio<0.5; grade 2, ratio 0.5 to 0.99; grade 3, 1 to 1.49; and grade

-quantitative measurement depending on

vena contracta width, proximal isovelocity surface area, hepatic vein flow reversal, RV or RA

enlargement, and the plethora of the inferior vena cava.11 The LV ejection fraction was

calculated using Simpson's biplane method.

Clinical Outcomes

Clinical arrhythmias were defined as spontaneous episodes associated with palpitation, dizziness,

or syncope with ECG documentation. Occurrence of clinical arrhythmias has been investigated

since the index electrocardiograms were taken. The index electrocardiograms were obtained

during the first visit as mentioned above. Regular clinical and electrocardiographic follow-up (3

to 6 month interval) was performed in all patients. If a patient reported symptoms suggesting

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arrhythmia at any time, ECG and 24-hour Holter monitoring were repeated. Ventricular

tachyarrhythmia included ventricular fibrillation (VF), ventricular tachycardia (VT), appropriate

implantable cardioverter-defibrillator (ICD) shock, and nonsustained VT ( 3 consecutive

ventricular beats at a rate of 100 beats/min with a duration of <30 seconds). Atrial

tachyarrhythmia included atrial tachycardia (AT), atrial fibrillation (AF), atrial flutter (AFL), and

atrioventricular reentrant tachycardia (AVRT) using AP. For the present study, tachycardia

episodes caused by AVRT using AP were not included when analyzing the relationship between

fQRS and arrhythmic events. Since fQRS is a marker of myocardial fibrosis, we focused on

specific relationships between fQRS and arrhythmias more directly related to myocardial

dysplasia/degeneration. Therefore, the AVRT with a bypass tract was analyzed separately. Open

heart surgery and cardiac death were also investigated.

Statistical Analysis

Continuous variables were expressed as medians (25th and 75th percentiles) and were compared

using the Mann-Whitney test. The results for categorical variables were described as percentages

and the Fisher’s exact test was performed to compare these results. Correlations between QRS

duration or fragmentation and the severity of disease were assessed by the Spearman rank

correlation coefficient. Crude survival in each group was assessed using the Kaplan–Meier

method and the log-rank test was applied. Hazard ratios (HR) with 95% confidence intervals (CI)

were computed using Cox regression models after the proportional hazards assumption was

tested based on correlations between survival rankings and Schoenfeld residuals. The overall C-

index was calculated using Cox survival methods to evaluate the discriminatory accuracy of

several electrocardiographic variables (see supplemental Table) for the occurrence of arrhythmic

events (12). All analyses were performed using SAS software version 9.2 (SAS Institute, Cary,

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North Carolina, USA). All p values were two-sided and results with a p value less than 0.05 were

considered statistically significant.

Results

Patient Demographics

Baseline characteristics of the 51 patients are summarized in Table 1. Median (25th and 75th

percentiles) age was 37 (31-45) years, and the median (25th and 75th percentiles) cardiothoracic

(CT) ratio was 0.55 (0.50-0.62). About half of the patients (27/51, 52.9%) were in New York

Heart Association functional class III-IV. Atrial septal defects were the most common associated

cardiac defect (n=19, 37.3%). In most of the patients (48/51, 94.1%), the right-sided chamber

was much larger than the left, with a combined RA and RV area of 53 (43-75) cm2 compared to a

combined LA and LV area of 37 (32-44) cm2 (P<0.001). The median (25th and 75th percentiles)

value of the EA severity index was 0.79 (0.63-0.94).

Comparison Between the fQRS and Non-fQRS Groups

Approximately two-thirds of the patients (35/51, 68.6%) showed

(fQRS group). fQRS occurred primarily in the inferior (26 patients) and precordial (25 patients)

leads. fQRS in the lateral leads was observed in only 5 patients. The detailed distribution of

fQRS complexes is presented in Figure 3.

The fQRS group had a worse functional class, a greater CT ratio, a longer PR interval, a

longer QRS duration, more frequent right bundle branch blocks (RBBB), and more frequent right

axis deviations compared to the non-fQRS group (Table 1 and 2). On echocardiographic

examination, apical displacement and regurgitation of the TV were more severe in patients with

fQRS versus those without (Table 2). Functional RV, LV, and LA areas indexed to BSA showed

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no significant differences between the two groups. However, aRV and RA enlargements were

more prominent in the fQRS group; therefore, the fQRS group showed a greater severity index

compared to the non-fQRS group (P<0.001). The indexed aRV area (Spearman’s r=0.51,

P<0.001), indexed RA areas (Spearman’s r=0.60, P<0.001), and Ebstein severity index

(Spearman’s r=0.58, P<0.001) were positively correlated with the extent of the fQRS (see

supplemental Figure 1).

Associations Between fQRS Complexes and Arrhythmic Complications

Table 3 summarizes clinical outcomes. Median follow-up duration (25th and 75th percentiles)

was 49 (25-116) months with no significant difference between the fQRS and non-fQRS groups

[49 (29-112) versus 51 (1-126) months, P=0.699]. Compared to the non-fQRS group, a greater

proportion of patients in the fQRS group underwent TV replacement/repair or a Fontan operation

due to severe TR and right heart failure. The incidence of AVRT with AP was not significantly

different between the two groups (fQRS versus non-fQRS group, 5/35 versus 4/16, P=0.436).

However, ventricular tachyarrhythmia (9/35, 25.7%), unexplained syncope (4/35, 11.4%), and

cardiac death due to right heart failure (1/35, 2.9%) were only found in patients with fQRS.

Sustained VT, appropriate shock for VF, and non-sustained VT episodes occurred in five, one,

and three patients with fQRS, respectively. The atrial tachyarrhythmic event (AF, AFL, and AT)

rate was also higher in the fQRS group (48.6% versus 18.8%, P=0.064). In addition, permanent

pacemaker implantation was performed only in patients with fQRS due to complete (n=2) or

advanced (n=1) AV block. Overall, total arrhythmic events occurred more frequently in the

fQRS group compared to the non-fQRS group during the follow-up (Figure 4). The presence of

fQRS in Cox regression analysis was independently associated with total arrhythmic events,

even after adjusting for relevant clinical, radiographic, echocardiographic, and

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electrocardiographic parameters (Table 4).

Discussion

New findings

The present study is the first to reveal a significant relationship between the presence of fQRS

and an increased risk of ventricular or atrial arrhythmic events. We also found fQRS to be

associated with poorer functional class, more severe TR, a larger right-sided chamber, and

greater severity of EA in adult patients with this cardiac defect.

Recently published data suggests that the fQRS detected in patients with EA reflects the

presence of RV dysfunction with greater aRV volume13. However, arrhythmic risk was not

evaluated in that study. Additionally, adult patients (>18 years old) accounted for only 60% of

their study population. Although there have been some studies dealing with arrhythmic

complications in adult patient groups, they only described the prevalence of a few types of

arrhythmias in a limited number of patients.2-5 Most of the previous data focused primarily on the

characteristics or management of AVRT with a bypass tract.14-16

In contrast, we evaluated the association between fQRS and arrhythmic risk as well as

the severity of the structural abnormality. Moreover, we tried to identify predictors for

arrhythmic events more directly associated with dysplasia/degenerative changes in the

atrial/ventricular myocardium; these arrhythmic complications will pose greater challenges to

clinicians than AVRT using bypass tracts especially in adult EA patients because of recent

advances in their long-term survival and in ablation technology. Our data show that

approximately 50% of adult patients with EA experienced arrhythmic complications, which is

consistent with previous studies.2,4,5,16 In addition, we found the presence of fQRS to be

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independently associated with overall arrhythmic events, even after adjusting for relevant clinical

and echocardiographic parameters.

fQRS Complexes and Risk of Ventricular Tachyarrhythmias

Fragmentation of QRS morphology on surface ECG reflects inhomogeneous ventricular

activation caused by myocardial scar in patients with a prior myocardial infarction.7,17 As the

myocardium is replaced by scar tissue following an infarction, myocardial conduction slows or

becomes blocked around the infarcted zone, resulting in a ‘zigzag’ course of activation.18 fQRS

was also associated with an increased risk of arrhythmic events in nonischemic dilated

cardiomyopathy patients.8

Several histopathologic studies on EA demonstrated that the atrialized portion of the RV

becomes disproportionately dilated and has extensive fibrosis with reduced numbers of

myocytes.19,20 Additionally, the abnormal signal observed during endocardial mapping of the

aRV was related to the bizarre configuration of the widened QRS complexes on surface ECG.21,22

They also showed that the aRV was particularly irritable, and therefore, could serve as a

substrate for VF.21,23 Indeed, in our study, patients in the fQRS group had significantly larger

aRV area and more frequent ventricular arrhythmic complications compared to the non-fQRS

group. Moreover, the extent of fQRS complexes was positively correlated with the aRV area

(Spearman’s r=0.51, P<0.001). Therefore, fQRS in adults with EA might signify a higher burden

of arrhythmogenic substrate. We previously reported that in adults with repaired tetralogy of

Fallot (TOF), myocardial fibrosis was predominant in the RV outflow tract, and that fQRS was

found at least twice as frequently in the right to mid precordial leads than in the inferior lead

showing a good spatial concordance between the fQRS and RV scarring.9 In the present study,

however, the most common locations of fQRS were the inferior and precordial leads, and fQRS

ischemic dilated

veral histopathologic studies on EA demonstrated that the atrialized portion of th

i

h

elated to the bizarre configuration of the widened QRS complexes on surface EC

sho ed that the aRV as partic larl irritable and therefore co ld ser e as a

verralalal hhhhisisisi tototoopappathhhololologic studies on EA demmmonononsstrated that tttheh aaaatrtrtrtrialized portion of th

isssps rrror portionattelly dddilllateddd andddd hhhhasss eextenennsiveve fibbbbrorooosisisiis wiiithhh redduucededede nummmmbbeb rsrs of f

99,20002000 AAAAdddddddititititiiionalllllly, ttthhhe abnorororormmmal siiiigngngngnalalal obsbbb ervedddd dududud riririring eeee ddnddocardididiialalala mmapappiiing fffof ttth

elateddd to thhhe bibibiizarre confffigigigurattiiion ffoff the widididden dded QQQRSRSRSRS ccccomplplpllexes on surffffacacaca eee e EC

hsh ded tthhatt thth RaRVV trtiic ll ll ii itit bablle dd thth fef ldld


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were negligible in the lateral leads. In EA, the aRV, or the inlet component, is the main site of

congenital dysplasia and subsequent degeneration. With further enlargement, the aRV could

occupy a greater proportion of the inferior wall of the heart, making fQRS complexes in the

inferior leads as frequent as that in precordial leads. Repolarization parameters such as QTc and

QRS/QT dispersions were measured worse in the fQRS group compared to the non-fQRS group.

Repolarization parameters therefore might also be associated with an increased susceptibility to

ventricular arrhythmia.

fQRS Complexes and Risk of Atrial Tachyarrhythmias

The degree of apical displacement, regurgitation of the TV, and RA enlargement were more

severe in the fQRS group than the non-fQRS group. The indexed RA areas were positively

correlated with the extent of the fQRS. These abnormalities could make patients with fQRS more

vulnerable to atrial tachyarrhythmias related to degenerative changes in the atria, such as AF,

AFL, and AT. As mentioned above, atrial tachyarrhythmias including AF, AFL, and AT tended

to occur more frequently in the fQRS group than in the non-fQRS group (48.6% versus 18.8%,

P=0.064).

fQRS Complexes and Risk of Bradyarrhythmias

The AV conduction system in EA, especially the right bundle branch traveling over the

dysplastic aRV portion, is abnormally formed and shows marked fibrosis. The AV node is also

compressed due to enlargement of the right-sided chambers.1,24,25 Additionally, chronic

hemodynamic stress in adult EA patients can aggravate right-sided chamber dilatation,

dysfunction, and fibrosis.1,2 All of these factors could predispose the development of

bradyarrhythmia. The longer PR intervals and more frequent RBBB observed in the fQRS group

might suggest more fibrosis within the right-sided chambers and in the right bundle branch and

nlargegemementnttt wwerere e momomomorr

h y

w S

to atrial tachyarrhythmias related to degenerative changes in the atria, such as A

A n

ore freq entl in the fQRS gro p than in the non fQRS gro p (48 6% ers s 18

he fQfQQfQRSRSRR ggggrorroupppp tthan the non-fQRS grouppp. ThTTT e indexed RAAA aaaareas were positively

wwwwitttth h the extennt of thththe fQQQRRSRR . TThTT eseese abbnnnormmalititittieieiesss cooulllddd maakee pppatattientttts wiwithh fQRQRQRS

to attttririrrialalal ttttachyhhh arrhhhh ttythhhhmias sss rererelated ddd totototo ddddeggeneratattativivivve chchchchannngggeg s iiin tttthe aaaatrtrtrtriiia, su hhchh as AAAA

AT. AAAs mentioioioonneddd d bbabove, atrialll tachhhhyayy rrhyhyhy hthhh iimias iiinclullul dididid nggg AFAFAFAF, AFAFAFFLL,L andndndnd AAAATTTT ten

ff ttll ii thth fQfQRSRS tthha iin tthhe ffQRQRSS (4(488 6%6% 1818


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12

more adverse hemodynamic impact on these structures. Although not statistically significant,

first degree AV block (24% versus 13%, P=0.464) was more prevalent in the fQRS group, and

permanent pacemakers were implanted only in patients showing fQRS due to advanced or

complete AV block.

Clinical Implications

In our study, lower functional class at the time of presentation, a greater CT ratio, more advanced

grade of EA, and a higher rate of corrective surgery were found in the fQRS group, which had a

larger average aRV area. These results are in agreement with previous studies that showed aRV

volume to be independently related to aerobic capacity, and that the volume of the aRV is a

novel CMR measure which may describe the severity of disease in adults with unrepaired

EA.12,26 On the other hand, QRS duration is considered a good surrogate marker for severity of

disease. The wider the QRS complex and the greater the degree of TR and RV enlargement, the

worse the clinical course.12, 27 Our data also showed that QRS duration was as good as QRS

fragmentation in predicting RV structural remodeling (see supplemental Figures 2) and

arrhythmic risks (see supplemental Figures 3).

Therefore, further investigation might be worthwhile in order to ascertain whether fQRS,

independently or in combination with QRS duration, could be a potential marker of worsening

right-sided heart dysplasia/dysfunction (see supplemental Figures 4 and supplemental Table).

Also, it would be useful to further investigate the association between fQRS and increased

vulnerability to atrial and/or ventricular tachyarrhythmia as well as bradyarrhythmia in larger

adult cohorts with this anomaly.

Study Limitations

This study has several limitations. Firstly, comparisons from this analysis are limited by their

studies that showewewewed ddd

olumme e ooffff ththththee RRaRaRV VVV isisisis a

R

n t

h t

c S

ion in predicting RV str ct ral remodeling (see s pplemental Fig res 2) and

R memememeasasasa ururreeee whwhwhicicich may describe the severrritititityy of disease in nn adddduuults with unrepaired

n thhhhe other handnd, QRQRQRS dududuurationon iiis consnssidereed aaa ggggoooooooodd suurrrroggatte d mamm rkeererr fofof r sevvverrrit

he wididididererer tttthhheh QQQQRSRSRSS complexxxx aaand thehehehe grerere tatter ttthehhh ddddeeegrerereree ofofofof TRTRTRTR and RRRRVVV V enlal rgementRRR

cliniciii alll course.ee 1222 2727712222, 272727 OOOur dddatta allllso shhhoh weddd hthhatt QQQQRSRSRSR dddurratatata ioii n nn wwwaw s as gggoodd d asasasas QQQQRS

iio iin didi tctiin RVRV ttr tt ll ddelili ((s lpl ttall FiFi 2)2) dnd


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retrospective design, in which unmeasured confounders may preclude any definite conclusion.

Therefore, prospective studies on a larger scale are needed to and to show

the clinical implications of fQRS complexes more definitely. Secondly, the study population was

relatively small, and the follow-up duration was short. Although, our cohort is one of the largest

adult-only groups. Thirdly, the extent of the cardiac fibrosis and the volumetric measurements

were not confirmed by biopsy or cardiac magnetic resonance (CMR) imaging. However, we

adopted a grading system to quantify the severity of EA, and our data correspond well to those

acquired from CMR examination.13

Conclusions

Fragmented QRS complexes on 12-lead ECG were found in approximately two-thirds of adult

patients with Ebstein’s anomaly. fQRS complexes were associated with larger atrialized right

ventricle, a more severe anomaly, and an increased risk of arrhythmic events in this patient group.

Conflict of Interest Disclosures: None.

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dddd QQQQRS complexexes oon 12-2-2--leadddd ECGCCG weweere ffooundndndnd iiin n n n aapppproooximmaatelelellyy y twoo-oo thtt iirdds ooof ff ad

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e HJ, Choe YH,, HuHuHuHuh hhhccccteteteteddd d bybybyby llllatatatateeee gagagagadodddolilililinniniuuuulogy ooffff fafffallllllllotttot. AmAmAA JJJJ CC

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h di 2003;16:777 802

majajajajerererer DS, CCCCululuullelelen nnn S,,S, SSSulululllilll vavaavan nnn IDIIDI , , SpSpSpieieiegegegelhaaltter DJDJDJDJ, , , WyWyyWysesesee RRRK,KK,K Deaaaeanfnfnfnfieieiei ldll JJJE.E.E.E OOOOutuuu cos wwiwiw th Ebstein's anooommalyyy... J AmAmAmA CCCooll CaCCarddiool. 11119999992;22;2 1999:1110411-10004646464 .

WAAAA, EnEnEnEn iriququez-SaSSS rano MMMM, FFoFoF sterr EEEE, GGGrGrayaybbburnnn PPPPAAAA, KKKKrafafafafttt CDCDCDD, Levivivivinnnen RRRRAAA,opouuulolololosss PPP,,,, OtOtOtttototoo CCCMMMM, QuQuQuQuininininononono essss MMMMAAAA,,, RaRR kokokoowswswsskikikik HHHH, StStStStewewewewararara ttt WJWJWJWJ,,, WaWaWaW ggggggg onononnerererer AAA,,,,NJ; AmAA ericii anannn SSSSociiietytyty off f EEEcE hoca drddioiii grgg appphyhyhy. ReRR commeneee dadd tititiooono s fffor ev laluauauauatititit ooono onative valalalvuvuvuvulalalar rrr rererer gugugugurgrgrgrgititiitataata ioioion nn wiwiwiwithththth ttwowowowo-d-d-d-dimmimimeneee sisisionononnalalalal aaanddndnd DDDDopopopopplplpplerererer eeeechchchchococococara diographh didi 20200303 1;166:777777 808022


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25. Ho SY, Goltz D, McCarthy K, Cook AC, Connell MG, Smith A, Anderson RH. The atrioventricular junctions in Ebstein malformation. Heart. 2000;83:444-449.

26. Tobler D, Yalonetsky S, Crean AM, Granton JT, Burchill L, Silversides CK, Wald RM. Right heart characteristics and exercise parameters in adults with Ebstein anomaly: New perspectives from cardiac magnetic resonance imaging studies. Int J Cardiol. 2013;165:146–150.

27. Brown ML, Dearani JA, Danielson GK, Cetta F, Connolly HM, Warnes CA, Li Z, Hodge DO, Driscoll DJ; Mayo Clinic Congenital Heart Center. The outcomes of operations for 539 patients with Ebstein anomaly. J Thorac Cardiovasc Surg. 2008;135:1120-1136.

E. Morbid anatomymyyy iiiinnggggicicicic aaaandndndnd cccclilililininininicacacacal lll

JA, Goldreyer BN, Josephson ME, Perloff JK, Scharf DL, Manchester JH, Shelbeld JW Jr. Electrophysiologic characteristics of Ebstein's anomaly of the tricuspic

ara T, Tsuchiya T, Takahashi N, Saikawa T, Yoshimatsu H. The characteristics oe Pr

a Ng O Millie P Richardson A Pittaro M Josephson ME Ventric lar

JA,A,A,A, GGGGolololo drdrdrd eyeeyererrr BBBN, Josephson ME, Perlooooffffffff JK, Scharf DLDD , MMaMM nchester JH, Shelbelllldd dd JJWJJ Jr. EEEEleeectctctctrorophphphp ysysysy ioiiiololologigigigicccc chhharararacccteteterir stticcs ofofof EEEEbsbbsb teeeinininin'sss aanononoomalyyyly oooofff the e e trtrtrt icicicusuusu picuuuulaaaation. 1975;552:9998887-999595959 .

ara T,TT,T TTTsssusuchhhhiyiii a T,T,TT TTTTakahhhhasasasa hhhhi N, SaSaSaSaikikikikawa TT,T,T YYYYooooshihihih mmmamatststssu H.HH TTTThe cccchahahaharacttterisiii tititics oelectrtrtrrogogogo rararam mm onononon tttthehehh aaatrtrtrriaiaiaialililiizezezeed dd riiighghghght t t veveveventnn riiiclclclc eee inininin aaaa ppppataatieieiientntntnt wwwwititith h h h EbEbEbEbstststs eieieie n'n'n'n sss ananananomomomo alalallyy.yy Prophphphhysyy iioi l.ll 222000000999;9 3232323 :222696969-22272727272.

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Table 1. Comparison of clinical characteristics between the fQRS group and the non-fQRS group

Total

(n=51)

fQRS (+)

(n =35)

fQRS (-)

(n =16 ) P value*

Demographics

Age†, years 37 (31-45) 36 (31-45) 41 (27-45) 0.604

Male gender, n (%) 18(35.3) 11(31.4) 7 (43.8) 0.529

Diabetes mellitus, n (%) 2 (3.9) 2 (5.7) 0 (0.0) 1.000

Hypertension, n (%) 6 (11.8) 6 (17.1) 0 (0.0) 0.159

NYHA class III~IV, n (%) 27(52.9) 23(65.7) 4 (25.0) 0.014

CT ratio† 0.55 (0.50-0.62) 0.58 (0.53-0.66) 0.49 (0.45-0.52) <0.001

8 (15.7) 8 (22.9) 0 (0.0) 0.045

Associated anomaly

Atrial septal defect, n (%) 19 (37.3) 16 (44.4) 3 (20.0) 0.123

Patent foramen ovale, n (%) 5 (9.8) 5 (13.9) 0 (0.0) 0.305

Mitral valve prolapse, n (%) 1 (2.0) 0 (0.0) 1 (6.7) 0.294

Ventricular septal defect, n (%) 1 (2.0) 1 (2.8) 0 (0.0) 1.000

*The P value is based on the Mann-Whitney test for continuous variables and the Fisher’s exact test for categorical variables.†Data represented as the median (25th and 75th percentiles).CT ratio, cardiothoracic ratio; NYHA, New York Heart Association

0 (0( .0)))

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0.55 (0.50-0.62) 000.5855 (0.53-0.66) 0.49 (0.45-0.52) <

888 (111155.5.7)))) 8888 (((2( 222.2 99)9 0 (0(0(0(0.0.0.00)))

nomamamam lylylyly

deffecececcttt,, nnn (%(%(%))) 191999 (3(( 7.7.7.7 3)3)3)3 16161616 (4(4(4( 444.4444)))) 333 (2(2(2(20.00 0)0)0)0)

men ovale, n nnn (%(%(%(%))) 5555 (9(99(9.88.8.8)))) 5555 (1((1(13.3.3.9)9)99) 0000 (0(0(0(0.0.00.0)))) by guest on June 24, 2018http://circep.ahajournals.org/

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Table 2. Comparison of electrocardiographic and echocardiographic variables

Variable Total(n=51)

fQRS (+)(n=35)

fQRS (-)(n=16 ) P value*

Electrocardiographic variables

PR interval†, msec 176 (162-193) 182 (163-200) 166 (138-182) 0.030

RBBB, n (%) 15(29.4) 15(42.9) 0 (0.0) 0.002

Right axis deviation, n (%) 26 (51.0) 23 (65.7) 3 (18.8) 0.003

QRS duration†, msec 119 (107-148) 135 (118-156) 99 (94-112) <0.001

Corrected QT†, msec 441 (416-486) 472 (428-498) 414 (406-444) 0.003

Corrected JT†, msec 314 (297-330) 311 (285-330) 299 (282-326) 0.422

QRS dispersion†, msec 26(20-40) 40(22-40) 20(15-36) 0.006

QT dispersion†, msec 40(28-80) 55(40-80) 35(20-74) 0.106

JT dispersion†, msec 60(28-80) 60(46-100) 33(20-60) 0.011

QRS preexcitation, n (%) 9 (17.6) 5 (14.3) 4 (25.0) 0.436

Echocardiographic variables

RA area†‡, cm2/m2 14.5(10.9-21.5) 17.1(12.3-24.3) 11.6(8.7-14.1) 0.004

Atrialized RV area†‡, cm2/m2 9.04(7.4-13.1) 9.7(8.0-14.5) 7.4(6.1-9.3) 0.013

Functional RV area†‡, cm2/m2 8.2(6.3-12.8) 9.1(6.2-13.8) 6.9(6.3-10.2) 0.204

LV area†‡, cm2/m2 15.0(12.3-18.6) 14.8(12.1-17.6) 17.7(12.4-19.2) 0.369

LA area†‡, cm2/m2 7.5(6.1-9.2) 7.4(6.1-9.5) 7.6(6.3-8.8) 0.958

LV ejection fraction†, % 60(54-65) 59(54-66) 60(53-64) 0.911

TV displacement†, mm/m2 1.9(1.3-2.6) 1.9(1.4-2.8) 1.5(1.1-2.1) 0.072

Severe TR, n (%) 25(49.0) 22(62.9) 3 (18.8) 0.006

Ebstein severity index† 0.79(0.63-0.94) 0.87(0.67-1.07) 0.63(0.44-0.74) 0.001 Ebstein severity grade, n (%) 0.030

1 5 (12.5) 1 (3.6) 4 (33.3)

2 28 (70.0) 20 (71.4) 8 (66.7)

3 4 (10.0) 4 (14.3) 0 (0.0)

4 3 (7.5) 3 (10.7) 0 (0.0)*The P value is obtained as described in Table 1. †Data represented as the median (25th and 75th percentiles).‡Each value is indexed to body surface area. RBBB, right bundle branch block; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; TR, tricuspid regurgitation; TV, tricuspid valve

20202020(1(1(1(15-5-5--36363636) ) ) )

35353535(2(2(2(20-0-00 74747474) )))

ion msec 60(28 80) 60(46 100) 33(20 60)

x

i

l2/ 2 15 0(12 3 18 6) 14 8(12 1 17 6) 17 7(12 4 19 2)

ion , msec 60(28 80) 60(46 100) 33(20 60)

xcccciiti aataa ion, n ((((%)%)% 9 9 9 9 (1( 7.7.6)6 555 (1(1(1(14.3)))3) 44 44 (2(2(2( 5.0)))

ioooogrgrgrgraphic variaablles

cmmm2/m/m/m/m2 1414144.5.5.5(1(1(1(10.9-9-9-21212121.5.5.55)))) 17171717.1.1.1.1(1(1(1(12.2.2.2 3-3-3-3-2424244.3.3.33))) 1111.6.6.6.6(8(8(8(8 77.77-11114.44.1)1)1)1

RV arararareaeaea†‡†‡††‡, cmcmcmm2222/m/m/m/ 2222 9.9..0404040 (7777.4.4.4.4-1-1-13.3.3.3 1)1)1)1 9.9.9.9.7(7(7(7(8.888 0-0-0-14141414.5.5.5) ) )) 7.777 4(4(4(4(6.6.6.6 1-1-1-9.9.9.9 3)3)3)3)

lll RRRVVV area†‡†‡,, cm22///m22 888.2(2(2(666.3-3-3-121212 88.8) )) 999.1(1(1(666.222-131313 88.8) ) ) 666.9(9(9(666.333-101010 22.2))) 222// 222 1515 00(1(122 33 1818 66)) 1414 88((1212 11 1177 6)6) 1717 77(1(122 44 1919 22))


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Table 3. Comparison of clinical outcomes

Total

(n=51)

fQRS (+)

(n =35)

fQRS (-)

(n =16 ) P value*

Total Arrhythmic events, n (%) 26 (51.0) 23 (65.7) 3 (18.8) 0.003

Bradyarrhythmia requiring PPM, n (%) 3 (5.9) 3 (8.6) 0 (0.0) 0.227

Tachyarrhythmia, n (%) 26 (51.0) 23 (65.7) 3 (18.8) 0.003

Atrial tachyarrhythmia, n (%) 20 (39.2) 17 (48.6) 3 (18.8) 0.064

Ventricular tachyarrhythmia, n (%) 9 (17.6) 9 (25.7) 0 (0.0) 0.043

Unexplained syncope, n (%) 4 (7.8) 4 (11.4) 0 (0.0) 0.295

Tricuspid valve repair/replacement, n (%) 27 (52.9) 22 (62.9) 5 (31.3) 0.036

Fontan operation, n (%) 1 (2.0) 1 (2.9) 0 (0.0) 1.000

Cardiac death, n (%) 1 (2.0) 1 (2.9) 0 (0.0) 1.000

*The P value is based on the Fisher’s exact test.PPM, permanent pacemake

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Table 4. Predictors for arrhythmic events in univariate and multivariable Cox regression analyses

CharacteristicsUnivariate analysis Multivariable analysis model 1 Multivariable analysis model 2*

HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value

NYHA class III~IV 1.72(0.76-3.90) 0.194 1.53(0.54-4.34) 0.421

2.13(0.85-5.34) 0.108 1.04(0.35-3.10) 0.951

LV ejection fraction 1.01(0.96-1.05) 0.876 1.01(0.95-1.07) 0.815

Severe tricuspid regurgitation 1.48(0.67-3.25) 0.335 1.46(0.56-3.82) 0.446

Atrialized RV area index 1.05(0.97-1.14) 0.200 1.02(0.92-1.13) 0.751

Ebstein’s anomaly severity index 1.45(0.41-5.07) 0.565 0.25(0.03-1.84) 0.809

QRS duration 1.01(1.01-1.03) 0.015 1.00(0.98-1.02) 0.844 1.01(0.99-1.02) 0.444

Corrected QT interval 1.01(0.99-1.01) 0.254 1.01(0.99-1.02) 0.527

fQRS 5.05(1.50-16.9) 0.009 5.91(1.07-32.6) 0.041 4.13(1.09-15.6) 0.036

* Multivariable analysis model 2 incorporated parameters attaining a P value<0.05 in univariate analysis. Abbreviations as in the Table 1 and 2.

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Figure Legends:

Figure 1. Fragmented QRS complexes observed in adult patients with Ebstein’s anomaly.

Dashed arrows indicate fragmentation of QRS complexes in precordial and inferior leads.

Figure 2. Measurement of the severity of Ebstein’s anomaly. Planimetry was performed in the

apical four-chamber view at end-diastole. In this case, the ratio of the combined area of the RA

and atrialized RV divided by the combined area of the RV proper, LA, and LV was 0.82, which

falls under severity grade 2.

RV, functional right ventricle; aRV, atrialized RV; RA, right atrium; LV, left ventricle; LA, left

atrium.

Figure 3. Detailed distribution of fQRS complexes. fQRS complexes occurred primarily in

inferior and precordial leads.

Figure 4. Arrhythmic event-free survival curves depending on the presence of fQRS

, and LV was 0.82222,, , , ww

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Detailed distribution of fQRS co lexes. fQRS co lexes occurred rimarily in

d precordial leads

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ddd pprerecocordrdrdiaiaialll leleleadadadss


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Shin Yi Jang, Ok Jung Lee, Jinyoung Song, I-Seok Kang and June HuhSeung-Jung Park, Seungmin Chung, Young Geun On, June Soo Kim, Ji-Hyuk Yang, Tae-Gook Jun,

Arrhythmic Risk and the Severity of the AnomalyFragmented QRS Complex in Adult Patients with Ebstein's Anomaly and Its Association with

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2013 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

published online November 14, 2013;Circ Arrhythm Electrophysiol.

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Supplemental Table. C-index calculated using Cox survival methods

C-index Lower 95% CI Upper 95% CI

QRS duration 0.784 0.387 0.999

Wide QRS 0.814 0.422 0.999

fQRS 0.841 0.455 0.999

Combined parameter* 0.751 0.348 0.999

C-index was computed to evaluate the discriminatory accuracy of several

electrocardiographic variables (QRS duration, wide QRS, fQRS, and combination of QRS

duration and fragmentation) for predicting the occurrence of arrhythmic events.

* Combined parameter refers to categorized electrocardiographic variable determined by

QRS duration and fragmentation; narrow non-fragmented (normal), narrow fragmented, wide

non-fragmented, and wide fragmented.

SUPPLEMENTAL MATERIAL

Spearman’s rho = 0.581

P<0.001

[A]


P<0.001

[B]

Supplemental Figure 1


P=0.018

[B]


P=0.001

[A]


0

20

40

60

80

Lowest Tertile Mid Tertile Highest Tertile

(%)

QRS duration

* P for trend (total arrhythmic events)=0.004 † P for trend (ventricular arrhythmic events)=0.050

*

†

Total Arrhythmic Events

Ventricular Arrhythmic Events


(%)

Total Arrhythmic Events

Ventricular Arrhythmic Events

*

†

* P for trend (total arrhythmic events)=0.002 † P for trend (ventricular arrhythmic events)=0.025

0

20

40

60

80

Normal QRS Narrow fQRS Wide fQRS


Supplemental Figure Legends

Supplemental Figure 1. The extent of fQRS and the severity of Ebstein's Anomaly

QRS fragmentation shows a significant positive correlation with the severity of Ebstein's anomaly.

Supplemental Figure 2. QRS duration and the severity of Ebstein's Anomaly

QRS duration seems to represent quite well the severity of Ebstein's anomaly. The degree of QRS widening

showed a significant positive correlation with the aRVAi (A) as well as with the Ebstein severity index (B). The Ebstein

severity index was calculated as described in the method section.

Supplemental Figure 3. QRS duration and arrhythmic burden

When our patients were divided into 3 groups depending on the degree of QRS widening, a clear trend

toward more frequent arrhythmic events (total and ventricular tachyarrhythmias) was noted in patients with longer QRS

duration.

Supplemental Figure 4. Combined QRS morphologic markers (duration & fragmentation) and arrhythmic burden.

The risk of arrhythmic events tended to rise as the abnormal features of QRS morphology (prolongation and

fragmentation) were added (P for trend = 0.002 and 0.025 in total and ventricular arrhythmic events, respectively).

fragmented qrs complex in adult patients with ebstein’s...

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