ventricular arrhythmia risk stratification in patients...

DOI: 10.1161/CIRCEP.114.001975

1

Ventricular Arrhythmia Risk Stratification in Patients with Tetralogy of

Fallot at the Time of Pulmonary Valve Replacement

Running title: Sabate Rotes et al.; Arrhythmia Management at PVR in Repaired TOF

Anna Sabate Rotes, MD1,2; Heidi M. Connolly, MD1; Carole A. Warnes, MD1;

Naser M. Ammash, MD1; Sabrina D. Phillips, MD1; Joseph A. Dearani, MD3;

Hartzell V. Schaff, MD3; Harold M. Burkhart, MD3; David O. Hodge, MS4;

Samuel J. Asirvatham, MD1; Christopher J. McLeod, MBChB, PhD1

1Division of Cardiovascular Disease, 3Division of Cardiovascular Surgery, 4Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN; 2Universitat

Autònoma de Barcelona, Barcelona, Spain

Correspondence:

Christopher J. McLeod, MBChB, PhD

Division of Cardiovascular Diseases

Mayo Clinic

200 First Street

Rochester, MN 55902

Tel: 507-255 4152

Fax: 507-255 2550

E-mail: [email protected]

Journal Subject Codes: [41] Pediatric and congenital heart disease, including cardiovascular surgery, [22] Ablation/ICD/surgery, [5] Arrhythmias, clinical electrophysiology, drugs

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DOI: 10.1161/CIRCEP.114.001975

2

Abstract:

Background - Most patients with repaired tetralogy of Fallot (TOF) require pulmonary valve

replacement (PVR), but the evaluation for and management of ventricular arrhythmia remains

unclear. This study is aimed at clarifying the optimal approach to this potentially life-threatening

issue at the time of PVR.

Methods and Results - A retrospective analysis was performed on 205 patients with repaired

TOF undergoing PVR at our institution between 1988 and 2010. Median age was 32.9 (range

25.6 years). Previous ventricular tachycardia (VT) occurred in 16 patients (8%) and 37 (16%)

had left ventricular (LV) dysfunction, defined as LV ejection fraction <50%. Surgical right

ventricular outflow tract cryoablation was performed in 22 patients (10.7%). The primary

outcome was a combined event including VT, out-of-hospital cardiac arrest, appropriate

implantable cardioverter-defibrillator therapy and sudden cardiac death. Freedom from the

combined event at 5, 10, and 15 years was 95, 90, and 79%, respectively. In the first year

following PVR, 2 events occurred. Conversely, in the 22 patients who underwent surgical

cryoablation, a single event occurred 7 years after PVR. A history of VT and LV dysfunction

were associated with higher risk for the combined event (HR 4.7, p=0.004 and HR 0.8, p=0.02

respectively).

Conclusions - Patients with repaired TOF undergoing PVR with history of VT and/or LV

dysfunction appear to be associated with a higher risk of arrhythmic events after operation.

Events in the first year after PVR are rare, and in select high risk patients, surgical cryoablation

does not appear to increase arrhythmic events and may be protective.

Key words: tetralogy of Fallot, ablation, arrhythmia

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Introduction

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect, and is typically

repaired with low risk and excellent long-term results.1-3 Most patients however do require

pulmonary valve replacement (PVR) later in life. To date, there is not a consistent approach in

the determination and management of SCD risk at the time of PVR. The clinical utility of

preemptive preoperative electrophysiological study (EPS) and surgical cryoablation at the time

of open repair is not agreed upon,4-6 but is common in practice. Despite programmed ventricular

stimulation being of diagnostic and prognostic value7 – the appropriate timing of EPS has not

been studied.

Prior to PVR for severe pulmonary regurgitation in TOF, the volume loaded and

dysfunctional right ventricle (RV) is vulnerable to ventricular arrhythmia;8 conceptually PVR

can reverse the volume overload and potentially mitigate against the development of ventricular

tachycardia (VT). Intracardiac mapping and ablation, however, have confirmed that the VT is

typically of a macroreentrant nature using the cardiac valves and ventricular scars as boundaries6,

7 – and therefore surgical ablation of the RV outflow tract (RVOT) presents a logical approach to

isolate diseased substrate.5, 9, 10

This study is aimed at clarifying the optimal approach to ventricular arrhythmia

management in TOF patients at the time of PVR, by highlighting 1) novel predictors of

ventricular arrhythmia, 2) whether EPS is of clinical utility; 3) identify the most suitable time to

perform the EPS for risk stratification and 4) whether RVOT cryoablation is of clinical utility.

Methods

Population

A total of 537 consecutive patients with the diagnosis of TOF had 641 surgeries between

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a (VT). Intracardiac mapping and ablation, however, have confirmed that the VT

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October 1988 and December 2010 in Mayo Clinic, Rochester, MN. From those, 205 patients

with TOF who had undergone previous complete repair and had reoperation to restore

pulmonary valve function were selected. All re-operations were performed at this institution, but

some initial repairs were undertaken elsewhere. Patients with concomitant pulmonary atresia,

absent pulmonary valve, atrioventricular canal, and previous conduit or PVR were excluded. The

study was approved by the Mayo Clinic Institutional Review Board, and all patients provided

consent for their data to be used for study purposes.

Descriptive and Baseline Data

Medical history, perioperative and follow-up data were collected using all available records.

An ECG at the time of PVR was available for all patients. Electrocardiograms were

analyzed by an independent observer who was blinded to the clinical outcome of each patient

(CJM). The criteria utilized for QRS fragmentation are well validated for other forms of cardiac

disease,11 and the ECG phenotype was broken into (i) notched QRS (ii) fragmented QRS or (iii)

normal ECG.

Holter monitoring before the PVR was available in 46 patients (22%). The degree of

ectopy was graded following the Lown criteria,12 although modified as described: 0 - No

ventricular ectopic beats, 1 - Occasional, isolated ventricular premature beats (VPB), 2 -

Frequent VPB (>1/minute or 30/hour), 3 - Multiform VPB, 4 - Repetitive VPB (a) Couplets (b)

Salvos: 3 or more VPBs, 5 - VT (>30 seconds). Nonsustained VT was defined as 4 or more

consecutive ventricular beats documented on a 12 lead-ECG, Holter recording, or ECG strips;

last

High risk for arrhythmia was considered when patients had documented sustained

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documented nonsustained VT or left ventricular (LV) dysfunction. Indications for performing an

EPS before surgery include unexplained syncope or near syncope and non-sustained VT on

Holter. Indications for ICD implant after surgery include VT or out-of-hospital cardiac arrest,

inducible VT at EPS, left ventricular ejection fraction (LVEF) < 35% and unexplained syncope.

Baseline echocardiographic data included qualitative assessments of right ventricular size

and function and quantitative LVEF (%) on the latest evaluation before PVR (at most 3 years

removed). RV dysfunction or dilatation was felt to be significant if graded to beat least

moderately severe. Cardiac MRI before PVR was performed in 35 patients either in our or an

outside institution.

Surgical Cryoablation

Open surgical RVOT ablation was began in our practice in 2000 as VT treatment or prophylaxis

based on preoperative conditions.13 During this procedure, a cryoablation lesion is placed to

connect the superior aspect of the ventricular septal defect patch to the pulmonary annulus. In

selected cases, a lesion grounding the ventriculotomy to the pulmonary or tricuspid annulus is

performed. See figure 1. The freezes are made for 90 to 120 seconds each with a 15

mm probe - Frigitronics (CooperVision, Inc, Lake Forest, Calif) and CryoCath (Medtronic,

Montreal, Quebec, Canada). Indications for surgical cryoablation of the RVOT include history

of non-sustained VT or VT, inducible VT at EPS that was not ablated and history of unexplained

syncope or near-syncope.

Outcome Data

The primary outcome was defined as combined event at follow-up, including VT, out-of-hospital

cardiac arrest, appropriate therapy in those with implantable cardioverter-defibrillator (ICD) and

SCD:

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- VT: sustained VT documented on a 12 lead-ECG, Holter recording, or ECG strips.

Sustained tachycardia defined as arrhythmia lasting > 30 seconds or of any length of time

if associated with hemodynamic compromise, requiring cardioversion or admission.5, 7

- Out-of-hospital cardiac arrest: documented cardiac arrest that needed resuscitation.

- Defibrillator discharges or anti-tachycardia overdrive pacing:

o Appropriate: triggered by VT or ventricular fibrillation documented by stored

intracardiac electrogram or cycle-length data in conjunction with patient's

symptoms immediately before and after device discharge.

o Inappropriate: triggered by a rapid ventricular rate exceeding the programmed

threshold rate as a consequence of supraventricular tachycardia, exercise-related

sinus tachycardia, or a malfunction of the device.

- SCD: based on autopsy reports. Two patients died suddenly and were considered to

succumb to SCD although no autopsy was performed.

Statistical analysis

Descriptive statistics are reported as proportions for discrete data and means and standard

deviations for continuous data, except for variables that are not normally distributed in which

case median and range are used. Discrete data was compared between groups using Fisher’s

exact test. Continuous data was compared using Wilcoxon rank-sum tests. Survival and free-

event times were estimated using Kaplan-Meier method with 95% confidence intervals. Survival

curves were compared by the log-rank test. Cox proportional hazards models were used for the

univariate analysis.

Results

A summary of the clinical characteristics is shown in table 1. All patients had at least one

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previous operation accounting for the TOF repair and 126 of them (62%) had a transannular

patch placed on the RVOT at that time. In addition, 95 patients (46%) had two and 35 (17%) had

three or more previous operations including palliative surgery, closure of persistent VSD and

other residual lesions. Preoperative mean indexed RV end-systolic volume was 102 ± 32 mL/m2,

RV end-diastolic volume 175 ± 45 mL/m2, and RV ejection fraction 42 ± 8 %. Their indexed LV

end-systolic volume was 31 ± 13 mL/m2, LV end-diastolic volume 72 ± 20 mL/m2, and LV

ejection fraction 56 ± 8 %.

Holter monitoring was abnormal for the majority of patients in whom it was available,

although no VT was detected. Exercise testing before the PVR revealed non-sustained VT in 1 of

the 92 patients for whom it was available; and 21 patients had repetitive VPBs in form of

couplets or salvos. An EPS was conducted in 40 patients (20%) at a median time of 5 days

before PVR, and pre-PVR ablation of VT was performed in 5 patients (3%). At the time of PVR,

45 patients (22%) ms, including patients with paced rhythm.

Complete follow-up was available for 200 patients (98%) during a median time of 6.7

years, maximum of 24 years.

The combined event occurred in 19 patients, including SCD in 5 patients, appropriate

ICD therapy in 7 patients, out-of-hospital cardiac arrest in 3 patients, and clinically identified

sustained VT in 4. Differences in the clinical history of this group compared with the non-event

group are detailed in Table 1. Freedom from the combined event is shown in figure 2. Freedom

from the combined event was 95.1% (CI 91.8 – 98.5) at 5 years, 90.1% (CI 84.9 – 95.6) at 10

years and 79.1% (CI 67.9 – 92.1) at 15 years.

ICD placement occurred in 23 patients at a median time of 1 month after the PVR (range

3 days to 23.5 years). A total of 7 patients had 18 appropriate discharges and 6 patients had 14

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inappropriate discharges during follow-up. Two patients had only inappropriate discharges.

Inappropriate discharges were due to oversensing in 43% and supraventricular tachyarrhythmia

in 57%.

Univariate risk factors for the combined event are detailed in table 2. Figure 3 shows the

survival curves for freedom from any event by history of VT, LVEF and QRS duration.

Importantly, patients with LVEF < 50% were over 3 times more likely to have RV dysfunction >

moderate, HR 3.0 (95% CI 1.4 - 6.8), p = 0.01.

QRS duration was found to be longer in patients with an LVEF < 50%; Median QRS 170

ms vs 158 ms, p = 0.02. However, no association between QRS duration and RV function was

found. All patients with prolonged QRS duration had a right bundle block pattern; therefore no

conclusion could be inferred about LV dyssynchrony and ventricular function.

QRS fragmentation was identified in 135 patients, while 13 patients were found to have

notched QRS morphologies. Twelve patients had paced QRS morphologies and were excluded.

QRS fragmentation was not predictive of the combined event. An entirely normal ECG without

PR, QRS or ST abnormality was noted in 10 patients and none of this group sustained any event

at follow-up.

Twenty-one patients died at follow-up. Three deaths occurred in the perioperative period

for an operative mortality of 1.5%; cause of death was myocardial infarction, postoperative

bleeding and RV failure respectively. Survival at 5, 10 and 15 years were 94.6% (CI 91.4 –

97.9), 84.6% (CI 78.3 – 91.5) and 81.7% (CI 73.6 – 90.7), respectively.

Surgical cryoablation

None of the 22 patients who underwent open surgical RVOT ablation died suddenly, sustained

an out-of-hospital cardiac arrest or VT episode during follow-up. Only one of the 22 had an

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appropriate ICD discharge 7 years after surgery. In contrast, 18 of the 183 patients without

surgical cryoablation sustained events: SCD (n=5), appropriate ICD therapy (n=6), out-of-

hospital cardiac arrest (n=3) or VT (n=4) at follow-up. For the majority, pre-operative baseline

risk factors were not significantly different between these groups (table 3), although patients in

the cryoablation group were older at PVR and were more likely to have inducible VT at EPS.

ICD implantation was more common in this group. Figure 4 shows the survival curve for

freedom from any event by surgical cryoablation.

Discussion

The results of this study highlight that any degree of LV dysfunction (LVEF < 50%) confers an

increased risk for ventricular arrhythmia/SCD in the TOF patient undergoing PVR. LV systolic

dysfunction with LVEF <50% is present in around a fifth of adults with repaired TOF.14 The data

have suggested that moderate to severe LV systolic dysfunction is predictive of arrhythmic

events.15 Results from this investigation propose that even a mild reduction in LVEF prior to

PVR is associated with increased risk. In addition, this study highlights that patients with a

history of clinical VT at the time of PVR have an increased risk of ventricular arrhythmia/SCD at

follow-up. This important and intuitive finding has not been previously reported in the literature.

Nonsustained VT had been associated with appropriate ICD shocks in patients with TOF

undergoing primary prevention ICD implantation.16 We found no association between

nonsustained VT and events at follow-up in our patient group.

This investigation confirms that a prolonged QRS duration is predictive of ventricular

arrhythmic events in patients with repaired TOF prior to PVR, yet interestingly, ECG criteria

such as QRS fragmentation or an entirely normal ECG is not positively or negatively predictive.

QRS fragmentation represents cardiac conduction delay and is thought to be a marker of fibrosis

s of this study highlight that any degree of LV dysfunction (LVEF < 50%) confer

risk for ventricular arrhythmia/SCD in the TOF patient undergoing PVR. LV sys

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and scar within the myocardium. It is a marker of increased mortality and ventricular arrhythmia

in patients with coronary disease17 and also portends a poor prognosis in those with

arrhythmogenic right ventricular dysplasia.11, 18, 19 It remains speculative as to why this feature is

not predictive of arrhythmic events in TOF – yet this morphology is especially common –

occurring in 70% of repaired TOF patients. We hypothesized that an entirely normal ECG

represents a less malignant phenotype. This appears to be the case in other forms of congenital

heart disease,20 and it is interesting to note that patients in our study group with a normal ECG

did not sustain any arrhythmic event.

Surgical cryoablation

A central message from this study is that surgical cryoablation in the RVOT is safe and

potentially reduces the risk of arrhythmic events after PVR. Importantly, surgical cryoablation

does not appear to be pro-arrhythmic. A major concern with any ablation procedure (done

percutaneously or via an open approach) centers on whether bidirectional block can be achieved

across a corridor of electrical conduction. If lesion depth is not transmural – damaged

myocardium can serve as substrate providing slow cardiac conduction and thereby providing one

of the key ingredients for reentrant arrhythmia. Intraoperative open EPS mapping is typically no

longer performed, and therefore lesion depth/discrete linear block cannot be confirmed during

open cryoablation cases. Although underpowered because of small numbers and low event rates

these data do suggest a trend towards surgical cryoablation of the RVOT being associated with

less post-PVR ventricular arrhythmic events. Only one patient sustained an appropriate ICD

discharge 7 years after the PVR/cryoablation procedure. This is especially important information

given that the literature is currently limited to only 9 patients from a small series and follow-up

limited to 5 years.5

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EP studies

A remaining question therefore in managing the risk of serious ventricular arrhythmia in TOF

patients with pulmonary regurgitation revolves around the need for an EPS and its optimal

timing. The highest risk group in the study is TOF/PVR patients with prior documentation of

VT; we suggest these patients undergo preoperative EPS to more carefully assess risk of

malignant events. It is a concern, however, that ventricular arrhythmia prior to PVR is in part

related to the volume overloaded RV, and improvement in the hemodynamic milieu with PVR

offloads the RV, reduces myocardial stretch and thereby allows for geometric and electrical

remodeling. A significant reduction in the incidence of monomorphic VT after PVR has been

previously recognized.5, 21 In these analyses, appropriate ICD therapy was not included as an

endpoint. Even though data from this current study does reflect a similar trend, with the

prevalence of VT decreasing after PVR, patients with history of VT have a higher risk of

ventricular arrhythmia/SCD at follow-up. The majority of events occurred in patients who did

not undergo pre- or post-operative EPS. These findings suggest that all patients with risk factors

for VT undergoing PVR should have an EPS pre- or post-operatively. Additional study is

required to determine whether this study can potentially be delayed until RV remodelling has

taken place.

Holter monitoring failed to detect sustained VT but interestingly VPBs and non-sustained

VT using Lown-grade criteria were not associated with arrhythmic events after PVR. Prior

studies evaluating ambulatory monitoring is mixed,22, 23 yet all patients in this report underwent

PVR which can improve arrhythmogenic substrate.

Patients with syncope do appear to be a high-risk group with the vast majority in this

cohort undergoing EPS, surgical cryoablation or ICD implantation.

ometric and electrtrrricicicicaa

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Limitations

The combination of endpoints (including VT and appropriate ICD therapies as a surrogate for

life-threatening events) provides greater statistical power to discern between risk factors. Yet it

must be acknowledged that these events are surrogates and not all ICD or VT events go on to

result in SCD. The retrospective historical nature of the study is inherently limited, but given the

small population with congenital heart disease, this is unfortunately integral to current

investigation in this setting. Recommendations for monitoring patients with pulmonary valve

regurgitation after TOF repair and determining optimal timing of PVR changed over the course

of the study period and thus testing and referral patterns varied during the study. Even though

preoperative Holter monitoring was available for a limited number of patients, we considered

worth including in the analysis as there are few publications with that many patients. On the

other hand, qualitative right ventricular dimensions and function were measured by

echocardiography given the small number of MRIs performed preoperatively. Even though the

surgical cryoablation analysis is underpowered because of small numbers and low event rates, to

our knowledge represents the larger number of patients ever studied.

Conclusion

Patients with repaired TOF undergoing PVR with a history of VT, QRS and/or LVEF

< 50%, are at high risk of arrhythmic events after operation. Our findings suggest that an EPS

should be strongly considered in this particularly high risk group before or after PVR. Surgical

cryoablation at the time of PVR does not appear to be pro-arrhythmic, and may be beneficial.

We recommend a comprehensive multidisciplinary preoperative evaluation for all TOF

patients with pulmonary valve regurgitation to determine the best timing of operation and the

extent of preoperative VT risk stratification. Based on these data we suggest that the preoperative

R changeg d over theheee ccccoo

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VT risk assessment include ECG, Holter, exercise testing and EPS for patients with high risk

features. We currently advise that TOF patients undergoing PVR who have preoperative

syncope, VT or abnormal EPS undergo surgical cryoablation or ICD implantation.

Future initiatives in this field should include multi-center collaborative studies to validate

these findings.

Funding Sources: Anna Sabate Rotes is supported by Fundació La Caixa, Av. Diagonal, 621, t.

2, pl. 4. 08028, Barcelona, Spain.

Conflict of Interest Disclosures: None.

References:

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2. Nollert G, Fischlein T, Bouterwek S, Bohmer C, Klinner W, Reichart B. Long-term survival in patients with repair of tetralogy of fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol. 1997;30:1374-1383.

3. Waien SA, Liu PP, Ross BL, Williams WG, Webb GD, McLaughlin PR. Serial follow-up of adults with repaired tetralogy of fallot. J Am Coll Cardiol. 1992;20:295-300.

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JG, Gersh BJ, Mair DD, Fuster V, McGoon MD, Ilstru DM, McGoon DC, Kirkln

G, Fischlein T, Bouterwek S, Bohmer C, Klinner W, Reichart B. Long-term survth repair of tetralog of fallot: 36 ear follo p of 490 s r i ors of the first ea

s::::

JGJGJG, Gersh BJBBB , MaMairiir DDD,D FFFusteteeter VV,V MMMcccGoooon MDMMM , , , Ilstrururuup DMDM, MMcMM Gooooooon DDC, KKKirklson GKGKGKGK. LLLong tt-term outcomomomome in ppppatatatatieiieients undeddd rgrgrgrg iioiingngngng suuurgrgrgr iciii llall repaiaiaia rrrr of tttt ttetraloll gy ngl JJJJ MMMedededd. 111999999993;3;3;3 32323229:9:9::595959593-33-5959595 9..

G, Fischleieiiein n n n T,TT,T, BBBBououououteteterwrwrwrwekeekek SSS,,,, BoBoBoBohmhmhmhmererere CCCC, , , , KlKlKlKliniininnenener r r W,WW,W, RRReieieieichchchcharararart t t t B.B.BB. LLLLonononng-g-g-g tettt rm survtthh iir ff ttettr lal fof ff lalllott: 3366 ffollll fof 449090 ii ff thth fifi tt


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10. Scherptong RW, Hazekamp MG, Mulder BJ, Wijers O, Swenne CA, van der Wall EE, Schalij MJ, Vliegen HW. Follow-up after pulmonary valve replacement in adults with tetralogy of fallot: Association between qrs duration and outcome. J Am Coll Cardiol. 2010;56:1486-1492.

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13. Downar E, Kimber S, Harris L, Mickleborough L, Sevaptsidis E, Masse S, Chen TCK, Genga A. Endocardial mapping of ventricular tachycardia in the intact human heart. Ii. Evidence for multiuse reentry in a functional sheet of surviving myocardium. J Am Coll Cardiol.1992;20:869-878.

14. Broberg CS, Aboulhosn J, Mongeon FP, Kay J, Valente AM, Khairy P, Earing MG, Opotowsky AR, Lui G, Gersony DR, Cook S, Ting JG, Webb G, Gurvitz MZ. Prevalence of left ventricular systolic dysfunction in adults with repaired tetralogy of fallot. Am J Cardiol.2011;107:1215-1220.

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16. Khairy P, Harris L, Landzberg MJ, Viswanathan S, Barlow A, Gatzoulis MA, Fernandes SM, Beauchesne L, Therrien J, Chetaille P, Gordon E, Vonder Muhll I, Cecchin F. Implantable cardioverter-defibrillators in tetralogy of fallot. Circulation. 2008;117:363-370.

17. Brenyo A, Pietrasik G, Barsheshet A, Huang DT, Polonsky B, McNitt S, Moss AJ, Zareba W. Qrs fragmentation and the risk of sudden cardiac death in madit ii. J Cardiovasc Electrophysiol. 2012;23:1343-1348.

18. Peters S. Qrs fragmentation in patients with arrhythmogenic right ventricular cardiomyopathy and complete right bundle branch block: A risk stratification. Eur Heart J Acute

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N BBBB, WOWOWOW LFLFLFL MMM.... ApAA proaches to sudden deaeaeaththtt from coronann ryyy hhheart disease. Circula300-00 11411 2.

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Cardiovasc Care. 2012;1:236-239.

19. Canpolat U, Kabakci G, Aytemir K, Dural M, Sahiner L, Yorgun H, Sunman H, Baris Kaya E, Tokgozoglu L, Oto A. Fragmented qrs complex predicts the arrhythmic events in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. J Cardiovasc Electrophysiol.2013;24:1260-1266.

20. McLeod CJ, Ackerman MJ, Nishimura RA, Tajik AJ, Gersh BJ, Ommen SR. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J Am Coll Cardiol.2009;54:229-233.

21. Oechslin EN, Harrison DA, Harris L, Downar E, Webb GD, Siu SS, Williams WG. Reoperation in adults with repair of tetralogy of fallot: Indications and outcomes. J Thorac Cardiovasc Surg. 1999;118:245-251.

22. Czosek RJ, Anderson J, Khoury PR, Knilans TK, Spar DS, Marino BS. Utility of ambulatory monitoring in patients with congenital heart disease. Am J Cardiol. 2013;111:723-730.

23. Gatzoulis MA, Balaji S, Webber SA, Siu SC, Hokanson JS, Poile C, Rosenthal M, Nakazawa M, Moller JH, Gillette PC, Webb GD, Redington AN. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of fallot: A multicentre study. The Lancet.2000;356:975-981.

oo oo BSBSBSBS.. UtUtUtUtililililitititity y yy ofofofof aaaambmbmbmbuuuu13;1111111111:777:723232323-77-77333030.

ulis MA, Balaji S, Webber SA, Siu SC, Hokanson JS, Poile C, Rosenthal M, NakJH, Gillette PC, Webb GD, Redington AN. Risk factors for arrhythmia and sudd

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ulisss MAMAMAM , BaBaBaB lajijiji SSS, Webber SA, Siu SC, HHHokokokkanson JS, PoPoP ile ee CC,CC Rosenthal M, NakJHJHJHH,,, Gilletteteee PPPC,CCC WWWebebebbbb b GDGDDGD,, ReReReR dididingngngtototon nn ANN. Riiisksksksk ffffaca totototorsrsrsr fororror arrhyhyhyhyththththmimm a a a anananand d d susususudd

atttth late after repepairr r oof tetettetrrralogygy ooof f fallooot: AA muuulltlticiciccenentreee studdyy. ThThThT e Laaaanccceet.97575757 -9-9-981.


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Table 1: Clinical characteristics for TOF patients undergoing PVR, and comparing patients that had an event at follow-up and those who did not

Combined event* Total

Past medical history Yes n = 19

Non = 186 N = 205

Age at initial repair, median (IQR) 6.8 (4.2, 12.0) 4.5 (2.2,7.6) 4.7 (2.4,8.6)

History of palliative surgery, N (%) 6 (32) 85 (46) 91 (44)

Number of previous interventions, median (IQR)

3.0(2.0, 3.0)

3.0(2.0, 3.0)

3.0(2.0, 3.0)

History of prior ventriculotomy, N (%) (N=180) 10 (59) 54 (33) 64 (36)

History of syncope, N (%) 3 (16) 16 (9) 19 (9)

Lown criteria 4a or 4b, N (%) (N=46) 3 (100) 28 (65) 31 (67)

Documented spontaneous NSVT, N (%) 0 (0) 21 (11) 21 (10)

NSVT inducible at EPS, N (%) (N=40) 1 (13) 3 (9) 4 (10)

History of VT, N (%) 5 (26) 11 (6) 16 (8)

VT inducible at EPS, N (%) (N=40) 6 (75) 15 (47) 21 (53)

History of ICD implantation, N (%) 4 (21) 11 (6) 15 (7)

Age at PVR surgery, median (IQR)

40.2(26.6,55.3)

31.6(19.7,45.1)

32.9(20.4,46.0)

Fragmented QRS at PVR, N (%) 14 (82) 121 (69) 135 (66)

QRS duration (ms) at PVR, median (IQR) 170 (160,198) 159 (138,176) 160 (142,176)

LV function (%), median (IQR) (N=189) 53 (45,57) 57 (51,63) 57 (51,62)

LVEF < 50%, N (%) (N=189) 7 (41) 28 (16) 35 (19)

RV dysfunction, N (%) (N=182) 5 (31) 19 (12) 24 (13)

RV dilatation, N (%) (N=194) 13 (68) 107 (61) 120 (62)

RVOT ablation at PVR, N (%) 1 (5) 21 (11) 22 (11)

* Combined event includes: ventricular tachycardia, out-of-hospital cardiac arrest, appropriate therapy in those with ICD and sudden cardiac death Abbreviations: EPS, electrophysiologic study; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; LVEF, left ventricular ejection fraction; NSVT, non-sustained ventricular tachycardia; PVR, pulmonary valve replacement; LV, left ventricle; RV, right ventricle; RVOT, right ventricular outflow tract; VT, ventricular tachycardia

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ucccibibiblel at EPEPEPE SS, N (%(%(%) (N=N=N=404040)))) 1 ((13) 3 (99) 4 (10

f VT,T,T,, N NN (%(%(%))) 555 (2(2(226)6)6) 1111111 (((6)6)6) 1616 (8

ble at EPS,,, N NNN (%(( ))) (((N=40) )) 6 (7(( 5))) 15 (((47444 ) )) 2121221 (((53

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Table 2: Risk factors for the combined event, univariate analysis

Risk factors HR 95% Confidence Interval p value

Univariate analysis

Previous palliation procedure 0.59 0.2 1.6 0.29

History of ventriculotomy 2.32 0.9 6.1 0.09

Age at initial Repair* 1.04 0.9 1.1 0.12

Number of previous interventions 1.04 0.6 1.8 0.89

History of VT 4.68 1.6 13.4 0.004

History of syncope 2.05 0.6 7.1 0.26

History of pacemaker implantation 2.38 0.7 8.2 0.17

History of ICD implantation 4.13 1.3 12.8 0.01

History of VT Cath ablation 2.77 0.4 21.2 0.33

Longer QRS duration at PVR † 1.16 1.0 1.3 0.02

ms at PVR 2.89 1.1 7.5 0.03

Fragmented QRS at PVR 1.55 0.4 5.5 0.50

Higher LVEF ( 5%)‡ 0.73 0.6 0.9 0.008

LVEF < 50% 3.62 1.4 9.4 0.008

RV dilatation 1.62 0.6 4.4 0.34

RV dysfunction 2.02 0.6 6.5 0.24

Older age at PVR § 1.26 1.1 1.5 0.006

RVOT ablation at surgery 0.85 0.1 6.4 0.87

*For every 1 year increase in age; †For every 10ms increase in QRS length; ‡For every 5% increase in LVEF;§For every 5 years increase in age. Abbreviations: HR, hazard ratio; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; NSVT, non-sustained ventricular tachycardia; PVR, pulmonary valve replacement; RV, right ventricle; RVOT, right ventricular outflow tract; VT, ventricular tachycardia

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Table 3: Summary of pre-operative risk factors comparing patients that did undergo cryoablation

at surgery and those who did not

Cryoablation at surgery

yes (n = 22) no (n = 183) p value

History of VT, N (%) 4 (18) 12 (7) 0.08

History of syncope, N (%) 3 (14) 16 (9) 0.44

History of ICD implantation, N (%) 5 (23) 10 (5) 0.01

Inducible VT at EPS, N (%) (N=40) 10 (83) 11 (39) 0.02

QRS duration (ms) at PVR, median (IQR) 159 (142,188) 160 (140,176) 0.92

Age at PVR (y), median (IQR) 42 (31,47) 31 (18,46) 0.02

LVEF (%), median (IQR) 55 (52,63) 57 (50,62) 0.80

Abbreviations: EPS, electrophysiologic study; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; LVEF, left ventricular ejection fraction; NSVT, non-sustained ventricular tachycardia; PVR, pulmonary valve replacement; RV, right ventricle; RVOT, right ventricular outflow tract; VT, ventricular tachycardia

16161616 ((((9)9)9)9) 0000

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Figure Legends:

Figure 1: Drawing showing surgical cryoablation lesions: 1, from ventricular septal defect patch,

across the pulmonary annulus and up to the pulmonary artery; and 2, from the right

ventriculotomy/patch up to the pulmonary annulus and/or proximally towards the tricuspid valve

annulus level.

Figure 2: Freedom from combined arrhythmic event (including ventricular tachycardia, out-of-

hospital cardiac arrest, appropriate therapy in those with ICD and sudden cardiac death)

Figure 3: Freedom from the combined event by risk factors. A. By history of ventricular

tachycardia, dashed line; no history of ventricular tachycardia, solid line. B. By LVEF < 50%,

dashed solid line. C. B ms, dashed line: < 180 ms, solid line.

Figure 4: Freedom from the combined event by surgical cryoablation, dashed line: patients that

had ablation at surgery; solid line: patients that did not.

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and Christopher J. McLeodJoseph A. Dearani, Hartzell V. Schaff, Harold M. Burkhart, David O. Hodge, Samuel J. Asirvatham Anna Sabate Rotes, Heidi M. Connolly, Carole A. Warnes, Naser M. Ammash, Sabrina D. Phillips,

Pulmonary Valve ReplacementVentricular Arrhythmia Risk Stratification in Patients with Tetralogy of Fallot at the Time of

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2014 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 21, 2014;Circ Arrhythm Electrophysiol.

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ventricular arrhythmia risk stratification in patients...

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