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DOI: 10.1161/CIRCEP.113.000170

1

Efficacy of Implantable Cardioverter Defibrillators in Young Patients with

Catecholaminergic Polymorphic Ventricular Tachycardia:

Success Depends on Substrate

Running title: Miyake et al.; Efficacy of ICD Therapy in CPVT

Christina Y. Miyake, MD1; Gregory Webster, MD2; Richard J. Czosek, MD3; Michal J. Kantoch,

MD5; Anne M. Dubin, MD1; Kishor Avasarala, MD4; Joseph Atallah, MD, CM, SM5

1Dept of Pediatrics, Lucile Packard Children’s Hospital, Stanford University, Palo Alto, CA;2Lurie Children’s Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL;

3The Heart Center, Cincinnati Children’s Medical Center, Cincinnati, OH;4Children’s Hospital Oakland, Oakland, CA; 5Stollery Children’s Hospital,

University of Alberta, Edmonton, Alberta, Canada

Correspondence:

Christina Y. Miyake, MD

Department of Pediatrics

Lucile Packard Children’s Hospital

Stanford University

750 Welch Road, Ste 325

Palo Alto, CA 94304

Tel: 650-723-7913

Fax: 650-725-8343

E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs, [22] Ablation/ICD/surgery

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DOI: 10.1161/CIRCEP.113.000170

2

Abstract:

Background - The effectiveness of implantable cardioverter-defibrillator (ICD) therapy for the

management of catecholaminergic polymorphic ventricular tachycardia (CPVT) in young

patients is not known. ICD discharges are not always effective and inappropriate discharges are

common, both resulting in morbidity and mortality.

Methods and Results - This is a multicenter, retrospective review of young patients with CPVT

and ICDs from 5 centers. ICD discharges were evaluated to determine arrhythmia mechanism,

appropriateness, efficacy of therapy, and complications. A total of 24 patients were included.

Median (IQR) ages at onset of CPVT symptoms and ICD implant were 10.6 (5.0 – 13.8) years

and 13.7 (10.7 – 16.3) years respectively. Fourteen patients received 140 shocks. Ten patients

(42%) experienced 75 appropriate shocks and 11 patients (46%) received 65 inappropriate

shocks. On actuarial analysis, freedom from appropriate shock at 1 year after ICD implant was

75%. Of appropriate shocks, only 43 (57%) demonstrated successful primary termination. All

successful appropriate ICD discharges were for ventricular fibrillation (VF). No episodes of

polymorphic ventricular tachycardia or bidirectional VT demonstrated successful primary

termination. The adjusted mean (95% CI) cycle length of successful discharges was significantly

shorter than unsuccessful discharges (168 (152-184) msec vs. 245 (229-262) msec, adjusted

p=0.002). Electrical storm occurred in 29% (4/14) and induction of more malignant ventricular

arrhythmias in 36% (5/14). There were no deaths.

Conclusions - ICD efficacy in CPVT depends on arrhythmia mechanism. Episodes of VF were

uniformly successfully treated whereas polymorphic and bidirectional VT did not demonstrate

successful primary termination. Inappropriate shocks, electrical storm and ICD complications

were common.

Key words: catecholaminergic polymorphic ventricular tachycardia, implanted cardioverter defibrillator, arrhythmia, pediatric, ventricular tachycardia, electrical storm

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DOI: 10.1161/CIRCEP.113.000170

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Introduction

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but highly malignant

disease with an estimated prevalence of 1:10,000.1 Early onset of symptoms has been associated

with a more malignant clinical course and sudden death rates have been reported to be as high as

25-50% by the age of 30 years. 2-6 Arrhythmias associated with CPVT are classically

polymorphic or bidirectional ventricular tachycardias triggered by adrenergic stimulation;

however, ventricular fibrillation (VF) and atrial arrhythmias can also be seen.5, 7-9 While anti-

arrhythmic therapy has been the first-line approach to managing these patients, implantable

cardioverter-defibrillators (ICDs) are also used as a treatment strategy.

Information regarding the use of ICDs in this patient population is limited and

conflicting. High rates of appropriate shocks have been reported but deaths have occurred

despite appropriate therapy. 3, 5, 6, 10, 11 Based on small case reports, it appears that ICD discharges

are sometimes but not always effective and therefore ICD implantation may not necessarily be

life-saving. 12 In fact, ICD implantation may potentially increase mortality risk. Death secondary

to lethal arrhythmias triggered by inappropriate discharges has occurred. 9 Despite these

concerns, there have been no previous studies evaluating appropriate and effective therapy in

these patients.

This study aimed to describe the appropriateness and effectiveness of ICD therapy in

young patients with CPVT, with an emphasis on factors associated with effective ICD therapy.

Methods

Study Population

We performed a multicenter retrospective review of young CPVT patients from 5 centers in the

United States and Canada who had an ICD placed between January 1999 through September

ppatients, impplanttabababablel

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mes but not always effective and therefore ICD implantation may not necessarily

12 In fact ICD implantation ma potentiall increase mortalit risk Death seco

ormmmmatatatatioioioonn n rereregagaardrdrdding the use of ICDs in thihihih s ss ppatient popuuulationononon is limited and

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DOI: 10.1161/CIRCEP.113.000170

4

2011. This study was conducted under IRB approval obtained separately at each participating

institution. Inclusion criteria included: 1) onset of CPVT symptoms before the age of 21 years,

2) diagnosis of CPVT made by genetic testing or clinical history as determined by a pediatric

electrophysiologist, and 3) presence of an implanted ICD.

Patient and ICD characteristics

Data collection included demographics, symptoms, dates of presentation and therapy, medical

management, length of follow-up and family history. Details regarding exercise testing, genetic

testing, and electrophysiology (EP) studies were collected. An exercise test or EP study was

considered positive for the purpose of the CPVT diagnosis if it documented a 3 beat run of

bidirectional (BDVT) or polymorphic ventricular tachycardia (PMVT). Indication for primary or

secondary prevention ICD was recorded. Secondary prevention was defined as documented

sustained or hemodynamically unstable ventricular tachycardia (VT), VF, or resuscitated cardiac

arrest. All ICD-related complications were recorded.

ICD discharge data

Each center submitted all available electrograms for each ICD discharge. Electrograms were

available for 119 (85%) of all discharges. A blinded committee reviewed and classified all ICD

discharge tracings and each tracing was independently reviewed by at least two pediatric

electrophysiologists. If electrograms were not available for an event, the event was classified as

reported by the patient’s treating electrophysiologist. Evaluation and adjudication of ICD

electrograms determined the following: 1) the arrhythmia initiating the ICD event detection (VF,

PMVT, BDVT, ventricular ectopy, or a supraventricular rhythm including sinus or atrial

tachycardia), 2) appropriate vs. inappropriate ICD discharge, 3) the termination pattern (primary

termination, secondary termination, spontaneous termination, or required a subsequent shock),

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prevention ICD was recorded. Secondary prevention was defined as documente

or hemodynamical unstable ventricular tachycardia , VF, or resuscitated ca

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and 4) whether the discharge resulted in a more malignant ventricular arrhythmia. A more

malignant ventricular arrhythmia was defined as a shock resulting in the conversion of a

supraventricular rhythm into a ventricular tachyarrhythmia, or the conversion of ventricular

ectopy or slow VT into a more rapid VT or VF (Figure 1A).

Arrhythmia substrate definitions were adapted from prior publications.13, 14 PMVT was

defined as an irregular tachycardia with electrograms demonstrating constant amplitude but shift

in morphology or axis and a mean cycle length (CL) >200msec. BDVT was defined as VT with

a consistent pattern of alternating QRS axis and morphology. VF was defined as an irregular VT

with a mean CL <200msec or if 75% of recorded CLs were <260msec. Mean CL was measured

by averaging all CLs used by the device to meet VF detect criteria. If electrograms were not

available, mean CL was calculated using the average ventricular rate reported by the device and

description of the tachyarrhythmia by the patient’s electrophysiologist was used to make the best

determination of the arrhythmia.

Appropriate therapy was defined as ICD discharges for VT (PMVT or BDVT) or VF.

Discharges were classified as inappropriate if a shock was delivered for noise, over-sensing,

sinus or other forms of supraventricular tachycardia, ventricular ectopy, or after spontaneous

termination of an arrhythmia (Figure 1A, 1B). A discharge was defined as effective if it resulted

in primary termination of the arrhythmia (Figure 2A). For the purposes of this study, if primary

termination did not occur but the patient did not have a subsequent shock, this was classified as

either 1) secondary termination or 2) spontaneous termination. Secondary termination was

arbitrarily defined as persistence of the tachyarrhythmia immediately after the shock, with

subsequent termination within 3 seconds after ICD discharge (Figure 2B). Spontaneous

termination was defined as arrhythmia termination greater than 3 seconds after the high voltage

defined as an irregegegeguluuu

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propriate therap as defined as ICD discharges for VT (PMVT or BDVT) or V

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discharge (Figure 2C). A discharge was defined as ineffective if an appropriate shock did not

terminate primarily and included shocks demonstrating secondary termination, spontaneous

termination or those that required subsequent defibrillation (Figure 1C, 2B, 2C). For the

purposes of this study, shock events without electrograms were classified as primary termination

if the clinical record described the shock as successful. Electrical storm was defined as 3

appropriate ICD discharges within 24 hours.

Statistical Analysis

Continuous variables are presented as mean with standard deviation (SD) or median with

interquartile ranges (IQR), depending on the normality of their distribution, and were analyzed

using the T-test or the Wilcoxon rank sum test. Categorical variables are presented as counts

with percentages and were analyzed using the Fisher Exact test or the Chi-square test. A

Kaplan-Meier survival curve was constructed in order to examine the time dependent freedom

from a first appropriate shock after ICD implantation. The one-year data is reported with 95%

confidence intervals (CI). The observed means and CI for successful vs. unsuccessful shock CL

ignoring repeated measures as well as the predicted population means and 95% CI from a

repeated measures mixed effects model considering multiple measurements for each subject are

reported. Data is reported as adjusted P-value. Statistically significant data were defined as a P-

value of <0.05. Data analysis was performed using SAS version 9.3 (SAS Institute Inc, Cary,

NC).

Results

Patient characteristics

A total of 24 patients (11 males, 13 female), each from different families, were included in this

study. The majority of patients were probands (23/24, 96%). No affected family members met

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inclusion criteria for this study. Demographic data and presenting symptoms are listed in Table

1. Median (IQR) age at onset of symptoms consistent with CPVT was 10.6 (5.0-13.8) years.

The majority of patients (67%) presented with a history of exertional or emotionally-triggered

syncope consistent with CPVT while 6 patients (25%) presented with aborted sudden cardiac

arrest. The median (IQR) time from initial symptoms to diagnosis was 4.0 (0.4-6.4) years. None

of the patients had a history of left sympathetic cardiac denervation.

Diagnostic testing

Diagnostic testing varied by center. Exercise stress tests and EP studies were not performed on

all patients prior to initiation of beta- blocker therapy or ICD implant. In total, 14 of 24 patients

(58%) underwent exercise stress testing prior to initiation of anti-arrhythmic medications and 13

patients (93%) had positive results. The remaining patient had single premature ventricular

contractions during exercise. A total of 9 patients underwent an EP study prior to initiation of

any anti-arrhythmic medication and 7 (78%) had spontaneous induction of PMVT after infusion

of isoproterenol or epinephrine. None of these patients had a pace-inducible ventricular

arrhythmia, but in 2 patients atrial tachycardia was pace-induced.

Genetic testing was performed in 16 of 24 (67%) patients and a probable candidate gene

mutation was identified in the ryanodine receptor (RyR2) in 10 (63%) patients (Table 2).

Among the remaining 6 patients who tested negative for ryanodine receptor defects, 3 patients

underwent further testing for Calsequestrin defects and each tested negative. Five patients (21%)

had a family history of CPVT.

Antiarrhythmic medications

Seventeen patients (71%) were on beta-blocker therapy prior to ICD placement. Patients not

receiving beta-blocker medications at implant either had an initial presentation of aborted cardiac

es were not pep rforrrrmememm

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3 had positive results. The remaining patient had single premature ventricular

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arrest (4) and/or the specific diagnosis of CPVT was made after ICD implantation (3). None of

the patients were on flecainide prior to ICD implant. All patients received beta-blocker therapy

after ICD implant. Antiarrhythmic therapy before and after ICD implantation is shown in Table

2.

ICD Data

The median (IQR) age at ICD implant was 13.7 (10.7-16.3) years. Indications for implantation

included aborted cardiac arrest (8 patients), syncope or VT on medical therapy (12 patients), and

history of syncope with documented sustained or non-sustained VT prior to medical therapy (4

patients). In total, indication for ICD implantation was primary prevention in 12 patients and

secondary prevention in 12 patients.

Single chamber devices were implanted in 14 patients (58%) while the remainder had

dual chamber systems. A total of 20 patients (83%) had transvenous and 4 (17%) had epicardial

systems. There were no subcutaneous systems. The majority (17 patients, 71%) received single

coil ICD leads. All patients underwent successful defibrillation threshold testing without

complication. Over a median (IQR) follow up time of 3.3 (1.1-5.8) years, 8 (33%) patients had a

total of 15 ICD related complications (8 lead failures/fractures or lead dislodgements, 1 device

recall, 1 improper setscrew, 4 pocket revisions and 1 subclavian vein stenosis).

ICD shocks

Among 24 patients, 14 (58%) experienced a total of 140 ICD discharges over a median (IQR)

follow-up time of 3.3 (1.1-5.8) years. Median (IQR) number of discharges per patient was 8 (1-

29). Three patients received only appropriate discharges and 4 patients received only

inappropriate discharges. The remaining 7 patients received both appropriate and inappropriate

discharges. Median (IQR) time to first appropriate shock was 1.3 (0.9-3.3) years and

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ber systems. A total of 20 patients (83%) had transvenous and 4 (17%) had epica

There were no subcutaneous systems. The majority (17 patients, 71%) received s

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inappropriate shock 1.7 (0.8-2.6) years.

Appropriate versus inappropriate shocks

Of 140 shocks, 75 (54%) were appropriate and involved 10/24 (42%) patients, while the

remaining 65 (46%) inappropriate discharges involved 11/24 (46%) patients (Figure 4). The first

appropriate ICD discharge was delivered for VF (mean±SD CL: 164±17msec) in 7 patients and

PMVT (mean±SD CL: 251±34 msec) in 3 patients. All appropriate shocks, including multiple

shocks per patient, were delivered for 43 VF (mean±SD CL: 155±21 msec), 29 PMVT

(mean±SD CL: 252±21 msec), and 3 BDVT (mean±SD CL: 245±5 msec). On actuarial survival

analysis, freedom from the first appropriate shock per patient was 75.0% (95% CI: 49.6-88.8) at

1 year after ICD implantation (Figure 5). The most common reasons for inappropriate

discharges were atrial tachycardia (24 events, 36%) and spontaneous termination of a ventricular

arrhythmia prior to ICD discharge (22 events, 34%). Spontaneous termination of 3 VF

(mean±SD CL: 153 25 msec), 14 PMVT (mean±SD CL: 277 36 msec), 2 BDVT (mean±SD

CL: 269 22 msec), and 5 ventricular ectopy (mean±SD CL: 286 19 msec) resulted in

inappropriate discharges.

A total of 24 shocks for AT (mean±SD CL: 269 29 msec) occurred among 8 patients, 3

of whom had dual chamber devices. Of the 18 shocks with available electrograms for review,

there was spontaneous AT termination prior to shock delivery in 2, primary termination in 5,

secondary termination in 3, spontaneous termination after an unsuccessful shock in 4, and in 4

patients subsequent shocks were delivered. Primary termination of 5 AT episodes occurred in 3

patients with single chamber devices; electrograms demonstrated a regular rhythm in 3 episodes

and an irregular rhythm in 2 episodes.

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a priorororor ttooo ICICICI D DDD dididischahhh rge (2(2(2(22222 eventststss, 34343434%)%)%)% . SSSSpooontntntn ananananeeousususs tter iimiinatitititionononon of 333 VFVFVFVF

CL: 11533 252 mmmmse )c)c), ,, 1414 PMVT ((m(mean±SDS CCCL: 2277 363363 msec)c)c)c), ,, 222 2 BDVT ((((memmemeaaan±S

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Mechanism of arrhythmia and pattern of termination

Arrhythmia mechanism resulting in ICD detection and discharge included 46 episodes of VF, 43

PMVT, 5 BDVT, 5 ventricular ectopy, and 24 atrial tachycardia. The remaining 17 ICD

discharges occurred due to lead fracture and noise (Figure 4 and 5).

Among 75 appropriate discharges, effective primary termination occurred in 43 (57%) (7

patients). All 43 episodes were for VF and therefore 100% of VF episodes that persisted to

defibrillation demonstrated primary termination. Electrograms were available for 39 of the 43

VF episodes. In the 4 episodes without electrogams, the primary electrophysiologist reported VF

and the mean arrhythmia CL range was 130-160msec. The 3 remaining VF episodes were

classified as inappropriate shocks because VF terminated prior to ICD discharge. Ineffective

ICD discharges were seen in 32 of the 75 (43%) appropriate discharges (3 patients). All 32

episodes were for PMVT (29) or BDVT (3). Of these 32 ineffective discharges, 5 (16%)

demonstrated secondary termination within 3 seconds, 15 (47%) demonstrated spontaneous

termination after 3 seconds, and 12 (37%) required one or more subsequent shocks. The

adjusted mean (95% CI) CL of ventricular arrhythmias resulting in successful termination was

significantly shorter than in those that did not primarily terminate (168 (152-184) msec vs. 245

(229-262) msec, adjusted p=0.002). The observed mean and CI for successful vs. unsuccessful

shocks, not taking into account repeated measures, was 163 msec (95%CI: 153-173 msec) and

251 msec (95% CI: 244-260 msec) respectively. Details regarding appropriate, inappropriate,

effective and ineffective discharges are listed in Figure 4. One patient exhausted ICD therapy

but survived after the VT eventually spontaneously terminated. Interestingly, reported

compliance with medical therapy, per shock, was higher in the successful (36/43 (84%)) vs. the

unsuccessful shock group (11/32 (34%)).

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ted secondary termination within 3 seconds, 15 (47%) demonstrated spontaneous

n after 3 seconds and 12 (37%) req ired one or more s bseq ent shocks The

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Primary versus secondary prevention

Two of 12 (17%) patients in the primary prevention group and 8 of 12 (67%) patients in the

secondary prevention group received an appropriate discharge. While none of the primary

prevention group had VF or an effective discharge, 7 of 12 (58%) patients who received an ICD

for secondary prevention had VF and received an effective shock.

Electrical storm and induction of more malignant arrhythmias

Twelve discharges (in 5 patients) or 8.5% of total shocks resulted in a more malignant

ventricular arrhythmia. The arrhythmias responsible for these ICD discharges included 3 PMVT,

8 AT, and 1 ventricular ectopy. In 11 of the 12 discharges, the shock-induced ventricular

arrhythmia eventually spontaneously terminated; however 5 discharges resulted in the patient

receiving at least 1 inappropriate shock secondary to committed device therapy. In 1 patient,

shock for an atrial tachycardia resulted in induction of PMVT and 3 subsequent shocks were

delivered with eventual secondary termination. Four of 14 patients (29%) who received ICD

therapy suffered electrical storm events secondary to ICD discharges. There were no patient

deaths.

Compliance with medications

Patients were thought to be noncompliant with medications at the time of 61 (44%) ICD

discharges. In 54 (38%) ICD discharges, patients were thought to be compliant with

medications. In the remaining 25 (18%) ICD discharges, compliance with medications could not

be determined by medical chart review.

Discussion

Young patients with CPVT are at high risk for life threatening arrhythmias and sudden death.2-4,

6, 10, 11, 15 Beta-blockers are not always effective2, 3, 6, 10, 12, 16 and in some patients, ICD and/or

schargeg s includedd 3333 PP

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a eventually spontaneously terminated; however 5 discharges resulted in the patie

at least 1 inappropriate shock secondary to committed device therapy. In 1 patien

an atrial tachycardia resulted in induction of PMVT and 3 subsequent shocks wer

w C

ffered electrical storm e ents secondar to ICD discharges There ere no patien

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withhhh eventualll sesess co ddndary yy terminatiioi n. Four offf 141444 pppatieii ntnttts (2(2(2999%)%)%)%) whohhh receieieieivevevev ddd d IC

ffff ded lle tct iri ll tst tts dda tt ICICDD didi hha TThhe tatiien


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12

left cardiac sympathetic denervation are being used as management strategies.17 However, death

can occur despite ICD implantation.9, 11 Reports have shown that ICD therapy can be ineffective

or dangerous9, 11, 12 but no mechanism for this phenomenon has been established. Furthermore,

previous studies have suggested that inappropriate discharges are secondary to supraventricular

arrhythmias3, 5, 6 (Table 1, online supplement). Our study found that 1) the rate of appropriate

therapy is high, but only half are effective, 2) effective therapy is likely related to arrhythmia

mechanism and 3) inappropriate therapy is due to both supraventricular arrhythmias and

spontaneous termination of arrhythmia prior to ICD discharge.

Patients with VF that persisted to defibrillation demonstrated 100% effective primary

termination. No episodes of PMVT or BDVT successfully terminated. Previous studies have

demonstrated the mechanism of arrhythmia origination for BDVT and PMVT in CPVT to be

abnormal calcium regulation and delayed after depolarizations (DADs).18-20 Modeling studies

suggest that origination and alternation of premature beats between the right and left bundle

branches of the purkinje system (the “Ping-Pong” mechanism) results in BDVT. When DADs

arise from multiple purkinje sites, PMVT ensues.21 PMVT may spontaneously terminate,

possibly explaining the high incidence of secondary or spontaneous termination seen after ICD

therapy in this cohort, or may degenerate into VF, the arrhythmia that is likely responsible for

sudden cardiac death in CPVT patients. BDVT and PMVT arise from focal DADs and

catecholamine surges following ICD discharge can increase further DADs. We therefore

speculate that BDVT and PMVT are less amenable to defibrillation, whereas VF is a large

wavefront of myocardial depolarization that will respond to ICD therapy. Arrhythmia substrate

and mechanism in CPVT patients may explain our findings of 1) successful defibrillation for VF,

2) unsuccessful therapy for BDVT and PMVT, and 3) the incidence of more malignant

00% %%% efeffffefffecttcttivivii e e prprp imimimimara

n a

ted the mechanism of arrhythmia ori nation for BDVT and PMVT in CPVT to b

c d

at origination and alternation of premature beats between the right and left bundle

f the p rkinje s stem (the “Ping Pong” mechanism) res lts in BDVT When DA

n. NNNNooo o epepepisisisi odooo esesess of PMVT or BDVT succececesssfully terminnatedddd... Previous studies ha

teeede the mechaninismmm oof arrrrhrhrhhythmhmhmh iaaa origginnatiioon fffforororr BBBBDVDVVTTT andd PMPMMMVVTV iiinn nn CPPVTVTT tooo b

calciiiumumuum rrrregegullll ttatiiion and dd delalalaayyyed afafffteteteter dededed popolllariizazaatitititionnnssss (DDDDADADADAD ))s).1811 -20202020 MoMoMM ded lililing stttud

at oriiigigigination aaaa ddndd alllterna ition off ff prpp emature bbeb ats bebbb twt eeennn n thhheee riririr ghghght and dd llell ftftftft bbbbunuuu dle

ff thth krkiinjje tte (t(thhe ““PiPi PP ”g” hha ini )) ltlt iin BBDVDVTT WhWh DDAA


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13

arrhythmias after ICD discharges.

CPVT patients are known to have atrial tachyarrhythmias5, 7, 8 9 but therapy for these

supraventricular arrhythmias has not been studied. Studies have demonstrated DADs in atrial

myocytes and decreased conduction velocities due to defects in RYR2 which can lead to atrial

arrhythmias and potential atrial fibrillation.22 A total of 8 patients received 24 shocks for AT.

Interestingly, 5 of these episodes (in 3 pts) demonstrated primary termination, 2 of which were

irregular tachycardias and 3 regular tachycardias. Primary termination seen in irregular ATs may

be explained by atrial fibrillation. Reasons for primary termination of regular AT seen in this

cohort are not clear and further studies are needed. Since each of these 3 patients had single

chamber devices, we cannot exclude the possibility of a reentrant supraventricular tachycardia.

A high rate of inappropriate therapy due to spontaneous rhythm termination prior to ICD

discharge was seen throughout this cohort. Overall, 46% of patients experienced an

inappropriate discharge, a significantly higher percentage than the published rates of 25-30% in

other pediatric device patients.23 Our study confirmed high rates of inappropriate discharge for

supraventricular arrhythmias, as previously reported 3, 5, 6 however, we also found that

spontaneous termination of ventricular arrhythmias accounted for an equally high rate of

inappropriate discharge. This has not been previously reported and is an important consideration

in terms of ICD programming for these patients.

Changes in ICD programming may help prevent unnecessary discharges and specific ICD

programming details (which vary among devices) need to be considered in this patient

population. In this study, all inappropriate shocks due to spontaneous termination prior to ICD

discharge may have been avoided. To avoid shocks secondary to ventricular ectopy and

nonsustained brief runs of PMVT after VT/VF termination, setting a single VF zone to a

f reggular AT seen iiiinn n n tht

e 3 papatititienenttstst hhhhadddad ssinininingglgl

evices, we cannot exclude the possibility of a reentrant supraventricular tachycar

hi rate of inappropriate therapy due to spontaneous rhythm termination prior to

w

ate discharge, a significantly higher percentage than the published rates of 25-30

atric de ice patients 23 O r st d confirmed high rates of inappropriate discharge

eviiicecececess,ss wwwweeee ccannnnnnnnot exclude the possibilityyy off a reentrant suprprprraavaa entricular tachycar

hiiiighhhh rate of inaappproooppriatetete therarapyyy duee ttto sppoontatattanenenen ouoouo s rhrhrhythmm teeermmim naaaatiiionono ppriooror to

was seseseseennenen tttthhhrou hhghhouttt thththis cccohohohohort. OvOvOvOvereer llalll,l,l 4446%6%6%6% oooofff papapapatienenennttts experieieieencncncnced an

ate diddd schhah rggge, aaaa sigigigi iinififificanttlylylyl hhhhigigigi hehh r pepp rcentat gegg tthahhh n hththheeee pupp blblblisisii hehhh ddd rates ofofofof 22225-555 30

tat iri dde ii tatiie tnts 232323 OO tst dd fnfiir dd hihi hgh tat ff iin iri tat didi hha


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14

substantially shorter CL (range 200-260msec) would have decreased reconfirmation intervals

and along with increasing redetect duration may have also helped limit shocks to sustained VF

episodes. While in this cohort of patients, the above programming adjustments may have limited

inappropriate shocks, device selection and programming should be individualized to each

specific patient.

Preventing inappropriate ICD shocks may particularly be important among CPVT

patients as we found that device therapy may be harmful. Among the 14 patients who received

device therapy, 5 (36%) suffered more malignant arrhythmias and 4 (29%) suffered electrical

storm. We suspect that ICD discharge results in catecholamine surges that potentiate further

DADs. These findings are quite concerning as patients with CPVT are sensitive to

catecholaminergic surges and hypothetically these surges could result in death. Despite these

potential concerns, as well as relatively high rates of defibrillation failure and inappropriate

device therapies, none of these events led to death in this cohort.

ICD therapy, while potentially life-saving, comes at a heavy cost in this patient

population. Compliance with medications is paramount and use of flecainide and/or left

sympathetic cardiac denervation may decrease the need for ICDs in the future; however, if ICDs

are implanted, programming needs to be adjusted to reduce the risks of inappropriate shocks and

mortality from therapy exhaustion. Extending detection times and altering reconfirmation rates

(to account for frequent spontaneous termination and ventricular ectopy) as well as adjusting

ICD detection rates to shorter CLs (for detection of VF rather than VT) may improve outcomes

for these patients. Specific rates and detection periods will need to be individually adjusted. The

authors found atrial arrhythmias to be frequent (57%) among patients who received shocks and

that dual chamber devices were often helpful in discriminating atrial versus ventricular

29%)) suffered elececcctrtrtrtrici

that ttt popop tette tntnttiaiiai tettet ffffururururththththe

h

miner c surges and hypothetically these surges could result in death. Des te the

oncerns, as well as relatively high rates of defibrillation failure and inappropriate

r

D therap hile potentiall life sa ing comes at a hea cost in this patient

heseeee ffffinininindididiingngngn s arararreeee quite concerning as patiiiienene ts with CPVTVV aarererere sensitive to

miiini eeere gic surgess aanddd hhhypototothetiiiiccallllyy thesesse suurrgesess ccccouoouo lld rreeesultt iin ddddeeath. DDDeesppiteee tttthe

oncerrrrnsnsns, as wellllll as r llelativelelele yy highghhh rrrratatateees offf ddded fifififibrbrbrbrilililllalalalatttit ononnn fffaiiilllure andndndnd iiinappropriiiattet

rapipipies, none ooof fff thhhhese eventst ledddd to dddeath iiin thihihih s cohhhoh rtt.

DD thth hihille tot titi lalll llifife ii tat hh tt iin tthihi titi tt


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15

arrhythmias; however further studies are needed in order to better understand atrial arrhythmias

in this population and determine if there is evidence to support the extra atrial lead burden.

Limitations

This is a retrospective study with a small patient population. Although 63% of patients who

underwent genetic testing were positive, only 42% of our patients had genetic confirmation of

their CPVT diagnosis. Electrograms at the time of ICD discharge were not available for all

events. Since some unknown electrograms were classified as successful on the basis of the

treating electrophysiologist’s note, without independent review of the tracings, we may have

overestimated the rate of successful discharges. The clinical definitions of arrhythmia

mechanism (VF, PMVT, BDVT) were based on prior published ICD studies, but there may be a

continuum in these mechanisms and this classification may not accurately reflect the cellular

arrhythmia substrate. Alternatively, the rate of the tachycardia may be important to successful

defibrillation. Although a mean CL of 163 msec during tachycardia could be rapid PMVT

susceptible to defibrillation, we felt that the electrograms and rate of tachycardias were most

consistent with VF. Rhythms suspected to be atrial tachycardia were based on identical

electrograms in arrhythmia and during sinus rhythm but a majority of patients had single

chamber ICDs. This limited our ability to distinguish atrial from ventricular tachycardias and we

may have misclassified certain arrhythmia mechanisms.

Conclusion

ICD efficacy in young patients with CPVT depends on arrhythmia substrate or tachycardia cycle

length. ICD therapy, while potentially life-saving for VF, may be ineffective for PMVT or

BDVT and pro-arrhythmic in a significant subset. Atrial arrhythmias and spontaneous

termination of ventricular arrhythmias prior to ICD discharge contribute to high rates of

tracinggs, we may y hahahahavv

ns of fff ararrhhhrh tytytthhhmhmiaiaii

m (VF, PMVT, BDVT) were based on prior published ICD studies, but there may

in these mechanisms and this classification may not accurate reflect the cellul

a s

o

e to defibrillation e felt that the electrograms and rate of tach cardias ere mo

m (VVVF,F,F,F PPPMVMVMVM T,,, BBBBDVT) were based on pririririororo published ICDCC ssssttut dies, but there may

iiini these mechahanismmms annndd dd thisisisi clallassifficccatioonn mammay y y y nonnon t acacaccuraatelyyyy rrefleeectctctc thehe ceeelluuul

a subsbsbsstrtrtrattatate. u AlAlAlA tttern ttatiiiively,y tttthehhehe ratee ofofofof tttthhheh tttachyhhh cacacacardrdrddiaiaiaa mmmayayayay bbbe imiii poooortrttrtaant tottt success

on. AlAlAlthhhoughghgh aaaa mean CCCL LL foff 16363636 msec duddd iiringgg tachyhyhyh cardrdrddiiaii couououuldldldd bbbe rapipipiidd dd PMPMPMPMVVT

tto dd fefibib irillll tatiio ffeltlt tthhatt thth lel ttr dnd tat fof tt hh drdiia


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inappropriate discharges. The risks and benefits of ICD therapy in patients with CPVT should be

carefully considered prior to implantation, particularly for primary prevention. Identifying those

at highest risk, as well as optimizing ICD configuration and programming may help improve

effectiveness and decrease related comorbidities. Left sympathetic cardiac denervation may also

be an important and alternative treatment strategy for these patients.17 A comparative evaluation

of different such strategies may prove clinically valuable.

Conflict of Interest Disclosures: Drs. Christina Miyake and Anne Dubin receive fellowship-funding support from Medtronic, Inc. No direct or indirect support was provided for this study. No other authors have any relationships to disclose.

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ssss pppprorororovivivividedededed d d d fofofofor r r r thththhisisisis sssstutututu

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rphp ic ventricular

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I, Khour A, Suleiman M, G stein L, Blich M, Lorber A, Boulos M. Im rtanctachycardia storms not terminated by implantable cardioverter defibrillators sho

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er-dededefififif brbrbrb ilililillalalaator rrr iiini a young female with catatateccholaminerggggic vvvenenene tricular tachycardiathmhmhmhm. 2006;3333:111484848486-1414148989899.

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22. King JH, Zhang Y, Lei M, Grace AA, Huang CL, Fraser JA. Atrial arrhythmia, triggering events and conduction abnormalities in isolated murine ryr2-p2328s hearts. Acta Physiol (Oxf).2013;2:308-323.

23. Berul CI, Van Hare GF, Kertesz NJ, Dubin AM, Cecchin F, Collins KK, Cannon BC, Alexander ME, Triedman JK, Walsh EP, Friedman RA. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. JAm Coll Cardiol. 2008;51:1685-1691.

nal ventricular tachchhhycycyy

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CME, Triedman JK, Walsh EP, Friedman RA. Results of a multicenter retrospecte ea

conononondududuductctioioioi n nn abbbnnonn rmalities in isolated muuuririirinne ryr2-p232822 s heheheh arts. Acta Physiol (O8-3-3-3- 22322 .

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Table 1. Characteristics of the entire cohort and a comparison of primary vs. secondary

prevention: data is presented as median ± IQR or count with (%).

Variables Total Cohort Primary prevention

Secondary prevention

*P

N=24 N=12 N=12

Sex (male) 11 (46%) 4 (33%) 7 (58%) 0.414Age at first CPVT symptom (yrs) 10.6 (5.0-13.8) 11.6 (5.0-13.3) 10.0 (4.5-14.6) 0.862

Symptoms 0.007Aborted cardiac arrest 6 (25%) - 6 (50%)Exertional syncope 12 (50%) 6 (50%) 6 (50%)Emotional syncope 4 (17%) 4 (33%) 0Other 2 (8%) 2 (17%) 0

Positive EST 13/14 (93%) 10/10 (100%) 3/4 (75%) 0.286Positive EP study 7/9 (78%) 5/6 (83%) 2/3 (67%) 0.999Genetic testing positive for RyR2 10/16 (63%) 4/7(57%) 6/9 (67%) 0.999

Medications prior to ICD 0.613Beta-blocker (single agent) 12 (50%) 7 (58%) 5 (42%)

Mixed anti-arrhythmics 5 (21%) 2 (17%) 3 (25%)None 7 (29%) 3 (25%) 4 (33%)

Total follow up (yrs) 6.1 (3.3-8.3) 6.1 (4.0-7.9) 6.2 (2.1-9.4) 0.840

Age at ICD implant (yrs) 13.7 (10.7-16.3) 13.7 (12.3-16.0) 13.3 (8.7-16.3) 0.707

Single chamber 14 (58%) 5 (42%) 9 (75%) 0.214Follow up post-ICD (yrs) 3.3 (1.1-5.8) 3.7 (1.0-6.4) 3.2 (1.8-5.7) 0.885Type of ICD shock 0.040

Appropriate only 3 (13%) 1 (8%) 2 (17%)Inappropriate only 4 (17%) 4 (33%) 0Appropriate &

Inappropriate7 (29%) 1 (8%) 6 (50%)

None 10 (42%) 6 (50%) 4 (33%)Medications after ICD 0.268

Beta-blocker (single agent) 16 (67%) 6 (50%) 10 (83%)Mixed anti-arrhythmics 8 (33%) 6 (50%) 2 (17%)

*P-values compare primary vs. secondary prevention. CPVT – catecholaminergic polymorphic ventricular tachycardia; VT – ventricular tachycardia; ICD –implantable cardioverter defibrillator; EST – exercise stress test; Mixed anti-arrhythmics – more than one beta blocker or beta blocker and other class of antiarrhythmic

00000

3////4444 (7(7(7(75%5%5%5%)))) 0.0.0.0.2/3333 (6(6(6(67%7%7%7%)))) 0.0

ting positive for RyR2 10/16 (63%) 4/7(57%) 6/9 (67%) 0.

sc

M

w

13131313.77.7 (((1212122.3.3.3. ---1616161 .0000))) 13131313.3.3.33 ((((8.8.8.777---1616161 .3)

ting popoposisisitititiveveve forrr RRRRyR2 10/16 (63%) 4/7(57%) 6/9 (67%) 0.

s prrrriiior to ICD 0.ckkkek rrrr (single ageentt) 12 (5000%%) 777 (5(5(5( 8%88%8 ) 5555 (42%%%%)))

Mixexexed dd anaa ti-arrrarrhrrr yyty hhmicccss 55 (2(2(221%%%))) 222 (1(1( 7%7%7%7 ) 333 (2((( 5%%5%%)777 (29%)%)) 33 (2((25%5%%) 4 (3(3(33%3%)

w up (y(y(y(yrsrsrs))) 6.6.6.6.111 (3333.3.3.33---8.8.8.8 3)3)3)3) 6.6.6.6 1111 (4(4(4(4.0.0.0--7.7.7.7 9)9)9)9 6.6.6.6.2222 (2(2(2(2.1.1.1---9.9.9.9 4)4)4)4) 0.

implant (yryryryrs)ss)s) 131311 .7.77 ((((1010100.7.7.77---1616161 .3.3.33)))) 0.


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Table 2. Patient

Patient SexAge at first sx (yrs)

Reason for ICD Meds pre-ICD Meds post -ICD

Follow up since

ICD (mo)

Total #shocks

Types of shocks

Gene Testing

1 F 5 P Bisoprolol Bisoprolol 13 0 - RYR2

2

M 14 S

Nadolol Propranolol Mexilitine

Sotalol

Nadolol 68 4 Both -

3 M 9 S Nadolol Nadolol 30 8 App Neg4 F 10 S - Metoprolol 68 8 Both RYR2

5M 12 P Nadolol Nadolol

Verapamil 56 2 Inapp -

6 M 14 P Metoprolol Metoprolol 97 18 Both -7 M 16 P - Atenolol 37 8 App Neg*8 F 5 P Atenolol Atenolol 11 0 - RYR29 F 6 P Atenolol Atenolol 4 0 - RYR2

10

F 11 P -

Metoprolol Nadolol

Diltiazem Verapamil Digoxin

71 5 Inapp Neg*

11 M 16 S - Atenolol 6 0 - RYR212 M 3 S - Propranolol 43 18 Both RYR213 F 4 P Atenolol Atenolol 51 1 Inapp -

14F 13 P Atenolol

MexilitineAtenolol

Flecainide 82 0 - -

15F 13 P - Nadolol

Mexilitine 104 0 - -

16M 13 S - Nadolol

Verapamil 34 3 Both Neg*

17F 16 P Atenolol

MexilitineAtenolol

Flecainide 7 0 - Neg

18M 3 P Atenolol Atenolol

Flecainide 29 3 Inapp RYR2

19 M 16 S Atenolol Atenolol 12 0 - RYR2

20F 5 S Atenolol

MexilitineAtenolol

Mexilitine 89 29 Both RYR2

21 F 10 S Atenolol Atenolol 65 16 App RYR2

22M 4 S Atenolol Sotalol

Digoxin Nadolol 33 0 - -

23 F 2 S Atenolol Atenolol 89 17 Both -24 F 15 S Atenolol Atenolol 1 0 - Neg

M – male; F – female; sx – symptoms; yrs – years; P – primary prevention; S – secondary prevention; mo – month; App – appropriate shocks; Inapp – inappropriate shocks; Both – appropriate and inappropriate shocks; Neg – negative; * – Calsequestrin was tested and result was negative

88 ApAppppppp0000 -00 -

Nadolol

11 P - NaNaNadododd lol

DilttiaazemVerrappamimimimilDigogoxin

7771 5 Inappppp

1616116 S --- AtAtAtenenolooloo 6666 000 -33 S - Prrropopoprararar nolol 43 1811 Both4444 PPPP AtAtA enenenenoolollll AtAtAtA enenenolololololololol 5151515 111 InInInapapapapp

131313 PPP Attenenolo olo MeMeMeMexixixilililititititinenenen

Attenenolo olo FlFFlFlecececcaaaaininniniddidideee 828282 000 -

NNaddolloll


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Figure Legends:

Figure 1: A) Inappropriate shock due to atrial tachycardia resulting in a more malignant

ventricular arrhythmia. Top EGM: RVtip to RVring, Bottom EGM: HVA to RVring, B)

Inappropriate shock due to spontaneous termination prior to ICD discharge. Top EGM: RVtip to

RVring, Bottom EGM: Can to RV coil, C) Appropriate but unsuccessful shock for polymorphic

ventricular tachycardia. Top EGM: RVtip to RVring, Bottom EGM: Can to RVcoil.

Figure 2: A) Appropriate shock for ventricular fibrillation with successful primary termination.

Top EGM: RVtip to RVring, Bottom EGM: Can to RVcoil, B) Unsuccessful shock with

secondary termination (termination <3 seconds of high voltage discharge). Top EGM: RVtip to

RVring, Bottom EGM: HVA to RVring. C) Unsuccessful shock of PMVT with spontaneous

termination following ICD discharge (termination > 3seconds after shock) results in device

redetection and inappropriate shock due to device commitment despite arrhythmia termination.

Top EGM: Atip to Aring, Bottom EGM: RVtip to RVcoil.

Figure 3: Appropriate versus inappropriate shocks and successful versus unsuccessful

termination. VF – ventricular fibrillation, PMVT – polymorphic ventricular tachycardia, BDVT

– bidirectional ventricular tachycardia, AT – atrial tachycardia, VEctopy – ventricular ectopy,

Spont Term – spontaneous termination of arrhythmia prior to ICD discharge, CL – cycle length,

Lead Fx – lead fracture.

Figure 4: Kaplan-Meier estimate of freedom from the first appropriate shock after ICD

ssfululll pppririiimamaryry ttttere mimimiminan

termination ermination <3 seconds of h h voltage discharg . Top EGM: RVt

o u

n following ICD discharge (termination > 3seconds after shock) results in device

n and inappropriate shock d e to de ice commitment despite arrh thmia terminat

RRVtVtVtVtipipipip ttoo oo RVRVRVriririinngn , Bottom EGM: Can tooo RRRVcoil, B) Unnnsuccccccccessful shock with

teeeermmmmination (tererminannationnn <3 ses cooonnds ooof higigh vovvoltltltagaaga e dddissschaargge)))). Top p EGEGE MM: RRRVVVt

ottommmm EEEGMGMGMG : HVHVHVHVA AAA ttto RVrVrVrVrininining. C)))) UnUnUnUnsuss ccessfululul ssshohohoh cckckc ooofff f PMPMPMP VVVTV wwwitititthhhh sponttttaneou

n follll owing gg ICICICCDDD D dididid schhah rggge (t(t(ter iimina ititiion > 333seco ddndds affffteeeer shhhocococck)k)k)k) res lullts iiin nnn dedededevvviv ce

dd iin iri tat hsh kk dd tto dd iic itit tnt dd ipitte hh thth imi tte iin tat


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22

implantation.

Figure 5: Arrhythmia mechanisms resulting in 140 ICD discharges. VF – ventricular fibrillation,

PMVT – polymorphic ventricular tachycardia, BDVT – bidirectional ventricular tachycardia, AT

– atrial tachycardia, Noise – noise on electrogram secondary to lead fracture, VE = ventricular

ectopy.


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Kishor Avasarala and Joseph AtallahChristina Y. Miyake, Gregory Webster, Richard J. Czosek, Michal J. Kantoch, Anne M. Dubin,

Polymorphic Ventricular Tachycardia: Success Depends on SubstrateEfficacy of Implantable Cardioverter Defibrillators in Young Patients with Catecholaminergic

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 May 11, 2013;Circ Arrhythm Electrophysiol.

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The online version of this article, along with updated information and services, is located on the

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is online at: Circulation: Arrhythmia and Electrophysiology Information about subscribing to Subscriptions:

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SUPPLEMENTAL MATERIAL

Table 1. Previous studies of CPVT patients with ICDs

# pts with

ICD

Age at onset of symptoms

# pts with appropriate

shocks

# pts with inappropriate

shocks

Reason for inappropriate

shocks

# pts with ineffective

shocks

Celiker et al Cardiol Young 2009

4

All children 3/4 (75%)

3/4 (75%)

TWO Incr HR

Lead fracture

Not reported

Marai et al Am J Cardiol 2009

6

Not reported 4/6 (67%)

Not reported

-

2/4 (50%)

Priori et al Circulation 2002

12 7 pts <21 yrs

4 pts >21 yrs 6/12

(50%)

Not reported

-

Not reported

Sy et al Heart Rhythm 2011

15

Not reported 4/15 (27%)

5/15 (33%)

SVT

Not reported

Hayashi et al Circulation 2009

16

20 +/- 11 yrs 4/16 (25%)

6/38 (38%)

Sinus tach Lead fracture

Not reported

Miyake et al

24 10 yrs

(2-16 yrs) 10/24 (42%)

11/24 (46%)

Atrial tach Spont term

Vectopy Lead fracture

8/14 (57%)

TWO – T wave oversensing; Incr HR – increase heart rate; tach – tachycardia; spont term – spontaneous

termination of arrhythmia prior to ICD discharge

efficacy of implantable cardioverter defibrillators in youn g...

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