HEREDITARY ARRHYTHMIA CORNER

Syncope and Exercise-Related Ventricular Tachycardia

James Gallagher,∗ David T. Huang,∗ Arthur A.M. Wilde,† and Spencer Z. Rosero,∗From the ∗University of Rochester Medical Center, Cardiology Division, Rochester, New York, USA; †HeartFailure Research Center, Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands

Ann Noninvasive Electrocardiol 2012;17(2):146–150

CASE PRESENTATION

A 15-year-old girl, a varsity basketballplayer, reported that she experienced multi-ple episodes of syncope over the past severalyears, occurring every two to three months.These are always associated with mild-to-moderate physical exertion, such as dancingor gym class, or just after exercise. Typically,these episodes have begun with head tinglingand blurriness of vision. Usually the amountof physical exertion at the time of syncopeis mild to moderate. She denies any palpita-tions, dyspnea, or angina at any time, includ-ing before or after syncope. She admits to oneepisode of syncope while swimming severalyears ago. She had been diagnosed as mostlikely neurally mediated syncope (NMS) andwas instructed to increase her dietary intakeof sodium and hydration. The patient insti-tuted these changes, but while jumping ropein front of her house, she passed out and wasfound by her father as she awoke.

Her medical history includes an uncompli-cated birth and no unusual illnesses, hospi-talizations, or surgeries. The patient does nottake any medications. She has a maternal un-cle who died in his sleep when he was inhis 50s. An ECG can be seen in Figure 1.During an exercise treadmill test, the patientexercised for 13.5 minutes with a modifiedBruce protocol before stopping for fatigue.

Address for correspondence: David T. Huang, M.D., Cardiology Division, University of Rochester Medical Center, 601 Elmwood Ave.,Box 679, Rochester, New York 14642. Tel: 585-275-4775; Fax: 585-242-9542; E-mail: avid_Huang@urmc.rochester.edu.

She developed increasingly frequent prema-ture ventricular contractions (PVCs) through-out the exercise which appeared unifocal andnever occurred more often than in bigeminy.These disappeared rapidly with recovery. A24-hour Holter monitor showed 131 PVCsand 5 beats of supraventricular tachycardia. Awaking and sleep-deprived electroencephalo-gram was normal. A transthoracic echocardio-gram showed her heart to be normal in sizeand function with no significant valvular ab-normalities with normal takeoff of coronaryarteries.

The patient subsequently had another syn-copal event which occurred when she was run-ning to “catch the bus” in the morning. She feltlightheaded, squatted down, and then experi-enced a syncopal event. She was not wearingher event monitor at the time. An EP studyperformed documented polymorphic ventric-ular tachycardia (VT) with rapid degenera-tion into ventricular fibrillation with tripleextra-stimuli (400.200.190.190 milliseconds)on an epinephrine drip. There were increasedPVCs and a ventricular bigeminal as well astrigeminal rhythm once on epinephrine. Animplantable loop recorder (ILR) was subse-quently placed. Several months later, whileplaying basketball, the patient experiencedlightheadedness and another syncopal event.ECG tracings of her loop recorder are shownin Figures 2A and B.

C©2012, Wiley Periodicals, Inc.

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Figure 1. Baseline ECG.

Dr Wilde: What is your interpretation of the clinicaland ECG findings in this case and what further diag-nostic or management strategy would you recommend?

Thank you for presenting this interesting case tome. This 15-year-old girl suffers from bottom line,exercise-related syncope, which must have startedaround age 10. The events do not occur duringpeak exercise but more at mild to moderate ex-ercise levels and, interestingly, one event occurredwhile swimming. Notably her family history is neg-ative for young (<40 years of age) sudden car-diac death or exercise-related arrhythmias, but noinformation is given on the size of the family (whichis of importance for a critical appraisal of thisinformation).

From the very beginning I would have been verysuspicious on a malignant arrhythmia syndrome.NMS is very unusual during exercise, but can oc-cur immediately after exercise. Moreover, NMS isextremely rare while swimming.

Before going into the details of the case it is im-portant to note that almost all causes of exercise-related events (i.e., arrhythmias) are inherited innature. Exceptions are mitral valve prolapse (notdemonstrable in this case), aberrant coronary ar-teries (excluded), and coronary artery disease (veryunlikely at this age). The remaining differential di-agnostic possibilities include long QT syndrome(LQTS, exercise-related events occur typically intype 1), catecholaminergic polymorphic ventricular

tachycardia (CPVT), and a subclinical cardiomypa-thy (arrhythmogenic cardiomyopathy [AC] or hy-pertrophic cardiomypathy [HCM]). A normal echodoes not exclude the latter possibilities but both be-come less likely. A MRI might be helpful in furtherinvestigating these possibilities.

Her baseline ECG is normal, although heart rateis relatively slow. The QTc interval is normal, butit is well known that it might only prolong dur-ing exercise or in the first minutes after exercise.1

A normal QTc interval during exercise or in thefirst minutes thereafter makes LQTS entity highlyunlikely.1 There might be a hint of early repolar-ization in the inferior leads with a horizontal ST-segment which has been associated with malignantoutcome.2 It is described that during exercise in-creasingly monomorphic ventricular extrasystolesappear, at most in a bigeminal pattern. Similar ec-topy occurred on an i.v. epinephrine drip. Finally,the internal loop recorder revealed intermittentpolymorphic ventricular tachycardia during exer-cise associated with a syncopal event.

This case is most typical for CPVT, a diagno-sis that should have been considered much ear-lier in time. Exercise-induced arrhythmias, alreadydemonstrated at the first exercise test, are abnor-mal and should be considered a red flag (!) andcertainly so when the medical history is fur-ther characterized by exercise-related syncope.Swimming-related events are typical for CPVT and

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Figure 2. (A) Implantable loop recorder tracings recorded during early phases of exer-cise. (B) Implantable loop recorder tracings recorded while playing basketball.

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not unusual the arrhythmias disappear at peak ex-ercise (unpublished data), providing a good expla-nation for the clinical and electrophysiological find-ings. Genetic testing typically reveals a mutation inthe Cardiac RyR(2) protein.3

As to management, immediate installment onmaximal tolerated beta-blocker therapy is war-ranted (preferably nadolol or propranolol). Treat-ment efficacy can usually be monitored by exercisetests and any ectopy exceeding isolated extrasys-toles should be considered an insufficient treat-ment result. As a potential second step I wouldadd flecainide, which has been shown to very ef-fective in high-risk patients.4 Left stellate ganglionablation might be considered as a first invasive stepin the presence of an insufficient response on com-bined drug treatment. (For review see van der Werfet al.5) ICD therapy could be considered, but it isvery important to realize that in this condition itmay prove to be pro-arrhythmic.5

Finally, immediate family members should be of-fered genetic testing in case the genetic test on yourpatient comes back positive or be offered clinicalcardiological testing (exercise test) in case genetictesting is not possible or negative (which does notexclude the diagnosis CPVT).

FURTHER HISTORY

Based on the ILR data, the recommendations atthis time were to admit the patient to the PediatricCardiology service for further evaluation and treat-ment, including the initiation of beta-blockers forher VT. An ICD was considered at that point, butrefused by the family.

The patient sought further evaluation and treat-ment at another institution and underwent an EPSand VT ablation. At follow-up several months later,the patient had an exercise treadmill stress testwhich showed her usual bigeminy was present, aswell as multifocal PVC pairing. A beta-blocker wasstill recommended and her restrictions regardingcompetitive sports were maintained since she wasclassified as having a catecholaminergic VT withcomplex presentation and history of several synco-pal episodes during exercise/stress. However, thepatient and family preferred that she should nottake beta blockade, and the patient continued toparticipate in sports activities.

The patient eventually graduated high school.She said she would start beta-blockers but declinedan ICD at that time. Shortly thereafter, the patient

was in dance class and experienced a cardiac arrest.CPR was administered and an AED was attachedto the patient with multiple shocks being deliveredbut were unsuccessful in resuscitating the patient.

Dr Wilde: Thank you for your insight so far. Wouldyou please comment on the effectiveness of therapyfor patients with CPVT, from pharmacologic agents toICD? please also share with us your thoughts aboutthe role of ablation for patients with CPVT.

The patient’s outcome is of course very unfor-tunate and includes elements of inappropriate de-cisions by doctors and the patient herself (or herparents). The latter relates to not taking the ad-vised beta-blocker therapy and not adhering to theappropriately given life style advises. The formerrelates to the immediate suggestion to implant anICD and to the performed ablation therapy. As dis-cussed in first term the diagnosis CPVT is highlylikely and beta-blocker therapy should have beeninstalled. Beta-blocker therapy is effective in themajority of patients but failure rates have been de-scribed in up to 35% of patients at 8 years’ follow-up, with fatal events in 6% during the same timeperiod.5 In the patient discussed an ICD “was con-sidered” but should, in this disease entity, reallybe regarded as a last resort option. In the past fewyears several case reports have appeared describ-ing a “proarrhythmic” effect of ICD therapy. (Seevan der Werf et al. 2011.5) Indeed, inappropriateshocks (i.e., shocks on atrial arrhythmias or shocksbased on mal sensing) lead to fear, anger, and painthat may (and has been shown to) start up a vi-cious circle of true ventricular arrhythmias andICD interventions and finally death. One shouldrealize that there is no randomized trial that showsthe benefit of ICD therapy in CPVT patients andgiven the above-described potential proarrhythmiceffects there is a need for such a study before ICDcan be implanted on a large scale.

In the meantime left stellate ganglion ablationand flecainide therapy have been described assuccessful treatment strategies in CPVT patientswho present with an insufficient response on beta-blocker treatment.4,5 This patient would have qual-ified for either option and given its documentedefficacy, also on the very long term in individual pa-tients, would have probably been still alive. Abla-tion therapy has been described, but only success-fully for atrial arrhythmias that triggered inappro-priate ICD interventions.6 The pathophysiologicalmechanism of CPVT arrhythmias relates to calciumoverload of myocardial cells triggering delayed

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afterdepolarizations and associated arrhythmiasand affects the whole heart. Recent mouse studiessuggest that particularly Purkinje fibers exhibit ahigh sensitivity to calcium overload.7 Human stud-ies suggest that the majority of initial ectopy origi-nates from the RVOT area,8 in my view making aPurkinje fiber origin less likely by the way. How-ever, whatever the exact arrhythmogenic mecha-nism, it is very unlikely that it is completely uni-focal, preventing successful (ventricular) ablationtherapy. In the two patients in whom it had beentried it proved to be unsuccessful.8

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2. Tikkanen M, Junttila J, Anttonen O, et al. Early re-polarization: Electrocardiographic phenotypes associatedwith favorable long-term outcome. Circulation 2011;123:2666–2673.

3. Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, et al. Com-prehensive open reading frame mutational analysis of theRYR2-encoded ryanodine receptor/calcium channel in pa-tients diagnosed previously with either catecholaminergicpolymorphic ventricular tachycardia or genotype negative,exercise-induced long QT syndrome. J Am Coll Cardiol2009;54:2065–2074.

4. van der Werf C, Kannankeril PJ, Sacher F, et al. Treat-ment with flecainide reduces exercise-induced ventriculararrhythmias in patients with catecholaminergic polymorphicventricular tachycardia. J Am Coll Cardiol 2011;57:2244–2254.

5. van der Werf C, Zwinderman AH, Wilde AAM. Therapeuticapproach for patients with catecholaminergic polymorphicventricular tachycardia: state of the art and future develop-ments. Europace 2012;14:175–183.

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7. Herron TJ, Milstein ML, Anumonwo J, et al. Purkinje cellcalcium dysregulation is the cellular mechanism that under-lies catecholaminergic polymorphic ventricular tachycardia.Heart Rhythm 2010;7:1122–1128.

8. Sumitomo N, Harada K, Nagashima M, et al. Catecholamin-ergic polymorphic ventricular tachycardia: electrocardio-graphic characteristics and optimal therapeutic strategies toprevent sudden death. Heart 2003;89:66–70.