J A C C : C A S E R E P O R T S V O L . 1 , N O . 1 , 2 0 1 9

ª 2 0 1 9 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

CASE REPORT

CLINICAL CASE

Unusual Cause of BidirectionalVentricular Rhythm

Praloy Chakraborty, DM,a Hermohander Singh Isser, DM,b Sudheer Arava, MD,c Mona Bhatia, MD,d

Kausik Mandal, DM,e Arshad Jahangir, MDf

ABSTRACT

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Bidirectional ventricular tachycardia (BDVT), a rare ventricular arrhythmia, is commonly caused by digitalis toxicity

or channelopathies and is rarely caused by aconite toxicity, myocarditis, infarction, or sarcoidosis. This paper

describes a patient with BDVT, recurrent syncope, myocardial disarray, and interstitial fibrosis on histology but

normal results on echocardiography with variants in the TTN, KCNH2, and GATA4 genes. (Level of Difficulty: Advanced.)

(J Am Coll Cardiol Case Rep 2019;1:21–6) © 2019 The Authors. Published by Elsevier on behalf of the

American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

PRESENTATION

An 11-year-old male patient presented with recurrenthistory of syncope during exercise for the previous 5years. There were no prodromal symptoms associated

EARNING OBJECTIVES

Work-up of patients with bidirectional VT tonarrow the differential diagnosis by stepwiseuse of ECG, exercise stress test, imaging,biopsy, and genetic testing.Importance of histology and genetic testingto assess for early manifestation of con-cealed form of a disease, for example, hy-pertrophic cardiomyopathy in this case.Management of bidirectional VT with beta-blockers and flecainide as recommended forCPVT, with monitoring for potential adverseeffects, use of ICD for secondary preventionof sudden death, and use of uncommonantiarrhythmic agent that effectively sup-pressed refractory VT in this patient in theacute setting and over the long term.

N 2666-0849

m the aDepartment of Cardiac Electrophysiology, Toronto General Hosp

logy, VardhmanMahavir Medical College and Safdarjung Hospital, Delhi, I

dical Science, New Delhi, India; dDepartment of Radiology and Imagin

epartment of Medical Genetics, Sanjay Gandhi Postgraduate Institute of

nter for Advanced Atrial Fibrillation Therapies, Aurora Cardiovascular Serv

thors have reported that they have no relationships relevant to the conte

nuscript received April 4, 2019; revised manuscript received May 1, 2019

with loss of consciousness or symptoms afterrecovery within 1 min. The patient was not takingmedications or dietary or herbal supplements.Physical examination was unremarkable except forthe presence of regularly irregular pulse. Restingelectrocardiography (ECG) results showed prematureventricular complexes (PVC) of the left bundlebranch block (LBBB) shape in lead V1 in the form ofventricular bigeminy (Figure 1A). Blood chemistry testresults were normal. Twenty-four-hour ambulatoryHolter monitor traces showed multiple PVCs(n ¼ 24,957 in 24 h) of LBBB (Figure 1A), and rightbundle branch block (RBBB) (Figure 1B), and severalshort runs of nonsustained ventricular rhythm, thelongest of which was of RBBB morphology shapes inV1 with alternating left and right frontal axes(Figure 1B).

MEDICAL HISTORY

No significant illnesses. No family history of cardiacdisorder or sudden death.

https://doi.org/10.1016/j.jaccas.2019.05.018

ital, Toronto, Ontario, Canada; bDepartment of Car-

ndia; cDepartment of Pathology, All India Institute of

g, Fortis Escorts Heart Institute, New Delhi, India;

Medical Sciences, Lucknow, India; and the fAurora

ices, Aurora Health Care, Milwaukee, Wisconsin. The

nts of this paper to disclose.

, accepted May 2, 2019.

Chakraborty et al. J A C C : C A S E R E P O R T S , V O L . 1 , N O . 1 , 2 0 1 9

Rare Cause of Bidirectional Ventricular Rhythm J U N E 2 0 1 9 : 2 1 – 6

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DIFFERENTIAL DIAGNOSIS

Bidirectional ventricular rhythm or tachycardia:catecholaminergic polymorphic ventricular tachy-cardia (CPVT); Andersen-Tawil syndrome (ATS);digoxin toxicity; aconitine toxicity; myocarditis;myocardial ischemia; familial hypokalemic periodicparalysis; sarcoidosis; tumor of the ventricle.

INVESTIGATIONS

Echocardiography demonstrated normal biventricularfunction, wall thickness, and chamber dimensions(Figure 2A). Exercise ECG failed to demonstrate anysigns of myocardial ischemia, sustained arrhythmias,or VT. The PVC frequency, however, increased withexercise. With the clinical history of exertional syn-cope anddocumented nonsustained slowbidirectionalventricular rhythm with structurally normal heart byechocardiography, cardiac channelopathy (CPVT vs.ATS) was believed to be the most probable diagnosiswith history negative for digoxin or aconitine useand normal imaging study results. Neuro-electrophysiological testing was negative for ATS.

MANAGEMENT

Treatment with a beta-adrenergic antagonist (meto-prolol tartrate, 25 mg twice daily) was started. Whenthe dose of beta-blocker was increased over the nextweek (metoprolol tartrate, 3 times a day), the patientdeveloped bradycardia without any decrease in PVCload. Hence, a combined therapy of reduced dosebeta-blocker (metoprolol tartrate, 25 mg twice daily)and flecainide (50 mg twice daily) was started undercontinuous cardiac monitoring. Twenty-four hoursafter the initiation of flecainide, while in his hospitalbed and not asleep, the patient went into cardiacarrest due to fast VT degenerating to ventricularfibrillation. The arrhythmia episode was detectedimmediately on the monitor and was cardioverted.The first biphasic 100-J shock failed, but successfulcardioversion to sinus rhythm was achieved with thesecond, 200-J shock. After direct current cardiover-sion, ECG recoding showed frequent multifocal PVCs.Considering the possibility of flecainide toxicity, thedrug was stopped, and the patient was treated withintravenous sodium bicarbonate. Sodium bicarbonateand conventional antiarrhythmic agents includingamiodarone failed to control the ectopy, but the patientsresponded dramatically to intravenous phenytoin. ECGin showed sinus rhythm with marked sinusarrhythmia, QTc of 0.39 s, and prominent U-wave inthe precordial lead with prolonged Q-U interval (0.51 s)(Figure 1C). Cardiac magnetic resonance tomography

with gadolinium showed the presence of a deep cryptat the left ventricular aspect of the septal myocar-dium with associated discrete delayed post-contrasthyperenhancement (Figure 2B). Endomyocardial bi-opsy from the interventricular septum demonstratedmyocyte disarray, increased interstitial fibrosis, andmyocyte hypertrophy (Figure 3). The same histologi-cal changes were seen in all 4 biopsy samples fromdifferent areas of the interventricular septum (2 fromthe mid septum and 2 from the apical septum).

With the histological changes suggestive ofhypertrophic cardiomyopathy (HCM) in the absenceof imaging evidence of ventricular hypertrophy,a diagnosis of phenotype-negative HCM (non-hypertrophic hypertrophic cardiomyopathy) wasconsidered, and genetic analysis using next genera-tion sequencing targeting the panel of 195 genesassociated with cardiomyopathies and channelo-pathies obtained (Strand Centre for Genomics andPersonalized Medicine, Bangalore, India). Three var-iants were found to be significant. A heterozygousnonsense variation in TTN (p.Ala6612LeufsTer6) wasclassified as pathogenic and 2 heterozygous missensevariations, one at KCNH2 (p.Val535Met) and the otherat GATA4 (p.Pro407Gln) were classified as variants ofunclear significance. Both of the patient’s parentswere asymptomatic and had normal baseline ECG,echocardiography, 24-h Holter monitoring, and ex-ercise ECG results. Genetic analysis showed that thepatient’s father harbored the same variation in theTTN and KCNH2 genes, whereas the mother carriedthe variation in the GATA4 gene.

With the clinical, electrocardiographic, imaging,histological, and genetic data, the patient’s conditionwas diagnosed as dual HCM and long QTU phenotypedue to variation in TTN and KCNH2. An insertablecardioverter-defibrillator was implanted. Treatmentwith beta-blocker and phenytoin was continued.

DISCUSSION

The expressed phenotype of this patient is a variablecombination of heart muscle disease and channelop-athy. In 1990, autopsy studies reported that suddencardiac death patients with a family history of HCMmay demonstrate widespread interstitial fibrosis withmyocardial disarray in the absence of ventricularhypertrophy (1,2). The increased availability ofgenetic analysis in HCM patients documented thefact that a subset of individuals in the familyof classical HCM patients carry the causative genemutation in the absence of classical ventricularhypertrophy (3). This subset of individuals was cate-gorized as a genotype positive/phenotype negative

FIGURE 1 Ventricular Premature Complexes and Slow Bidirectional

Ventricular Rhythm

(A) Resting electrocardiogram of premature ventricular complexes in the form of ven-

tricular bigeminy. (B) 24-h Holter monitor traces demonstrating a run of nonsustained

slow ventricular rhythm with right bundle branch block morphology in V1 but alternating

left and right frontal axis. (C) ECG in sinus rhythm with sinus arrhythmia, a QTc complex

of 0.39 s, and a large U-wave in the precordial lead with a QTU interval of 0.51 s.

J A C C : C A S E R E P O R T S , V O L . 1 , N O . 1 , 2 0 1 9 Chakraborty et al.J U N E 2 0 1 9 : 2 1 – 6 Rare Cause of Bidirectional Ventricular Rhythm

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(GþP�) or a nonhypertrophic hypertrophic cardiomy-opathy phenotype. Detection of myocardial cryptsin cardiac magnetic resonance imaging has beensuggested as a marker of GþP� HCM (4); however, thisis not specific for HCM and can be observed inpatients with left ventricular hypertrophy or ischemicheart disease (5). Although the natural history ofGþP� subsets is reported to be mostly benign (6),there are reports of sudden cardiac arrest in Gþ familymembers of HCM patients in the absence of leftventricular hypertrophy (7). Endomyocardial biopsyin this patient demonstrated myocardial disarray,myocyte hypertrophy, and nucleomegaly suggestiveof HCM. Autopsy studies have reported thatmyocardial disarray may be found in some areas ofnormal heart (8). In the present patient, however,widespread disarray was documented in all biopsysamples obtained from the apical and mid septumand was associated with increased interstitial fibrosis,and pathological changes in cardiomyocytes reducethe possibility of “physiological disarray.” The pa-tient had a history of recurrent exertional syncopewith spontaneous recovery over the previous 5 yearsand developed cardiac arrest only after initiationof flecainide therapy. There is the possibility thatflecainide sustained VT due to a re-entrant mecha-nism with slowing of conduction within the myocar-dium along the fibrotic area, thus creating aproarrhythmic milieu within the microscopic struc-tural abnormality in an otherwise grossly normalheart. Alternatively, flecainide could have exertedproarrhythmic effects due to its mild potassiumchannel blocking properties, predisposing to prolon-gation of repolarization and triggered activity,particularly if the repolarization reserve was alreadyreduced, which is a possibility due to reduction in therapid component of the delayed rectifier current (IKr)that may result from the KCNH2 variant. Bradycardiawith flecainide has been described with sinoatrialconduction delays but seems unlikely in this patient.

The genetic test revealed a variation in the TTNgene, which encodes Titin, a sarcomeric protein.TTN mutations have been reported in HCM as well asin dilated cardiomyopathy. The variation identified(c.19831delC) is predicted to cause a frame shift andconsequently premature termination of the protein(p.Ala6612LeufsTer6), which could result in a loss-of-function. Although the identified variant seems to bea novel mutation, a variation immediately proximalto the site described in this patient has been reportedas “disease causing” in a patient with dilated car-diomyopathy (9). Whether the novel variant identi-fied in the TTN gene in this patient with a structurallynormal heart, according to echocardiography, but

FIGURE 2 Echocardiographic and CMR Images of the Proband Heart

(A) Apical 4-chamber view of 2-dimensional echocardiogram showing normal wall thickness and chamber dimensions. (B) CMR image of

4-chamber phase sensitive inversion recovery view demonstrating a linear myocardial crypt (arrow) seen on 3D balanced turbo field-echo

sequence images enhancing post-contrast on delayed images. There was no evidence of ventricular septal defect or ventricular hypertrophy.

CMR ¼ cardiac magnetic resonance.

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with histological characteristics of HCM (myocytedisarray, interstitial fibrosis, and myocyte hypertro-phy), is an early manifestation of concealed HCM or ofdilated cardiomyopathy is not known. This can onlybe determined by long-term follow-up that mayreveal time-dependent expression of the phenotype.

In this patient, features such as episodes of non-sustained slow, bidirectional ventricular rhythm,PVCs of 2 different patterns, unique response of thearrhythmia to phenytoin and prominent U-wave insinus rhythm ECG are interesting characteristics.BDVT and characteristic U-wave abnormality is afeature of ATS that presents with modest prolonga-tion of QT and prominent U-wave and prolong QUinterval, as was observed in the patient. A range of10% to 15% of patients with genetically defined LQTSmay present with baseline normal QTc (10). Phenytoin, aClass Ib antiarrhythmic agent, can reduce the dura-tion of the action potential by inhibiting the slowsodium current and the inward calcium current in theplateau phase of action potential in Purkinje fibers(11), and clinical reports of phenytoin effectiveness intorsades de pointes, even in refractory cases, has beenpublished (12). The unique response of arrhythmia tophenytoin may be a phenotypical expression of thecomplex electrophysiological milieu in the patientwith myocardial disarray, fibrosis, and mutations inthe TTN and KCNH2 genes.

The patient harbors a variation in KCNH2 gene thatencodes the potassium voltage-gated channel sub-family H member 2 protein, which plays a role in the

transport of potassium ions across the cell membraneduring repolarization through the rapid component ofthe delayed rectifier Kþ channels IKr. Pathogenicvariations in the KCNH2 gene have been shown to beassociated with the autosomal dominant Romano-Ward long QT syndrome (loss of function) and shortQT syndrome (gain of function). The identifiedvariant in the present patient has been previouslyreported in a proband and his mother with LQTS2 (13),both with normal QT intervals (QTc <450 ms), butwith a prominent U-wave, such as in the patient,suggesting contributory role of the variation in theexpressed phenotype.

The association between HCM and QTc prolonga-tion has been reported with prolongation of repolar-ization attributed to the sheer mass of ventricularmyocardium (14,15) and electrical remodelling withdown-regulation of repolarizing Kþ channels. Recentstudies, however, reported concomitant LQT-relatedgene mutations associated with QT interval prolon-gation in HCM patients (16) in whom the ECG changesmay appear earlier than those with ventricularhypertrophy alone (17).

In the present study, both the child and his fatherharbored the same variation in TTN and KCNH2 gene,but the father lacked the variation in the GATA4 gene,which could have influenced the selective expressionof disease phenotype in the proband. Thus, theGATA4 variation could be acting as a genetic modifierin the patient, as previously reported for patientswith HCM (18).

FIGURE 3 Histological Changes on Endomyocardial Septal Biopsy Samples of the Proband Heart

(A) Endomyocardial biopsy fragment (arrows) showed mild hypertrophy with nucleomegaly, myocyte disarray (hematoxylin and eosin [H&E]

stain; original magnification �10]). (B) Intermyofiber fibrosis (blue arrow) (Masson trichrome [MT] stain; original magnification �40). In-

flammatory cell infiltrate was absent.

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FOLLOW-UP

During 3 years’ follow-up, this patient has beenasymptomatic, without any clinical VT or any signif-icant ventricular arrhythmia, documented on 24 hambulatory ECG monitoring. Follow-up echocardiog-raphy has so far failed to demonstrate any ventricularhypertrophy or dilatation.

CONCLUSIONS

BDVT with structurally normal heart has beendescribed in at least 2 channelopathies, CPVT andATS. To the best of the present authors’ knowledge,BDVT has not been reported with any spectra of HCM.This study reports a rare case of BDVT in a patientwith combined phenotype of nonhypertrophic hy-pertrophic cardiomyopathy with prominent U waveand a prolonged QTU interval. Under autosomaldominant conditions, the absence of a family history

can be explained by variable penetrance or expres-sion of the abnormal genes; in the present case, it isproposed that GATA4 could have acted as a geneticmodifier for TTN and KCNH2 in the proband, givingrise to a complex phenotype of variable combinationof heart muscle and electrical disease not observed inthe parents.

ACKNOWLEDGMENTS The authors thank JenniferPfaff and Susan Nord, Aurora Cardiovascular andThoracic Service Line, Aurora Health Care, Milwaukee,Wisconsin, for their editorial assistance, and BrianMiller and Brian Schurrer for help with the figures.

ADDRESS FOR CORRESPONDENCE: Dr. PraloyChakraborty, Department of Cardiac Electrophysi-ology, Toronto General Hospital, 200 Elizabeth Street,Toronto, Ontario M5G 2C4, Canada. E-mail: praloyc@hotmail.com.

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KEY WORDS bidirectional ventriculartachycardia, sarcoidosis, ventriculararrhythmia, ventricular bigeminy, ventriculartachycardia