Flecainide Suppresses Bidirectional Ventricular Tachycardia and Reverses Tachycardia-Induced Cardiomyopathy in Andersen-Tawil Syndrome OSCAR A

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Flecainide Suppresses Bidirectional Ventricular Tachycardia and Reverses Tachycardia-Induced Cardiomyopathy in Andersen-Tawil Syndrome OSCAR A. PELLIZZON,´ M.D.,∗ LUIS KALAIZICH, M.D.,∗ LOUIS J. PTA´ CEK,ˇ M.D.,† MARTIN TRISTANI-FIROUZI, M.D.,† and MARIO D. GONZALEZ, M.D.‡ From the ∗Department of Cardiology, School of Medical Sciences, National University of Rosario, Argentina; †Department of Pediatric of Cardiology, University of Utah, Salt Lake City, Utah, USA; and ‡Penn State College of Medicine, Heart & Vascular Institute, Hershey, Pennsylvania, USA

BVT and Andersen-Tawil Syndrome. Bidirectional ventricular tachycardia (BVT), although a rare arrhythmia in the general population, is frequently observed in patients with Andersen-Tawil syndrome and long QT interval. However, the pharmacologic treatment of this arrhythmia remains unknown. In the present study, we documented the favorable antiarrhythmic action of flecainide in a young woman with sustained BVT and Andersen-Tawil syndrome. She presented with incessant BVT that could only be terminated with flecainide. During sinus rhythm, a prolonged QT interval was observed. Genetic studies revealed a mutation in the K+ channel gene KCNJ2. Over a 4-year follow-up period, recurrence of her arrhythmia occurred twice. The first episode was due to noncompliance and resolved with resumption of flecainide therapy. The second recurrence was associated with a tachycardia-induced cardiomyopathy and resolved when the dose of flecainide was increased from 200 to 300 mg daily. This report suggests that flecainide can be effective in controlling BVT associated with Andersen-Tawil syndrome and indicates that the left ventricular dysfunction is secondary to the arrhythmia and not due to an associated phenotypic manifestation of the disorder. (J Cardiovasc Electrophysiol, Vol. 19, pp. 95-97, January 2008.)

bidirectional ventricular tachycardia, long QT syndrome, Andersen-Tawil syndrome, ﬂecainide

Case Report During a 4-year follow-up period, the patient had two re- A 16-year-old female was referred for evaluation of sus- currences of BVT. The first episode was due to noncompliance tained bidirectional ventricular tachycardia (BVT) associated and the arrhythmia disappeared when the patient resumed fle- with dizziness. The patient had no known heart disease, was on cainide treatment. The second episode occurred 3 years later no medications, and had no family history of heart disease or while on flecainide and was associated with congestive heart sudden death. Physical examination was normal except for mild failure and globally depressed left ventricular function (ejection symmetric lower extremity weakness. Serum laboratory assess- fraction 25%). The arrhythmia was controlled when the daily ments, chest x-ray, echocardiography, and cardiac magnetic res- dose of flecainide was increased to 300 mg. A repeat echocardio- onance imaging were all normal. On admission, an electrocar- gram obtained 3 months later showed a normal left ventricular diogram showed BVT with alternating QRS complexes (Fig. 1). function (ejection fraction 55%), consistent with a tachycardia- Atrial and ventricular transesophageal stimulation failed to ter- induced cardiomyopathy. minate the arrhythmia. Multiple drugs given intravenously were also unsuccessful, including lidocaine, propranolol, diltiazem, potassium chloride, and magnesium sulfate. Administration of oral flecainide 100 mg twice a day suppressed the arrhythmia Discussion and allowed resumption of sinus rhythm with a distinct long QT Bidirectional ventricular tachycardia (BVT) is a rare ar- interval and biphasic T waves (Fig. 2). Genetic analysis demon- + rhythmia, characterized by QRS complexes with alternating strated an R67W mutation in the K channel gene KCNJ2. 1-3 The patient refused ICD implantation and was discharged on morphologies. The more common type of BVT is a pattern of right bundle branch block with alternating left anterior and flecainide therapy. A complete cardiovascular evaluation of her 2 parents and three brothers disclosed no abnormalities. left posterior hemiblock. Bidirectional VT can occur during digitalis toxicity,1,2 but in some patients no obvious abnormalities are found.3 Recently, this arrhythmia has been reported in patients This study was supported by an MDA grant. carrying a mutation of the KCNJ2 gene located in the chro- mosome 17q23, causing variable phenotypic abnormalities , Address for correspondence: Mario D. Gonzalez, M.D., Penn State Heart known as Andersen-Tawil syndrome.4 5 This gene encodes & Vascular Institute, Penn State Milton S. Hershey Medical Center, 500 for the α subunit of the potassium channel Kir2.1, resulting University Drive, P.O. Box 850, Hershey, PA 17033-0277. Fax: (717) 531- in a prolonged QT interval, BVT, torsades de pointes, and pe- 4077; E-mail: [email protected] riodic paralysis.6 Andersen-Tawil syndrome can present as 7,8 Manuscript received 16 April 2007; Revised manuscript received 25 May an autosomal dominant or sporadic disorder. Ventricular 2007; Accepted for publication 29 May 2007. arrhythmias associated with the Andersen-Tawil syndrome are characteristically aggravated during hypokalemia, and doi: 10.1111/j.1540-8167.2007.00910.x some patients can develop ventricular fibrillation.9 Although 96 Journal of Cardiovascular Electrophysiology Vol. 19, No. 1, January 2008

Figure 1. Electrocardiogram showing bidirectional ventricular tachycardia on admission. A regular wide complex tachycardia is observed (cycle length 440 ms). The QRS complexes show alternating polarities (open ar- rows). Sporadically, a captured beat is observed (ﬁlled arrow). Leads V1 and V2 suggest alternating right bundle branch block (RBBB) and left bundle branch block (LBBB) mor- phology. In contrast, V6 and inferior leads are consistent with RBBB with alternating left anterior and posterior hemiblock. This apparent discrepancy can be due to the masking effect of hemiblocks in right precordial leads mas- querading RBBB as LBBB.

flecainide has been recently reported to be effective in treating Andersen-Tawil syndrome from other forms of long QT in polymorphic ventricular tachycardia in the Andersen-Tawil which the oscillations occur during phase 2 or early phase syndrome,10 effective treatment for BVT has not. However, 3 of the action potential. Therefore, intracellular calcium effective pharmacologic treatment has not been reported. In overload and triggered activity appear as the likely mecha- the present case, flecainide suppressed BVT acutely and over nisms for the arrhythmias associated with the Andersen-Tawil a 4-year period, although it required close monitoring to re- syndrome.9 In this regard, the sodium-calcium exchanger- duce recurrences. The mechanism by which flecainide sup- dependent “late” oscillatory potentials (delayed after depo- pressed BVT in our patient is not fully understood. How- larizations) resemble those observed during digitalis toxicity ever, calcium overload and sodium currents elicited by the under experimental conditions.11In fact, tetrodotoxin (a spe- sodium/calcium exchanger may explain the antiarrhythmic cific and potent sodium channel blocker) reduces calcium action of flecainide in our patient. In patients with Andersen- overload and arrhythmias associated with digitalis intoxica- Tawil syndrome and BVT, the markedly prolonged QT in- tion.11 Therefore, a common mechanism, i.e., calcium over- 5 terval is the result of a depressed IK1 current, leading to load and enhanced sodium-calcium exchange, may explain calcium overload and oscillations during the terminal phase the presence of BVT during both digitalis toxicity, as well of the action potential. These “late” oscillations distinguish as in patients with Andersen-Tawil syndrome. Under these

Figure 2. Twelve-lead electrocardiogram obtained after the BVT was suppressed by flecainide, demonstrating sinus rhythm and a markedly prolonged QT interval (770 ms) with biphasic T waves. Pellizzon´ et al. BVT and Andersen-Tawil Syndrome 97 conditions, a potent sodium channel blocker like flecainide Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptáˇcek LJ: Mutations can reduce the oscillatory potentials that initiate BVT. In sup- in Kir2.1 cause the developmental and episodic electrical phenotypes port of this hypothesis, in rabbit myocardium, inhibition of of Andersen syndrome. Cell 2001;105:511-519. 5. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, sodium channels by flecainide and other class I antiarrhyth- Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, mic drugs alter the sodium-calcium exchange, resulting in a Ptacek LJ, Tawil R: Functional and clinical characterization of KCNJ2 decrease in calcium through the exchanger and the calcium mutations associated with LQT7 (Andersen syndrome). J Clin Invest content in the sarcoplasmic reticulum.12,13 2002;110:381-388. 6. Andersen ED, Krasilnikoff PA, Overad H: Intermittent muscular weak- The present case also demonstrates that flecainide can not ness, extrasystoles, and multiple developmental abnormalities: A new only eliminate sustained BVT in the Andersen-Tawil syn- syndrome? Acta Paediatr Scand 1971;60:559-564. drome, but also can normalize the depressed left ventric- 7. Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir ular function, suggesting that these patients can develop a C, Griggs RC: Andersen’s syndrome: Potassium-sensitive periodic tachycardia-induced cardiomyopathy. This observation sug- paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994;35:326-330. gests that the left ventricular dysfunction is not necessarily 8. Peters S, Schulze-Bahr E, Peters S, Etheridge SP, Tristani-Firouzi M: another phenotypic manifestation of this entity, but rather the Sudden death in Andersen-Tawil syndrome. Europace 2007;9:162-166. result of an incessant ventricular arrhythmia. 9. Moss AJ, Kass RS: Long QT syndrome: From channels to cardiac arrhythmias. J Clin Invest 2005;115:2018-2024. 10. Bokenkamp R, Wilde AA, Schalij MJ, Blom NA: Flecainide for recur- rent malignant ventricular arrhythmias in two siblings with Andersen- References Tawil syndrome. Heart Rhythm 2007;4:508-511. 11. Gonzalez MD, Vassalle M: Role of oscillatory potential and pace- 1. Schwensen C: Ventriculartachycardia as the result of the administration maker shifts in digitalis intoxication of the sinoatrial node. Circulation of digitalis. Heart 1922;9:199-203. 1993;87:1705-1714. 2. Rosenbaum MB, Elizari MV, Lazzari JO: The mechanism of bidirec- 12. Ito K, Nagafuchi K, Taga A, Yorikane R, Koike H: Possible involve- tional tachycardia. Am Heart J 1969;78:4-12. ment of altered Na+Ca2+ exchange in negative inotropic effects of 3. Martini B, Buja GF, Canciani B, Nava A: Bidirectional tachycardia: A class I antiarrhythmic drugs on rabbit and rat ventricles. J Cardiovasc sustained form, not related to digitalis intoxication, in an adult without Pharmacol 1996;26:355-361. apparent cardiac disease. Jpn Heart J 1988;29:381-87. 13. Takahara A, Sugiyama A, Hashimoto K: Effects of class I antiarrhyth- 4. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsun- mic drugs on the digitalis-induced triggered activity arrhythmia model: oda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark A rationale for the short-term use of class I drugs against triggered J, Deymeer F, George AL Jr, Fish FA, Hahn A, Situ A, Ozdemir C, arrhythmias. Heart Vessels 2004;19:43-48.