95 Flecainide Suppresses Bidirectional Ventricular Tachycardia and Reverses Tachycardia-Induced Cardiomyopathy in Andersen-Tawil Syndrome OSCAR A. PELLIZZ ´ ON, M.D., ∗ LUIS KALAIZICH, M.D., ∗ LOUIS J. PT ´ A ˇ CEK, 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 A 16-year-old female was referred for evaluation of sus- tained bidirectional ventricular tachycardia (BVT) associated with dizziness. The patient had no known heart disease, was on no medications, and had no family history of heart disease or sudden death. Physical examination was normal except for mild symmetric lower extremity weakness. Serum laboratory assess- ments, chest x-ray, echocardiography, and cardiac magnetic res- onance imaging were all normal. On admission, an electrocar- diogram showed BVT with alternating QRS complexes (Fig. 1). Atrial and ventricular transesophageal stimulation failed to ter- 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 and allowed resumption of sinus rhythm with a distinct long QT interval and biphasic T waves (Fig. 2). Genetic analysis demon- strated an R67W mutation in the K+ channel gene KCNJ2. The patient refused ICD implantation and was discharged on flecainide therapy. A complete cardiovascular evaluation of her parents and three brothers disclosed no abnormalities. This study was supported by an MDA grant. Address for correspondence: Mario D. Gonzalez, M.D., Penn State Heart & Vascular Institute, Penn State Milton S. Hershey Medical Center, 500 University Drive, P.O. Box 850, Hershey, PA 17033-0277. Fax: (717) 531- 4077; E-mail: [email protected]Manuscript received 16 April 2007; Revised manuscript received 25 May 2007; Accepted for publication 29 May 2007. doi: 10.1111/j.1540-8167.2007.00910.x During a 4-year follow-up period, the patient had two re- currences of BVT. The first episode was due to noncompliance and the arrhythmia disappeared when the patient resumed fle- cainide treatment. The second episode occurred 3 years later while on flecainide and was associated with congestive heart failure and globally depressed left ventricular function (ejection fraction 25%). The arrhythmia was controlled when the daily dose of flecainide was increased to 300 mg. A repeat echocardio- gram obtained 3 months later showed a normal left ventricular function (ejection fraction 55%), consistent with a tachycardia- induced cardiomyopathy. Discussion Bidirectional ventricular tachycardia (BVT) is a rare ar- rhythmia, characterized by QRS complexes with alternating morphologies. 1-3 The more common type of BVT is a pattern of right bundle branch block with alternating left anterior and left posterior hemiblock. 2 Bidirectional VT can occur during digitalis toxicity, 1,2 but in some patients no obvious abnor- malities are found. 3 Recently, this arrhythmia has been reported in patients carrying a mutation of the KCNJ2 gene located in the chro- mosome 17q23, causing variable phenotypic abnormalities known as Andersen-Tawil syndrome. 4,5 This gene encodes for the α subunit of the potassium channel Kir2.1, resulting in a prolonged QT interval, BVT, torsades de pointes, and pe- riodic paralysis. 6 Andersen-Tawil syndrome can present as an autosomal dominant or sporadic disorder. 7,8 Ventricular arrhythmias associated with the Andersen-Tawil syndrome are characteristically aggravated during hypokalemia, and some patients can develop ventricular fibrillation. 9 Although
in Andersen-Tawil SyndromeOSCAR A. PELLIZZON, M.D.,∗ LUIS KALAIZICH, M.D.,∗ LOUIS J. PTACEK, 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 & VascularInstitute, Hershey, Pennsylvania, USA
BVT and Andersen-Tawil Syndrome. Bidirectional ventricular tachycardia (BVT), although a rarearrhythmia in the general population, is frequently observed in patients with Andersen-Tawil syndromeand long QT interval. However, the pharmacologic treatment of this arrhythmia remains unknown. Inthe present study, we documented the favorable antiarrhythmic action of flecainide in a young womanwith sustained BVT and Andersen-Tawil syndrome. She presented with incessant BVT that could only beterminated with flecainide. During sinus rhythm, a prolonged QT interval was observed. Genetic studiesrevealed a mutation in the K+ channel gene KCNJ2. Over a 4-year follow-up period, recurrence of herarrhythmia occurred twice. The first episode was due to noncompliance and resolved with resumption offlecainide therapy. The second recurrence was associated with a tachycardia-induced cardiomyopathy andresolved when the dose of flecainide was increased from 200 to 300 mg daily. This report suggests thatflecainide can be effective in controlling BVT associated with Andersen-Tawil syndrome and indicates thatthe left ventricular dysfunction is secondary to the arrhythmia and not due to an associated phenotypicmanifestation of the disorder. (J Cardiovasc Electrophysiol, Vol. 19, pp. 95-97, January 2008.)
bidirectional ventricular tachycardia, long QT syndrome, Andersen-Tawil syndrome, flecainide
Case ReportA 16-year-old female was referred for evaluation of sus-
tained bidirectional ventricular tachycardia (BVT) associatedwith dizziness. The patient had no known heart disease, was onno medications, and had no family history of heart disease orsudden death. Physical examination was normal except for mildsymmetric lower extremity weakness. Serum laboratory assess-ments, chest x-ray, echocardiography, and cardiac magnetic res-onance imaging were all normal. On admission, an electrocar-diogram showed BVT with alternating QRS complexes (Fig. 1).Atrial and ventricular transesophageal stimulation failed to ter-minate the arrhythmia. Multiple drugs given intravenously werealso unsuccessful, including lidocaine, propranolol, diltiazem,potassium chloride, and magnesium sulfate. Administration oforal flecainide 100 mg twice a day suppressed the arrhythmiaand allowed resumption of sinus rhythm with a distinct long QTinterval and biphasic T waves (Fig. 2). Genetic analysis demon-strated an R67W mutation in the K+ channel gene KCNJ2.The patient refused ICD implantation and was discharged onflecainide therapy. A complete cardiovascular evaluation of herparents and three brothers disclosed no abnormalities.
This study was supported by an MDA grant.
Address for correspondence: Mario D. Gonzalez, M.D., Penn State Heart& Vascular Institute, Penn State Milton S. Hershey Medical Center, 500University Drive, P.O. Box 850, Hershey, PA 17033-0277. Fax: (717) 531-4077; E-mail: [email protected]
Manuscript received 16 April 2007; Revised manuscript received 25 May2007; Accepted for publication 29 May 2007.
doi: 10.1111/j.1540-8167.2007.00910.x
During a 4-year follow-up period, the patient had two re-currences of BVT. The first episode was due to noncomplianceand the arrhythmia disappeared when the patient resumed fle-cainide treatment. The second episode occurred 3 years laterwhile on flecainide and was associated with congestive heartfailure and globally depressed left ventricular function (ejectionfraction 25%). The arrhythmia was controlled when the dailydose of flecainide was increased to 300 mg. A repeat echocardio-gram obtained 3 months later showed a normal left ventricularfunction (ejection fraction 55%), consistent with a tachycardia-induced cardiomyopathy.
Discussion
Bidirectional ventricular tachycardia (BVT) is a rare ar-rhythmia, characterized by QRS complexes with alternatingmorphologies.1-3 The more common type of BVT is a patternof right bundle branch block with alternating left anterior andleft posterior hemiblock.2 Bidirectional VT can occur duringdigitalis toxicity,1,2 but in some patients no obvious abnor-malities are found.3
Recently, this arrhythmia has been reported in patientscarrying a mutation of the KCNJ2 gene located in the chro-mosome 17q23, causing variable phenotypic abnormalitiesknown as Andersen-Tawil syndrome.4,5 This gene encodesfor the α subunit of the potassium channel Kir2.1, resultingin a prolonged QT interval, BVT, torsades de pointes, and pe-riodic paralysis.6 Andersen-Tawil syndrome can present asan autosomal dominant or sporadic disorder.7,8 Ventriculararrhythmias associated with the Andersen-Tawil syndromeare characteristically aggravated during hypokalemia, andsome patients can develop ventricular fibrillation.9 Although
96 Journal of Cardiovascular Electrophysiology Vol. 19, No. 1, January 2008
Figure 1. Electrocardiogram showing bidi-rectional ventricular tachycardia on admis-sion. A regular wide complex tachycardia isobserved (cycle length 440 ms). The QRS com-plexes show alternating polarities (open ar-rows). Sporadically, a captured beat is ob-served (filled arrow). Leads V1 and V2 suggestalternating right bundle branch block (RBBB)and left bundle branch block (LBBB) mor-phology. In contrast, V6 and inferior leads areconsistent with RBBB with alternating left an-terior and posterior hemiblock. This apparentdiscrepancy can be due to the masking effectof hemiblocks in right precordial leads mas-querading RBBB as LBBB.
flecainide has been recently reported to be effective in treatingpolymorphic ventricular tachycardia in the Andersen-Tawilsyndrome,10 effective treatment for BVT has not. However,effective pharmacologic treatment has not been reported. Inthe present case, flecainide suppressed BVT acutely and overa 4-year period, although it required close monitoring to re-duce recurrences. The mechanism by which flecainide sup-pressed BVT in our patient is not fully understood. How-ever, calcium overload and sodium currents elicited by thesodium/calcium exchanger may explain the antiarrhythmicaction of flecainide in our patient. In patients with Andersen-Tawil syndrome and BVT, the markedly prolonged QT in-terval is the result of a depressed IK1 current,5 leading tocalcium overload and oscillations during the terminal phaseof the action potential. These “late” oscillations distinguish
Figure 2. Twelve-lead electrocardiogram obtained after the BVT was suppressed by flecainide, demonstrating sinus rhythm and a markedly prolonged QTinterval (770 ms) with biphasic T waves.
Andersen-Tawil syndrome from other forms of long QT inwhich the oscillations occur during phase 2 or early phase3 of the action potential. Therefore, intracellular calciumoverload and triggered activity appear as the likely mecha-nisms for the arrhythmias associated with the Andersen-Tawilsyndrome.9 In this regard, the sodium-calcium exchanger-dependent “late” oscillatory potentials (delayed after depo-larizations) resemble those observed during digitalis toxicityunder experimental conditions.11In fact, tetrodotoxin (a spe-cific and potent sodium channel blocker) reduces calciumoverload and arrhythmias associated with digitalis intoxica-tion.11 Therefore, a common mechanism, i.e., calcium over-load and enhanced sodium-calcium exchange, may explainthe presence of BVT during both digitalis toxicity, as wellas in patients with Andersen-Tawil syndrome. Under these
Pellizzon et al. BVT and Andersen-Tawil Syndrome 97
conditions, a potent sodium channel blocker like flecainidecan reduce the oscillatory potentials that initiate BVT. In sup-port of this hypothesis, in rabbit myocardium, inhibition ofsodium channels by flecainide and other class I antiarrhyth-mic drugs alter the sodium-calcium exchange, resulting in adecrease in calcium through the exchanger and the calciumcontent in the sarcoplasmic reticulum.12,13
The present case also demonstrates that flecainide can notonly eliminate sustained BVT in the Andersen-Tawil syn-drome, but also can normalize the depressed left ventric-ular function, suggesting that these patients can develop atachycardia-induced cardiomyopathy. This observation sug-gests that the left ventricular dysfunction is not necessarilyanother phenotypic manifestation of this entity, but rather theresult of an incessant ventricular arrhythmia.
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