Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature

EP Europace, Jun 2011

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). While pharmacological therapy with beta-blockers and/or Ca2+ antagonists is often unreliable, a recent study has demonstrated that flecainide can effectively suppress arrhythmia in a murine model of CPVT as well as clinically in two human subjects suffering from CPVT. We here present the case of an 11-year-old boy suffering from CPVT-1 as well as a review of the current relevant literature. After resuscitation due to VF at age 9, an automated implantable cardioverter–defibrillator (ICD) was implanted in 2007. Under beta-blocker therapy, repeated shocks were delivered due to either fast ventricular tachycardia (VT) or VF. This persisted under additional therapy with verapamil. Implantable cardioverter–defibrillator routine interrogations showed frequent non-sustained VT with an average of 8.8 per day. Additionally, the patient suffered from impaired physical performance due to decreased chronotropic competence. In July 2009, flecainide was added to the beta-blocker/verapamil regimen, resulting in a plasma level of 0.20 mg/L. No ICD shock or sustained VT occurred until December 2010. Genetic testing revealed an RyR2 receptor mutation. The case demonstrates the challenge of diagnosis and management of CPVT. It furthermore supports recent experimental evidence that the class 1 antiarrhythmic drug flecainide can suppress CPVT. The presented case supports a novel strategy in treating CPVT with the class I antiarrhythmic agent flecainide.

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Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: . Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature Christian Pott 0 3 Dirk G. Dechering 0 3 Florian Reinke 0 3 Adam Muszynski 0 3 Stephan Zellerhoff 0 3 Alex Bittner 0 3 Julia K o?be 0 3 Kristina Wasmer 0 3 Eric Schulze-Bahr 0 1 3 Gerold Mo? nnig 0 3 Stefan Kotthoff 2 3 Lars Eckardt 0 3 0 Department of Cardiology and Angiology, University Hospital Mu ?nster , Albert-Schweitzer Strasse 33, 48149 Mu ?nster , Germany 1 Institute for Genetics of Heart Diseases (IfGH), University Hospital Mu ?nster , Mu ?nster , Germany 2 Pediatric Cardiology, University Hospital Mu ?nster , Mu ?nster , Germany 3 Division of Cardiology, Electrophysiology Section, University of Utah School of Medicine , 30 North 1900 East, Room 4A100, Salt Lake City, UT , USA CASE REPORT doi:10.1093/europace/euq517 Online publish-ahead-of-print 2 February 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). While pharmacological therapy with beta-blockers and/or Ca2+ antagonists is often unreliable, a recent study has demonstrated that flecainide can effectively suppress arrhythmia in a murine model of CPVT as well as clinically in two human subjects suffering from CPVT. We here present the case of an 11-year-old boy suffering from CPVT-1 as well as a review of the current relevant literature. After resuscitation due to VF at age 9, an automated implantable cardioverter - defibrillator (ICD) was implanted in 2007. Under beta-blocker therapy, repeated shocks were delivered due to either fast ventricular tachycardia (VT) or VF. This persisted under additional therapy with verapamil. Implantable cardioverter - defibrillator routine interrogations showed frequent non-sustained VT with an average of 8.8 per day. Additionally, the patient suffered from impaired physical performance due to decreased chronotropic competence. In July 2009, flecainide was added to the beta-blocker/verapamil regimen, resulting in a plasma level of 0.20 mg/L. No ICD shock or sustained VT occurred until December 2010. Genetic testing revealed an RyR2 receptor mutation. The case demonstrates the challenge of diagnosis and management of CPVT. It furthermore supports recent experimental evidence that the class 1 antiarrhythmic drug flecainide can suppress CPVT. The presented case supports a novel strategy in treating CPVT with the class I antiarrhythmic agent flecainide. Case We here present the case of an otherwise healthy boy born in 1998 and suffering from CPVT. A time line on the clinical events and the diagnostic and therapeutic measures of the case is given in Table 1. The child had suffered from recurrent syncope since age 3. Although usually episodes occurred one to two times per year, an accumulation occurred in 2006 (six episodes) and during January 2007 (two episodes). Typically, the episodes appeared to be triggered by sudden stressful events such as noises, physical pain, physical movement, or fear. The patient?s mother reported that some of the episodes were preceded by a sudden headache. The episodes consisted of unconsciousness usually lasting for seconds. On recovery the boy was described as pale and appeared stunned. A minority of the episodes were described to be associated with stiffness of the arms and urination. The patient was admitted to the Department of Neuropediatrics at our institution. Physical and neurological examinations were normal. EEG testing did not reveal evidence for epilepsy. Tilt table and Schellong testing Table 1 Time line of clinical events and diagnostic and delivered normal results. Twenty-four-hour Holter monitortherapeutic procedures ing revealed multiple polymorphic VES up to bi- and trigeDate Event/procedure mini. Subsequently, the patient was referred to the . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Department of Pediatric Cardiology for further diagnostics. January 1998 Birth of the patient No ECG abnormalities were observed at rest (Figure 1). Approx. since 2001 Recurrent syncopes ( 1 ? 2/year) Exercise testing revealed polymorphic ventricular extrasySince 2006 Accumulation of syncopes toles under physical stress (Figure 2). 2006/2007 Neurological evaluation: negative Cardiac imaging studies revealed no evidence for a strucTilt table and Schellong test: negative tural heart disease: echocardiography was normal and left E2x4ehrcHisoeltteerstminogn:isttorerisnsg-:inmduulcteipdleinpcorleyamseoropfhVicEVSES and right heart catheterization demonstrated normal haeEchocardiography and MRI: normal modynamics with a normal right and left ventricle. Cardiac Electrophysiological testing: no monomorphic VT MRI with gadolinium application did not reveal any abnormor supra-ventricular tachycardia ality. During electrophysiological testing, polymorphic VES February 2007 Loop recorder implantation but no sustained VT or supraventricular tachycardia Initiation of verapamil therapy occurred. During orciprenaline administration, spontaneous May 2007 Ventricular fibrillation and cardiopulmonary polymorphic VES occurred that were similar to those ICDreismuspcliatnattiaotinon observed during stress testing (Figure 2). Addition of beta-blocker therapy As it remained unclear whether the recurrent syncope November ? Recurrent ICD shocks was related to the stress-induced tachycardia, a loop recorFebruary 2008 Dose escalation of verapamil and beta-blocker der was first implanted (February 2007). Since even low medication, resulting in clinically relevant doses (12.5 mg/day) of atenolol caused significant bradycarbradycardia dia, pharmacological therapy was switched to verapamil. A June 2010 Initiation of flecainide therapy permanent dose of 90 mg verapamil/day was well tolerated Domseeddiec-aetsiocnalation of beta-blocker and verapamil and the patient was dismissed under this regimen. Since July 2009 No further ICD shocks, no further clinically No further syncope had occurred and no tachycardia was relevant bradycardia evident when a routine loop recorder control was conducted on 27 April 2007. On 19 May 2007 the boy was For dosages of the respective agents, we refer to the full text. woken up by his mother after he had fallen asleep during VES, ventricular extrasystoles; VT, ventricular tachycardia; ICD, implantable a car ride. He collapsed and was immediately resuscitated cardioverter ?defibrillator. by his mother and shortly thereafter by emergency medical personnel. Cardiopulmonary resuscitation was conducted and sinus rhythm was restored by defibrillation. Subsequent loop recorder analysis revealed a polymorphic VT with degeneration into VF (Figure 3). Thereafter, an ICD system was implanted. Additional drug therapy with bisoprolol was begun. After stepwise increase, a permanent dose of 7.5 mg/day (0.35 mg/kg body weight) was well tolerated. Neurological and physical recovery of the boy was complete and he was dismissed from the hospital. Under this regimen, the patient was free of relapse until ICD shock delivery occurred in November 2007 and twice again on 11 February 2008. Implantable cardioverter ? defibrillator interrogation revealed fast VT or VF corresponding to the relevant episodes. Subsequently, verapamil was again added to the beta-blocker medication (now bisoprolol 5 mg and verapamil 90 mg/day). After further shock delivery due to sustained VF under this regimen in July 2008, antiarrhythmic medication was escalated to 110 mg verapamil + 5 mg bisoprolol/day and then after further shock delivery in May 2009 to 120 mg verapamil + 5 mg bisoprolol/day. Under a combination of bisoprolol and verapamil, the patient complained about reduced physical performance. Significant bradycardia was observed, resulting in antibradycardic pacemaker stimulation at 40 bpm during daytime hours. Baseline frequency was increased to 60 bpm, resulting in a high percentage of time stimulated. On 2 July, flecainide was added to the antiarrhythmic medication consisting of the beta-blocker and the Ca2+ antagonist. Titration of flecainide to a permanent dose of 90 mg/day was well tolerated. Chronic administration of this dosage resulted in a plasma level of 0.20 mg/L. Simultaneously, verapamil was reduced to 60 mg/day. Routine ICD interrogations in September and November 2009 revealed a reduction of non-sustained VTs by almost a factor of 7 from 8.8 to 1.3 episodes/day. No VF, syncope, or shock delivery occurred until December 2010. Genetic analysis revealed no CASQ2 gene mutation; a cascade screening approach of the RYR2 gene led to the identification of a published missense mutation (c. 14311 G.A, p. V4771I) in heterozygous state as the cause for CPVT. Discussion and review of the current literature Only ICD implantation can reliably prevent SCD, therefore, it is generally agreed upon that in the setting of CPVT and documented VF or haemodynamically instable VT, ICD implantation is the first-line therapy. However, our case emphasizes the need for additional pharmacological therapy to avoid repeated ICD shock delivery. These events can have a traumatizing impact and can severely limit the patient?s everyday activities and quality of life?may it be by repeated de facto shock delivery or the fearful expectation of these. The case presented here adds to the clinical experience that beta-blockers and Ca2+ antagonists do not reliably suppress CPVT.1,3 In addition, the medical history of our patient demonstrates the adverse effects that chronic medication with beta-blockers and verapamil may have on physical performance by reducing chronotropic competence, thus?at least in our case?further severely reducing quality of life. The recent report by Watanabe et al.8 is the first to consider a class I antiarrhythmic for the treatment of CPVT. The authors demonstrate a suppression of VT/VES in a transgenic murine model of CPVT and two patients suffering from CPVT by administration of flecainide. An additional case report on this topic has recently been published on a patient suffering from CPVT in which beta-blocker therapy was effective. Yet, other than in our case?where betablocker therapy was ineffective?beta-blocker therapy had to be terminated due to severe side effects and flecainide therapy was initiated as a substitute, which proved to be equally successful as beta-blocker therapy.9 The molecular mechanisms of CPVT-induced arrhythmia are comparatively well understood: mutations of either the cardiac ryanodine receptor4?as has been confirmed in our case?or calsequestrin5 facilitate spontaneous Ca2+ release events from the SR. The sudden increase in cytosolic Ca2+ activates the Na+/Ca2+ exchanger, resulting in an electrical inward current that may depolarize the cellular membrane to a potential from where a new?premature?action potential is triggered. Flecainide would act on two levels of this mechanistic cascade (i) by reducing RyR open probability, thus reducing spontaneous SR Ca2+ release, and (ii) by inhibition of Na+ current. Thus, the antiarrhythmic actions of flecainide in the setting of CPVT associated with either RYR2- or CASQ2-mutations are plausible. Results from several groups (C. Pott et al., submitted)10 ? 12 have provided evidence that the cardiac Na+/Ca2+ exchanger could function as a direct mediator of afterdepolarizations?most likely since the level of Ca2+induced membrane current is a direct function of the expression and activity level of the Na+/Ca2+ exchanger.13,14 Since this would also hold true for CPVT-associated arrhythmia, an alternative future therapy in CPVT may be the pharmacological inhibition of the Na+/ Ca2+ exchanger, although the agents in question have so far only been tested in animal models. Figure 3 Readout of the reveal device with temporal corre- In comparison, flecainide offers the unique advantage of being an lation to the resuscitation event. Initially, sinus rhythm is approved drug that has been in use since 1972 and has few adverse observed. Subsequently, an accumulation of polymorphic ven- effects in everyday use. The CAST trial has shown that class I tricular extrasystoles and then the development of a fast poly- antiarrhythmics are associated with an increased rate of SCD15 in tmacohrypchaicrdviaentthreicnuelavrotlvaechsyincatordviaenatrreicoulbasrefirvberdill.aTtihoen. ventricular sptorustc-tinufraarlcthepaarttiednitsse; ahsoe.wNeveevre,rCthPeVleTsst,yopinceallsyhoisunldotfoalslosowciathteed uws uitahl precautions such as closely monitoring QRS width when administering class I antiarrhythmics in CPVT patients, and flecainide therapy should be combined with beta-blocker therapy. As a matter of course, the data currently available are not substantial enough to uncritically advocate flecainide as the first-line medical therapy in CPVT patients implanted with an ICD. A larger patient population has to be investigated, including long-term follow-up. Nevertheless, flecainide treatment may be a promising strategy to increase the quality of life in patients suffering from CPVT. First, it may reduce or even totally suppress ICD shock delivery. Secondly, the adverse effects of high-dose beta-blocker or verapamil therapy could be avoided. Acknowledgements Ryr2 gene analysis has been kindly performed by Doris Bo? ckelmann. Conflict of interest: none declared. Funding L.E. holds the Peter Osypka Professorship of Experimental and Clinical Electrophysiology. C.P. has received a returnee fellowship of the Deutsche Forschungsgemeinschaft (Po 1004-1/2) and a research grant by the University of Mu?nster Medical Faculty (IMF Po 12 06 07). C.P. and L.E. have received a research grant by Sanofi. E.S-B. has a grant by the Leducq Fondation (Transatlantic Network of Excellence: Preventing sudden cardiac death). Right atrial perforation at the end of an atrial fibrillation ablation procedure Gaston R. Vergara, Lori McMullan, and Nassir F. Marrouche* A 74-year-old man with chronic atrial fibrillation underwent ablation under conscious sedation. After sheath removal from the left atrium, the patient flexed his thighs, resulting in a ?foetal position? developing tamponade due to an right atrial (RA) appendage perforation from sheath migration. This illustrates the importance of close monitoring during sedation weaning, recommending removal of all sheaths prior to sedation withdrawal. Introduction Atrial fibrillation (AF) ablation is an invasive procedure associated with complications. In a large ?real-world? survey by Cappato et al.1 from 8745 patients, the incidence of major complications was 6%, including four deaths (two major cerebral thromboembolisms, one extrapericardial perforation, and an unknown cause). Major complications include death, stroke, cardiac perforation with tamponade, pulmonary vein stenosis .50%, and atrial ? oesophageal fistula. The incidence of cardiac tamponade reported ranges from 0.6 to 1.2%1,2 depending on the series. Case A 74-year-old man with pectus excavatum and symptomatic AF was referred for ablation. He underwent uneventful AF ablation under conscious sedation; however, towards the end of the procedure and once both sheaths were pulled in the RA and inferior vena cava, the patient moved despite his restraints. He flexed his legs and thighs, achieving a nearly foetal position. Over the next few minutes he became hypotensive. Since the patient was fully anticoagulated with heparin (ACT 300 ? 350 s), he received protamine and fresh frozen plasma. An echocardiogram confirmed the diagnosis of pericardial effusion with tamponade. He underwent echocardiogram and fluoroscopy-guided standard subxyphoid pericardiocentesis, but due to his pectus excavatum the procedure was difficult (Figure 1). Pericardiocentesis was performed with a 15 cm needle and an 8.3F drain. Intrapericardial position of the drainage was confirmed with agitated saline contrast injection. Due to the tamponade he became pulseless, requiring chest compressions resulting in dislodgement of the pericardial drain. The patient was then transferred to the operating room where he underwent repair of a 6 mm perforation of the RA appendage. He was discharged a few days later without neurologic sequelae. Discussion To the best of our knowledge, this is the first report of a right atrial appendage perforation following an AF ablation. We believe that migration of one of the transseptal sheaths was the culprit since all other catheters were already removed. This was supported by continuous intraprocedural real-time imaging with intracardiac echo, which did not reveal any pericardial effusion. In this case, a patient recovering from sedation could have moved involuntarily with enough strength to release his restraints. Conscious sedation has been described by several experienced groups as safe for AF ablation.3 Furthermore, by allowing/keeping 1. 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Lahat H , Pras E , Olender T , Avidan N , Ben-Asher E , Man O et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel . Am J Hum Genet 2001 ; 69 : 1378 - 84 . 6. Wilde AA , Bhuiyan ZA , Crotti L , Facchini M , De Ferrari GM , Paul T et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia . N Engl J Med 2008 ; 358 : 2024 - 9 . 7. Mohamed U , Gollob MH , Gow RM , Krahn AD . Sudden cardiac death despite an implantable cardioverter - defibrillator in a young female with catecholaminergic ventricular tachycardia . Heart Rhythm 2006 ; 3 : 1486 - 9 . 8. Watanabe H , Chopra N , Laver D , Hwang HS , Davies SS , Roach DE et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans . Nat Med 2009 ; 15 : 380 - 3 . 9. Biernacka EK , Hoffman P . Efficacy of flecainide in a patient with catecholaminergic polymorphic ventricular tachycardia . Europace 2010 ; 13 : 129 - 30 . 10. Milberg P , Pott C , Fink M , Frommeyer G , Matsuda T , Baba A et al. Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3 . Heart Rhythm 2008 ; 5 : 1444 - 52 . 11. Pogwizd SM , Bers DM . Cellular basis of triggered arrhythmias in heart failure . Trends Cardiovasc Med 2004 ; 14 : 61 - 6 . 12. Sipido KR , Volders PG , de Groot SH , Verdonck F , Van de Werf F , Wellens HJ et al. Enhanced Ca2+ release and Na+/Ca2+ exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis . Circulation 2000 ; 102 : 2137 - 44 . 13. Pott C , Goldhaber JI , Philipson KD . Homozygous overexpression of the Na+ - Ca2+ exchanger in mice: evidence for increased transsarcolemmal Ca2+ fluxes . Ann N Y Acad Sci 2007 ; 1099 : 310 - 4 . 14. Pott C , Philipson KD , Goldhaber JI . Excitation-contraction coupling in Na+ - Ca2+ exchanger knockout mice: reduced transsarcolemmal Ca2+ flux . Circ Res 2005 ; 97 : 1288 - 95 . 15. Pratt CM . The cardiac arrhythmia suppression trial. Introduction: the aftermath of the CAST-a reconsideration of traditional concepts . Am J Cardiol 1990 ; 65 : 1B - 2B .


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Pott, Christian, Dechering, Dirk G., Reinke, Florian, Muszynski, Adam, Zellerhoff, Stephan, Bittner, Alex, Köbe, Julia, Wasmer, Kristina, Schulze-Bahr, Eric, Mönnig, Gerold, Kotthoff, Stefan, Eckardt, Lars. Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature, EP Europace, 2011, 897-901, DOI: 10.1093/europace/euq517