Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature
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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.
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
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.
Ryr2 gene analysis has been kindly performed by Doris Bo? ckelmann.
Conflict of interest: none declared.
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
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.
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.
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.
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
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