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Case Report
Acta Cardiol Sin 2011;27:115-9
The Impact of Verapamil on Catecholamine
Polymorphic Ventricular Tachycardia
Jen-Fu Liu
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a disease of mutation of family genes associated
with exercise-induced syncope or sudden death. We report a case of a 27-year-old female with CPVT who had
experienced several episodes of syncope and had been prescribed beta-blocker regularly. Sudden onset of
ventricular arrhythmia occurred and the patient was resuscitated but remained in comatose state. During her
hospitalization, the refractory intermittent ventricular arrhythmia was finally terminated adjuvantly by use of
verapamil, while the current standard therapy for CPVT was definitely not useful. Therefore, we report this case
accompanied by a review of the current literature.
Key Words:
Catecholamine polymorphic ventricular tachycardia · Sudden cardiac death · Verapamil
INTRODUCTION
death initially. This disorder is characterized by adrenergically induced ventricular arrhythmia, usually in
the form of bidirectional or polymorphic VT in the absence of a structural heart disease or prolonged QT
interval.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial condition associated with exercise-induced syncope or sudden cardiac death in young
adults. The disease is mostly caused by a mutation in the
cardiac ryanodine channel gene that leads to abnormal
increase in intracellular Ca2+ concentration, leading to
arrhythmia due to a cascade of delayed after-depolarization and triggered activity. Current evidence suggests
that the primary therapy for CPVT is beta blockade and
placement of implantable cardioverter defibrillator (ICD).
However, Mohamed et al. recently reported the case of a
young girl with CPVT who died eventually despite
beta-blockers and appropriate ICD therapies.
CPVT is usually seen in children and young adults
who present with exercise-induced syncope or sudden
CLINICAL REPORT
The 27-year-old female had initial episode of syncope at the age of 12 and three other episodes of syncope within the next 2 years. Each attack of syncope
lasted from seconds to 1 or 2 minutes, followed by spontaneous recovery. In the past years, she had consulted
several medical centers in Taiwan and America where
indefinite arrhythmia was diagnosed and beta-blocker
(kerlone) was prescribed for ordinary use.
The patient was sent to a hospital in the neighborhood when she became unconscious and pulseless, having undetectable blood pressure and no spontaneous
respirations. She was transferred to our hospital for
personal reasons five days later. Upon arrival at the ER,
her initial electrocardiographic survey (ECG) showed
ventricular tachycardia/fibrillation (VT/VF). Sinus rhythm with complete right-bundle branch-like pattern
Received: August 14, 2010
Accepted: December 30, 2010
Division of Cardiology, Tungs’ Taichung MetroHarbor Hospital,
Jen-Teh Junior College of Medicine, Nursing and Management.
Address correspondence and reprint requests to: Dr. Jen-Fu Liu,
Division of Cardiology, Tungs’ Taichung MetroHarbor Hospital,
Jen-Teh Junior College of Medicine, Nursing and Management, No.
699, Sec. 1, Chungchi Road, Wu-Chi township, Taichung, Taiwan.
Tel: 886-4-2658-1919 ext. 4305; E-mail: [email protected]
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Jen-Fu Liu
Moreover, deep comatose state and hypoxic-ischemic
encephalopathy was revealed by serial brain computed
tomography, which was compatible with diffuse brain
edema inciting ischemic-hypoxic insults.
As the patient was moved into the coronary care unit
(CCU), immediate oral beta-blocker, bisoprolol (1.25
mg/tablet) twice per day and intravenous amiodarone in
continuous drip were given. We shifted gradually to oral
mexiletine (150 mg/tablet) 600 mg per day with caution.
Ventricular arrhythmia persisted, and we then shifted
from amiodarone to lidocaine (2-3 mg/min) to try to
(RBBB) (Figure 1A) and without obvious ST depression
or elevation (Figure 1B) was recorded after three monophasic direct current defibrillations at 200 J and endotracheal tube intubation. Her echocardiographic study
did not reveal any specific structural or hemodynamic
findings. The laboratory test results were as follows:
white blood cell: 15,060/ml, magnesium: 1.9 mg/dl, calcium: 7.3 mg/dl, potassium: 2.9 mg/dl. Her cardiac enzymes were markedly elevated: creatine kinase (CK):
5494 U/l, CK-MB: 32.8 U/l, troponin I: 32.0 mg/l, all of
which were probably related to defibrillation therapy,
A
B
Figure 1. (A) The onset of resting electrocardiogram at emergency room after defibrillation. (B) The subsequent resting electrocardiogram showed
normal sinus rhythm without delta wave nor QT interval prolongation (QTc: 383 ms).
Acta Cardiol Sin 2011;27:115 -9
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Verapamil and Catecholamine Polymorphic Ventricular Tachycardia
visiting time (Figures 2A, B, C). Verapamil, which is responsive to some ventricular arrhythmias, was used. 1
Fortunately, frequent VPEs disappeared regardless of
further physical stimulation including pain and respiratory rehabilitation. No further episode of malignant
cardiac dysarrhythmia occurred.
In order to define the diagnosis and to optimize the
dosage of beta-blocker, electrophysiologic study (EPS)
with isoproterenol test was planned. Eventually, the EPS
avoid long-QT phenomenon. A review of telemetry monitoring in the CCU revealed that sinus tachycardia was
followed by bidirectional VT which was in turn converted into VF. CPVT was suspected due to typical
bidirectional VT, which was probably triggered by sinus
tachycardia. Although various anti-arrhythmic drugs
were attempted, incremental bidirectional ventricular
premature ectopics (VPEs) did show up and, in times,
exacerbated to spontaneous VF on and off during family
A
B
C
D
Figure 2. (A) The initial onset electrocardiogram showed multiple bidirectional ventricular premature ectopics (VPEs). (B) The subsequent
electrocardiogram showed continuous bidirectional VPEs. (C) Spontaneous onset of ventricular fibrillation and self-limitation. (D) The sequencing
figure showed a gene mutation(R2401 H) in the exon 47 of RyR2, heterozygous pattern at the seventh base from the left side. (arrow head)
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Jen-Fu Liu
therapy including aggressive suppression of polymorphic ventricular tachycardia (PVT) by anti-arrhythmia
drugs such as calcium-channel blocker 5 and bilateral
thoracic sympathectomy have been found to be effective.6
This patient’s ECG (Figure 1A) showed CRBBBlike pattern, and atypical Brugada syndrome was initially diagnosed. In patients who are suspected to have
this disease, their arrhythmia may be detected by 24hour continuous monitoring ECG or induced by exercise
treadmill testing. In this patient, transient increase in
tachycardia may have been induced by the daily contact
of family during visit in CCU, and, in turn, have transformed into bidirectional VPEs. Finally, CPVT might
degenerate into PVT or VF.
The activity of CPVT appears to be triggered by a
burst in the sympathetic tone. Hence, the focus of treatment is to suppress adrenergic activity. Therefore, betablockers are effective for the acute phase and maintenance treatment.1 However, the symptoms recurred despite of the administration of sufficient dose of betablockers, lidocaine or amiodarone in this case. Frequent
and easily-inducible VPEs suddenly disappeared after
using verapamil.
Normally, small calcium currents through L-type
calcium channel in the cell membrane of cardiomyocytes
trigger a large calcium flow from sarcroplasmic reticulum (SR). Verapamil can further reduce the amplitude of
delayed depolarization (DAD) below the threshold required for triggering ventricular arrhythmia. The evidence of other calcium-channel blocker-related arrhythmia for CPVT seems insufficient. However, betablocker would prevent the adrenergic augmentation of
the calcium flow of the SR through the genetically defective ryanodine channel.5,7 Beta-adrenergic receptor
promote ryanodine channel phosphorylation and opening ryanodine channel boost the calcium flow from SR
to depolarize the myocyte at the end of the action potential that creating DAD.8 Generally. CPVT was a heterogeneous genetic basis with gene mutation for ryanodine
channel (CPVT1) and calcium-buffering protein calsequestrin (CPVT2). Screening for LQT genes, such as
KCNJ2, may be considered in females with bidirectional/polymorphic VT when negative findings are obtained for the gene mutation of ryanodine channel and
calcium-buffering protein calsequestrin.9
In summary, we have presented a novel ryanodine
and ICD implant were not performed because of disagreement from the patient’s family. However, after a
written informed consent was obtained for genetic analysis, genetic screening for the gene mutations of ryanodine channel and calcium buffering protein calsequestrin was performed using DNA extracted from the
patients’ peripheral blood lymphocytes by the standard
polymerase chain reaction (PCR) method.
PCR analysis revealed an abnormal band in exon 47
of RyR2, which was not observed in unrelated healthy
individuals. DNA sequencing confirmed a G to A transition leading to substitution of histidine to arginine 2401,
R2401H (Fig 2D).2 No other mutation was observed in
KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes
of this patient. Pedigree genetic screening for her mother,
sister and brother showed no mutation either. Other
family members were not available.
DISCUSSION
From 1975 to 1995, CPVT has been defined as the
occurrence of malignant ventricular arrhythmia in response to exercise, isoproterenol infusion or any form of
adrenergically-mediated stimulation.1,3 The characteristics of CPVT include normal QT-interval and bidirectional morphology of ventricular premature ectopic
beats. There were some case reports among Chinese in
Mainland China and Japanese, but none in Taiwanese.
This report describes a young female who had previously received beta-blockers for undefined arrhythmia,
ends up with the diagnosis of CPVT and treated completely with verapamil as adjuvant agent in spite of there
being ICD.
CPVT is a potentially lethal disease and difficult to
diagnose, because of normal resting ECG and absence of
obvious symptom in most afflicted individuals. A typical
finding on ECG is VT with 180-degree alternation of the
QRS axis. CPVT cannot be inducible by programmed
electrical stimulation.1 Its mortality rates range from 20
to 31% in untreated patients and 10% in those who are
treated with beta-blockers.4 Treatment options may consist of beta-blockade and ICD implantation but are not
completely effective in some instances. Appropriate selection of candidates for ICD therapy is difficult as dependable risk stratification is lacking. Other adjuvant
Acta Cardiol Sin 2011;27:115 -9
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Verapamil and Catecholamine Polymorphic Ventricular Tachycardia
Rhythm Society. Circulation 2006;114:E385-484.
2. Aizawa Y, Ueda K, Komura S, et al. A novel mutation in
FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic
polymorphic ventricular tachycardia. Int J Cardiol 2005;99:
343-5.
3. Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional
tachycardia in a child. A study using his bundle electrography. Br
Heart J 1975;37:339-44.
4. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular
characterization of patients with catecholaminergic polymorphic
ventricular tachycardia. Circulation 2002;106:69-74.
5. Rosso R, Kalman JM, Rogowski O, et al. Calcium channel
blockers and beta-blockers versus beta-blockers alone for preventing exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2007;4:1149-54.
6. Scott PA, Sandilands AJ, Morris GE, et al. Successful treatment
of catecholaminergic polymorphic ventricular tachycardia with
bilateral thoracoscopic sympathectomy. Heart Rhythm 2008;5:
1461-3.
7. Laitinen PJ, Brown KM, Piippo K, et al. Mutations of the cardiac
ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 2001;103:485-90.
8. Chen YJ, Chen TC, Chen SA, et al. Cardiac cellular electrophysiology, voltage clamp, and patch clamp. Acta Cardiol Sin
2009;25:59-63.
9. Tester DJ, Arya P, Will M, et al. Genotypic heterogeneity and
phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing. Heart Rhythm 2006;3:800-5.
10. Chan YH, Wu CT, Yeh YH, Kuo CT. Reappraisal of Luo-Rudy
dynamic cell model. Acta Cardiol Sin 2010;26:69-80.
11. Chan YH, Wu LS, Yeh YH, et al. Possible targets of therapy for
catecholaminergic polymorphic ventricular tachycardia: insight
from a theoretical model. Circ J 2011 (in press).
12. Watanabe H, Chopra N, Laver D, et al. Flecainide prevents
catecholaminergic polymorphic ventricular tachycardia in mice
and humans. Nat Med 2009;15:380-3.
channel mutation in a patient with CPVT. This R2401H
mutation is located at the FKBP12.6 binding region of
the ryanodine channel.2 The ventricular arrhythmia may
be related to Ca2+ overload in the conducting tissue and
precipitated by adrenergic stimuli or inhibited by betablocking drug. 10,11 Further studies focus on using flecainide to reduce release of Ca2+ from SR and to inhibit
the Ca2+ signaling pathway mediated by ryanodine channel.12 But flecanide is not available at out hospital. As in
our case, patients presenting with sudden cardiac arrest
can be mistaken as idiopathic VF and suffer from the
sequelae of resuscitation. Therefore, clinicians should
carefully analyze the triggering factors of VF in healthy
individuals.
ACKNOWLEDGEMENT
The PCR analysis for gene mutation was performed
at Professor Lin-Ping Lai’s laboratory, National Taiwan
University Hospital, Taipei, Taiwan.
REFERENCES
1. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006
Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of
the American College of Cardiology/American Heart Association
Task Force and the European Society of Cardiology Committee
for Practice Guidelines (writing committee to develop Guidelines
for Management of Patients with Ventricular Arrhythmias and the
Prevention of Sudden Cardiac Death): developed in collaboration
with the European Heart Rhythm Association and the Heart
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