Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with brugada syndrome

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Volume 13, No. 7, July 2002Copyright 2002 by Futura Publishing Company, Inc., Armonk, NY 10504-0418 Prevention of Ventricular Fibrillation by Cilostazol,
an Oral Phosphodiesterase Inhibitor,
in a Patient with Brugada Syndrome
TAKESHI TSUCHIYA, M.D., KEIICHI ASHIKAGA, M.D., TOSHIHIRO HONDA, M.D., MAKOTO ARITA, M.D.* From the Cardiovascular Center, Saiseikai Kumamoto Hospital, Kumamoto, and *Yufuin-kohseinenkin Hospital, Oita, Japan Cilostazol and Brugada Syndrome. We report the case of 67-year-old man with Brugada syn-
drome, in whom daily episodes of ventricular brillation (VF) occurred every early morning for 4 days.
The episodes of VF were completely prevented by an oral administration of cilostazol, a phosphodiesterase
inhibitor. This effect was con rmed by the on-and-off challenge test, in which discontinuation of the drug
resulted in recurrence of VF and resumption of the drug again prevented VF. This effect may be related
to the suppression of Ito secondary to the increase in heart rate and/or to an increase in Ca21 current (ICa)
due to an elevation of intracellular cyclic AMP concentration via inhibition of phosphodiesterase activity.
This drug might have an anti-VF potential in patients with Brugada syndrome. (J Cardiovasc Electro-
physiol, Vol. 13, pp. 698-701, July 2002) Brugada syndrome, cilostazol, ventricular brillation Introduction
dated condition and without any antiarrhythmic agents. Sinus
node recovery time, AV nodal function, and HV interval were
Brugada syndrome is characterized by an ECG pattern of all normal. VF was induced with triple extrastimuli applied to
right bundle branch block and ST segment elevation in leads the right ventricular apex. Intravenous application of pil-
sicainide, a Class IC antiarrhythmic drug, at a dose of 0.1
1 through V3.1 -4 Isoproterenol is reported to be effective in normalizing ST segment elevation, leading to suppression mg/kg led to augmentation of ST elevation in leads V through
of ventricular brillation (VF) via enhancement of inward V (Fig. 2).6 An implantable cardioverter de brillator (ICD;
GEM-II VR 7229CX, Medtronic, Inc., Minneapolis, MN, USA)
Ca).3 However, to date there is no report on effective oral drugs to be used for prevention of VF in was implanted in our hospital on January 17, 2001. The patient
was discharged with no antiarrhythmic drug treatment.
After discharge, the patient experienced several anti-VF
phodiesterase type III inhibitor, is known to increase ICa and shocks on January 30, 2001 and February 4, 5, 6, and 7, 2001.
heart rate by elevating the level of intracellular cyclic AMP All episodes occurred during sleep between 2 and 5 o’clock
via an inhibitory effect on phosphodiesterase activity.8,9 We (Fig. 3). He was readmitted to our hospital on February 6. The
report the case of a patient with Brugada syndrome in whom electrograms stored in the ICD and the ECG recordings ob-
daily episodes of VF were completely prevented by oral tained from Holter ECG or heart monitor revealed that sinus
bradycardia with a mean cycle length of 1,123 6
preceded the episodes of VF, which were effectively terminated
Case Report
with 30-J DC shock. Premature ventricular contractions show-
A 67-year-old man was admitted to our hospital because of
ing QRS morphology similar to the premature ventricular beat
frequent episodes of convulsion during sleep. Twelve-lead
that triggered VF were observed frequently before VF occur-
ECG showed sinus rhythm with transient ST segment eleva-
rence (Fig. 3).
tion in leads V through V associated with a right bundle
On February 7, 2001, cilostazol 200 mg/day was given to
branch block pattern (Fig. 1). QT interval was normal. Exten-
prevent bradycardia during sleep and to increase I
sive investigation, which included echocardiography, left and
hibiting phosphodiesterase activity. As shown in the top panel
right ventriculography, coronary angiography, and biopsy
of Figure 3, the VF episode was completely prevented for 12
specimen obtained from the right ventricular septum, did not
days after administration of cilostazol. The drug was discon-
show any structural heart disease. The late potential was con-
tinued on February 19 in order to con rm the preventive effect
sidered to be positive. Brugada syndrome was diagnosed after
of this drug on VF. VF episodes resumed at 3:46 on February
documentation of VF during convulsion. Continuous intrave-
20 and at 2:38 on February 21. Administration of cilostazol 200
nous infusion of isoproterenol completely suppressed the oc-
mg/day was restarted, which again resulted in complete abo-
currence of VF.
lition of VF episodes. The dosage was reduced from 200 to 100
After obtaining written informed consent, electrophysi-
mg/day in order to examine whether a low dose of cilostazol
ologic study using a standard technique was performed 1 day
could prevent VF. However, the latter regimen resulted in
later. The study was performed with the patient in a nonse-
reappearance of VF episodes 5 days after reduction. The dos-
age was increased back to 200 mg/day, which nally led to the
complete disappearance of VF. The patient was discharged
with cilostazol 200 mg/day and has experienced no recurrence
Address for correspondence: Takeshi Tsuchiya, M.D., Cardiovascular Cen- of VF episodes and shock delivery from the ICD during fol-
ter, Saiseikai Kumamoto Hospital, Chikami 5-3-1, Kumamoto, 861-4193 low-up of 13 months.
Japan. Fax: 81-96-326-3045; E-mail: [email protected] Holter ECGs were recorded at baseline (February 1 and 6),
Manuscript received 17 January 2002; Accepted for publication 11 April 3 and 7 days after administration of cilostazol 200 mg/day
(February 10 and 14), 2 days after discontinuation of cilostazol
Tsuchiya et al. Cilostazol and Brugada Syndrome
Figure 1. Twelve-lead ECG showing spontaneous
transient ST segment elevation. Although ST segment
elevation was not clear at baseline, it became evident
on leads V2 through V4 during spontaneous transient
ST segment elevation. Arrows indicate ST segment
elevation.
(February 20), 5 days after the dosage was decreased from 200
of the disease.10-12 The ionic and cellular basis for ST to 100 mg/day (March 1), and 26 days after resumption of the
segment elevation in Brugada syndrome is hypothesized to dosage increased from 100 to 200 mg/day (March 28). Table 1
be due to an outward shift in the balance of the membrane shows the minimal heart rate, total beat counts, and number of
ionic currents at the end of phase 1 and phase 2 of the action premature ventricular contractions for every hour from 12:00
A.M. to 7:00 A.M. for each Holter ECG recording. It is evident
potential, in which an outward current is mainly due to that cilostazol increased both the minimal heart rate and total
activation of the transient outward current Ito and the inward beat count during early morning and abolished the occurrence
current is mainly due to the activation of ICa and an inac- of VF. There was no difference in the number of premature
tivating component of INa.3,12 The net outward shift of this ventricular contractions among the various conditions.
current balance leads to loss of the dome or phase 2 of the action potential.12 Such changes may affect the right ven- Discussion
tricular epicardium more markedly than the endocardium.
This is the rst report to describe a patient with Brugada These changes produce a marked voltage gradient in the syndrome in whom daily VFs were completely prevented by membrane potential between the endocardial and epicardial oral administration of cilostazol, a phosphodiesterase type sides of the right ventricular muscle bers during phase 2 (a change corresponding to the characteristic ST segment ele- Brugada syndrome is suggested to be a primary electrical vation in leads V1 through V3 seen on the ECGs of patients disease, and mutations in the cardiac sodium channel gene with Brugada syndrome). They also produce nonuniform SCN5A have been found in patients with the familial form repolarization in some restricted areas of the ventricular Figure 2. Twelve-lead ECG showing ST segment eleva-
tion after intravenous injection of pilsicainide 60 mg.
Although ST segment elevation was not clear at baseline,
it became evident after pilsicainide injection. Arrows
indicate ST segment elevation.
Journal of Cardiovascular Electrophysiology Vol. 13, No. 7, July 2002
Figure 3. Time course and ECG recordings of
ventricular brillation (VF) episodes. Arrows in
the top panel indicate VF episodes. Numbers on
the ECG recordings indicate sinus cycle lengths
preceding VF episodes. See text for discussion.
myocardium, a good substrate for the development of reen- increases ICa secondary to elevation of intracellular levels of trant arrhythmias.12 A variety of pathophysiologic condi- cyclic AMP.3,12 It also has been reported that DDD pacing tions and pharmacologic interventions that either increase at a relatively high rate is effective in decreasing Ito (and the membrane outward currents or reduce the inward cur- hence suppressing VF), possibly because the repriming time rents should produce loss of the action potential dome in the of Ito channels is reported to be fairly long.7 Quinidine, a right ventricular epicardium and facilitate the occurrence of vagolytic Class I antiarrhythmic agent that blocks Ito, is VF.12 Phase 2 of the action potential could be abolished by known to be able to restore the action potential dome, reducing inward Na current as predicted by the ST seg- normalize ST segment abnormality, and prevent the occur- ment elevation after application of pilsicainide (cf. Fig. 2, rence of VF in experimental models of this syndrome.12 arrows)6 and restored by increasing the inward current, e.g., However, to date there is no convincing report on oral drug by enhancing ICa (present study) or by decreasing the out- treatment for VF in patients with Brugada syndrome.
ward Ito current, e.g., by application of quinidine as re- Cilostazol, a new phosphodiesterase type III inhibitor, is used primarily as a strong antiplatelet agent, but it has been Isoproterenol is known to be especially effective in sup- pressing ST elevation on leads V1 through V3 in patients contractive function.9 All of these effects were secondary to with Brugada syndrome and restoring the action potential an increased level of cyclic AMP caused by inhibition of dome in the models of this syndrome, because it markedly phosphodiesterase type III activity in guinea pig ventricular Minimal Heart Rate and Total Beats Count for Every One Hour During 12:00 A.M. to 7:00 A.M. in the Various Conditions Condition
Baseline 1
Baseline 2
Cilostazol (200 mg)
Cilostazol (100 mg)
VF Episode (time)
Numbers in parentheses indicate number of premature ventricular contractions for every 1 hour.
HR Tsuchiya et al. Cilostazol and Brugada Syndrome
myocytes and papillary muscles.9 Based on these ndings 3. Miyazaki T, Mitamura H, Hiyoshi S, Soejima K, Aizawa Y, Ogawa S: and our present observations, it is reasonable to believe that Autonomic and antiarrhythmic drug modulation of ST segment eleva- this drug has antiarrhythmic ef cacy for preventing VFs tion in patients with Brugada syndrome. J Am Coll Cardiol 1996;27:1061-1070.
often seen in patients with Brugada syndrome, because it 4. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR: increased ICa by inhibiting phosphodiesterase activity in the The Brugada syndrome: Clinical, electrophysiological and genetic ventricular myocyte and decreased Ito by increasing heart aspects. J Am Coll Cardiol 1993;3:5-15.
rate, which again was secondary to increased I 5. Shimizu W, Antzelevitch C, Suyama K, Kurita T, Taguchi A, Aihara N, Takaki H, Sunagawa K, Kamakura S: Effect of sodium channel It is possible that the recurrent episodes in this patient blockers on ST segment, QRS duration, and corrected QT interval inpatients with Brugada syndrome. J Cardiovasc Electrophysiol 2000; represent a spontaneous cluster because these VF storms occur in patients with primary electrical disease.
6. Fujiki A, Usui M, Nagasawa H, Mizumaki K, Hayashi H, Inoue H: ST In conclusion, cilostazol was administered for frequent segment elevation in the right precordial leads induced with class IC VFs occurring in a patient with Brugada syndrome. The antiarrhythmic drugs: Insight into the mechanism of Brugada syn- drug was found to be very effective in preventing VF. The drome. J Cardiovasc Electrophysiol 1999;10:214-218.
7. Lee KL, Lau CP, Tse HF, Wan SH, Fan K: Prevention of ventricular favorable action of cilostazol is attributed to (1) enhanced brillation by pacing in a man with Brugada syndrome. J Cardiovasc ICa followed by restoration of the action potential dome (phase 2) and subsequent abolition of nonuniform repolar- 8. Atarashi H, Endoh Y, Saitoh H, Kishida H, Hayakawa H: Chrono- ization, and (2) indirect suppression of I tropic effects of cilostazol, a new antithrombolic agent, in a patient heart rate (cf. Table 1) in a particular part of the right with bradyarrhythmias. J Cardiovascular Pharmacol 1998;31:534-539.
ventricular myocardium. Therefore, cilostazol might be use- 9. Matsui K, Kiyosue T, Wang J-C, Dohi K, Arita M: Effects of pimopendan on the L-type Ca2 current and developed tension in ful in preventing the occurrence of VF, an event often guinea-pig ventricular myocytes and papillary muscle: Comparison encountered in patients with Brugada syndrome. However, with IBMX, milrinone and cilostazol. Cardiovasc Drugs Ther 1999; further studies are needed to establish the clinical usefulness of this drug for prevention of ventricular tachyarrhythmias 10. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Oritz-Lopes R, WangZ, Antzelevitch C, O’Brien RE, Schulze-Bahr E, Keating MT, Towbin References
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