Cilostazol attenuates ventricular arrhythmia induction and improves defibrillation efficacy in swine

Cilostazol attenuates ventricular arrhythmiainduction and improves defibrillation efficacy inswine

Natnicha Kanlop, Krekwit Shinlapawittayatorn, Rattapong Sungnoon,Punate Weerateerangkul, Siriporn Chattipakorn, and Nipon Chattipakorn

Abstract: Previous reports demonstrated that cilostazol, a phosphodiesterase 3 inhibitor, affected cellular electrophysiologyand reduced episodes of ventricular fibrillation (VF) in patients with Brugada syndrome. However, its effects on VF induc-tion and defibrillation efficacy have never been investigated. We tested the hypothesis that cilostazol increases the VFthreshold (VFT) and decreases the upper limit of vulnerability (ULV) and the defibrillation threshold (DFT). A total of 48pigs were randomly assigned to defibrillation and VF induction studies. The diastolic pacing threshold (DPT), VFT, ULV,DFT, and effective refractory period were determined before and after the infusion of cilostazol at 6 mg/kg, 3 mg/kg, orvehicle. The DPT was significantly increased after administration of 3 and 6 mg/kg cilostazol. The ULV and DFT weresignificantly decreased after administration of 6 mg/kg cilostazol only. The ULV in the 6 mg/kg group had 12% lowerpeak voltage and 25% lower total energy, and the DFT had 13% lower peak voltage and 25% lower total energy. TheVFT was not altered in any experimental group. This study shows that cilostazol administration significantly increased theDPT, which was associated with significantly reduced DFT and ULV.

Key words: cilostazol, phosphodiesterase 3, ventricular fibrillation threshold, defibrillation threshold, upper limit of vulner-ability, arrhythmia inducibility.

Resume : Des rapports anterieurs ont demontre que le cilostazol, un inhibiteur de la phosphodiesterase III, influe surl’electrophysiologie cellulaire et reduit les episodes de fibrillation ventriculaire (FV) dans le syndrome de Brugada. Toute-fois ses effets sur l’induction de la FV et l’efficacite de la defibrillation n’ont jamais ete examines. Nous avons verifiel’hypothese que le cilostazol augmente le seuil de FV (SFV), et diminue la limite maximale de vulnerabilite (LMV) et leseuil de defibrillation (SDF). Nous avons reparti 48 porcs au hasard dans des groupes d’induction de fibrillation ventricu-laire et de defibrillation. Nous avons determine le seuil de stimulation diastolique (SSD), la periode refractaire efficace, leSVF, la LMV et le SDF, avant et apres la perfusion 6 mg/kg de cilostazol, de 3 mg/kg, ou d’un vehicule. L’administrationde cilostazol a augmente le SDF de maniere significative. La perfusion de 6 mg/kg a augmente significativement la LMVet le SDF. La LSV du groupe 6 mg/kg a eu une tension de crete de 12 % inferieure et une energie totale de 25 % infe-rieure. Le SDF de ce groupe a eu une tension de crete de 13 % inferieure et une energie totale de 25 % inferieure. Le SFVest demeure stable chez tous les groupes experimentaux. Ainsi, l’administration de cilostazol a augmente significativementle SSD, ce qui a ete associe a une reduction significative du SDF et de la LMV.

Mots-cles : cilostazol, phosphodiesterase 3, seuil de fibrillation ventriculaire, defibrillation, limite maximale de vulnerabi-lite, inductibilite d’arythmies.

[Traduit par la Redaction]

Introduction

Cilostazol is a selective phosphodiesterase 3 (PDE3) in-hibitor (Cone et al. 1999). Because of its potent effect onvasodilatation and antiplatelet aggregation, cilostazol wasapproved by the US Food and Drug Administration for clau-dication treatment (Dawson et al. 1998). The antiarrhythmiceffects of cilostazol were first presented in atrial bradyar-rhythmia (Atarashi et al. 1998). Previous studies demon-strated that cilostazol affected the automaticity of the heartby increasing heart rates in patients and improving symp-toms in bradycardic atrial fibrillation, sick sinus syndrome,and Wenckebach type atrioventricular (AV) block (Madias2003). In patients with third-degree AV block, cilostazol in-creased heart rates and increased the ventricular escape ratewithout the abolishment of AV block or a change in the fre-

Received 19 March 2009. Accepted 4 November 2009.Published on the NRC Research Press Web site at cjpp.nrc.ca on20 April 2010.

N. Kanlop, K. Shinlapawittayatorn, R. Sungnoon, andP. Weerateerangkul. Cardiac Electrophysiology Unit,Department of Physiology, and Cardiac ElectrophysiologyResearch and Training Center, Faculty of Medicine, Chiang MaiUniversity, Chiang Mai, Thailand.S. Chattipakorn. Faculty of Dentistry, and CardiacElectrophysiology Research and Training Center, Faculty ofMedicine, Chiang Mai University, Chiang Mai, Thailand.N. Chattipakorn.1 Cardiac Electrophysiology Unit, Departmentof Physiology; Cardiac Electrophysiology Research and TrainingCenter, Faculty of Medicine; and Biomedical EngineeringCenter, Chiang Mai University, Chiang Mai, Thailand.

1Corresponding author (e-mail: [email protected]).

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Can. J. Physiol. Pharmacol. 88: 422–428 (2010) doi:10.1139/Y09-127 Published by NRC Research Press

quency of premature ventricular beats (Kodama-Takahashiet al. 2003). Also, cilostazol has been shown to decrease at-rial natriuretic peptide (ANP) and brain natriuretic peptide(BNP) concentrations (Madias 2003), hormones presentingin AV asynchrony and heart failure (Mair et al. 2001).

In a recent case report on Brugada syndrome patients, itwas shown that ventricular fibrillation (VF) episodes werecompletely abolished after oral administration of cilostazolat 200 mg/day (Tsuchiya et al. 2002). However, VF recurredwhen cilostazol was discontinued or reduced to 100 mg/day.In a 1-year follow-up of 3 patients with implanted cardi-overter defibrillators, no VF occurred during cilostazol treat-ment (Tsuchiya et al. 2002). Recently, cilostazol has beenshown to directly activate mitochondrial Ca2+-activated K+

channels, thus protecting the myocardium from ischemicand (or) reperfusion injury.(Fukasawa et al. 2008).

Despite this possible beneficial effect, direct investigationhas never been tested regarding the effects of cilostazol onVF induction and defibrillation. In the present study, wetested the hypotheses that (i) cilostazol decreases VF induci-bility by increasing VF threshold (VFT) and decreasing theupper limit of vulnerability (ULV), and that (ii) cilostazolimproves defibrillation efficacy by decreasing the defibrilla-tion threshold (DFT).

Materials and methods

Animal preparation and electrode placementForty-eight male and female Landrace pigs (25–30 kg)

were used in this study. The animals were cared for in ac-cordance with the Guide to the Care and Use of Experimen-tal Animals (Olfert et al. 1993) and with the InstitutionalAnimal Care and Use Committees of the Faculty of Medi-cine, Chiang Mai University. In each pig, anesthesia was in-duced with a combination of atropine (0.04 mg/kg), telazol(4.4 mg/kg), and xylazine (2.2 mg/kg) and maintained with1.5%–3.0% isoflurane delivered in 100% oxygen (Shinlapa-wittayatorn et al. 2006). The surface electrocardiogram (leadII), arterial oxygen tension (PaO2), end-tidal CO2, femoralarterial blood pressure (BP), core temperature, respiratoryrate, blood gases, and electrolytes were monitored through-out the study. Under artificial respiration, a catheter with a34 mm platinum-coated titanium coil electrode (Guidant)was inserted into the right ventricular (RV) apex. A 68 mmelectrode catheter was placed at the junction between theright atrium and the superior vena cava (Chattipakorn et al.2000a). These 2 electrodes were used for shock delivery.The acute experiments were divided into 2 series: a VF in-duction study (series 1, n = 24) and a defibrillation study(series 2, n = 24). Pigs were randomly designated to 1 ofthese 2 series. In each series, the pigs were divided into 3groups (n = 8 each). All parameters in the VF induction anddefibrillation studies were determined before and after cilos-tazol or vehicle administration. In these cases, both BP andheart rate (HR) were determined from the data recorded be-fore VFT, ULV, and DFT determination before drug or sal-ine administration. The drug was infused for 50 min. At theend of the infusion, we waited for another 20 min before thedetermination of electrophysiological parameters (i.e., BPand HR) began.

Diastolic pacing threshold and effective refractory periodmeasurement

A train of 10 S1 stimuli was delivered through a pacingelectrode with a stimulation pulse of 5 ms at the tip of anRV catheter, beginning at 0.1 mA, with 500 ms intervals.The pacing current was increased in 0.1 mA increments un-til all S1 stimuli elicited a ventricular response. This currentwas defined as the diastolic pacing threshold (DPT). The ef-fective refractory period (ERP) was determined by deliver-ing an S2 stimulus after the last S1 stimulus. The S1–S2interval was initially set at 350 ms and was reduced in10 ms steps until an S2 stimulus was unable to elicit a ven-tricular response. This S1–S2 interval was defined as anERP (Kanlop et al. 2008).

VF induction and ULV determination protocolThe interval between the last S1 and the peak T wave was

determined 3 times from the lead II electrocardiogram. Theaverage of these intervals was used as a coupling interval todeliver an S2 stimulus (S1–S2 coupling interval) (Chattipa-korn et al. 2000b, 2000c, 2006; Rodrıguez and Trayanova2003; Swerdlow et al. 2003). The S2 shock was biphasicand was delivered by shocking electrodes with a Ventak ex-ternal cardioverter-defibrillator (ECD) (Guidant). The initialshock strength was set at 100 V. If the shock induced VF,the shock strength was decreased in 10 V steps until VFwas not induced (Compos et al. 1997; Malkin and Hoffmeis-ter 2000). If the shock did not induce VF, the strength wasincreased in 10 V steps until VF was induced (Compos et al.1997; Malkin and Hoffmeister 2000). The lowest shockstrength required to induce VF is defined as the VFT (Lak-kireddy et al. 2006).

For ULV determination, the coupling interval between thelast S1 and the peak T wave was determined again. An S2stimulus was then delivered at an initial shock strength of400 V. The shock strength was increased or decreased aftera 3-reversal up/down protocol (Chattipakorn et al. 2000b)The lowest shock strength above the VFT that was unableto induce VF was defined as the ULV. There was a mini-mum interval of 4 min between VF episodes to allow theheart to return to physiological conditions (Sungnoon et al.2008).

Defibrillation protocolVF was induced by delivering a 60 Hz AC current

through the tip of the RV electrode. Defibrillation shockswere delivered with defibrillation electrodes after VF wasinduced for 10 s. For episodes in which defibrillation wasunsuccessful, a rescue shock was delivered to restore sinusrhythm. A minimum interval of 4 min was allowed be-tween VF episodes. The defibrillation shock strength wasinitially set at 400 V and was increased or decreased afterthe 3-reversal up/down protocol (Chattipakorn et al. 2000a).The lowest shock strength required for successful defibrilla-tion after the third reversal was defined as the DFT.

Cilostazol preparationCilostazol solution was prepared as an aqueous stock

solution (Hakaim et al. 1999; Saitoh et al. 1993). A50 mg cilostazol (Pletal) tablet was dissolved in normalsaline just before the experiment to form a concentration

Kanlop et al. 423

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of 0.5 mg/mL. The solution was then filtered using What-man No. 1 filter paper until a clear solution was obtained.

A previous study reported that the pharmacologicaleffects were demonstrated with an infusion of cilostazol3 mg/kg body weight in the in vivo model (Hakaim et al.1999). Therefore, in the present study, we started by intra-venously administering cilostazol at a dose of 6 mg/kg,3 mg/kg, or vehicle (100 mL saline) in groups I, II, and III,respectively, over 50 min, to investigate their effects onfibrillation induction and defibrillation efficacy.

Statistical analysisValues are expressed as means ± SE in both VF induction

and defibrillation studies. Analysis of covariance (ANCOVA)was used to assess whether the inequality of the baselinevalues affected the results after treatment. Comparisons ofvariables before and after drug or saline administration(within-group comparison) were performed individually ineach group by using the paired 2-tailed Student’s t test. Val-ues of p < 0.05 were considered statistically significant.

ResultsThe basic cardiac electrophysiological and hemodynamic

parameters (DPT, ERP, S1–S2 coupling interval, HR, sys-tolic BP (SBP), and diastolic BP (DBP)) in all experimentalgroups are shown in Table 1. After the drug administrationin groups I (cilostazol 6 mg/kg) and II (cilostazol 3 mg/kg),the DPT (tested DPT) was significantly higher (p = 0.01 inboth groups) than the DPT before drug administration (con-trol DPT). In group III, vehicle (saline) did not change theDPT compared with baseline. The ERPs were not differentin any of the experimental groups. The S1–S2 coupling in-terval before and after drug administration was not differentin any of the groups. Both concentrations of cilostazol andvehicle administration did not change systolic BP, diastolicBP, or HR.

In the VF induction study, the number of VF episodes re-quiring defibrillation shocks before drug administration was7.4 ± 0.5, 6.8 ± 0.4, and 7.0 ±0.3 episodes in groups I, II,and III, respectively, and after drug administration was6.3 ± 0.3, 7.0 ± 0.6, and 7.1 ± 0.3 episodes, respectively. Ithas been shown that the VF episodes were not significantlydifferent in any of the groups. The peak voltage, total en-ergy, impedance, and pulse width of VFT before and afterdrug or vehicle administration were not changed in any ofthe experimental groups (Fig. 1). From the analysis of cova-riance, the tested ULV was found to be affected by the base-

line ULV. Despite this effect, the tested ULV was stillsignificantly (p < 0.05) decreased after 6 mg/kg cilostazoladministration (Figs. 2A, 2B). In the 6 mg/kg group, peakvoltage was reduced by 12% and total energy was reducedby 25%. The impedance and pulse width were not signifi-cantly changed in any of the experimental groups (Figs. 2C,2D). Furthermore, in group I, the ULV – VFT windowwidth, calculated by subtracting the VFT from the ULV,was shown to significantly decrease compared with theULV – VFT window width before drug administration. Thiseffect was not shown in groups II or III. (Table 2)

In the defibrillation study, before drug administration, VFwas induced 7.1 ± 0.6, 7.5 ± 1.0, and 9.1 ± 0.5 episodes ingroups I, II, and III, respectively; after drug administration,VF was induced 6.9 ± 1.0, 6.9 ± 0.6, and 9.0 ± 0.5 episodes,respectively. It has been shown that the VF episodes werenot significantly different in any of the groups. The testedDFT was affected by the baseline DFT. However, 6 mg/kgcilostazol significantly decreased the DFT from thebaseline.(Figs. 3A, 3B). In the 6 mg/kg group, peak voltagewas reduced by approximately 13% and total energy was re-duced by approximately 25%. The peak voltage and totalenergy for the DFT before and after drug or saline adminis-tration were not different in groups II or III. The impedanceand pulse width were not significantly changed in any of thegroups (Figs. 3C, 3D).

DiscussionThe major findings of this study are as follows: (i) admin-

istration of both 3 and 6 mg/kg cilostazol significantly in-creased the DPT; and (ii) a 6 mg/kg cilostazol infusionsignificantly decreased the ULV and the DFT.

Effects of cilostazol on myocardial stabilizationIn the past, there was disagreement over the use of PDE3

inhibitors in patients with cardiac disease, since the inhibi-tors facilitate the incidence of arrhythmia in this group ofpatients (Feldman et al. 1993; Packer et al. 1991). Previousstudies investigated the effects of PDE3 inhibitors, such asamrinone, milrinone, and enoximone, on cardiac electrophy-siological parameters by measuring HR, QTc (corrected QTinterval), and atrial or ventricular ERP (Goldstein et al.1986; Miles et al. 1989; Naccarelli et al. 1984). However,the effects of cilostazol on the DPT and ERP have neverbeen investigated.

It is known that PDE3 has many isoforms, and that PDE3inhibitory drugs demonstrate different effects depending on

Table 1. Electrophysiological and hemodynamic parameters measured before and after drug or saline administration in Landrace pigs.

Group I, cilostazol 6 mg/kg Group II, cilostazol 3 mg/kg Group III, control

Before After Before After Before AfterDiastolic pacing threshold, mA 0.40±0.06 1.40±0.20** 0.40±0.07 0.90±0.08** 0.40±0.07 0.6±0.07Effective refractory period, ms 273±9 293±9 233±8 253±12 234±8 246±6S1–S2 coupling interval, ms 308±11 324±14 262±8 265±15 258±10 266±11Systolic blood pressure, mm Hg 121±6 113±5 122±7 120±5 120±5 123±9Diastolic blood pressure, mm Hg 78±6 79±6 82±6 78±3 74±5 77±8Heart rate, beats/min 86±3 86±5 99±5 106±4 99±5 103±3

Note: The control group received 100 mL saline (vehicle). Values are means of 8 animals per group. **, Significant at p = 0.01 vs. before drugadministration (within group).

424 Can. J. Physiol. Pharmacol. Vol. 88, 2010


Fig. 1. Effects of cilostazol on electrophysiological parameters for the ventricular fibrillation threshold before and after drug administration(n = 8 pigs per group).

Fig. 2. Effects of cilostazol on electrophysiological parameters for the upper limit of vulnerability before and after drug administration.*, Significant at p < 0.05 vs. before drug administration (within group, n = 8).

Kanlop et al. 425


the PDE3 isoform they inhibit (Atarashi et al. 1998; Cone etal. 1999; Hambleton et al. 2005). In this study, ERP was notchanged from baseline after cilostazol administration. Thisfinding is similar to that reported previously using otherPDE3 inhibitors (Goldstein et al. 1986; Miles et al. 1989;Naccarelli et al. 1984). However, the effect of a PDE3 in-hibitor on the DPT has never been investigated. In ourstudy, cilostazol increased the DPT. It is possible that theeffect of cilostazol on the DPT is similar to or differentfrom previously tested PDE3 inhibitors, because of the dif-ferent isoforms that each drug inhibits. This hypothesis re-mains to be tested.

Recently, Fukasawa and colleagues (2008) demonstratedthat cilostazol promotes the electrical stability of myocar-dium in ischemic and (or) reperfusion injury in isolatedhearts by directly activating mitochondrial Ca2+-activated K+

(mitoKCa) channels, leading to an attenuation of Ca2+ over-load in mitochondria and the stabilization of Ca2+ homeosta-sis. Furthermore, in normal hearts, cilostazol is known to

activate L-type Ca2+ channels using a cAMP-activatedprotein kinase A pathway (Verde et al. 1999).

Effects of cilostazol on defibrillation efficacyIn this study, we demonstrated that cilostazol 6 mg/kg in-

creased defibrillation efficacy by significantly decreasing theDFT. The DFT was not significantly changed after the infu-sion of cilostazol 3 mg/kg. Since uniform dispersion of re-fractoriness is an important determinant of successfuldefibrillation, one possible explanation for this observationis that cilostazol decreases the degree of dispersion of re-fractoriness in a dose-dependent manner. Future studies areneeded to test this hypothesis.

Effects of cilostazol on VF inductionIn the present study, the administration of cilostazol 6 mg/kg

significantly decreased the ULV, and the proportion of ULVreduction was similar to the proportion of DFT reduction. Pre-vious studies have demonstrated a close correlation between

Table 2. The mean ventricular fibrillation induction window width (ULV – VFT) in the 3 treatment groups.

Group I, cilostazol 6 mg/kg Group II, cilostazol 3 mg/kg Group III, control

Before After Before After Before AfterVoltage, V 416±31 360±16* 410±22 407±20 349±19 362±13Energy, J 16±2 12±1* 17±1 17±1 11±3 12±2

Note: ULV, upper limit of vulnerability; VFT, ventricular fibrillation threshold. Values are means of 8 animals per group.*, Significant at p < 0.05 vs. before drug administration (within group).

Fig. 3. Effects of cilostazol on electrophysiologic parameters for the defibrillation threshold before and after drug administration. *, Sig-nificant at p < 0.05 vs. before drug administration (within group, n = 8).



the ULV and the DFT (Green et al. 2003; Rodrıguez andTrayanova 2003). Our study has shown that both dosages ofcilostazol increased the DPT. It is possible that the DPT in-creased by cilostazol decreases the sensitivity of the myocar-dium to any premature stimulus. According to the ULVhypothesis for defibrillation, shocks weaker than the ULVfail to defibrillate because they fall into the vulnerable pe-riod, thus reinitiating VF (Chen et al. 1986). Our results areconsistent with such reports. Regarding the reentrant mecha-nism, the important factors for VF initiation and sustainedVF are the initiation of new wave fronts, an increased dis-persion of refractoriness that leads to unidirectional block,and a decreased conduction velocity (Rodrıguez and Traya-nova 2003).

Study limitationsThis study was performed in normal pig hearts. The ef-

fects of cilostazol on VF induction or defibrillation may bedifferent in diseased hearts, such as those in patients withBrugada syndrome or myocardial infarction. Also, it is pos-sible that cilostazol 6 mg/kg increases the VFT, but that theVFT protocol used in our study was not sensitive enough(10 V steps) to detect it. This may explain why VFT didnot significantly change after cilostazol administration.Since the plasma level of cilostazol was not measured, therelationship between plasma concentration and the observedeffects remains to be investigated. The definite mechanismresponsible for this dose-dependent effect of cilostazol onthe ULV and the DFT was not elucidated in this study be-cause of technical limitations. Our DPT and ERP results donot predict total electrical stability, since they were deter-mined at only a single site. Although it is possible that DPTincreases with time because of electrode contact changes ortissue damage, it is likely that the increase in DPT by cilos-tazol in our study was due to the effect of the drug itself be-cause saline did not change the DPT. Furthermore, thevascular effect of cilostazol was not observed in this study.It is possible that these effects were masked by the effects ofthe deep general anesthesia with fluid maintenance that wasused to keep the animal under physiological conditionsthroughout the study.

ConclusionCilostazol alters cardiac electrophysiology by increasing

the DPT and decreasing the ULV and DFT. These findingsindicate that cilostazol can decrease VF inducibility by re-ducing the ULV and can improve defibrillation efficacy byreducing the shock energy required to successfully defibril-late the heart.

AcknowledgmentsThis study was supported by the Young Investigator Re-

search Fund, Chiang Mai University (N.K.); the Faculty ofMedicine Endowment Fund, Chiang Mai University (N.K.);and the Thailand Research Fund, grants RTA 5280006(N.C.) and RMU 5180007 (S.C.).

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Cilostazol attenuates ventricular arrhythmia induction and improves defibrillation efficacy in swine

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