Ventricular Arrhythmia Induced by Sodium Channel Blocker in Patients With Brugada Syndrome

Journal of the American College of Cardiology Vol. 42, No. 9, 2003 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00 Published by Elsevier Inc. doi:10.1016/s0735-1097(03)01124-0 Electrophysiologic Disorders Ventricular Arrhythmia Induced by Sodium Channel Blocker in Patients With Brugada Syndrome Hiroshi Morita, MD,* Shiho Takenaka Morita, MD,* Satoshi Nagase, MD,* Kimikazu Banba, MD,* Nobuhiro Nishii, MD,* Yoshinori Tani, MD,* Atsuyuki Watanabe, MD,* Kazufumi Nakamura, MD,* Kengo Fukushima Kusano, MD,* Tetsuro Emori, MD,* Hiromi Matsubara, MD,* Kazumasa Hina, MD, Toshimasa Kita, MD, Tohru Ohe, MD, FACC* Okayama, Japan OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We administered pilsicainide chloride, a class Ic pure sodium channel blocker, to patients with Brugada syndrome (BS) and evaluated the occurrence of ventricular arrhythmia (VA) and T-wave alternans (TWA). Ventricular arrhythmia and TWA are sometimes induced by a sodium channel blocker challenge test in BS patients, but the significance of the induced VA and TWA is not known. Pilsicainide was administered to 65 patients with BS (10 symptomatic and 55 asymptomatic patients), and the occurrence of VA, TWA, and change of electrocardiogram were evaluated. Electrophysiologic study was performed in 57 patients, and the induction of VA by programmed electrical stimulation (PES) was evaluated. Ventricular arrhythmia was not induced by administration of pilsicainide in 55 patients (no-va group). Administration of pilsicainide-induced VA in 10 patients (Pil-VA group) and polymorphic ventricular tachycardia in four patients. Pilsicainide-induced VA in 60% of the symptomatic patients but in only 7% of asymptomatic patients (p 0.01). ST level, QTc, and indexes of cardiac conduction in the Pil-VA group were not different from those in the no-va group. Ventricular fibrillation was induced by PES in 67% of the patients in the Pil-VA group and in 33% of the patients in the no-va group. In six cases, macroscopic TWA occurred in association with pilsicainide-induced VA, but TWA occurred in only one patient without pilsicainide-induced arrhythmia. Administration of a sodium channel blocker results in induction of not only ST-elevation but also VA and TWA in patients with BS. (J Am Coll Cardiol 2003;42:1624 31) 2003 by the American College of Cardiology Foundation In 1992, Brugada et al. (1) reported eight patients with right bundle branch block and persistent ST-segment elevation in right precordial leads. These patients experienced syncope episodes, and polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced by programmed electrical stimulation (PES). Brugada-type electrocardiogram (ECG) was unmasked and augmented by antiarrhythmic drug (class Ia or Ic) challenge test (2 8). Administration of a sodium channel blocker induces change in cardiac ion channel function and results in morphologic change in action potential and phase 2 reentry at the right ventricular free wall in patients with Brugada syndrome (9 12). If the antiarrhythmic drug causes phase 2 reentry, ventricular arrhythmia (VA) is expected to occur after administration of a class Ia or Ic antiarrhythmic drug. In this study, we, therefore, examined the effects of administration of an antiarrhythmic drug in patients with Brugada-type ECG. We used pilsicainide chloride, which is classified as a class Ic From the *Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama, Japan; and the Department of Cardiovascular Medicine, Cardiovascular Center Sakakibara Hospital, Okayama, Japan Okayama, Japan. Manuscript received February 24, 2003; revised manuscript received April 23, 2003, accepted June 3, 2003. antiarrhythmic drug and has been shown to have a pure sodium channel-blocking effect (13,14). METHODS Patients. The subjects of this study were 64 male patients and a female patient with Brugada-type ECG (10 symptomatic and 55 asymptomatic patients), and the mean age of the subjects was 47 12 years. Brugada-type ECG was defined as J wave (higher than 0.2 mv) and ST-segment elevation (higher than 0.1 mv) (15). Symptomatic patients had recurrent syncope episodes of unknown origin (three patients) or had been resuscitated from cardiac arrest or VF (seven patients). All of the subjects had right bundle branch block with spontaneous ST-segment elevation without drug provocation, and patients who showed Brugada-type ECG only after the class I antiarrhythmic challenge test were not included in this study. There were no patients from the same family. Various cardiac imaging techniques, including echocardiography and right ventriculography, were performed in all patients, but no abnormalities were found. The risks of the electrophysiologic study and drug test were explained to each patient, and written informed consent was obtained from all patients.

JACC Vol. 42, No. 9, 2003 November 5, 2003:1624 31 Morita et al. Sodium Channel Blocker and Brugada Syndrome 1625 Abbreviations and Acronyms HV His-ventricle PES programmed electrical stimulation PVC premature ventricular contraction TWA T-wave alternans VA ventricular arrhythmia VF ventricular fibrillation VT ventricular tachycardia Electrophysiologic study. The electrophysiologic study was performed in 57 patients (10 symptomatic and 47 asymptomatic patients), and induction of VA was attempted without the use of any antiarrhythmic drugs. The criterion for induction of VA was induction of sustained polymorphic VT or VF by PES from the right ventricular apex, right ventricular outflow tract, or left ventricle. The protocol of ventricular stimuli included up to three extrastimuli (two basic cycle lengths of 600 and 400 ms) and rapid ventricular pacing, with the coupling interval of the extrastimuli not being 180 ms and the ventricular rate of rapid burst pacing not exceeding 270 beats/min. The electrophysiologic study was performed as reported previously (16). Pharmacologic challenge with a sodium channel blocker. Pilsicainide chloride was administered to all patients, orally at a dose of 150 mg in 18 patients and intravenously at a dose of 1 mg/kg over a 6-min period in 47 patients. ST level was measured at the J points in leads V 1 and V 2, and the difference between the ST levels before and after administration of pilsicainide (augmentation of ST level) was calculated. PQ interval, QRS interval, QTc interval, Hisventricle (HV) interval, and depth of S wave in leads II and V 5 were measured before and after administration of pilsicainide. Occurrence of VA and macroscopic T-wave alternans after administration of pilsicainide were also evaluated. The VA during the pilsicainide test included frequent occurrence of ventricular premature beat (PVC) ( 1 beats/ min) and polymorphic VT (at least 3 beats). Statistical analysis. Quantitative values are expressed as means 1 SD. Statistical significance in differences was analyzed by Mann-Whitney U test for unpaired values and Student t test for paired values (the values before and after administration of pilsicainide). A value of p 0.05 was considered statistically significant. Table 1. Electrocardiographic Changes Before and After Administration of Pilsicainide Group All Patients (n 65) Pil-VA ( ) (n 10) Pil-VA ( ) (n 55) p Value* ST level Lead V 1 Before pilsicainide (mv) 0.13 0.07 0.14 0.08 0.13 0.07 0.90 After pilsicainide (mv) 0.26 0.16 0.30 0.15 0.25 0.16 0.21 Lead V 2 Before pilsicainide (mv) 0.26 0.12 0.28 0.15 0.26 0.12 0.95 After pilsicainide (mv) 0.61 0.33 0.61 0.22 0.60 0.34 0.52 Augmentation of V 1 ST level (mv) 0.13 0.11 0.16 0.08 0.12 0.12 0.17 Augmentation of V 2 ST level (mv) 0.34 0.26 0.33 0.13 0.34 0.27 0.75 PQ interval Before pilsicainide (s) 0.17 0.02 0.18 0.03 0.17 0.02 0.51 After pilsicainide (s) 0.22 0.03 0.22 0.03 0.22 0.03 0.84 QRS interval Before pilsicainide (s) 0.09 0.01 0.10 0.02 0.09 0.01 0.08 After pilsicainide (s) 0.11 0.02 0.13 0.03 0.11 0.01 0.04 QTc interval Before pilsicainide (s) 0.40 0.04 0.41 0.05 0.40 0.03 0.41 After pilsicainide (s) 0.43 0.03 0.45 0.05 0.43 0.03 0.22 HV interval Before pilsicainide (ms) 38 8 39 5 37 9 0.68 After pilsicainide (ms) 56 8 57 8 56 9 0.51 Left axis deviation Before pilsicainide 14/65 (22%) 3/10 (30%) 11/55 (20%) 0.48 After pilsicainide 25/65 (38%) 3/10 (30%) 22/55 (40%) 0.55 Depth of S-wave Lead II Before pilsicainide (mv) 0.28 0.22 0.21 0.28 0.29 0.21 0.09 After pilsicainide (mv) 0.45 0.26 0.36 0.36 0.47 0.24 0.14 Lead V 5 Before pilsicainide (mv) 0.44 0.31 0.40 0.32 0.44 0.31 0.48 After pilsicainide (mv) 0.75 0.38 0.65 0.39 0.77 0.38 0.26 Data are presented as the mean value SD. *p value for difference between patients of Pil-VA ( ) and Pil-VA ( ). Pil VA ( ) patients with pilsicainide-induced ventricular arrhythmia; Pil VA ( ) patients without pilsicainide-induced ventricular arrhythmia.

1626 Morita et al. JACC Vol. 42, No. 9, 2003 Sodium Channel Blocker and Brugada Syndrome November 5, 2003:1624 31 Figure 2. Pilsicainide-induced ventricular tachycardia in case 9. (a) shows control electrocardiogram before administration of pilsicainide. (b) shows nonsustained polymorphic ventricular tachycardia immediately after administration of pilsicainide. Figure 1. Pilsicainide-induced ventricular arrhythmia. (a) shows electrocardiogram (ECG) after administration of pilsicainide in case 3. A couplet of premature ventricular contraction (PVC) occurred, and QRS morphology of the PVC was left bundle branch block with inferior axis. (b) shows ECG after administration of pilsicainide in case 5. A triplet of PVC occurred, and QRS morphology of PVC was left bundle branch block with superior axis. RESULTS ECG change after administration of pilsicainide. Table 1 shows ECG changes induced by administration of pilsicainide. ST levels in leads V 1 and V 2, PQ interval, QRS interval, QTc interval, and HV interval were augmented after the pilsicainide test compared with those values before the pilsicainide test (p 0.01). The percentage of patients with left axis deviation (QRS axis 30 degrees) and the depth of S wave in leads II and V 5 increased after administration of pilsicainide (p 0.01). VA induced by pilsicainide administration. No VA was observed before administration of pilsicainide in any of the patients. Pilsicainide-induced VA in 10 (15%) of the 65 patients (Figs. 1 and 2, Table 2). Pilsicainide induced VA in 60% of the symptomatic patients (six patients) but in only 7% of the asymptomatic patients (four patients) (p 0.01). Polymorphic VT occurred after administration of pilsicainide in four patients (three symptomatic patients and one asymptomatic patient), and frequent PVC occurred in other patients. In two symptomatic patients, 0.1 g/min of isoproterenol infusion was started because of frequent PVC (case 7) and incessant polymorphic VT (case 9). Ventricular arrhythmia was diminished after starting infusion of isoproterenol in both cases, but VF re-occurred 1 h after cessation of isoproterenol infusion (7 h after administration of pilsicainide) in case 9 (Fig. 3). The VA occurred within 15 min (mean time: 5.8 3.1 min) after intravenous administration of pilsicainide, but late occurrence of VA (4 h and 7 h after intravenous administration) was observed in two cases (cases 7 and 9) (Table 2). ST levels in lead V 1 and V 2, augmentation of ST level, PQ interval, QTc interval, HV interval, and depth of S wave before and after administration of pilsicainide did not influence the occurrence of pilsicainide-induced VA (Table 1). In patients with pilsicainide-induced VA, QRS interval after administration of pilsicainide was slightly longer than that in patients without pilsicainide-induced arrhythmia. Ventricular fibrillation was induced by PES in 34% of the patients (22 patients). Programmed electrical stimulation induced VF in 67% of the patients with pilsicainide-induced arrhythmia (six patients) but in only 33% of the patients without pilsicainide-induced arrhythmia (16 patients). Characteristics of premature ventricular contractions. There were two types of QRS morphology of pilsicainideinduced PVC. Eight of the 10 patients with PVC showed QRS morphology of the left bundle branch block with inferior axis (Fig. 1a), and the same PVC preceded polymorphic VT in two patients (Fig. 2). In two patients, PVC showed QRS morphology of the left bundle branch block with superior axis, and the same PVC induced polymorphic VT (Fig. 1b). The coupling interval of pilsicainide-induced VA was 0.41 0.04 s. T-wave alternans (TWA) induced by pilsicainide administration. Administration of pilsicainide induced manifest TWA in right precordial leads in 7 (11%) of the 65 patients. T-wave alternans occurred in 6 (60%) of 10 patients with pilsicainide-induced VA but in only one (2%) of the 55 patients without pilsicainide-induced arrhythmia (Figs. 4 and 5). T-wave alternans did not occur before administration of pilsicainide. ST levels in leads V 1 and V 2, augmentation of ST level, PQ interval, QRS interval, QTc interval, HV interval, and depth of S wave before and after administration of pilsicainide did not influence the occurrence of macroscopic TWA.

JACC Vol. 42, No. 9, 2003 November 5, 2003:1624 31 Morita et al. Sodium Channel Blocker and Brugada Syndrome 1627 Table 2. Pilsicainide-Induced VA in Patients With Brugada-Type ECG Case Age Gender Symptom ST Morphology Without Pilsicainide EPS Administration of Pilsicainide Pilsicainide Induced VA Onset of VA 1 50 M asymptomatic coved not induced IV PVC 11 min 2 27 M asymptomatic coved VF IV PVC 5 min 3 41 M asymptomatic saddle back VF IV P-VT 9 min 4 75 M asymptomatic coved NA IV PVC 5 min 5 41 M VF saddle back VF IV P-VT 6 min 6 42 M VF saddle back VF IV PVC 4 min 7 55 M VF coved VF IV PVC 4 h 8 56 M VF coved not induced PO PVC 60 min 9 55 M VF coved VF IV P-VT 1 min, 7 h 10 41 M syncope coved not induced IV P-VT 5 min EPS electrophysiological study; IV intravenously; M male; NA not assessed; PO per oral; PVC premature ventricular contraction; P-VT polymorphic ventricular tachycardia; TWA T-wave alternans; VA ventricular arrhythmia; VF history of ventricular fibrillation. TWA DISCUSSION Brugada et al. (3) reported that sodium channel blocking agents unmasked the typical Brugada-type ECG pattern, that is, right bundle branch block with ST-segment elevation in right precordial leads, and enabled identification of patients at risk for sudden death. Moreover, some studies have shown the efficacy of a sodium channel blocker for diagnosis and determination of the characteristic ECG changes in patients with Brugada syndrome (2 8,17 20). It has been suggested that genetic sodium channel dysfunction can explain the ST-elevation and the occurrence of VA, which are exaggerated by administration of the sodium channel blocker (9 12). It was, therefore, thought that provocation and exaggeration of the Brugada-type ECG pattern by administration of a sodium channel blocker would enable risk stratification of patients. However, later studies showed that Brugada-type ECG pattern that was provoked only by a sodium channel blocker was not a predictor of the prognosis of patients with Brugada syndrome (21,22). It has recently been reported that administration of a sodium channel blocker resulted in not only enhancement of ST-segment elevation but also other characteristic ECG changes in patients with Brugada syndrome. Pilsicainide chloride, which is classified as a class Ic antiarrhythmic drug and has been shown to have a pure sodium channel-blocking effect (13,14), was used for evaluation of patients with Brugada-type ECG in this study. Induction of VA by administration of a sodium channel blocker. Some studies have shown that administration of a sodium channel blocker resulted in induction of STelevation and VA, but detailed evaluation was not carried out in these studies. Occurrence of VF in some patients with Brugada syndrome after administration of a sodium channel blocker has been reported recently (19,21,23,24), and Wilde et al. (17) recommended that drug tests should be discontinued if PVC is evident. A total of 15% of patients in the present study showed VA after administration of the sodium channel blocker, and the occurrence of arrhythmia was not associated with indexes of repolarization (level of ST-segment and QTc interval) or with indexes of depolarization (PQ interval, HV interval, and depth of S wave) before and after administration of pilsicainide or results of electrophysiologic study. QRS interval after administration of pilsicainide only showed slight prolongation in patients with pilsicainide-induced arrhythmia. Four patients in the present study showed nonsustained VT after administration of the sodium channel blocker. Although VT was selflimiting in three patients, a cluster of rapid VT events occurred incessantly, and implantable cardioverter defibrillator discharged shocks in one patient. Careful monitoring should be performed after administration of a sodium channel blocker, because VA occurred even several hours after injection of the drug in this study. Because VA after administration of the sodium channel blocker occurred in half of the symptomatic patients but in only a few of the asymptomatic patients, these arrhythmias might be an indicator of high-risk patients. The VA after administration of the sodium channel blocker might have originated in the right ventricular outflow tract in most cases in this study, because the QRS morphology of arrhythmia showed left bundle branch block with inferior axis. Some studies have shown that VF was frequently induced at the right ventricular outflow tract by PES and that spontaneous PVC frequently originated in the right ventricular outflow tract, which might be a critical site in Brugada syndrome (16,25 27). Although the term proarrhythmia should be defined as the occurrence of various arrhythmias after administration of antiarrhythmic drugs, it is suggesting that the occurrence of VAs after administration of a sodium channel blocker is specific to patients with Brugada-type ECG, because the incidence of pilsicanide-induced VA was high and it was associated with typical ECG changes in patients with Brugada-type ECG in the present study. Induction of macroscopic TWA by a sodium channel blocker. As another ECG change after administration of pilsicainide, some patients showed TWA in right precordial leads. Manifest TWA has been reported to occur in patients with Brugada syndrome in various situations such as after

Figure 3. Intracardiac electrogram during pilsicainide-induced ventricular tachycardia by an implantable cardioverter defibrillator in case 9. (a) Incessant polymorphic ventricular tachycardia occurred immediately after intravenous administration of pilsicainide. (b) Ventricular fibrillation occurred 7 h after injection of pilsicainide, and it was terminated by implantable cardioverter defibrillator therapy. 1628 Morita et al. JACC Vol. 42, No. 9, 2003 Sodium Channel Blocker and Brugada Syndrome November 5, 2003:1624 31

JACC Vol. 42, No. 9, 2003 November 5, 2003:1624 31 Morita et al. Sodium Channel Blocker and Brugada Syndrome 1629 Figure 4. Occurrence of T-wave alternans after administration of pilsicainide in case 4. (a) shows control electrocardiogram before administration of pilsicainide. (b) shows premature ventricular contraction (PVC) and manifest T-wave alternans in right precordial leads after administration of pilsicainide: PVC occurred on a deep inverted T wave. Arrows larger inverted T wave in lead V 2. administration of a sodium channel blocker, during atrial pacing, and during febrile illness (23,24,28 30). It is thought that TWA shows instability of repolarization (31). Both depolarization and repolarization abnormalities might influence the pathogenesis of Brugada syndrome (10,25,32), and electrical instability of the repolarization phase would cause VA. Ikeda et al. (26) reported microvolt TWA alternans that was induced by exercise in 16% of Brugada patients but was not a predictor of patients at high risk. In their patients, TWA was induced by exercise, but exercise tests frequently cause attenuation of ST-segment levels in patients with Brugada syndrome (33); thus, the mechanism of development of microvolt-twa and that of development of TWA induced by a sodium channel blocker should be different (26). Because TWA induced by a sodium channel blocker occurred together with exaggeration of ST level and VA, it is thought that TWA results from the same pathologic depolarization and repolarization abnormalities in patients with Brugada syndrome. Clinical implication. Because the occurrence of VA and TWA after administration of a sodium channel blocker are phenomena-specific to symptomatic patients with Brugada syndrome, risk stratification of the Brugada syndrome could be performed by these phenomena. Sodium channel blockers have frequently been used for treatment of atrial fibrillation, and some patients have shown Brugada-type ECG after administration of a sodium channel blocker. Clinicians should pay attention to not only ST-elevation but also to the Figure 5. Occurrence of T-wave alternans after administration of pilsicainide in case 9. (a) shows control electrocardiogram before administration of pilsicainide. (b) shows small but manifest T-wave alternans after administration of pilsicainide. Arrows T waves of larger amplitude.

1630 Morita et al. JACC Vol. 42, No. 9, 2003 Sodium Channel Blocker and Brugada Syndrome November 5, 2003:1624 31 occurrence of TWA and VA because patients in whom these phenomena occur have a concealed form of Brugada syndrome, and lethal VA will occur in some patients after administration of a sodium channel blocker. Study limitations. We were not able to detect genetic abnormalities, and responses to sodium channel blockade and abnormal late potentials might depend on the genotype. However, determination of genotype in Brugada syndrome is difficult, because it has been reported that prevalence of mutations in the cardiac sodium channel was only 15% (6). We used both intravenous administration and per oral administration of pilsicainide, but we did not compare the serum drug concentrations after administration by these two methods. ST level and occurrence of VA after administration of pilsicainide might be influenced by the method of administration. However, considering the half-lives of the drugs and the risks of drug tests for patients with Brugada syndrome, intravenous injection is superior to per oral administration. Conclusions. Administration of pilsicainide induced VA in 15% of the patients and manifest TWA in 11% of the patients. The occurrence of VA after administration of pilsicainide was not associated with the indexes of depolarization and repolarization. T-wave alternans occurred in association with VA. The occurrence of VA and TWA after administration of a sodium channel blocker are phenomenaspecific to Brugada syndrome. Acknowledgment The authors thank Miyuki Fujiwara for excellent technical assistance. Reprint requests and correspondence: Dr. Hiroshi Morita, Department of Cardiovascular Medicine, Okayama University Graduate School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: hmorita@cc.okayama-u.ac.jp. REFERENCES 1. Brugada P, Brugada J. 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