MINI-FOCUS ISSUE: BRUGADA SYNDROME: CLINICAL RESEARCH
Longer Repolarization in the Epicardium at the Right Ventricular Outflow Tract Causes Type 1 Electrocardiogram in Patients With Brugada Syndrome
Satoshi Nagase, MD*,
Kengo Fukushima Kusano, MD,
Hiroshi Morita, MD,
Nobuhiro Nishii, MD,
Kimikazu Banba, MD,
Atsuyuki Watanabe, MD,
Shigeki Hiramatsu, MD,
Kazufumi Nakamura, MD,
Satoru Sakuragi, MD and
Tohru Ohe, MD
Departments of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Manuscript received May 4, 2007;
revised manuscript received September 24, 2007,
accepted October 17, 2007.
* Reprint requests and correspondence: Dr. Satoshi Nagase, Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. (Email: snagase{at}cc.okayama-u.ac.jp).
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Abstract
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Objectives: We examined the relationship between repolarization abnormality and coved-type ST-segment elevation with terminal inverted T-wave (type 1 electrocardiogram [ECG]) in patients with Brugada syndrome (BrS).
Background: Recent experimental studies have suggested that accentuation of the right ventricular action potential (AP) notch preferentially prolongs epicardial AP causing inversion of the T-wave.
Methods: In 19 patients with BrS and 3 control subjects, activation-recovery intervals (ARIs) and repolarization times (RTs) in the epicardium and endocardium were directly examined with the use of local unipolar electrograms at the right ventricular outflow tract. Surface ECG, ARI, and RT were examined before and after administration of pilsicainide.
Results: Type 1 ECG was observed in 10 of the 19 BrS patients before the administration of pilsicainide and in all of the 19 patients after the administration of pilsicainide. We found that ARI and RT in the epicardium were shorter than those in the endocardium in all 9 BrS patients without type 1 ECG under baseline conditions and in all control subjects regardless of pilsicainide administration. However, longer epicardial ARI than endocardial ARI was observed in 8 of the 10 BrS patients manifesting type 1 ECG under baseline conditions and in all of the BrS patients after the administration of pilsicainide. Also, epicardial RT was longer than endocardial RT in all patients manifesting type 1 ECG regardless of pilsicainide administration.
Conclusions: Our data provide support for the hypothesis that the negative T-wave associated with type 1 BrS ECG is due to a preferential prolongation of the epicardial AP secondary to accentuation of the AP notch in the region of the right ventricular outflow tract.
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Abbreviations and Acronyms
| | ARI = activation-recovery interval | | ARIc = activation-recovery interval corrected for heart rate | | AT = activation time | | BrS = Brugada syndrome | | ECG = electrocardiogram | | RT = repolarization time | | RVOT = right ventricular outflow tract | | V1(3ics) = surface ECG lead V1 at the third intercostal space | | V2(3ics) = surface ECG lead V2 at the third intercostal space | | V1(4ics) = surface ECG lead V1 at the fourth intercostal space | | V2(4ics) = surface ECG lead V2 at the fourth intercostal space | | VF = ventricular fibrillation |
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Brugada syndrome (BrS) is characterized by ST-segment elevation in right precordial leads and an episode of ventricular fibrillation (VF) (1,2). Recent experimental studies have suggested that a prominent transient outward current-mediated action potential notch in epicardial cells, but not that in endocardial cells, creates a transmural voltage gradients and thus causes ST-segment elevation (3). When epicardial repolarization precedes endocardial repolarization, the T-wave remains positive. In this condition, saddleback-type electrocardiogram (ECG) was observed. Further accentuation of the notch leads to preferential prolongation of the epicardial action potential, which results in the development of coved-type ST-segment elevation and terminal inverted T-wave (type 1 ECG) in right precordial leads in BrS (4–6). A definitive diagnosis of BrS is made when a type 1 ECG is observed, and type 1 ECG can be unmasked by sodium channel blockers even in symptomatic patients (2,7–9).
In a clinical study, Kurita et al. (10) found a prominent action potential notch and prolongation of repolarization in the epicardium but not in the endocardium at the right ventricular outflow tract (RVOT) in 3 patients with BrS during open chest surgery with monophasic action potential recording.
Prolongation of the QT interval also has been reported in patients with BrS. Prolongation of the QT interval is more prominent in right precordial leads than in left precordial leads, presumably because of a preferential prolongation of action potential duration in the right ventricular epicardium secondary to accentuation of the action potential notch (11,12). An overlap between BrS and long-QT syndrome also has been reported (13,14).
Recent studies have demonstrated that the activation-recovery interval (ARI) approximates the action potential duration at each site in several experimental and clinical studies (15,16). Recently, we have reported successful recording of an epicardial electrogram at the RVOT in patients with BrS by the use of an electrical guide wire introduced into the conus branch of the right coronary artery (17).
Accordingly, we measured epicardial and endocardial ARIs directly at the RVOT to examine the epicardial and endocardial action potentials in patients with BrS, and we demonstrated a correlation between morphology of surface ECG and ARI in the epicardium and endocardium. We also measured activation time (AT) and repolarization time (RT). Because the administration of a sodium channel blocker can unmask type 1 ECG in right precordial leads, we examined the effect of injection of a pure sodium channel blocker, pilsicainide, on the morphology of surface ECG and each parameter in the epicardium and endocardium in patients with BrS.
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Methods
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Patients.
Nineteen patients with BrS and 3 control subjects were included in this study. We defined BrS as the manifestation of type 1 ECG, which is characterized by a coved-type ST-segment elevation  2 mm (0.2 mV) followed by a negative T-wave in leads V1 or V2 at the third or fourth intercostal space in the presence or absence of a class IC antiarrhythmic drug (pilsicainide) (2). This type of repolarization pattern was described previously by Wilde et al. (7). Patient characteristics are shown in Table 1.
Routine examinations, including cardiac echocardiography, coronary angiography, right and left ventriculography, and radionucleography, showed no evidence of structural heart disease in any of the patients. One of the control subjects was diagnosed as having idiopathic VF with no ST-segment elevation, and the remaining 2 control subjects had incomplete right bundle branch block in surface ECG. Brugada-type ECG was not observed under baseline conditions or after pilsicainide injection in any of the control subjects.
Electrophysiologic study.
A maximum of 3 ventricular extrastimuli were delivered from right ventricular apex and RVOT unless VF was induced at a previous step in all patients with BrS and control subjects. We induced VF by programmed electrical stimulation in 11 patients with BrS but was not induced in control subjects. We examined ARIs, ATs, and RTs in the epicardium and endocardium simultaneously using local unipolar electrograms at the RVOT with a 0.05- to 400-Hz bandwidth under baseline conditions and after intravenous injection of a pure sodium channel blocker, pilsicainide, at a dose of 1 mg/kg during a 6-min period. The ARI and RT were corrected for heart rate by Bazett’s formula and named ARIc and RTc (18). To record the epicardial electrogram directly, we introduced an electrical guidewire (Flo Wire, Cardiometrics, Mountain View, California) into the conus branch of the right coronary artery, which runs on the surface of the free wall at the RVOT (Fig. 1). The epicardial mapping has been described in detail previously (17). A local unipolar electrogram at the endocardium was recorded by a quadripolar 6-F deflectable catheter positioned at the endocardium at the free wall at the RVOT. We defined ARI as the interval between times of minimum derivative of the QRS and maximum derivative of the T-wave in a unipolar electrogram (15). We defined AT as the interval between the beginning of the surface QRS complex and minimum derivative of the QRS. We defined RT as the interval between the beginning of the surface QRS complex and maximum derivative of the T-wave (Fig. 2). For analysis of ARI, AT, and RT, the analog data were digitized at a sampling rate of 1,000 samples/s and stored on a floppy disk, then transferred to a personal computer with the analysis program developed by our institution (S.H.). The difference in ARI/ARIc was defined as the value of epicardial ARI/ARIc minus endocardial ARI/ARIc. Accordingly, if epicardial ARI is longer than endocardial ARI, the difference in ARI is positive. The difference in AT and RT/RTc were defined as epicardial AT minus endocardial AT and epicardial RT/RTc minus endocardial RT/RTc. Because recent studies have shown that the site of maximum ST-segment elevation in body surface ECG coincides with the RVOT and because the RVOT corresponds to leads V1 and V2 at the third intercostal space (3ics), surface ECG also was recorded at the 3ics in leads V1 and V2 in addition to the standard V1 and V2 at the fourth intercostal space (4ics) (19–21). We defined that type 1 ECG was present if type 1 ECG was recorded in more than one of the surface ECG leads, including V1(3ics), V2(3ics), V1(4ics), or V2(4ics). Electrophysiologic study and genetic analysis were performed according to the protocol approved by the Ethics Committee of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences. Written informed consent was obtained from all patients.
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Figure 1 Catheter Position
Fluoroscopic right anterior oblique (RAO) (A) and left anterior oblique (LAO) (B) views of the position of the electrical guidewire for epicardial mapping (RVOT-epi), as well as the quadripolar catheter at the endocardium of the free wall at the RVOT for endocardial mapping (RVOT-endo).
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Figure 2 Example of Surface Electrocardiograms (II, V2, and V5) and Intracardiac Unipolar Electrogram at the RVOT
Activation-recovery interval (ARI), repolarization time (RT), and activation time (AT) were measured at the right ventricular outflow tract (RVOT).
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Mutation analysis of SCN5A.
Genetic screening was performed in all patients with BrS. All 28 exons of SCN5A were amplified with polymerase chain reaction from deoxyribonucleic acid isolated from peripheral leukocytes using intronic primers. Polymerase chain reaction products were subjected to direct sequencing of all coding regions.
Statistical analysis.
Quantitative values are expressed as means ± standard deviation values. We compared ARI/ARIc, RT/RTc, and AT before and after the administration of pilsicainide administration by means of a paired t test. Differences in ARI/ARIc, RT/RTc, and AT before and after pilsicainide administration also were compared by means of a paired t test. We used the Student t test to compare ARI/ARIc, RT/RTc, and AT between the epicardium and endocardium. Student’s t test also was used for comparison of differences in ARI/ARIc, RT/RTc, and AT between BrS patients and control subjects. Differences in ARI/ARIc between SCN5A mutation careers and noncareers also were compared by means of a Student t test. A value of p < 0.05 was considered statistically significant.
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Results
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Figure 3
shows representative surface ECGs and unipolar electrograms in a control subject (Fig. 3A) and 2 patients with BrS (Figs. 3B and 3C) under baseline conditions and after pilsicainide injection.
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Figure 3 Patient Examples
Representative surface ECGs and unipolar electrograms in a control subject (A) and in 2 patients with Brugada syndrome (B and C) under baseline conditions (left panels) and after pilsicainide administration (right panels). (A) Brugada-type ECG was not observed in surface ECGs. Under baseline conditions, the epicardial ARI (221 ms) was shorter than the endocardial ARI (244 ms). After the administration of pilsicainide, the epicardial ARI (208 ms) was still shorter than the endocardial ARI (230 ms). (B) Under baseline conditions, type 1 ECG was observed in lead V2(3ics) (*), and the epicardial ARI (239 ms) was longer than the endocardial ARI (187 ms). After the administration of pilsicainide, type 1 ECG was still observed in lead V2(3ics) (*), and epicardial ARI (222 ms) was longer than endocardial ARI (190 ms). (C) Under baseline conditions, type 1 ECG was not observed in any of the surface ECG leads, and the epicardial ARI (210 ms) was shorter than endocardial ARI (248 ms). However, after administration of pilsicainide, the epicardial ARI, but not the endocardial ARI, was markedly prolonged (260 ms), and type 1 ECG appeared in lead V2(3ics) (*). The epicardial ARI was 18 ms longer than the endocardial ARI (242 ms). Numbers indicate ARI. ARI = activation-recovery interval; ECG = electrocardiogram; RVOT-epi = uniploar electrogram of the epicardium at the right ventricular outflow tract; RVOT-endo = uniploar electrogram of the endocardium at the right ventricular outflow tract; * = type 1 ECG.
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As shown in Figure 3A, Brugada-type ECG was not observed under baseline conditions or after pilsicainide injection in the control subject (Patient #3). Epicardial ARI was always shorter than endocardial ARI both before and after pilsicainide injection. The epicardial ARI was 23 ms shorter than the endocardial ARI under baseline conditions and was 22 ms shorter than the endocardial ARI after pilsicainide injection. The difference in ARI was thus defined as –23 ms before and –22 ms after pilsicainide injection.
As shown in Figure 3B, type 1 ECG was observed in lead V2(3ics), and epicardial ARI (239 ms) was longer than endocardial ARI (187 ms), and the difference in ARI was therefore defined as +52 ms under baseline conditions in the Brugada patient (Patient #1).
As shown in Figure 3C, type 1 ECG was not observed in all of the surface ECG leads, and epicardial ARI (210 ms) was shorter than endocardial ARI (248 ms) under baseline conditions in the Brugada patient (Patient #16). The epicardial ARI was 38 ms shorter than the endocardial ARI, and the difference in ARI was thus defined as –38 ms. However, after administration of pilsicainide, the epicardial ARI, but not the endocardial ARI, was markedly prolonged (260 ms). Type 1 ECG appeared after pilsicainide administration in lead V2(3ics). The epicardial ARI was 18 ms longer than the endocardial ARI, and the difference in ARI was thus defined as +18 ms.
Table 2
shows electrophysiologic data in all patients. Type 1 ECG was observed in 10 of the 19 patients with BrS under baseline conditions and in all of the patients with BrS after administration of pilsicainide. Pilsicainide administration significantly prolonged epicardial ARI/ARIc from 222.9 ± 16.3 ms/248.0 ± 22.2 ms to 235.1 ± 22.2 ms/268.9 ± 24.9 ms (p < 0.001/p < 0.001) but did not prolong endocardial ARI/ARIc (219.3 ± 17.0 ms/243.6 ± 18.1 ms vs. 213.6 ± 17.4 ms/244.3 ± 18.7 ms; p = NS/p = NS) in patients with BrS. And epicardial ARI/ARIc were significantly longer than endocardial ARI/ARIc after pilsicainide administration in BrS (p < 0.01/p < 0.01). Pilsicainide administration significantly prolonged the difference in ARI/ARIc from +3.6 ± 22.0 ms/+4.4 ± 24.6 ms to +21.5 ± 13.7 ms/+24.6 ± 15.7 ms (p < 0.001/p < 0.001) in patients with BrS.
Figure 4
shows the relationship between differences in ARIc, RTc, and AT and appearance of type 1 ECG. In all control subjects, the epicardial ARIc was always shorter than the endocardial ARIc, and the difference in ARIc was always <0 ms. Type 1 ECG was not observed under baseline conditions and also after pilsicainide administration in the control subjects. However, under baseline conditions, all nine BrS patients without type 1 ECG had a difference in ARIc of <0 ms, and 8 of 10 BrS patients with type 1 ECG had a difference in ARIc of more than 0 ms. The difference in ARIc with type 1 ECG was significantly larger than that without type 1 ECG under baseline conditions (p < 0.0001). After administration of pilsicainide, type 1 ECG appeared and the difference in ARIc was more than 0 ms in all patients with BrS (Fig. 4A). Epicardial RTc was always longer than endocardial RTc in patients manifesting type 1 ECG regardless of pilsicainide administration. The difference in RTc with type 1 ECG was significantly larger than that without type 1 ECG in BrS patients under baseline conditions (p < 0.00001) (Fig. 4B). The difference in AT with type 1 ECG was also significantly larger than that without type 1 ECG in BrS patients under baseline conditions (p < 0.05) (Fig. 4C). However, the difference in AT was a less critical as a factor determining type 1 ECG than was the difference in RTc or ARIc. Accordingly, type 1 ECG was closely related to the prolongation of repolarization in the epicardium compared to that in the endocardium.
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Figure 4 Relationship Between Appearance of Type 1 ECG and Each Parameter
Relationship between appearance of type 1 electrocardiogram (ECG) and differences in activation-recovery interval corrected for heart rate (ARIc) (A), repolarization time corrected for heart rate (RTc) (B), and activation time (AT) (C) in control subjects (Control) and in patients with Brugada syndrome (Brugada) under baseline conditions (Baseline) and after the administration of pilsicainide (After Pilsicainide). (A) Type 1 ECG was closely related to the prolongation of ARIc in the epicardium compared with that in the endocardium. The difference in ARIc with type 1 ECG was significantly larger than that without type 1 ECG under baseline conditions (p < 0.0001). After the administration of pilsicainide, type 1 ECG appeared and the difference in ARIc was more than 0 ms in all patients with Brugada syndrome. (B) Epicardial RTc was always longer than endocardial RTc in patients manifesting type 1 ECG regardless of pilsicainide administration. The difference in RTc with type 1 ECG was significantly larger than that without type 1 ECG in Brugada syndrome patients under baseline conditions (p < 0.00001). (C) The difference in AT with type 1 ECG was significantly larger than that without type 1 ECG in Brugada syndrome patients under baseline conditions (p < 0.05). However, the difference in AT was a less critical factor determining type 1 ECG than was the difference in RTc or ARIc. Open black circles = type 1 ECG was recorded in surface ECG without SCN5A mutation; open blue circles = type 1 ECG was recorded in surface ECG with SCN5A mutation; open diamonds = type 1 ECG was not recorded in surface ECG.
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Mutation of the SCN5A gene was identified in 4 of the 19 patients (Patient #1, R282H; Patient #2, IVS21+1 g>a; Patient #3, R1913C; Patient #9, Y416C) with BrS. The differences in ARI/ARIc and RT/RTc between epicardium and endocardium were significantly larger in 4 SCN5A mutation carriers than that in 15 noncarriers before pilsicainide administration (Figs. 4A and 4B). However, the differences between the 2 groups disappeared after pilsicainide was administered.
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Discussion
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Main findings of the study.
The results of this study show that type 1 ECG is closely related to the prolongation of repolarization in the epicardium compared with that in the endocardium in BrS. The administration of pilsicainide, a pure sodium channel blocker, exaggerated the prolongation of repolarization in the epicardium, which contributed to the development of type 1 ECG in BrS. In the control subjects, ARI/ARIc and RT/RTc in the epicardium were always shorter than those in the endocardium regardless of pilsicainide administration.
Mechanism of type 1 ECG.
Recent experimental studies have suggested that a prominent transient outward current-mediated action potential notch during phase 1 depolarization in the epicardium, but not in the endocardium, gives rise to a transmural voltage gradient, which is responsible for prominent ST-segment elevation in BrS. When epicardial repolarization precedes endocardial repolarization, the T-wave remains positive. However, further accentuation of the notch causes longer action potential duration in the epicardium than in the endocardium due to a delay in the onset of the second upstroke and phase 3, which results in a coved-type ST-segment elevation and inversion of the T-wave (type 1 ECG) (4–6). In the present study, we were able to record epicardial and endocardial unipolar electrograms simultaneously in all patients. And we could demonstrate longer action potential duration in the epicardium than that in the endocardium using ARI and RT, and we found a close correlation between prolongation of repolarization in the epicardium and type 1 ECG.
Prolongation of RT in the epicardium could be also explained by conduction slowing at the RVOT instead of transmural repolarization differences. Delayed activation at the epicardial cell could result in later termination of repolarization than endocardial cell, which could demonstrate terminal inverted T-wave (22,23). Coronel et al. reported that minor transmural gradient in RT causes dynamic T-wave change and that activation delay is also an important factor in determining transmural gradient in RT (24). In the present study, we also showed the mild prolongation of AT in the epicardium in patients with type 1 ECG. However, the difference in AT was a less critical as a factor determining type 1 ECG than was the difference in RT/RTc or ARI/ARIc in our study.
SCN5A mutation.
It has been reported that mutation of the SCN5A gene was identified in approximately 10% to 20% of patients with BrS (2,25). In this study, SCN5A mutation was identified in 4 of the 19 patients with BrS. The differences in ARI/ARIc and RT/RTc between the epicardium and endocardium were significantly larger in SCN5A mutation carriers than in noncarriers before the administration of pilsicainide. Because the number of BrS patients was small and their clinical backgrounds and mutation sites were heterogeneous, the mechanism underlying this phenomenon is unclear.
Pilsicainide administration.
Pilsicainide administration developed ventricular arrhythmias in 4 patients (Patient #8, VF; Patients #4, #10, and #13, premature ventricular contractions; Patient #11, nonsustained polymorphic ventricular tachycardia) (26). However, no difference was observed in any of the parameters between the patients with and without pilsicainide-induced ventricular arrhythmias. And the distinctive finding, such as phase 2 re-entry, was not apparent in the initiation of ventricular arrhythmia at the epicardium and endocardium.
Study limitations.
We were able to record electrograms only at the site where the conus branch of the right coronary artery runs through. Therefore, we could not perform detailed mapping in the epicardium at the RVOT. We attempted to introduce the guidewire into the conus branch in more than 50 patients with BrS. However, we were able to successfully introduce the guidewire deeply at the RVOT in only about 50% patients due to technical problems and location of the conus branch.
Marked shortening of ARI in the epicardium was not demonstrated under baseline conditions or after pilsicainide administration in this study. However, we could not rule out the possibility of "loss of dome" configuration of action potential in another epicardial site, because detailed mapping in the epicardium at the RVOT was very difficult. The aggregated action potentials in the endocardium, epicardium and midmyocardium could cause an averaging effect that prolongs ARI and RT and mask marked shortening of repolarization.
The number of control subjects examined in this study was relatively small. However, because type 1 ECG was not observed before and after pilsicainide administration in any of the control subjects and since the main purpose of this study was to investigate the relationship between appearance of type 1 ECG and alteration of action potential in patients with BrS, a large number of control subjects was not necessary in this study.
Because recent studies have shown that pilsicainide also blocked the K+ channel current of the human ether-a-go-go-related gene (HERG) and could cause QT prolongation, we could not completely exclude the possibility that pilsicainide administration directly prolonged action potential duration in the epicardium (27).
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Acknowledgments
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The authors are grateful to Shigemi Urakawa, Makiko Taniyama, Jyun Iwasaki, Wakako Sumida, Aya Miura, Daiji Miura, Kaoru Kobayashi, Miyuki Fujiwara, and Masayo Oomori for their excellent technical assistance.
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Abstract
Methods