Brugada syndrome, introduced as a clinical entity in

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1 A New Criteria Differentiating Type and Brugada Patterns From Ordinary Incomplete Right Bundle Branch Block Kimie Ohkubo, 1 D, Ichiro Watanabe, 1 D, Yasuo Okumura, 1 D, Sonoko Ashino, 1 D, asayoshi Kofune, 1 D, Koichi Nagashima, 1 D, Toshiko Nakai, 1 D, Satoshi Kunimoto, 1 D, Yuji Kasamaki, 1 D, and Atsushi Hirayama, 1 D Summary The type 1 (coved) ECG pattern is diagnostic for Brugada syndrome; types and require antiarrhythmic drug challenge to confirm its presence. We evaluated a 1lead ECGbased criterion to differentiate between ordinary incomplete right bundle branch block () and true type and patterns that evolve toward type 1 during drug challenge. The subjects were patients (1 men, 1 woman; mean age, 46.8 ± 1. years) referred for drug challenge (1 mg/kg pilsicainide, iv). In magnified ECG lead V1 and/or V with an pattern, the baseline angle defined as the cross section of the upslope of the r wave with the downslope of the r wave was measured and compared between patients responding negatively versus positively to drug challenge, and was found to be significantly smaller in patients responding negatively (0. ± 1., n = 6, versus 8.7 ± 16.5, n = 1; P = 0.00). This ECGbased method successfully discriminates between the ordinary pattern and druginduced evolution toward a type 1 Brugada ECG. (Int Heart J 011; 5: 1516) Key words: Brugada syndrome, Right bundle branch block, Antiarrhythmic drug test, QRS angle Brugada syndrome, introduced as a clinical entity in 1, is a genetic disorder that increases the risk of sudden death secondary to ventricular tachycardia/fibrillation (VT/VF) in patients with structurally normal hearts. 1,) The syndrome is estimated to be responsible for 4% of all sudden deaths and at least 0% of sudden deaths among patients with a structurally normal heart. ) Inheritance of Brugada syndrome occurs via an autosomal dominant mode of transmission with variable penetrance involving several genes. SCN5A, which codes for the α subunit of the cardiac sodium channel, 4) is mutated in 0%0% of Brugada syndrome patients. 5) utations in the GPD1L gene 6) and the CACNA1 and CACNB genes 7) have also been identified, but these mutations occur infrequently. The typical STsegment elevation in the precordial leads that characterizes Brugada syndrome electrocardiographically can be transitory, vary over time, or be modified by various factors such as vagal tonus, body temperature, and medications. 8,) The elevation can have a saddleback appearance with a J wave amplitude of mm and terminal portion of STsegment elevation of 1 mm, and then either a positive or biphasic T wave (type electrocardiogram [ECG]), or it can be characterized by either a saddleback or coved appearance with an STsegment elevation of < 1 mm (type ECG). 10) The decisive diagnostic criterion for Brugada syndrome is a type 1 ECG pattern (coved STsegment elevation mm at its peak followed by a negative T wave, with little or no isoelectric separation) that appears either spontaneously or after administration of a sodium channel blocker. ) Although risk stratification for sudden cardiac death is complex and predictions have varied according to the series of patients studied, it has been shown that asymptomatic patients whose type 1 ECG appears only after a sodium channel blocker test have a lower arrhythmic risk. 111) A type or ECG pattern in the absence of a type 1 pattern after administration of a sodium channel blocker is not diagnostic for Brugada syndrome, and previous reports have shown the absence of inducibility of VT/VF during electrophysiologic study in patients responding negatively to such drug challenge. 14) The present study was designed to evaluate a new ECG criteria that differentiates between ordinary incomplete right bundle branch block () and true type and patterns evolving toward the type 1 Brugada ECG pattern by sodium channel blocker challenge, without drug challenge test. ethods Subjects: Since 15, we have collected data on unrelated patients, all between the ages of 4 and 76 years (mean age, 46.8 ± 1. years), referred to our hospital for evaluation of a Brugadatype like ECG. Structural heart disease was ruled out by echocardiographic study and treadmill exercise test. Results of hematologic and serologic tests were normal. Two patients had suffered episodes of syncope, and 1 had a family history of unexplained sudden death. The patients who experienced syn From the 1 Division of Cardiology, Department of edicine, Nihon University School of edicine, Tokyo, Japan. Address for correspondence: Ichiro Watanabe, D, Division of Cardiology, Department of edicine, Nihon University School of edicine, 01 Oyaguchikamimachi, Itabashiku, Tokyo , Japan. Received for publication September 8, 010. Revised and accepted January 4,

2 160 OHKUBO, ET AL Int Heart J ay 011 Figure 1. easuring the terminal QRS angle. The angle between the axis of the upslope of the S wave and that of the downslope of the r wave is measured on the baseline ECG. cope underwent brain computed tomography, electroencephalography, and headup tilt test, the results of which were all normal. No patient had received any medication before the initial evaluation and drug challenge test. Pharmacologic test: After informed consent was obtained, 1 mg/kg pilsicainide was administered intravenously over 10 minutes to each patient. Pilsicainide administration was terminated prematurely if the ECG pattern was changed to coved type ECG and ST elevation reached > mm. Brugada syndrome was diagnosed when the ECG converted to the diagnostic type 1 pattern after the pilsicainide administration. ) Standard and signalaveraged ECG: The investigators in charge of ECG analysis were blinded to the results of the pharmacologic test. A V1 and/or V lead ECG showing a type or type Brugada type ECG pattern, or pattern (rsr configuration with QRS duration 10 ms) with STsegment elevation were analyzed. The angle formed by a line drawn parallel to the steepest portion of the upslope of the r wave and a line drawn parallel to the steepest downslope portion of the r wave (terminal QRS angle) (Figure 1) was measured. If was shown in both chest leads, the lead with the greater angle was used for analysis. The ECG was magnified by 4 times and an upslope line was drawn at the end of the S wave and a downslope line was drawn just after the R or J point. Therefore, usually the angle became wider than that measured at a more steep point of the upslope of the S wave and downslope of the R wave. To ensure the reproducibility of the measurements, two authors (TN, SK) measured the angle without information on the patient initially, and if the measured angle was within a difference of 5 degrees, the larger value was adopted. However, if the difference exceeded 5 degrees, a third author (YK) measured the angle and the initial angle that was closest to the third author s value was adopted. A baseline signalaveraged ECG derived from Frank X, Y, and Z leads (ART EPX, Arrhythmia Research Technology, Inc., Austin, TX, USA) was recorded during sinus rhythm in 0 of the patients. We averaged 50 cycles to reach a noise level of 0.4 μv. The filtered QRS duration, root mean square voltage of the terminal 40 ms of the filtered QRS complex (RS40), and duration of the lowamplitude signal (< 40 μv) in the terminal filtered QRS complex (LAS40) were measured. Late potentials were considered positive when the RS40 was < 0 μv and LAS > 8 ms. Electrophysiologic study: If patients responded positively to the drug challenge, a comprehensive electrophysiologic study was performed after written informed consent was obtained. The study was conducted with subjects in a fasting, drugfree, and nonsedated state. After access to the right femoral vein was obtained at sites, steerable quadripolar catheters (6F) with an interelectrode distance of 5 mm (BiosenseWebster, Diamond Bar, CA, USA) were positioned in the right ventricle. Endocardial potentials were filtered to recording frequencies of 0500 Hz and recorded on a BARD computer system (LabSystem PRO, Lowell, A, USA). Programmed electrical stimulation from the right ventricular apex and right ventricular outflow tract was performed at twice diastolic threshold strength and a pulse of ms duration with a pulse generator (BD0, Fukuda Denshi Co., Tokyo). An S 1 S interval was applied after 8 beats of drive pacing (S 1 ) at basic cycle lengths of 600 ms and 400 ms. The S 1 S interval was decreased in 10ms steps until the effective refractory period (ERP) of the right ventricle was reached. When polymorphic VT or VF that lasted > 5 seconds and required DC shock was not induced with a single premature beat, up to extrastimuli (S until the ERP was reached, S to 1 ms and S 4 to 1 ms) were delivered. Genetic analysis: Genetic analysis of the SCN5A gene was performed in 1 patients with Brugada syndrome, but no mutation was found. Followup: All patients who responded positively to the pharmacologic test and/or showed inducible VT/VF were followedup at 45 month intervals at our outpatient clinic to determine their survival status and status of their symptoms. ean followup was 74. ±.0 months (115 months). Statistical analyses: Values are presented as the mean ± SD. Differences in the angle between patients with Brugada ECG pattern and patients with were analyzed by ann Whitney s Utest, and the sensitivity and specificity of the angle in differentiating patients with Brugada syndrome and patients with was fitted by receiveroperating characteristic (ROC) curves and statistical values were calculated with Fisher s exact probability test. All statistical analyses were performed with JP 8 software (SAS Institute, Cary, NC, USA). P < 0.05 was considered significant. Results Test results: Thirteen of the patients responded positively to the pilsicainide challenge test. Ten of these 1 patients showed a type Brugada ECG pattern, and the other patients showed a type Brugada ECG pattern. The characteristics of these patients are shown in Table I. Results of genetic analysis for an SCN5A mutation were negative in all 1 patients. with an early repolarization pattern was found in the remaining patients (Table II). Standard ECG: The terminal QRS angle was compared between patients who responded negatively to the pilsicainide challenge (Figure ) and those who responded positively (Figure ), and an ROC curve was drawn to identify the optimal discriminative cutoff value. The angle was significantly smaller in patients who responded negatively to the drug challenge than in patients who responded positively (0. ± 1. versus

3 Vol 5 No DIFFERENTIATION OF BRUGADA SYNDROE FRO IRBBB 161 Table I. Characteristics of Patients With a Type or Type Brugada ECG Upon Pilsicainide Challenge Patient Age (years) Sex ECG type Symptoms LPs Angle ( ) VF induction S1/S/S/S4 QRS width r height (mv) F Syncope Syncope RVOT 400/0/00 RVA 600/0/0 RVA 600//00 RVOT 400/00/10/10 RVOT 600/10/10 RVOT 600/0/00 RVOT 600/70/70/00 RVOT 400/0/1 RVOT 400/10/1 RVOT 400/0/10/10 RVA 500/50/10 RVA 600/0/10 RVOT 600/0/10/ LP indicates late potential;, present;, absent; RVOT, right ventricular outflow tract; and RVA, right ventricular apex. Table II. Characteristics of Patients With With STT Elevation Patients Age (years) Sex ECG type Symptoms LPs Angle ( ) QRS width r height (mv) N.A N.A Figure. Baseline ECG and ECG upon pilsicainide challenge in a patient with a type (angle: ) Brugada ECG. The arrow indicates ST segment elevation after administration of pilsicainide. LP indicates late potential;, present;, absent; and, incomplete right bundle branch block. Table III. Angles in Patients With BrugadaType ECG and With STT Elevation Type n = 10 Type n = n = LPpositive 7/10 / 0/7 Angle ( ) 8. ± ± ± 1. * (8.7 ± 16.5) QRS width 10.0 ± ± ± 0.0 (.4 ± 14.1) r height (mv) 0.74 ± ± ± 0.51 Figure. Baseline ECG and ECG upon pilsicainide challenge in a patient with an incomplete right bundle branch block () pattern with STT elevation (angle: 1 ). Note the negative response to pilsicainide challenge despite widening of the QRS complex (right). (0.78 ± 0.4) LP indicates late potential and, incomplete right bundle branch block. * P = 0.00 versus Type Type, P = 0.05 versus Type Type, P = 0.65 versus Type Type. 8.7 ± 16.5, P = 0.00; Table III). The optimal baseline cutoff angle as shown by the ROC curve was º, which yielded a sensitivity of %, specificity of 56%, positive predictive value of 76%, and negative predictive value of % for conversion to the type 1 Brugada ECG pattern upon pilsicainide administration. The type Brugada ECG was characterized by a 8. ± 14 angle, and the type Brugada ECG was characterized by a 8. ±. angle. The difference was not significant. Signalaveraged ECG: Late potentials were present in 7 of the 10 patients (70%) with a type ECG pattern, in of the patients (%) with a type ECG pattern, and 0 of the 7 patients (0%) with with ST segment elevation (Tables I and II).

4 16 OHKUBO, ET AL Int Heart J ay 011 Electrophysiologic and angiographic studies: Coronary angiograms and left ventriculograms obtained from the 1 patients who responded positively to the drug challenge were normal. Polymorphic VT or VT requiring DC shock for termination was induced by programmed ventricular stimulation in all patients with a type or type Brugada ECG pattern (Table I). An ICD was implanted in 4 patients with a type Brugada ECG pattern but in 0 patients with a type Brugada ECG pattern. Discussion The major finding of our study was that the angle formed at the juncture of the upslope of the S wave and downslope of the r wave in the terminal portion of the QRS complex on the 1lead ECG in patients who responded positively to pilsicainide challenge with a type or type Brugada ECG was significantly larger than that in those who responded negatively. A spontaneous type 1 Brugada ECG has been shown to identify patients at risk for cardiac arrest. 11,15) However, daily spontaneous fluctuations in the ST segment have been associated with a high risk for subsequent cardiac events in patients with Brugada syndrome. 16,17) Sodium channel blockers have been used effectively to unmask Brugada syndrome, ) and recent studies have revealed a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent STsegment elevation and right bundle branch block. 18) The presence or absence of coved type STsegment elevation during sodium channel blocker challenge denotes a profound electrophysiologic difference; the absence of inducibility during electrophysiologic study may be responsible for the good prognosis of patients with a type or type ECG pattern that does not convert to a type 1 pattern. 1) However, sodium channel blocker challenge sometimes induces severe ventricular arrhythmia and thus poses its own risks. 0,1) Study limitations: First, the QRS angle in this study was measured by a manual method. Thus, in some patients with dull S wave, it was difficult to measure the QRS angle because it was difficult to determine the steepest upslope and downslope point. It should be determined by the first derivative of the ECG if possible. None of our patients experienced an arrhythmic event or ICD discharge during the followup period. However, our study group was very small, so it is not possible to draw a definitive conclusion regarding the usefulness of the angle for differentiating Brugada type ECG and, and also the prognosis of patients with a type or Brugada ECG pattern converted to a type 1 pattern. Our study did not include the ECG pattern of upper intercostals precordial leads that has been shown to increase the diagnosis of type 1 Brugada type ECG in patients with type or type Brugada type ECG. ) Furthermore, Brugada type ECG pattern has been reported to fluctuate over time, and typical ECG changes do not exhibit a stable expression, but undergo variable changes in the degree and shape. 11) A drug challenge test with class I antiarrhythmic drugs was also reported to have negative results in patients with previously coved type ECG pattern and with a previously positive drug challenge test with the same drug. ) Conclusions: Our findings suggest that our ECGbased method successfully discriminates between patients with an ordinary pattern and those with an ECG pattern that evolves into a type 1 Brugada ECG pattern during sodium channel blocker challenge. References 1. Brugada P, Brugada J. 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Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation 00; 108: Eckardt L, Probst V, Smits JP, et al. Longterm prognosis of individuals with right precordial STsegmentelevation Brugada syndrome. Circulation 005; 111: Evain S, Briec F, Kyndt F, et al. Sodium channel blocker tests allow a clear distinction of electrophysiological characteristics and prognosis in patients with a type or Brugada electrogram pattern. Heart Rhythm 008; 5: Gehi AK, Duong TD, etz LD, Gomes JA, ehta D. Risk stratification of individuals with the Brugada electrocardiogram: a metaanalysis. J Cardiovasc Electrophysiol 006; 17: Ikeda T, Takami, Sugi K, izusawa Y, Sakurada H, Yoshino H. Noninvasive risk stratification of subjects with a Brugadatype electrocardiogram and no history of cardiac arrest. Ann Noninvasive Electrocardiol 005; 10: Tatsumi H, Takagi, Nakagawa E, Yamashita H, Yoshiyama. 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5 Vol 5 No DIFFERENTIATION OF BRUGADA SYNDROE FRO IRBBB 16 hearts. Circulation 000; 101: Evain S, Briec F, Kyndt F, et al. Sodium channel blocker tests allow a clear distinction of electrophysiological characteristics and prognosis in patients with a type or Brugada electrocardiogram pattern. Heart Rhythm 008; 5: orita H, orita ST, Nagase S, et al. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol 00; 4: Chinushi, Komura S, Izumi D, et al. Incidence and initial characteristics of pilsicainideinduced ventricular arrhythmias in patients with Brugada syndrome. Pacing Clin Electrophysiol 007; 0: Priori S, Napolitano C, Gasparini, et al. Clinical and genetic heterogeneity of right bundle branch block and STsegment elevation syndrome: A prospective evaluation of 5 families. Circulation 000; 10: 5015.