Brugada syndrome, which was introduced as a clinical

Transcription

1 Prolonged QRS Duration in Lead V and Risk of LifeThreatening Ventricular Arrhythmia in Patients With Brugada Syndrome Kimie Ohkubo, MD, Ichiro Watanabe, MD, Yasuo Okumura, MD, Sonoko Ashino, MD, Masayoshi Kofune, MD, Koichi Nagashima, MD, Tatsuya Kofune, MD, Toshiko Nakai, MD, Satoshi Kunimoto, MD, Yuji Kasamaki, MD, and Atsushi Hirayama, MD Summary Brugada syndrome is an inherited disorder that predisposes some patients to sudden cardiac death. It is not well established which Brugada syndrome patients are at risk of lifethreatening arrhythmias. We investigated whether standard lead electrocardiograms (ECG) can identify such patients. The subjects were 5 men with Brugada syndrome (mean age, 50. ±.4 years). Documented ventricular fibrillation or aborted sudden cardiac arrests were judged to be related to the Brugada syndrome. Ten patients (mean age, 49.6 ± 4.9 years) were symptomatic, and 5 (mean age, 50. ±.5 years) were asymptomatic. We determined the PR interval, QRS duration, and QT interval from baseline lead ECG leads II and V as well as the J point elevation amplitude of lead V. The QRS interval was measured from QRS onset to the J point in leads II and V. The only significant difference between the symptomatic and asymptomatic patients was the QRS duration measured from lead V. The mean QRS interval was 9.0 ±.9 ms in symptomatic patients versus 08. ± 5.9 ms in asymptomatic patients (P = 0.0). A QRS interval in lead V 0 ms was found to be a possible predictor of a lifethreatening ventricular arrhythmia and/or syncope (P = 0.0). Prolonged QRS duration as measured on a standard lead ECG is associated with ventricular arrhythmia and could serve as a simple noninvasive marker of vulnerability to lifethreatening cardiac events in patients with Brugada syndrome. (Int Heart J 0; 5: 980) Key words: Brugada syndrome, Sudden death, Ventricular fibrillation, QRS width Brugada syndrome, which was introduced as a clinical entity in 99, is a genetic disorder that increases the risk of sudden death secondary to ventricular tachycardia/fibrillation (VT/VF) in patients with structurally normal hearts.,) The syndrome is estimated to be responsible for 4% of all sudden deaths and at least 0% of sudden deaths in patients with structurally normal hearts. ) Inheritance of Brugada syndrome occurs via an autosomal dominant mode of transmission with variable penetrance involving several genes. SC N5A, which codes subunit I Na of sodium channel α, is mutated in 0%0% of Brugada syndrome patients. 4,5) Mutations in the GPDL gene 6) and the CACNA and CACNB genes 7) have also been identified, but these gene variations are infrequent. The typical ST segment 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. 8,9) This elevation can have a saddleback appearance with a J wave amplitude of mm and an elevation in the terminal portion of the ST segment of mm, and then either a positive or biphasic T wave (type electrocardiogram [ECG]) or can be characterized by either a saddleback or coved appearance with an ST segment elevation of < mm (type ECG). 0) The vulnerability of individuals with the Brugada sign to sudden cardiac death or a lifethreatening ventricular tachyarrhythmia is not well established. Previous studies have shown that prior events (syncope or aborted sudden cardiac arrest), family history of sudden cardiac death, spontaneous type Brugada ECG (coved ST segment elevation mm at its peak followed by a negative T wave, with little or no isoelectric separation), male sex, inducibility of VT or VF during electrophysiologic (EP) study are linked to an increased risk of lifethreatening arrhythmias, but the findings remain controversial. 08) Noninvasive ECG markers, such as relatively large fluctuations in the ST segment elevation, rj interval, a prolonged T peak T end interval, fragmented QRS complexes on lead ECG, and late potentials on a signalaveraged ECG, have been shown to be more common in symptomatic than in asymptomatic patients. 94) Thus, we conducted a retrospective study to determine whether it is possible to noninvasively identify patients with a Brugadatype ECG who are at high risk for a potentially lethal cardiac event. Methods Subjects: The subjects were 5 unrelated patients who ranged in age from 4 to 76 years (all men, mean age, 50. ±.4 years) and were referred to our hospital for evaluation of Bru From the Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan. Address for correspondence: Ichiro Watanabe, MD, Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 0 Oyaguchikamimachi, Itabashiku, Tokyo 7860, Japan. Received for publication October, 00. Revised and accepted December,

2 Vol 5 No QRS WIDTH IN BRUGADA SYNDROME 99 gada syndrome between 995 and 009. Ten patients (mean age, 49.6 ± 4.9 years) were symptomatic, and 5 (mean age, 50. ±.5 years) were asymptomatic. Structural heart disease was excluded by echocardiography and treadmill exercise testing. Hematologic and serologic test results were normal. Five patients had a history of aborted sudden cardiac arrest, and 5 patients had suffered syncopal episodes. A family history of unexplained sudden death was present in 4 patients. Patients with a history of aborted sudden cardiac arrest or syncope underwent brain computed tomography, electroencephalography, and headup tilt test, the results of which were all normal. No patient had received medications before the initial evaluation. Thirty of the 5 patients consented to genetic testing; no SC N5A mutation was found. All coronary angiograms and left ventriculograms appeared normal. All patients provided written informed consent for pilsicainide challenge and electrophysiologic testing. Pharmacologic challenge test: Pilsicainide, mg/kg, was administered intravenously over 0 minutes in patients with a type or type Brugada ECG. Brugada syndrome is diagnosed when type or type ST segment elevation is observed in more than right precordial lead under baseline conditions and conversion to the diagnostic type ECG pattern occurs after pilsicainide administration. ) Standard and signalaveraged ECG: The investigators in charge of ECG analysis were blinded to the clinical backgrounds and pharmacologic and electrophysiologic test results for the subjects. The PR interval, QRS duration, QT interval, and J point amplitude were measured from ECG leads II and V (Figure ). A baseline signalaveraged ECG obtained from Frank X, Y, and Z leads (ART 00 EPX, Arrhythmia Research Technology, Inc, Austin, Texas, USA) was recorded during sinus rhythm in all 5 patients. We averaged 50 cycles to reach a noise level 0.4 μv. The filtered QRS duration, root mean square voltage of the terminal ms of the filtered QRS complex (RMS ), and duration of the lowamplitude signal (< μv) of the terminal filtered QRS complex (LAS ) were measured. Late potentials were considered positive when RMS was < 0 μv and LAS > 8 ms. Electrophysiologic study: Comprehensive electrophysiologic study was performed in all 5 patients 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 (BARD Lab Pro, BARD Electrophysiology, Lowell, MA, 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 S interval was applied after 8 beats of drive pacing (S ) at basic cycle lengths of 600 ms and 0 ms. The S S interval was decreased in 0ms steps until the effective refractory period of the right ventricle was reached. When VF that lasted > 5 seconds and required DC shock was not induced with a single premature beat, extrastimuli (S until the effective refractory period was reached, S to 80 ms) were delivered. Followup: In general, patients were followedup at 4 to 5month intervals at our outpatient clinic to determine the status of their symptoms. Followup ranged from 6 to 84 months (mean, 84.5 ±. months). All patients were alive during followup without ICD discharge. Data analysis: Patients were classified into groups: those who were symptomatic (n = 0) and those who were not (n = 5). Baseline ECG and signalaveragedecg variables were compared between the groups. Values are presented as the mean ± SD. Betweengroup differences in lead ECG and signalaveraged ECG variables were analyzed using the MannWhitney U test, and in the Brugada type ECG pattern, inducibility of VT/VF and the presence of late potentials were analyzed using Fisher s exact probability test. A P < 0.05 was considered statistically significant. Results Figure. QRS duration in lead V in a symptomatic patient with a Brugada ECG versus an asymptomatic patient with a Brugada ECG. The QRS interval was measured from the onset of the Q wave to the peak of the J wave. Baseline clinical data: The general characteristics of the study patients are summarized in Table I. Baseline Brugada ECG patterns were as follows: type in 4 patients, type in 0 patients, and type in patients. ECG types did not differ significantly between the symptomatic and asymptomatic patients (Table II). Pharmacologic test results: Pilsicainide challenge was positive in all patients with a type or type Brugada ECG. Standard lead ECG: Standard lead ECG variables are shown per group in Table II, and some individual examples are shown in Figures. Of all the standard ECG variables that were analyzed, only the QRS duration in lead V differed significantly between symptomatic and asymptomatic patients; it was significantly longer in symptomatic patients (9.0 ±.9 ms versus 08. ± 5.9 ms, P = 0.0). None of the other variables (QRS duration in lead II, PR interval in leads II and V, QT interval in leads II and V, and J point amplitude in lead II differed significantly between the groups of patients. A receiver operating characteristic (ROC) curve was drawn to identify the optimal baseline discriminative QRS width cutoff val

3 00 OHKUBO, ET AL Int Heart J March 0 Table I. Clinical Characteristics of Patients With a Brugada ECG Patient Age (years) ECG type Symptom FQRS RMS LAS LPs Figure. J point amplitude in lead V in a symptomatic versus asymptomatic patient. The J point was measured from the baseline to the peak of the J wave. indicates sudden cardiac arrest (aborted); FQRS, filtered QRS duration; RMS, root mean square voltage of the terminal ms in the filtered QRS complex; LAS, duration of lowamplitude signals < μv in the terminal filtered QRS complex; and LPs, late potentials. Figure. QRS duration in lead II in a symptomatic versus asymptomatic patient. The QRS interval was measured from the onset of the Q wave to the peak of the J wave. Lead V ECG type versus, PR interval QRS duration QT interval J point amplitude (mv) Lead II PR interval QRS duration QT interval Table II. ECG Variables per Study Group Symptomatic patients 4/6 7.0 ± ± ± ± ± 0.0. ± ± 5.7 Asymptomatic patients 9/ ± ± ± ± ± ± 4..0 ± 5.9 P ue. A QRS width of 0 ms yielded a sensitivity of 77.8%, specificity of 86.4%, positive predictive value of 8.%, and negative predictive value of 87.0%. Electrophysiologic study: Polymorphic VT or VF requiring DC shock for termination was induced by programmed ven Table III. SignalAveraged ECG Variables per Study Group Late potentials Filtered QRS Duration RMS (μv) LAS Symptomatic Asymptomatic P 6/0 4. ±. 4.9 ± ±.9 4/5 4. ± ± ± tricular stimulation in all the patients. An implantable cardioverterdefibrillator was implanted in 8 patients with a type ECG, patients with a type ECG, and 4 patients with a type ECG. Signalaveraged ECG: According to signalaveraged ECGs, late potentials were positive in 0 (57%) of the 5 patients (Table I) and did not differ in prevalence between symptomatic and asymptomatic patients (60% versus 56%, respectively). Filtered QRS, RMS, and LAS were 4. ±. ms versus 4. ± 8. ms, 4.9 ± 5.7 μv versus 9.8 ± 9.5 μv, and

4 Vol 5 No QRS WIDTH IN BRUGADA SYNDROME 0 9. ±.9 ms versus.8 ±.5 ms, respectively, in symptomatic versus asymptomatic patients. None of these variables differed significantly between the groups. Signalaveraged ECG variables did not differ significantly between the symptomatic and asymptomatic patients (Table III). Discussion The major finding of the present study was that the duration of the QRS complex on the baseline lead ECG in patients with symptoms was significantly longer than in those without symptoms. A spontaneous type Brugada ECG has been shown to identify patients at risk of cardiac arrest.,5,8) However, daily spontaneous fluctuations in the ST segment are also associated with a high risk for subsequent arrhythmic events in patients with Brugada syndrome. 9,0) Sodium channel blockers have been used to unmask Brugada syndrome. ) Although previous studies yielded a similar incidence of potentially lethal arrhythmias in patients with transient versus persistent ST segment elevation and right bundle branch block, they have also shown the effectiveness of sodium channel blockers in unmasking the syndrome, and thus, identifying patients at risk. 5) The presence or absence of covedtype ST segment elevation during sodium channel blocker challenge denotes a profound electrophysiologic difference. That is, the absence of inducibility during electrophysiologic study may be responsible for the good prognosis of patients with a type or ECG pattern that does not convert to a type pattern. 6) However, sodium channel blocker challenge sometimes induces severe ventricular arrhythmias; thus, it requires careful observation. 7,8) Atarashi, et al reported that S wave width 0.08 s in V and ST elevation 0.8 mv in V were highly specific indicators of ventricular fibrillation. 9) Takagi, et al reported that QRS rj interval in lead V (99 ± 9 ms versus 9 ± 4 ms, P = 0.00) and QRS duration in lead V6 (04 ± 8 ms versus 96 ± ms, P = 0.0) were longer in the VF group than that in the asymptomatic group. 0) Junttila, et al also reported that the mean QRS duration in V lead was 5 ± 6 ms in symptomatic versus 04 ± 9 ms in asymptomatic patients (P < 0.00) and the optimized cutoff point of V QRS 0 ms gave an odds ratio of.5 for being symptomatic. ) However, Ikeda, et al reported that mean QRS duration measured automatically by computerized ECG > 0 ms did not differentiate high risk for subsequent events in subjects with a Brugada type ECG, 9) and Tatsumi et al reported that QRS duration (rj interval in lead V6) did not differ between symptomatic versus asymptomatic Brugada syndrome (85 ± versus 80 ± ms). 0) Previous reports also demonstrated that filtered QRS duration was longer and RMS was smaller when measured from signalaveraged ECG in symptomatic patients. 4,) Furthermore, Tatsumi et al reported that the daily fluctuations in rj interval in leads V, V, and V6 were significantly larger in symptomatic patients on lead ECG, and daily fluctuations in filtered QRS duration and LAS were significantly larger in symptomatic patients. 0) In the present study, the results were similar to those of Junttila, et al ) however, the presence of late potential and filtered QRS duration, RMS, and LAS did not differ between symptomatic and asymptomatic Brugada syndrome. It might be possible that the lack of differences in filtered QRS duration, RMS, and LAS between symptomatic and asymptomatic Brugada patients in the present study was due to ) differences in measured leads, ie, V lead in lead ECG and vector magnitude of X, Y, and Z leads in signalaveraged ECG; ) differences in filter setting, ie, time constant >. s and a lowpass filter 50 Hz in lead ECG and 50 Hz filter in signalaveraged ECG; ) parameters (filtered QRS duration, RMS and LAS ) in signalaveraged ECG might show more daily fluctuations than QRS duration in lead ECG. Longterm study in a large group of patients is needed to confirm our findings. Conclusion: Our findings suggest that a simple ECGbased method can successfully discriminate between patients with a Brugada ECG who are at risk for a lifethreatening ventricular arrhythmia and those who are not at such risk. References. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 99; 0: 96.. Brugada J, Brugada R, Brugada P. Right bundlebranch block and STsegment elevation in leads V through V: a marker for sudden death in patients without demonstrable structural heart disease. Circulation 998; 97: Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 005; : (Review) 4. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 998; 9: Antzelevitch C, Brugada P, Brugada J, Brugada R, Towbin JA, Nademanee K. Brugada syndrome: 9900: a historical perspective. J Am Cardiol 00; 4: (Review) 6. London B, Michalec M, Mehdi H, et al. Mutation in glycerol phosphate dehydrogenase like gene (GPDL) decreases cardiac Na current and causes inherited arrhythmias. Circulation 007; 6: Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Lossoffunction mutations in the cardiac calcium channel underlie a new clinical entity characterized by STsegment elevation, short QT intervals, and sudden cardiac death. Circulation 007; 5: Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol 996; 7: Antzelevitch C, Brugada R. Fever and Brugada syndrome. Pacing Clin Electrophysiol 00; 5: 579. (Review) 0. Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 00; 06: 9. (Review). Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation 00; 08: Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 00; 05:.. Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a metaanalysis. J Cardiovasc Electrophysiol 006; 7: Eckardt L, Probst V, Smits JP, et al. Longterm prognosis of individuals with right precordial STsegmentelevation Brugada syndrome. Circulation 005; : 576.

5 0 OHKUBO, ET AL Int Heart J March 0 5. Glatter KA, Chiamvimonvat N, Viitasalo M, Wang Q, Tuteja D. Risk stratification in Brugada syndrome. Lancet 005; 66: Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 008; 5: Kamakura S, Ohe T, Nakazawa K, et al. Longterm prognosis of probands with Brugadapattern STelevation in leads VV. Circ Arrhythm Electrophysiol 009; : Probst V, Veltmann C, Eckardt L, et al. Longterm prognosis of patients diagnosed with Brugada syndrome: Results from the FIN GER Brugada Syndrome Registry. Circulation 00; : Ikeda T, Takami MM, Sugi K, Mazusawa Y, Sakurada H, Yoshino H. Noninvasive risk stratification of subjects with a Brugadatype electrocardiogram and no history of cardiac arrest. Ann Noninvasive Electrocardiol 005; 0: Tatsumi H, Takagi M, Nakagawa E, Yamashita H, Yoshiyama M. Risk stratification in patients with Brugada syndrome: analysis of daily fluctuations in lead electrocardiogram (ECG) and signalaveraged electrocardiogram (SAECG). J Cardiovasc Electrophysiol 006; 7: Castro Hevia J, Antzelevitch C, Tornés Bárzaga F, et al. Tpeak Tend and TpeakTend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the Brugada syndrome. J Am Coll Cardiol 006; : Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of Brugada syndrome. Circulation 008; 8: Ikeda T, Sakurada H, Sakabe K, et al. Assessment of noninvasive markers in identifying patients at risk in the Brugada syndrome: insight into risk stratification. J Am Coll Cardiol 00; 7: Ajiro Y, Hagiwara N, Kasanuki H. Assessment of markers for identifying patients at risk for lifethreatening arrhythmic events in Brugada syndrome. J Cardiovasc Electrophysiol 005; 6: Brugada R, Brugada J, Antzelevitch C, et al. Sodium channel blockers identify risk for sudden death in patients with STsegment elevation and right bundle branch block but structurally normal hearts. Circulation 000; 0: 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: Morita H, Morita ST, Nagase S, et al. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol 00; 4: Chinushi M, Komura S, Izumi D, et al. Incidence and initial characteristics of pilsicainideinduced ventricular arrhythmias in patients with Brugada syndrome. Pacing Clin Electrophysiol 007; 0: Atarashi H, Ogawa S; Idiopathic Ventricular Fibrillation Investigators. New ECG criteria for highrisk Brugada syndrome. Circ J 00; 67: Takagi M, Yokoyama Y, Aonuma K, et al. Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with brugada syndrome: multicenter study in Japan. J Cardiovasc Electrophysiol 007; 8: 4.. Junttila MJ, Brugada P, Hong K, et al. Differences in lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients. J Cardiovasc Electrophysiol 008; 9: 80.. Huang Z, Patel C, Li W, et al. Role of signalaveraged electrocardiograms in arrhythmic risk stratification of patients with Brugada syndrome: a prospective study. Heart Rhythm 009; 6: 566.