European Heart Journal (2001) 22, doi: /euhj , available online at on

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1 European Heart Journal (00), doi:0.053/euhj.00.69, available online at on New electrocardiographic leads and the procainamide test for the detection of the in sudden unexplained death syndrome survivors and their relatives S. Sangwatanaroj, S. Prechawat, B. Sunsaneewitayakul, S. Sitthisook, P. Tosukhowong and K. Tungsanga 3 Division of Cardiology, Division of Nephrology, Department of Medicine, 3 Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Aims Sudden unexplained death syndrome occurs in previously healthy South-east Asian young adults without any structural cause of death. The common electrocardiographic (ECG) change in sudden unexplained death syndrome survivors is right bundle branch block and ST elevations in leads V to V 3, which are similar to the ECG pattern in the Brugada syndrome (). It is difficult to diagnose the -lead ECG in sudden unexplained death syndrome survivors and their family members because the ECG could be transiently normalized. We proposed using the higher intercostal space V to V 3 lead ECG, together with procainamide to detect the. Methods and Results Among 0 ventricular fibrillation cardiac arrest patients, 3 sudden unexplained death syndrome survivors and their relatives (n=88) were studied using the single standard -lead ECG and the new six higher intercostal space V to V 3 lead ECG ( V to V 3 and V to V 3 ). Ten sudden unexplained death syndrome survivors and relatives (n=48) who had a normalized ECG were also infused with procainamide (0 mg. kg i.v.) to unmask the and both ECG methods were recorded. Forty healthy individuals and 3 spouses served as the control group. Prior to the procainamide infusion, the could be detected in nine sudden unexplained death syndrome survivors (69 %) and three (3 4%) relatives standard ECG and in (9 3%) and nine (0 %) new six-lead ECG. After the procainamide infusion, the could be demonstrated in seven sudden unexplained death syndrome survivors (70%) and seven (4 6%) relatives with the standard ECG and in nine (90%) (P=0 6) and 3 (47 9%) (P=0 0004) new six-lead ECG, respectively. All the controls were negative for the. Conclusions Our data suggest that the new higher intercostal space lead ECG, with or without the procainamide test is helpful in detecting the in sudden unexplained death syndrome survivors and their relatives. (Eur Heart J 00; : 90 96, doi:0.053/euhj ) 00 The European Society of Cardiology Key Words: Sudden unexplained death syndrome, the Brugada syndrome, the, electrocardiographic leads, procainamide. See page 3, doi: 0.053/euhj for the Editorial comment on this article Introduction Manuscript submitted December 000, accepted 6 March 00, and published online 4 August 00. Correspondence: Somkiat Sangwatanaroj, MD, Division of Cardiology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Rama 4 Road, Patumwan, Bangkok 0330, Thailand X/0/90+07 $35.00/0 Sudden unexplained death syndrome is one of the major causes of death in Thai young men. It has been defined (by the US-CDC in 984) as any unexpected death in a person at least years of age, born in, or with at least one parent born in Vietnam, Cambodia, Laos, Thailand, the Philippines or other South-east Asian country, and a post-mortem examination revealing no underlying 00 The European Society of Cardiology

2 Electrocardiography in the Brugada syndrome 9 cause of death []. In probable or presumptive sudden unexplained death syndrome (PSUDS) the victim would have at least four of the following criteria for a witnessed case, and at least three for a non-witnessed case: () age 0 50 years; () event taking place during sleep or a short nap; (3) victim known to be healthy until immediately before the event; (4) agonal respiration or difficulty in breathing before death; (5) waking is difficult or unsuccessful; (6) no necropsy is performed []. Therefore a PSUDS survivor, whose cause of arrest cannot be identified after intensive investigations, is called a sudden unexplained death syndrome survivor or near sudden unexplained death syndrome (NSUDS). The majority of NSUDS had documented ventricular fibrillation, cardiac arrest and the characteristic ECG pattern of the Brugada syndrome (): right bundle branch block and ST-segment elevation in leads V to V [3,4] 3. Transient normalization of this ECG pattern in Brugada syndrome patients may lead to under-diagnosis [5]. However, sodium channel blockers such as ajmaline, procainamide and flecainide can unmask the in many Brugada syndrome patients [6]. We hypothesized that higher intercostal space leads V to V 3 ( V to V 3 and V to V 3 )(Fig. ) should be helpful in detecting the because () the was a reflection of conduction delay localized in the right ventricular anterior wall and the right ventricular outflow tract by isochrone mapping [7]. The ECG lead position could be extended to cover the sites where abnormal repolarization prevails; () the recent report of improved detection of coronary artery disease by exercise ECG use of right precordial leads along standard six left precordial leads [8] gave us the idea that the more ECG leads we utilized, the greater the chance of detecting the in highly suspect cases; (3) one of our patients Brugada syndrome who survived his second idiopathic ventricular fibrillation cardiac arrest did not have an ECG characteristic of the in the conventional -lead ECG of his immediate post-cardiac arrest tracing, but did have it in leads V, V and V and similar manifestations were also found in other NSUDS patients (Fig. ) and their family members [9]. Shimizu et al. [0] also recently reported that recordings of leads V to V 3 in the -lead ECG in the parasternal second or third intercostal space would be helpful in the diagnosis of the Brugada syndrome in Japanese patients, and that the sodium channel blocker (disopyramide) could accentuate ST segment elevation not associated with a shift of location of the maximum ST segment elevation in Brugada syndrome patients. Very few ECG data for NSUDS patients and none of their families are available. The purpose of this study is to determine the usefulness of the higher intercostal space V to V 3 lead ECG, by comparing the ECG patterns of NSUDS and their relatives using the standard -lead and the new six higher intercostal space lead ECG ( V to V 3 and V to V 3 ) with and without intravenous procainamide. MAL AAL MCL V V V V V Methods V 3 V We define an NSUDS patient as a survivor of cardiac arrest from documented/witnessed ventricular fibrillation or as a PSUDS survivor in whom polymorphic ventricular tachycardia/ventricular fibrillation could be induced by electrophysiology. The subjects were previously healthy Thais, and extensive investigations, including biochemical study, echocardiography, coronary angiography, left and right ventriculography and electrophysiology, could reveal no cause of cardiac arrest. The NSUDS patient who has not undergone extensive investigation and has no structural heart disease/conditions to explain the cause of ventricular tachycardia/ventricular fibrillation is known as a presumptive near sudden unexplained death syndrome (PNSUDS) patient. From June 997 to November 000, we studied ventricular tachycardia/ventricular fibrillation cardiac arrest victims who were referred, or admitted, to the Department of Medicine, King Chulalongkorn Memorial Hospital. The standard V 3 V 3 MCL V 4 AAL MAL Figure The standard precordial positions of conventional chest leads V to V 6 (open circles) and the higher intercostal space ECG leads: V to V 3 and V to V 3 (open squares) are shown. The lead V is just to the right of the sternum in the third intercostal space; the lead V to the left of the sternum in the third intercostal space; the lead V 3 is one intercostal space higher than standard lead V 3 ; the lead V and V are just to the right and left, respectively, of the sternum in the second intercostal space; the lead V 3 is two intercostal spaces higher than standard lead V 3. MAL=mid-auxillary line; AAL=anterior auxillary line; MCL=mid-clavicular line. V 5 V 6 Eur Heart J, Vol., issue 4, December 00

3 V V V 9 S. Sangwatanaroj et al. V V V V 3 V 3 V 3 Figure The initial standard ECG leads V to V 3 of a near sudden unexplained death syndrome (NSUDS) showed no typical right bundle branch block or ST elevation typical of the Brugada syndrome (Brugada sign) but when the new higher intercostal space ECG leads ( V to V 3 and V to V 3 ) were employed, the coved types of the Brugada syndrome were revealed in lead V and the saddle-back type in leads V and V. -lead ECG and new six higher intercostal space lead ECG ( V to V 3 and V to V 3 )(Fig. ) were recorded after resuscitation. The other investigations, including complete blood count, urinary analysis, blood chemistry, electrolyte, chest X-ray, echocardiography with Doppler study, left- and right-sided cardiac catheterization with coronary angiography and left/right ventriculography were also performed to exclude organic heart disease and other causes of ventricular tachycardia/ventricular fibrillation. Those who had no known causes of malignant ventricular arrhythmia were included. We performed the electrophysiological study and programmed electrical stimulation at the right ventricular apex and outflow tract in three cycle-lengths in all NSUDS and PSUDS survivors who gained consciousness and were able to sign the informed consent. The PSUDS survivors in whom ventricular tachycardia/ ventricular fibrillation could not be induced with programmed electrical stimulation were excluded from the study. The NSUDS patients were treated with either beta-blocker or implantable cardioverter defibrillator. We define the as an ECG with right bundle branch block and ST-segment elevation in the right precordial leads, and looking similar to the ECGs in publications by Brugada [3]. A questionable Brugada sign is defined as an ECG tracing of QRS abnormalities and ST-segment elevation in the right precordial leads whose abnormality was of a lesser degree than the abnormal ECG shown in the original publications by Brugada [3]. It is consistent with (but not a definite). We define a negative as a normal ECG, or an ECG with minor ST-T changes dissimilar to those shown in the original publications by Brugada [3]. If the standard -lead ECG showed no or a questionable in leads V to V 3, 0 mg.kg of procainamide was intravenously administered in 0 min, patient being continuously monitored in the intensive care unit. The procainamide test was positive when the post-procainamide ECG demonstrated a greater than 0 mv down-sloping ST-segment elevation in any of the leads V to V 3, V to V 3 and V to V 3 in the immediate post-procainamide ECG compared with baseline ECG. We performed the standard -lead and new six higher intercostal space lead ECGs in the healthy relatives of NSUDS patients, together procainamide test (0 mg. kg intravenously in 0 min) in the emergency room or intensive care unit where cardiopulmonary resuscitation facilities were available, if the ECG showed questionable or negative. The relatives of NSUDS with symptomatic heart disease or evidence of coronary artery disease were excluded from the procainamide test. The pedigree of sudden Eur Heart J, Vol., issue 4, December 00

4 Electrocardiography in the Brugada syndrome 93 Table Comparison of the rate of detection of the by the conventional -lead ECG new six higher intercostal space lead ECG ( V to V 3 and V to V 3 ) in near sudden unexplained death syndrome patients, their relatives and normal controls -lead ECG unexplained death syndrome families was drawn using the as the phenotype and the genetic mode of transmission was determined. The protocol was approved by the Faculty of Medicine Ethical Committee and informed consent was obtained from all subjects before the study. Statistical analysis was made for the chi-squared test for the difference between the two ECG methods and a P value <0 05 was considered as statistically significant. Results six higher intercostal space lead ECG NSUDS, no. (%) (n=3) 9 (69 ) (9 3) Relatives, no. (%) (n=88) 3 (3 4) 9 (0 ) Controls, no. (%) (n=53) 0 (0) 0 (0) NSUDS=near sudden unexplained death syndrome. Twenty patients with unexplained ventricular fibrillation cardiac arrest were admitted to hospital. All but one were males and the mean age was years. Seven patients were excluded because invasive cardiovascular studies to elucidate the aetiologies of ventricular fibrillation were incomplete. Thirteen patients were diagnosed as NSUDS after extensive investigations according to the protocol. These and their 88 relatives were studied, together with 53 healthy adults and spouses of the first degree relatives, who served as controls. Procainamide tests were performed in 0 (out of 3) NSUDS patients who had transient normalization of the, in 48 relatives who had negative or questionable on the standard -lead and new six higher intercostal space lead ECG (Fig. 3), and in 3 healthy controls. The was detected in nine (69 %) of the NSUDS patients by the conventional -lead ECG compared with (9 3%) by the new six-lead ECG (P=0 3). Of the relatives, three (3 4%) were revealed to have the by the -lead ECG and nine (0 %) by new six-lead ECG (P=0 07) (Table ). There were similar findings in the procainamide groups: seven NSUDS patients (70%) by the -lead ECG compared with nine (90%) by the new six-lead ECG (P=0 6), seven (4 6%) relatives by the -lead ECG and 3 (47 9%) by new six-lead ECG (P=0 0004) (Table ). None of the controls or spouses had a positive by both methods Table Comparison of the rate of detection of the by the conventional -lead ECG new six higher intercostal space lead ECG ( V to V 3 and V to V 3 ) after intravenous injection of 0 mg. kg of procainamide in near sudden unexplained death syndrome patients, their relatives and normal controls -lead ECG with or without procainamide. No ventricular arrhythmia or serious side-effects were observed during the procainamide test. In one eight-member NSUDS family (SSR), the - lead ECG alone, the -lead post-procainamide ECG and the six higher intercostal space lead ECG alone, showed a positive in one and a questionable in another (Fig. 4(a)). However, five positive s were detected by the new six-lead post-procainamide ECG (Fig. 4(b)). Individuals I. and II.5 were healthy until they suddenly unexpectedly died in their sleep in the fourth decade of life without any obvious cause of death (PSUDS). Using presumptive sudden unexplained death and the as the phenotype, the pedigree of the SSR family clearly demonstrates the mode of transmission of autosomal dominance with complete penetrance, as reported in the Brugada syndrome []. Discussions six higher intercostal space lead ECG NSUDS, no. (%) (n=0) 7 (70 0) 9 (90 0) Relatives, no. (%) (n=48) 7 (4 6) 3 (47 9)* Controls, no. (%) (n=3) 0 (0) 0 (0) NSUDS=near sudden unexplained death syndrome. *P<0 00. In this study we demonstrate that the higher intercostal space V to V 3 lead ECG ( V to V 3 and V to V 3 ) is superior to the conventional -lead ECG in the detection of the in both sudden unexplained death syndrome survivors (NSUDS) and their relatives. Moreover, intravenous procainamide administration plus the higher intercostal space leads ECG was able to unmask the in 0 more relatives (n=48) when compared higher leads alone, and in two more NSUDS patients (n=0) when compared post-procainamide -lead ECG. Our data show that the post-procainamide six higher intercostal space lead ECG is the most sensitive method for detecting the in both NSUDS patients and the relatives. It was suggested that flecainide administration is a sensitive and specific test for detecting the among patients carrying genetic mutations for the Eur Heart J, Vol., issue 4, December 00

5 94 S. Sangwatanaroj et al. Baseline Post-procainamide V to V 3 V to V 3 V to V 3 V to V 3 (a) (b) (c) (d) Figure 3 The pre- and post-procainamide ECGs of a relative of a near sudden unexplained death syndrome patient. (a) Baseline ECG leads V to V 3 showed no right bundle branch block or ST elevation typical of the Brugada syndrome (); (b) baseline higher intercostal space ECG leads V to V 3 (Fig. ) indicate a questionable (arrow) in lead V ; (c) post-procainamide ECG leads V to V 3 showed a positive ; (d) post-procainamide ECG leads V to V 3 also showed a positive (arrow) at lead V. Brugada syndrome []. Even through procainamide is less potent than flecainide, utilization of the higher intercostal space leads could increase the power to detect the. With the method of procainamide administration (0 mg intravenously in 0 min) recommended by Brugada et al. [3], no serious side-effects from procainamide have been reported in the Brugada syndrome; however, one patient developed ventricular fibrillation during ajmaline administration []. Flecainide can be safely used to maintain sinus rhythm in patients with ventricular arrhythmia and no structural heart disease. It has recently been reported that flecainide can induce ventricular tachycardia and fibrillation in patients treated for atrial fibrillation [4]. The efficacy and safety of sodium channel blockers in this condition should be elucidated in future investigations new six higher intercostal space ECG. Our data confirm the recent Japanese study on the 87-lead body surface map in Brugada syndrome patients [0]. The study indicated that the second and third intercostal space V to V 3 lead ECG, alone or with sodium channel blockers, would be helpful in the detection of the. For the first time, we have extended the study to relatives and have found that the new six-lead ECG is more sensitive than the conventional ECG in the detection of the. The difference is significant procainamide test in the relatives group (P<0 00), but is not significant in the NSUDS group, possibly due to the small number of the latter. The ECG findings in the SSR family members demonstrated that the conventional -lead ECG, plus the procainamide test and new six-leads alone are not enough to detect the in healthy relatives of sudden unexplained death syndrome patients. Therefore it is mandatory to perform the procainamide test new six-lead ECG to identify the phenotype of the family members Brugada syndrome. The lack of phenotype genotype correlation in some family members of Brugada syndrome patients [5] or incomplete penetrance and variable responses to sodium channel blockade [6] maybe due to inadequate efficacy of procainamide, ajmaline or the flecainide test conventional -lead ECG to unmask the. Moreover it is conceivable to expect a higher prevalence of the in an apparently healthy population by using the new six higher intercostal space lead ECG [7 9] as well as in idiopathic ventricular fibrillation patients. Study limitations The diagnosis of the in our patients was exclusively based on an ECG only, without genotype analysis. The only gene associated Brugada syndrome is the cardiac sodium channel gene (SCN5A) []. At least three mutations of this gene cause Brugada syndrome and sodium channel mutation might Eur Heart J, Vol., issue 4, December 00

6 Electrocardiography in the Brugada syndrome 95 (a) (b) I II III? IV Figure 4 A pedigree of one near sudden unexplained death syndrome patient (NSUDS) (SSR). Circles indicate females; squares, male; open symbol, unaffected status; open symbol with question mark, questionable ; closed symbol, NSUDS; stippled, positive ; stippled with slash, presumptive sudden unexplained death syndrome (PSUDS). (a) Pedigree phenotype of the by the -lead ECG with procainamide, and the new six-lead ECG alone. (b) The same pedigree with phenotypes of a positive by the new six-lead ECG procainamide test and PSUDS clearly demonstrate the autosomal dominant mode of transmission. be present in only a small proportion of patients Brugada syndrome [0]. We still have to rely on this ECG marker () for the diagnosis of the Brugada syndrome in survivors of idiopathic polymorphic ventricular tachycardia or ventricular fibrillation arrest and their healthy relatives although the specificity of the is questionable [0,]. In subjects without documented or suspected ventricular tachycardia/ ventricular fibrillation, the specificity of ST elevation following administration of a class I drug is still not clear [,3]. Clinical implications The new six-lead ECG ( V to V 3 and V to V 3 ) with procainamide is safe, easy to perform and should be helpful in the detection of the in sudden unexplained death syndrome, especially in the relatives of the NSDUS patients. We propose this method as a screening tool for the Brugada syndrome in sudden unexplained death syndrome survivors from polymorphic ventricular tachycardia/ventricular fibrillation cardiac arrest and their healthy relatives. It could also be used as a surrogate marker to assess therapeutic efficacy of antiarrhythomogenic intervention. We thank Professor Chitr Sitthi-Amorn for his excellent advice and support. This work has been supported by Thailand Research Fund (RTA/08/540). References [] Parrisk RG, Tucker M, Ing R, Encamacion C, Ebergardt M. Sudden unexplained death syndrome in Southeast Asian refugees: A review of CDC surveillance. MMWR CDC Surveil Summ 987; 36: 43SS 53SS. [] Tatsanavivat P, Chirawatkul A, Klungboonkrong V et al. Sudden and unexplained deaths in sleep (Lai Tai) of young men in rural north-eastern Thailand. Int J Epidemiol 99; : [3] 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: Eur Heart J, Vol., issue 4, December 00

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