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Sudden death in high-risk family members: Brugada syndrome
Sudden Death in High-Risk Family Members: Brugada Syndrome Pedro Brugada,
MD,
Ramon Brugada,
MD,
and Josep Brugada,
MD
Brugada syndrome (an electrocardiographic pattern of right bundle branch block, ST segment elevation in leads V1 to V3, and sudden death) is genetically determined and caused by mutations in the cardiac ion channels. The mode of inheritance of the disease is autosomal dominant in half of familial forms. Sudden death may, however, occur from a variety of causes in relatives and patients with this syndrome. Twenty-five Flemish families with this syndrome with a total of 334 members were studied. Affected members were recognized by means of the typical electrocardiogram of the syndrome, either occurring spontaneously or after the intravenous administration of antiarrhythmic drugs. Sudden deaths in these families were classified as related or not to the syndrome by analysis of the data at the time of the event, mode of inheritance of the disease, and data provided by survivors. Of the 25 families with the syndrome, 18 were symptomatic (at least 1 sudden death related to the syndrome) and 7 were asymptomatic (no sudden deaths related to the syndrome). In total, there were 42 sudden cardiac deaths (12% incidence). Twenty-four sudden deaths were related to the syndrome and
all happened in symptomatic families. Eighteen sudden deaths (43% of total sudden deaths) were not related to the syndrome (9 cases) or were of unclear cause (9 cases). Three of them occurred in 2 asymptomatic families and the remaining 15 in 5 symptomatic families. A total of 24 of the 50 affected members (47%) and 18 of the 284 unaffected members (6%) had aborted sudden death. This difference in the incidence of sudden death was statistically significant (p <0.0001). Patients with aborted sudden death caused by the syndrome were younger than patients with sudden death of other or unclear causes (38 ⴞ 4 years vs 59 ⴞ 3 years respectively; p ⴝ 0.0003). In families at high risk of sudden death because of genetically determined diseases, the main cause of sudden death remains the disease itself. However, almost half of sudden deaths are caused by unrelated diseases or from unclear causes. Accurate classification of the causes of sudden death is mandatory for appropriate analysis of the causes of death when designing preventive treatments. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;86(suppl):40K– 43K
1992 we described a syndrome characterized by of syncope or sudden death caused by Irapidnepisodes polymorphic ventricular arrhythmias in patients
or who has syncopal episodes caused by documented polymorphic ventricular tachycardia. However, the decision regarding in whom and when to implant a cardioverter defibrillator in asymptomatic carriers of the disease remains difficult. In a previous publication we5 could not find any clinical or electrophysiological predictors for recurrence of the ventricular arrhythmias (or for the first occurrence in asymptomatic carriers). In other genetically determined diseases, a family history of sudden death frequently has been predictive of the occurrence of sudden death.15,16 However, sudden death has many different possible causes and it is not necessarily related to the genetically determined diseases in affected families. Since 1990, we undertook a prospective study of the syndrome of right bundle branch block, ST segment elevation, and sudden death by including wherever possible clinical, angiographic and electrophysiologic information from patients presented to us by colleagues from all over the world. This project has entered a new phase with the opening of an Internet website (http://www.brugada.crtia.be) that allows direct registration of patient data. However, participation in databases has some limitations, such as the impossibility of standardizing diagnostic, treatment, and follow-up approaches, particularly since both wealthy and poor countries are involved in the registry. To avoid biases caused by these limitations, in the present study we analyze data on the incidence and
1
with structurally normal hearts who have a peculiar electrocardiogram (Figure 1). The electrocardiogram shows ST segment elevation in the right precordial leads V1 to V3 and a pattern mimicking a right bundle branch block. Since our description of the syndrome, the number of cases identified worldwide has increased dramatically.2–13 All publications confirm the malignant character of this syndrome. Sudden death may occur irrespective of the previous occurrence of symptoms such as syncope.2–13 We14 recently reported the first 3 mutations associated with this syndrome. These mutations affect the function of the sodium channel encoded by the gene SCN5A. Both genetic and clinical data confirm that the mode of inheritance of this syndrome is autosomal dominant. The only effective treatment to protect against sudden death is, at present, the implantable cardioverter defibrillator.3– 8 The decision is straightforward to implant a cardioverter defibrillator in a patient with the syndrome who has survived an episode of cardiac arrest From the Cardiovascular Research and Teaching Institute, Aalst, Belgium; Baylor College of Medicine, Houston, Texas, USA; and Unitat d’Arritmias, Hospital Clinic, Barcelona, Spain. Address for reprints: Pedro Brugada, MD, Cardiovascular Research and Teaching Institute, Aalst, Cardiovascular Center, OLV Hospital, Moorselbaan 164, 9300, Aalst, Belgium.
40K
©2000 by Excerpta Medica, Inc. All rights reserved.
0002-9149/00/$ – see front matter PII S0002-9149(00)01300-X
TABLE 1 Antiarrhythmic Drugs Given Intravenously to Unmask Patients with Brugada Syndrome but a Normal Electrocardiogram Under Basal Conditions Drug Ajmaline Flecainide Procainamide
FIGURE 1. Twelve-lead electrocardiogram from a young athlete who was resuscitated from almost sudden death caused by a rapid polymorphic ventricular tachycardia. Note the elevation of the ST segment in leads V1 to V3 and the right bundle branch block–like pattern in lead V1. Paper speed is 25 mm/sec.
cause of sudden death in 25 Flemish families with the syndrome being followed by us.
PATIENTS AND METHODS A total of 25 families living in the Flemish area of Belgium were included in this prospective study. The 25 families consisted of 334 members (192 men and 142 women). The number of members was 2– 47 per family. Age ranged from 6 months to 92 years (mean 52 ⫾ 27 years). There were 18 families with at least 1 aborted sudden death related to the syndrome—symptomatic families—and 7 families with no death or other symptoms related to the disease—asymptomatic families. The symptomatic families consisted of a total of 209 members (125 men, 84 women). The asymptomatic families consisted of 125 members (67 men, 58 women) (no significant differences in sex distribution between symptomatic and asymptomatic families). Identification of affected members: Three different methods were used to identify affected individuals: 1. A resting electrocardiogram showing the typical electrocardiogram was considered diagnostic of the disease (Figure 1). 2. In family members with a normal resting electrocardiogram, ajmaline, flecainide, or procainamide was given intravenously under continuous electrocardiographic monitoring (Table 1). Miyazaki et al17 showed that these antiarrhythmic drugs may
Dose 0.7 mg/kg body weight in 5 min 2 mg/kg body weight in 10 min 10 mg/kg body weight in 10 min
modulate the ST segment elevation in patients with the syndrome. We have shown that there is a 100% correlation between the results of the test and the genotype.18 Thus, family members showing a typical electrocardiogram after the administration of one of these drugs were considered carriers of the disease. An example is shown in Figure 2. 3. Informed consent to all parts of this study was obtained from all individuals. Classification of the causes of sudden death: In the syndrome of right bundle branch block and ST elevation, death often occurs unexpectedly and without any warning symptoms. Because death is caused by a sudden and rapid polymorphic ventricular arrhythmia, death is instantaneous, and only instantaneous death was considered possibly related to the disease. Death was considered related to the disease when the treating physicians documented the ventricular arrhythmia in a patient having the typical electrocardiogram of the syndrome.2 Death was also considered related to the disease in patients known to have the typical electrocardiogram and dying suddenly at night, a feature quite common in this syndrome. By definition, affected members had no evidence of any other heart disease. Sudden death was considered not related to the disease when there was clear evidence for another cause (for instance myocardial infarction) and was considered of unclear cause when the cause was not evident and the mode of inheritance made it unlikely or impossible that the victim had the disease.
RESULTS Of the 334 family members, 50 (15%) were affected. There was a total of 42 aborted sudden deaths (patients resuscitated from sudden cardiac death) giving an incidence of 12% for the total population. Twenty-four sudden deaths were related to the disease and occurred in affected members. That gave an incidence of sudden death of almost 50% in affected members. There was no sudden death from other causes in affected members. Eighteen sudden deaths occurred in the 284 members without evidence of the disease (an incidence of 6%; p ⬍0.0001 as compared with the incidence of sudden death in affected members). No sudden death could be attributed to the syndrome in nonaffected members. Nine sudden deaths were of unclear cause, but the mode of inheritance of the disease made it unlikely that the syndrome was responsible for it. The other 9 sudden deaths were caused by myocardial infarction as assessed from the circumstances of the event. Of importance, of the total 18 sudden deaths not related to the A SYMPOSIUM: ELECTRICAL THERAPIES FOR THE HEART
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FIGURE 2. Twelve-lead electrocardiogram of an individual affected by the syndrome but with a normal electrocardiogram under basal conditions. The effects of the administration of 50 mg intravenous ajmaline are shown. Note the appearance of the typical electrocardiogram during the administration of the drug with ST elevation in leads V1 to V3.
syndrome, 15 sudden deaths occurred in 5 symptomatic families and 3 in 2 asymptomatic families. When we compared data of patients dying suddenly because of the syndrome with patients dying suddenly without relation to the syndrome, we found no differences in the distribution of gender: 17 of the 24 patients dying because of the syndrome and 16 of those dying suddenly from other or unclear causes were male. However, there was a significant difference in terms of mean age: 38 ⫾ 4 years in patients dying related to the syndrome versus 59 ⫾ 3 in patients dying without relation to the syndrome (p ⫽ 0.0003; difference between means 21 ⫾ 4 years; confidence intervals 10 –32 years). Of the 18 symptomatic families, 7 had a previous history of sudden cardiac death and 11 did not. In all the 7 families with a previous history of sudden death, sudden deaths related to the syndrome occurred. Sudden death not related to the syndrome also occurred, however, in 5 of these 7 families. Of the 7 asymptomatic families, only 1 had a previous history of familial sudden death. In this family 2 sudden cardiac deaths occurred that were unrelated to the syndrome. In 1 additional asymptomatic family without a previous family history of sudden cardiac death, 1 sudden cardiac death not related to the syndrome occurred during follow-up. When data from symptomatic and asymptomatic families were considered together, a relation could not be found between a family history of sudden cardiac 42K THE AMERICAN JOURNAL OF CARDIOLOGY姞
death and sudden death related to the syndrome (Table 2). A type-2 error cannot be excluded because of the small sample size.
DISCUSSION This study shows that the exact causes of sudden death have to be carefully studied and classified before giving to each sudden death a mechanistic significance when analyzing families with hereditary diseases that can cause sudden death. Of the 42 sudden deaths that occurred in the 25 families affected with the syndrome of right bundle branch block, ST elevation, and sudden death, only 24 sudden deaths (57%) were clearly related to the syndrome. The other 43% deaths were either not related to the familial disease or of unclear cause. This is of importance when analyzing possible risk factors for sudden death with the aim of recognizing individual members who may benefit from effective preventive therapies. At present, we still do not know how to identify those asymptomatic individuals affected by the disease who may become symptomatic in the future.5 In many other familial diseases, a family history of sudden death has been found predictive of further episodes of sudden cardiac death.16 That was not the case in our study once the exact causes of sudden cardiac death were analyzed in a very critical way. It is not appropriate to conclude that sudden death was due to the disease in a family with a genetic disorder predisposing to sudden arrhythmic death.
VOL. 86 (9A)
NOVEMBER 2, 2000
TABLE 2 Relation Between Family History of Sudden Cardiac Death and Sudden Cardiac Death Related to the Syndrome of Right Bundle Branch Block, ST Segment Elevation, and Sudden Death: 25 Affected Families Family History of Sudden Death (No. of Families) ⫹ Sudden death related to Brugada syndrome ⫹ ⫺
⫺
7 1
5 12 p⫽NS
NS ⫽ not significant.
Ideally, the exact causes of sudden death must be known. However, as shown in this study, this is not an easy task. Even after careful analysis of the circumstances of death with the survivors and witnesses, the cause of sudden death in 9 of 42 sudden deaths (21%) remained totally unclear; although a myocardial infarction was strongly suspected as cause of death in another 9 patients (21%), a definite proof of this diagnosis was not available.
LIMITATIONS In the present study, the most important limitation remains the exact classification of the causes of sudden cardiac death. This limitation is, however, almost universally present in any study analyzing any aspect of sudden cardiac death. Another important limitation is the unavailability of genotypic characterization of all studied members. Genetic defects are quite difficult to investigate, and therefore we did not consider it appropriate to withhold the present information.
CONCLUSIONS In families affected by a hereditary disease causing sudden death and with an autosomal dominant pattern of transmission, most sudden deaths are related to the disease in affected members. Unaffected members, on the contrary, may die suddenly because of other diseases. About one fifth of sudden deaths are of unclear cause and they occur both in symptomatic and asymptomatic families with the syndrome of right bundle branch block, ST segment elevation, and sudden
death. When assessing risk factors for sudden death in these families, accurate classification of the causes of sudden death is mandatory to avoid overestimation of the prognostic value of a family history of sudden death. 1. Brugada P, Brugada J. Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol 1992;20:1391–1396. 2. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, Tunsanga K, Kuasirikul S, Malasit P, Tansupasawadikul S, Tatsanavivat P. Arrhythmogenic markers for the sudden unexplained death syndrome in Thai men. Circulation 1997;96:2595–2600. 3. Tatsanavivat P, Chiravatkul A, Klungboonkrong V, Chaisiri S, Jarerntanyaruk L, Munger RG, Saowakontha S. Sudden and unexplained deaths in sleep (Laitai) of young men in rural northeastern Thailand. J Epidemiol 1992;21:904 –910. 4. Brugada J, Brugada P. Further characterization of the syndrome of right bundle branch block, persistent ST segment elevation and sudden death. J Cardiovasc Electrophysiol 1997;8:325–331. 5. Brugada J, Brugada R, Brugada P. Right bundle branch block and ST segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998;97:457– 460. 6. Atarashi H, Ogawa S, Harumi K, Hayakawa H, Sugimoto T, Okada R, Murayama M, Toyama J. Characteristics of patients with right bundle branch block and ST-segment elevation in right precordial leads. Am J Cardiol 1996; 78:581–583. 7. Kanasuki H, Ahnishi S, Ohtuka M, et al. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation 1995;95:2277–2285. 8. D’Onofrio A, Cuomo S, Musto B, Boccalatte A. Right bundle branch block, persistent ST-segment elevation in V1–V3 and sudden cardiac death: always a distinct syndrome? G Ital Cardiol 1995;25:1171–1175. 9. Matsuo K, Shimizu W, Kurita T, Inagaki M, Aihara N, Kamakura S. Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:508 –512. 10. Kobayashi T, Shintani U, Yamamoto T, Shida S, Isshiki N, Tanaka T, Ohmoto Y, Kitamura M, Kato S, Misaki M. Familial occurrence of electrocardiographic abnormalities of the Brugada-type. Intern Med 1996;35:637– 640. 11. Viskin S, Belhassen B. Clinical problem-solving: when you live only twice. N Engl J Med 1995;332:1221–1225. 12. Belhassen B, Viskin S. Idiopathic ventricular tachycardia and fibrillation. J Cardiovasc Electrophysiol 1993;4:356 –358. 13. Alings M, Wilde A. Brugada syndrome: clinical data and suggested pathophysiological mechanisms. Circulation 1999;99:666 – 673. 14. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–296. 15. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vinvent GM. Multiple mechanisms in the long QT syndrome: current knowledge, gaps and future directions. Circulation 1996;94:1996 –2012. 16. Priori SG, Barhanin J, Hauer RN, Haverkamp W, Jongsma HJ, Kleber AG, McKenna WJ, Roden DM, Rudy Y, Schwartz K, Schwartz PJ, Towbin JA, Wilde A. Genetic and molecular basis of cardiac arrhythmias. Eur Heart J 1999;20: 174 –195. 17. 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 1996;27:1061–1070. 18. Brugada J, Brugada R, Wang Q, Potenza D, Brugada P, Towbin J. Unmasking of genotype and phenotype abnormalities by administration of class I antiarrhythmic drugs in patients with sudden death (abstract). Eur Heart J 1998;19: 557.
A SYMPOSIUM: ELECTRICAL THERAPIES FOR THE HEART
43K
MD,
Ramon Brugada,
MD,
and Josep Brugada,
MD
Brugada syndrome (an electrocardiographic pattern of right bundle branch block, ST segment elevation in leads V1 to V3, and sudden death) is genetically determined and caused by mutations in the cardiac ion channels. The mode of inheritance of the disease is autosomal dominant in half of familial forms. Sudden death may, however, occur from a variety of causes in relatives and patients with this syndrome. Twenty-five Flemish families with this syndrome with a total of 334 members were studied. Affected members were recognized by means of the typical electrocardiogram of the syndrome, either occurring spontaneously or after the intravenous administration of antiarrhythmic drugs. Sudden deaths in these families were classified as related or not to the syndrome by analysis of the data at the time of the event, mode of inheritance of the disease, and data provided by survivors. Of the 25 families with the syndrome, 18 were symptomatic (at least 1 sudden death related to the syndrome) and 7 were asymptomatic (no sudden deaths related to the syndrome). In total, there were 42 sudden cardiac deaths (12% incidence). Twenty-four sudden deaths were related to the syndrome and
all happened in symptomatic families. Eighteen sudden deaths (43% of total sudden deaths) were not related to the syndrome (9 cases) or were of unclear cause (9 cases). Three of them occurred in 2 asymptomatic families and the remaining 15 in 5 symptomatic families. A total of 24 of the 50 affected members (47%) and 18 of the 284 unaffected members (6%) had aborted sudden death. This difference in the incidence of sudden death was statistically significant (p <0.0001). Patients with aborted sudden death caused by the syndrome were younger than patients with sudden death of other or unclear causes (38 ⴞ 4 years vs 59 ⴞ 3 years respectively; p ⴝ 0.0003). In families at high risk of sudden death because of genetically determined diseases, the main cause of sudden death remains the disease itself. However, almost half of sudden deaths are caused by unrelated diseases or from unclear causes. Accurate classification of the causes of sudden death is mandatory for appropriate analysis of the causes of death when designing preventive treatments. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;86(suppl):40K– 43K
1992 we described a syndrome characterized by of syncope or sudden death caused by Irapidnepisodes polymorphic ventricular arrhythmias in patients
or who has syncopal episodes caused by documented polymorphic ventricular tachycardia. However, the decision regarding in whom and when to implant a cardioverter defibrillator in asymptomatic carriers of the disease remains difficult. In a previous publication we5 could not find any clinical or electrophysiological predictors for recurrence of the ventricular arrhythmias (or for the first occurrence in asymptomatic carriers). In other genetically determined diseases, a family history of sudden death frequently has been predictive of the occurrence of sudden death.15,16 However, sudden death has many different possible causes and it is not necessarily related to the genetically determined diseases in affected families. Since 1990, we undertook a prospective study of the syndrome of right bundle branch block, ST segment elevation, and sudden death by including wherever possible clinical, angiographic and electrophysiologic information from patients presented to us by colleagues from all over the world. This project has entered a new phase with the opening of an Internet website (http://www.brugada.crtia.be) that allows direct registration of patient data. However, participation in databases has some limitations, such as the impossibility of standardizing diagnostic, treatment, and follow-up approaches, particularly since both wealthy and poor countries are involved in the registry. To avoid biases caused by these limitations, in the present study we analyze data on the incidence and
1
with structurally normal hearts who have a peculiar electrocardiogram (Figure 1). The electrocardiogram shows ST segment elevation in the right precordial leads V1 to V3 and a pattern mimicking a right bundle branch block. Since our description of the syndrome, the number of cases identified worldwide has increased dramatically.2–13 All publications confirm the malignant character of this syndrome. Sudden death may occur irrespective of the previous occurrence of symptoms such as syncope.2–13 We14 recently reported the first 3 mutations associated with this syndrome. These mutations affect the function of the sodium channel encoded by the gene SCN5A. Both genetic and clinical data confirm that the mode of inheritance of this syndrome is autosomal dominant. The only effective treatment to protect against sudden death is, at present, the implantable cardioverter defibrillator.3– 8 The decision is straightforward to implant a cardioverter defibrillator in a patient with the syndrome who has survived an episode of cardiac arrest From the Cardiovascular Research and Teaching Institute, Aalst, Belgium; Baylor College of Medicine, Houston, Texas, USA; and Unitat d’Arritmias, Hospital Clinic, Barcelona, Spain. Address for reprints: Pedro Brugada, MD, Cardiovascular Research and Teaching Institute, Aalst, Cardiovascular Center, OLV Hospital, Moorselbaan 164, 9300, Aalst, Belgium.
40K
©2000 by Excerpta Medica, Inc. All rights reserved.
0002-9149/00/$ – see front matter PII S0002-9149(00)01300-X
TABLE 1 Antiarrhythmic Drugs Given Intravenously to Unmask Patients with Brugada Syndrome but a Normal Electrocardiogram Under Basal Conditions Drug Ajmaline Flecainide Procainamide
FIGURE 1. Twelve-lead electrocardiogram from a young athlete who was resuscitated from almost sudden death caused by a rapid polymorphic ventricular tachycardia. Note the elevation of the ST segment in leads V1 to V3 and the right bundle branch block–like pattern in lead V1. Paper speed is 25 mm/sec.
cause of sudden death in 25 Flemish families with the syndrome being followed by us.
PATIENTS AND METHODS A total of 25 families living in the Flemish area of Belgium were included in this prospective study. The 25 families consisted of 334 members (192 men and 142 women). The number of members was 2– 47 per family. Age ranged from 6 months to 92 years (mean 52 ⫾ 27 years). There were 18 families with at least 1 aborted sudden death related to the syndrome—symptomatic families—and 7 families with no death or other symptoms related to the disease—asymptomatic families. The symptomatic families consisted of a total of 209 members (125 men, 84 women). The asymptomatic families consisted of 125 members (67 men, 58 women) (no significant differences in sex distribution between symptomatic and asymptomatic families). Identification of affected members: Three different methods were used to identify affected individuals: 1. A resting electrocardiogram showing the typical electrocardiogram was considered diagnostic of the disease (Figure 1). 2. In family members with a normal resting electrocardiogram, ajmaline, flecainide, or procainamide was given intravenously under continuous electrocardiographic monitoring (Table 1). Miyazaki et al17 showed that these antiarrhythmic drugs may
Dose 0.7 mg/kg body weight in 5 min 2 mg/kg body weight in 10 min 10 mg/kg body weight in 10 min
modulate the ST segment elevation in patients with the syndrome. We have shown that there is a 100% correlation between the results of the test and the genotype.18 Thus, family members showing a typical electrocardiogram after the administration of one of these drugs were considered carriers of the disease. An example is shown in Figure 2. 3. Informed consent to all parts of this study was obtained from all individuals. Classification of the causes of sudden death: In the syndrome of right bundle branch block and ST elevation, death often occurs unexpectedly and without any warning symptoms. Because death is caused by a sudden and rapid polymorphic ventricular arrhythmia, death is instantaneous, and only instantaneous death was considered possibly related to the disease. Death was considered related to the disease when the treating physicians documented the ventricular arrhythmia in a patient having the typical electrocardiogram of the syndrome.2 Death was also considered related to the disease in patients known to have the typical electrocardiogram and dying suddenly at night, a feature quite common in this syndrome. By definition, affected members had no evidence of any other heart disease. Sudden death was considered not related to the disease when there was clear evidence for another cause (for instance myocardial infarction) and was considered of unclear cause when the cause was not evident and the mode of inheritance made it unlikely or impossible that the victim had the disease.
RESULTS Of the 334 family members, 50 (15%) were affected. There was a total of 42 aborted sudden deaths (patients resuscitated from sudden cardiac death) giving an incidence of 12% for the total population. Twenty-four sudden deaths were related to the disease and occurred in affected members. That gave an incidence of sudden death of almost 50% in affected members. There was no sudden death from other causes in affected members. Eighteen sudden deaths occurred in the 284 members without evidence of the disease (an incidence of 6%; p ⬍0.0001 as compared with the incidence of sudden death in affected members). No sudden death could be attributed to the syndrome in nonaffected members. Nine sudden deaths were of unclear cause, but the mode of inheritance of the disease made it unlikely that the syndrome was responsible for it. The other 9 sudden deaths were caused by myocardial infarction as assessed from the circumstances of the event. Of importance, of the total 18 sudden deaths not related to the A SYMPOSIUM: ELECTRICAL THERAPIES FOR THE HEART
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FIGURE 2. Twelve-lead electrocardiogram of an individual affected by the syndrome but with a normal electrocardiogram under basal conditions. The effects of the administration of 50 mg intravenous ajmaline are shown. Note the appearance of the typical electrocardiogram during the administration of the drug with ST elevation in leads V1 to V3.
syndrome, 15 sudden deaths occurred in 5 symptomatic families and 3 in 2 asymptomatic families. When we compared data of patients dying suddenly because of the syndrome with patients dying suddenly without relation to the syndrome, we found no differences in the distribution of gender: 17 of the 24 patients dying because of the syndrome and 16 of those dying suddenly from other or unclear causes were male. However, there was a significant difference in terms of mean age: 38 ⫾ 4 years in patients dying related to the syndrome versus 59 ⫾ 3 in patients dying without relation to the syndrome (p ⫽ 0.0003; difference between means 21 ⫾ 4 years; confidence intervals 10 –32 years). Of the 18 symptomatic families, 7 had a previous history of sudden cardiac death and 11 did not. In all the 7 families with a previous history of sudden death, sudden deaths related to the syndrome occurred. Sudden death not related to the syndrome also occurred, however, in 5 of these 7 families. Of the 7 asymptomatic families, only 1 had a previous history of familial sudden death. In this family 2 sudden cardiac deaths occurred that were unrelated to the syndrome. In 1 additional asymptomatic family without a previous family history of sudden cardiac death, 1 sudden cardiac death not related to the syndrome occurred during follow-up. When data from symptomatic and asymptomatic families were considered together, a relation could not be found between a family history of sudden cardiac 42K THE AMERICAN JOURNAL OF CARDIOLOGY姞
death and sudden death related to the syndrome (Table 2). A type-2 error cannot be excluded because of the small sample size.
DISCUSSION This study shows that the exact causes of sudden death have to be carefully studied and classified before giving to each sudden death a mechanistic significance when analyzing families with hereditary diseases that can cause sudden death. Of the 42 sudden deaths that occurred in the 25 families affected with the syndrome of right bundle branch block, ST elevation, and sudden death, only 24 sudden deaths (57%) were clearly related to the syndrome. The other 43% deaths were either not related to the familial disease or of unclear cause. This is of importance when analyzing possible risk factors for sudden death with the aim of recognizing individual members who may benefit from effective preventive therapies. At present, we still do not know how to identify those asymptomatic individuals affected by the disease who may become symptomatic in the future.5 In many other familial diseases, a family history of sudden death has been found predictive of further episodes of sudden cardiac death.16 That was not the case in our study once the exact causes of sudden cardiac death were analyzed in a very critical way. It is not appropriate to conclude that sudden death was due to the disease in a family with a genetic disorder predisposing to sudden arrhythmic death.
VOL. 86 (9A)
NOVEMBER 2, 2000
TABLE 2 Relation Between Family History of Sudden Cardiac Death and Sudden Cardiac Death Related to the Syndrome of Right Bundle Branch Block, ST Segment Elevation, and Sudden Death: 25 Affected Families Family History of Sudden Death (No. of Families) ⫹ Sudden death related to Brugada syndrome ⫹ ⫺
⫺
7 1
5 12 p⫽NS
NS ⫽ not significant.
Ideally, the exact causes of sudden death must be known. However, as shown in this study, this is not an easy task. Even after careful analysis of the circumstances of death with the survivors and witnesses, the cause of sudden death in 9 of 42 sudden deaths (21%) remained totally unclear; although a myocardial infarction was strongly suspected as cause of death in another 9 patients (21%), a definite proof of this diagnosis was not available.
LIMITATIONS In the present study, the most important limitation remains the exact classification of the causes of sudden cardiac death. This limitation is, however, almost universally present in any study analyzing any aspect of sudden cardiac death. Another important limitation is the unavailability of genotypic characterization of all studied members. Genetic defects are quite difficult to investigate, and therefore we did not consider it appropriate to withhold the present information.
CONCLUSIONS In families affected by a hereditary disease causing sudden death and with an autosomal dominant pattern of transmission, most sudden deaths are related to the disease in affected members. Unaffected members, on the contrary, may die suddenly because of other diseases. About one fifth of sudden deaths are of unclear cause and they occur both in symptomatic and asymptomatic families with the syndrome of right bundle branch block, ST segment elevation, and sudden
death. When assessing risk factors for sudden death in these families, accurate classification of the causes of sudden death is mandatory to avoid overestimation of the prognostic value of a family history of sudden death. 1. Brugada P, Brugada J. Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol 1992;20:1391–1396. 2. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, Tunsanga K, Kuasirikul S, Malasit P, Tansupasawadikul S, Tatsanavivat P. Arrhythmogenic markers for the sudden unexplained death syndrome in Thai men. Circulation 1997;96:2595–2600. 3. Tatsanavivat P, Chiravatkul A, Klungboonkrong V, Chaisiri S, Jarerntanyaruk L, Munger RG, Saowakontha S. Sudden and unexplained deaths in sleep (Laitai) of young men in rural northeastern Thailand. J Epidemiol 1992;21:904 –910. 4. Brugada J, Brugada P. Further characterization of the syndrome of right bundle branch block, persistent ST segment elevation and sudden death. J Cardiovasc Electrophysiol 1997;8:325–331. 5. Brugada J, Brugada R, Brugada P. Right bundle branch block and ST segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998;97:457– 460. 6. Atarashi H, Ogawa S, Harumi K, Hayakawa H, Sugimoto T, Okada R, Murayama M, Toyama J. Characteristics of patients with right bundle branch block and ST-segment elevation in right precordial leads. Am J Cardiol 1996; 78:581–583. 7. Kanasuki H, Ahnishi S, Ohtuka M, et al. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation 1995;95:2277–2285. 8. D’Onofrio A, Cuomo S, Musto B, Boccalatte A. Right bundle branch block, persistent ST-segment elevation in V1–V3 and sudden cardiac death: always a distinct syndrome? G Ital Cardiol 1995;25:1171–1175. 9. Matsuo K, Shimizu W, Kurita T, Inagaki M, Aihara N, Kamakura S. Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:508 –512. 10. Kobayashi T, Shintani U, Yamamoto T, Shida S, Isshiki N, Tanaka T, Ohmoto Y, Kitamura M, Kato S, Misaki M. Familial occurrence of electrocardiographic abnormalities of the Brugada-type. Intern Med 1996;35:637– 640. 11. Viskin S, Belhassen B. Clinical problem-solving: when you live only twice. N Engl J Med 1995;332:1221–1225. 12. Belhassen B, Viskin S. Idiopathic ventricular tachycardia and fibrillation. J Cardiovasc Electrophysiol 1993;4:356 –358. 13. Alings M, Wilde A. Brugada syndrome: clinical data and suggested pathophysiological mechanisms. Circulation 1999;99:666 – 673. 14. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–296. 15. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vinvent GM. Multiple mechanisms in the long QT syndrome: current knowledge, gaps and future directions. Circulation 1996;94:1996 –2012. 16. Priori SG, Barhanin J, Hauer RN, Haverkamp W, Jongsma HJ, Kleber AG, McKenna WJ, Roden DM, Rudy Y, Schwartz K, Schwartz PJ, Towbin JA, Wilde A. Genetic and molecular basis of cardiac arrhythmias. Eur Heart J 1999;20: 174 –195. 17. 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 1996;27:1061–1070. 18. Brugada J, Brugada R, Wang Q, Potenza D, Brugada P, Towbin J. Unmasking of genotype and phenotype abnormalities by administration of class I antiarrhythmic drugs in patients with sudden death (abstract). Eur Heart J 1998;19: 557.
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