Proportion and prognosis of healthy people with coved or saddle-back type ST segment elevation in the right precordial leads during 10 years follow-up

Masao Sakabea, Akira Fujikia,*, Masanao Tanib, Kunihiro Nishidaa, Koichi Mizumakia and Hiroshi Inouea

a The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
b Cardiovascular Division, Itoigawa General Hospital, Niigata, Japan

* Corresponding author. Akira Fujiki, MD, The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. Tel.: +81-76-434-7295 Fax: +81-76-434-5026
E-mail address: fujiki{at}ms.toyama-mpu.ac.jp

Received 9 February 2003; revised 22 May 2003; accepted 2 June 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 
Aims The aim of this study was to investigate long-term proportion and prognosis of healthy subjects with right precordial ST segment elevation without family history of sudden death.

Methods and results We followed up electrocardiograms (ECGs) of 3339 healthy subjects (male/female 2646/693) who underwent periodical medical examination form 1992 to 2001 to determine the relationship between year-to-year changes of ST segment morphology and the risk of fatal arrhythmias. Inclusion criterion was defined as presenting either coved or saddle back type ST segment elevation (>0.2mV) in the right precordial leads. The cumulative total subjects who showed Brugada-like ECG changes at least once throughout the follow-up period were 69 (male/female 67/2; age 47.9±8.9 years, 2.1% of total subjects). During a follow-up period, annual mean proportion of coved or saddle back type ST elevation in the right precordial leads was 1.22±0.23% (0.88–1.88%). The morphological pattern of ST segment elevation was saddle-back in 77.3±7.9% and coved in 22.7±7.9% of subjects. Throughout the follow-up period, 39 subjects (56.5%) showed changes in ST segment elevation pattern. Twenty-nine subjects (42.0%) showed normalization of ST segment elevation at least once. Sixty-nine subjects were followed for a period of one to 10 years (median 4 years, interquartile range 4–8 years). Only one subject with persistent saddle-back type ST elevation had episodes of ventricular fibrillation (VF).

Conclusions The average proportion of healthy subject who had coved or saddle-back type of ST elevation in the right precordial leads without family history of sudden death was 1.22% and the risk of fatal arrhythmias was low (1/393.5 subject-years).

Key Words: Brugada syndrome • Sudden death • Ventricular fibrillation • Healthy population


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 
In 1992, Brugada and Brugada1reported eight patients who showed a right bundle branch block pattern with ST segment elevation in the right precordial leadswithout structural heart disease, and aborted sudden cardiac death. Since then, etiology, electrophysiologicalmechanism and genetics of this syndrome have been studied extensively. Amiodarone or beta-adrenergic blocking agents do not protect sudden death, but an implantable cardioverter defibrillator (ICD) does.2,3Thus, at present ICD is the only effective device for prevention of sudden cardiac death in patients with Brugada syndrome.4Recent agenda has focused on the risk evaluation of asymptomatic patients who show Brugada-like ECG (coved or saddle-back type of ST elevation in the right precordial leads) but have never experienced any episodes.

Brugada et al. reported that asymptomatic patients recognized by chance or discovered in a family study have a 8% incidence of arrhythmic events during a mean follow-up period of 27±29 months,2whose outcome were significantly benign comparing with symptomatic subjects. There are, however, only a few published reports that investigate the prevalence of cardiac events and prognosis of healthy subject having Brugada-like ECG without family history of Brugada syndrome and there are no established guidelines for management of these subjects. Therefore, this study was undertaken to determine the proportion and prognosis of healthy subjects having coved or saddle-back type of ST elevation in the right precordial leads without family history of sudden cardiac death.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 
Proportion of Brugada-type ECG and relationship of year-to-year variability of ST segment to the risk of fatal arrhythmias were determined prospectively in asymptomatic healthy subjects who had underwent periodical medical examination from April 1992 to January 2001. The end-points were defined as unexpected sudden death, syncopal attack and proved fetal arrhythmia.

2.1. Subjects and study design
A total of 3339 subjects (male/female 2646/693; age >18 years) received periodical medical examinations for a general health checkup from 1992 to 2001. Brugada-like ECG pattern was defined as ST segment elevation (>0.2mV) in the right precordial leads with or without right bundle branch block pattern. Secondary causes that could lead to ST segment elevation in the right precordial leads were excluded by clinical history, physical examination, blood test, chest roentgenogram, and transthoracic echocardiography routinely.

The pattern of ST segment elevation was classified as either coved or saddle-back type.5According to consensus report6we defined coved type as a prominent coved ST segment elevation followed by a negative T wave with little or no isoelectric separation without any provocation (without class I antiarrhythmic drug challenge), which was equivalent to type 1. Saddle-back type was characterized as a gradually descending ST segment elevation with a positive or biphasic T wave which was equivalent to type 2.

The onset of Brugada-like ECG sign and the time course of ST elevation pattern were determined by annual recording of 12-lead ECG. All ECGs were recorded at a standard gain of 1mV/10mm and a paper speed of 25mm/s. Three cardiologists read ECG and made diagnosis with agreement of at least two of them.

2.2. Follow-up
We prospectively conducted follow-up study of all subjects from 1992 to 2001. During the follow-up period, all subjects were interviewed about their condition. The time course of ST segment elevation was classified into three categories; (1) sustained saddle-back type, (2) sustained coved type, or (3) fluctuated ST elevation pattern. Subjects who dropped out of the follow-up program were interviewed about their condition by telephone in February 2001.

2.3. Statistical analysis
Data are presented as mean±SD. The median and quartiles were used with regard to follow-up period. A chi-square test was used to assess statistical difference of the ratio of ST segment morphology. A P value of <0.05 was considered statistically significant. The proportion of Brugada-like ECG was summarized as number and percentage of patients.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 
During 10 years follow-up period, the average percentage of participation to periodical medical examinations was 86.9±7.0% among 3339 subjects and the mean proportion of subjects who showed Brugada-like ECG was 1.22±0.23% (Table 1). The pattern of saddle-back type ST elevation was seen more frequently than coved type (77.3±7.9% vs 22.7±7.9%, P<0.005).


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Table 1 Proportion of coved or saddle-back type ST elevation in the right precordial leads

 
The cumulative total subjects who showed Brugada-like ECG changes at least once throughout the follow-up period were 69 (male/female 67/2; age 47.9±8.9 years, 2.1% of total subjects). Only 3 subjects showed prolonged PR interval (max 0.22s). They were followed for a period of one to 10 years (median 4 years, interquartile range 4–8 years). Throughout the follow-up period, the pattern of ST elevation was maintained in 30 (43.5%) subjects (saddle-back type 25 and coved type 5), and fluctuated in 39 (56.5%) subjects (Fig. 1). In the latter group, 29 subjects showed temporal or continuous normalization of ECG during the follow-up period.



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Fig. 1 Annual changes of ECG of a 59-year-old man without any episode of ventricular arrhythmias during follow-up period. Pattern of ST segment elevation during follow up period changed. In 1995 typical coved type of ST elevation was seen.

 
Among them, a 36-year-old man with persistent saddle-back type ST elevation (Fig. 2) had a syncopal episode 4 years after the initial medical check up. Holter ECG and 2D-echocardiogram showed no abnormality and no further examination was performed at that time. Three years later he underwent electrophysiological study because of recurrence of nocturnal syncopal attack. Ventricular fibrillation (VF) was induced with double extrastimuli applied to the right ventricular outflow tract (Fig. 3). After implantation of ICD, the spontaneous occurrence of VF episode was documented with ICD memory (Fig. 4A). ECG recorded immediately after an episode of VF revealed a sign of coved type ST elevation (Fig. 4B).



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Fig. 2 Annual changes of ECG of a 36-year-old man with an episode of ventricular fibrillation during follow-up period. Pattern of ST segment was fixed as saddle–back type for 9 years.

 


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Fig. 3 Ventricular fibrillation induced by extrastimulation. Ventricular fibrillation was induced with double extrastimuli (S1S1=400ms, S1S2=260ms, S2S3=210ms) applied to the right ventricular outflow tract in the same patient as shown in Fig. 2.

 


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Fig. 4 Spontaneous ventricular fibrillation episode (ICD recording) and coved type of ST change just after syncope. ICD confirmed the occurrence of spontaneous ventricular fibrillation and effectively terminated it. Immediately after an episode of ventricular fibrillation, ECG showed coved type of ST elevation in the same patient as shown in Fig. 2.

 
Five subjects had dropped out of follow-up by January 2001 because of retirement from company. None of the remaining subjects suffered from unexpected sudden death, syncopal attack and fatal arrhythmia. Taken together, in subjects with Brugada-like ECG, we experienced only one subject who had episodes of VF among 393.5 subject-years.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 
The present study revealed that the average proportion of coved or saddle-back type of ST elevation in the right precordial leads who had no family history of sudden death was 1.22% and the risk of fatal arrhythmias was 0.25%/year.

4.1. Proportion of Brugada sign and variation over time
Data on the proportion of Brugada sign in healthy population are limited. Matsuo et al.7reported that the prevalence of the Brugada-type ECG was 146.2 in 100 000 persons or incidence was 14.2 per 100 000 person-years. They also revealed that mortality is significantly higher in people with the Brugada-type ECG than in control subjects.7So far as we know, this was the only report that investigated the prevalence, incidence and long-term prognosis in general population. Although they documented seven subjects suffering from unexpected sudden death, the occurrence of fatal ventricular arrhythmias was not documented in their death. In addition, previous reports7–11did not evaluate the relationship between year-to-year variation of ST segment morphology and risk of fatal arrhythmias.

Our data demonstrated that the average proportion of Brugada-like ECG during 10 years was 1.22±0.23%, which was similar to previous data (0.05–6%).7–10The difference in proportion may be due to age distribution, race of subjects and difference of diagnostic criteria for Brugada ECG sign. In our study population 29 of 69 subjects (42.0%) showed temporal normalization of ECG during the follow-up period. Normalization of ST segment pattern might lead to an underestimation of proportion of subjects with Brugada-like ECG. According to the study for symptomatic Brugada syndrome, patients displaying transient normalization of the ECG pattern were at a similar risk for VF and sudden death as those with persistent ST elevation.12

4.2. Risk stratification of asymptomatic subjects with Brugada ECG sign
It is still unclear about natural history and risk of sudden cardiac death of asymptomatic form of Brugada syndrome. Takenaka reported electropharmacological and electrophysiological characteristics of an asymptomatic patient of Brugada syndrome.13Although asymptomatic subjects could have the same arrhythmogenic substrate as symptomatic Brugada syndrome, the pharmacological intervention could not predict clinical arrhythmic events14and the value of programmed electrical stimulation for risk stratification is still controversial.11,15

Brugada et al. reported arrhythmic events in 16 of 190 asymptomatic subjects (8%) during a follow up period of 27±29 months.2The incidence was much higher as compared with other reports,14,16because their population included subjects discovered in a family of overt Brugada syndrome. For isolated asymptomatic subjects, previous studies14,16indicated the prognosis was relatively benign as in the present study. Risk of sudden death per year among healthy subjects with Brugada ECG sign ranged from 0.01%7to 0.39%10in Japan. In the present study, annual rate of sudden cardiac death with asymptomatic subject showing Brugada-like ECG was estimated approximately as 0.25% (1/393.5). Our subjects with Brugada-like ECG but without prior syncopal episodes could be at an intermediate risk as Priori et al.described.11

French investigators9reported the prevalence of saddle-back type ST elevation in subjects who had no evidence of structural heart disease was 6% and of coved type ST elevation was 0.1%. They suggested that the clinical significance of persistent saddle-back type ST elevation is uncertain, because of the difficulty to differentiate that type from early repolarization syndrome.9All the patients in the original article reported by Brugada et al. showed coved type ST elevation and Japanese investigators suggested that coved type ST elevation might be a warning sign of lethal ventricular arrhythmias.16

The latest consensus report classified ST segment morphology into three types.6Our study population belonged to type 1 or 2, and the patient who suffered from VF episode had shown type 2 of ST segment morphology (Fig. 2). Priori et al. also reported that the morphology of ST segment elevation (whether saddle-back or coved) could not be an outcome predictor.11Although the patient with VF episode had persistent saddle-back ST elevation during annual medical examination, he showed marked coved type ST change just after VF episode. The day-to-day and year-to-year variations of ST segment elevation have been reported in some previous reports17,18and there was a correlation between the augmentation of ST segment elevation and occurrence of ventricular extrasystoles or VF in symptomatic patients.17,19Further studies are needed to establish the optimal diagnostic criteria for the risk of VF episode and sustained saddle-back type ST elevation could not be free from the risk of sudden cardiac death.


    5. Study Limitations
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 
The present study was limited for several reasons. First, thorough examination to exclude structural heart disease was lacking. Unless subjects complained of possible cardiovascular symptoms, further invasive examination was not performed for periodic medical check up. Secondly, distribution of gender was not even because of male predominance (male: female=4: 1) for our medical check up program. This could contribute relatively high prevalence of Brugada-like ECG.20Thirdly, the participation of periodical medical examinations was not complete (mean 86.9%). Fourthly, although no subject had syncope during follow-up period except 36-year male with ICD, we could not exclude the possibility of occurrence of asymptomatic ventricular tachyarrhythmic events among other subjects with Brugada-like ECG. Finally, the major limitation was too small event rates to employ survival analysis technique and to determine the predictors for risk of sudden death.

Although limited for these reasons, the present study revealed cardiovascular risk would be low for asymptomatic subjects with Brugada-like ECG sign discovered by chance at annual medical check up who had no family history of sudden cardiac death.


    Acknowledgments
 
We thank Masato Mikawa, MD, Akira Ohno, MD, and Hiroko Sugimori, MD for cooperation of the follow-up study.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study Limitations
 References
 

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