Epidemiology of Arrhythmias and Sudden Cardiac Death in Asia

13 Pages·2013·1.13 MB·English

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Circulation Journal CARDIOVASCULAR EPIDEMIOLOGY IN ASIA
Official Journal of the Japanese Circulation Society
http://www.j-circ.or.jp
Epidemiology of Arrhythmias and
Sudden Cardiac Death in Asia
Nobuyuki Murakoshi, MD, PhD; Kazutaka Aonuma, MD, PhD
Cardiac arrhythmias are cardiac rhythm disorders that comprise an important epidemiological and public health
problem. Cardiac arrhythmias are significantly associated with increased risks of cardiovascular complications and
sudden death, consequently leading to decreased quality of life, disability, high mortality, and healthcare expense.
Atrial fibrillation (AF) is the most common sustained arrhythmia, and has been further increasing with the aging of
society. Although the prevalence is relatively lower in Asians than in Westerners, the prognostic impacts on stroke
and mortality in Asians are comparable. Sudden cardiac death (SCD) occurs in approximately 40 cases per 100,000
persons annually in each country of Asia. Most cases are caused by myocardial infarction and ventricular fibrillation
in out-of-hospital cardiac arrest cases, but the proportion of myocardial infarction is lower in Asia than in Western
countries. The primary electrophysiological disorders related to channelopathies, such as long QT syndrome, short
QT syndrome, Brugada syndrome, early repolarization syndrome, and catecholaminergic polymorphic ventricular
tachycardia, are estimated to be responsible for 10% of SCDs. Implantable cardioverter-defibrillator implantation has
become established as an effective secondary prevention for SCD, and numbers have been increasing annually
worldwide. New insights into arrhythmic diseases have been emerging from epidemiological, clinical, and genetic
research, and contribute to improvements in diagnosis and prognosis.
Key Words: Arrhythmia; Atrial fibrillation; Epidemiology; Sudden cardiac death; Ventricular fibrillation
countries, the number of people with AF in Japan is expected
Epidemiology of Arrhythmias
to continue to increase with the aging of society from 0.83
Atrial Fibrillation million in 2010 to 1.05 million in 2030.6
Atrial fibrillation (AF) is the most common sustained arrhyth- Hypertension is the most common underlying disease, and
mia and is diagnosed by the ECG findings of irregular RR in- is prevalent in 30–60% of patients with AF.4,9–11 Of the under-
tervals and f waves. It affects more than 2.3 million individuals lying heart diseases, Asian patients with AF are less likely to
in the USA, and has been further increasing with the aging of have coronary artery disease, but more likely to have valvular
society.1 Table 1 summarizes the age- and sex-specific preva- disease compared with Westerners with AF.7,9–11
lences of AF reported from the USA, Europe, and Asia.1–6 The The incidence rate of AF is also higher in Western than in
prevalence of AF increases with age, being approximately 1% Asian countries, with 6.2 per 1,000 person-years for men and
in the general population and increasing from 0.1% among 3.8 per 1,000 person-years for women in the USA (age 55–65
adults younger than 55 years to 9% among octogenarians in years),12 4.1 per 1,000 person-years for men and 1.3 per 1,000
the USA.1 It is higher in men than in women for each age person-years for women in Japan (mean age, 67.5 years),13
group. The prevalence of AF is estimated to be 0.7% in South and 1.68 per 1,000 person-years for men and 0.76 per 1,000
Korea (1.2% in men and 0.4% in women; mean age: 54.6±10.8 person-years for women in China (mean age, 52.5 years).7 The
years),3 0.77% in China (0.91% in men and 0.65% in women; most well-known risk factors of AF incidence are age, male
mean age: 52.5±22.4 years),4 1.1% in Taiwan (1.4% in men sex, hypertension, diabetes mellitus, obesity, hyperthyroidism,
and 0.7% in women; mean age: 54.9 years),7 and 0.86% in and structural heart disease.12,14–16 For each advancing decade
Japan (1.35% in men and 0.43% in women).6 In a large-cohort of age, the risk of developing AF increases by nearly 2-fold.
study in California, the adjusted odds ratios (OR) of AF among Structural heart diseases, such as myocardial infarction (MI),
Blacks, Hispanics, and Asians relative to Whites as the refer- cardiomyopathy, and valvular disease, are the strongest risk
ence were 0.49, 0.58, and 0.68, respectively.8 Taking these factors for developing AF, and independently associated with
reports together, the prevalence of AF is lower in Asians than 3–5-fold higher risk of new onset of AF.10 In addition, inflam-
in Westerners, and is estimated to be approximately 0.7–1.1% mation, metabolic syndrome, sleep apnea, and chronic kidney
in Asians older than 40 years. However, similar to Western disease have been identified as risk factors for AF.13,17–19 On
Received September 4, 2013; accepted September 4, 2013; released online September 20, 2013
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
Mailing address: Nobuyuki Murakoshi, MD, PhD, Cardiovascular Division, Institute of Clinical Medicine, Faculty of Medicine, Univer-
sity of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan. E-mail: [email protected]
ISSN-1346-9843 doi: 10.1253/circj.CJ-13-1129
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]
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MURAKOSHI N et al.
Table 1. Age- and Sex-Specific Prevalences of Atrial Fibrillation in Epidemiological Surveys
Area/authors/year published
USA Netherlands South Korea China Singapore Japan
Go et al1 Ott et al2 Jeong et al3 Zhou et al4 Yap et al5 Inoue et al6
2001 1997 2005 2008 2008 2009
Age (years)
Overall
<40 – – – 0.00 – –
40–44 – – 0.1　　 0.14 – 0.14
45–50 – – 0.29 –
50–54 0.2　　 – 0.5　　 0.54 – 0.45
55–59 0.7　　 0.6 0.51 0.5
60–64 1.5　　 0.9　　 1.04 1.7 1.03
65–69 2.5　　 2.3 2.2　　 1.56 0.9
70–75 4.3　　 1.7　　 2.82 1.4 2.09
75–79 6.3　　 6.3 1.9　　 3.78 1.2
80–85 8.9　　 4.0　　 7.48 5.8 3.19
>85 9.9　　 11.8
Total 0.95 3.0 0.7　　 0.77 1.4 0.86
Men
<40 – – – 0.00 – –
40–44 – – 0.12 0.24 – 0.24
45–50 – – 0.29 –
50–54 0.2　　 – 0.7　　 0.53 – 0.78
55–59 0.9　　 0.9 0.46 1.6
60–64 1.7　　 1.8　　 1.08 2.5 1.94
65–69 3.0　　 3.0 3.9　　 1.84 1.3
70–75 5.0　　 2.5　　 3.02 3.2 3.44
75–79 7.3　　 7.6 3.4　　 4.82 1.4
80–85 10.3　　　　 4.5　　 7.54 11.1 4.43
>85< 11.1　　　　 13.2
Total 1.1　　 3.3 1.2　　 0.91 2.7 1.35
Women
<40 – – – 0.00 – –
40–44 – – 0.06 0.05 – 0.04
45–50 – – 0.28 –
50–54 0.1　　 – 0.4　　 0.55 – 0.12
55–59 0.4　　 0.3 0.55 0.0
60–64 1.0　　 0.2　　 1.00 1.1 0.42
65–69 1.7　　 1.8 1.0　　 1.27 0.7
70–75 3.4　　 1.1　　 2.58 0.0 1.12
75–79 5.0　　 5.2 0.5　　 2.60 1.0
80–85 7.2　　 3.5　　 7.40 1.5 2.19
>85 9.1　　 10.6
Total 0.8　　 2.7 0.4　　 0.65 0.61 0.43
the other hand, AF also occurs in subjects without any un- ZFHX3) have been identified as common susceptibility genes
derlying heart disease, which is known as “lone AF”, and ac- for AF in European and Japanese populations.26
counts for 10–30% of patients with AF. ECGs are reported to Most importantly, AF is strongly associated with an ap-
be useful for risk stratification of AF patients, with P-wave proximately 3–5-fold increased risk of stroke, consequently
prolongation and/or PR interval prolongation, left ventricular resulting to higher morbidity and mortality.27 Among patients
hypertrophy, ST-segment and T-wave (ST-T) abnormalities, with AF, the risk of stroke depends on the presence of other
and premature complexes as predictive findings for AF.20–23 stroke risk factors. Specifically, the following factors are as-
Echocardiographic abnormalities are also predictive for AF sociated with an increased risk for stroke incidence: (1) prior
susceptibility. Left atrial enlargement, left ventricular hyper- history of stroke or transient ischemic attack; (2) hypertension;
trophy, and left ventricular systolic and diastolic dysfunction (3) age; (4) diabetes; and (5) congestive heart failure. AF pa-
are independent predictors of AF.24,25 Recently, a genome- tients aged less than 65 years without stroke risk factors have
wide association study for AF identified several genomic loci a low stroke rate of 1% per year, in contrast to 8.1% per year
associated with AF, 4 of which (PITX2, PRRX1, CAV1, and in the subgroup aged >75 years with 1 or more risk factors.28
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Arrhythmias and SCD in Asia
Figure 1. Hazard ratios of atrial fibrillation (AF) for cardiovascular (CV) events (stroke or stroke death, cardiovascular death, and
all-cause death) in Asia. Among 9,483 subjects of the Japanese general population (4,154 men) from NIPPON DATA 80, the
multivariate-adjusted relative risks (95% CI) of AF were 2.69 (1.42–5.10), 2.76 (1.81–4.20), and 1.88 (1.37–2.58) for stroke death,
cardiovascular death, and all-cause death, respectively. In 3,560 Chinese subjects from the Chin-Shan Community Cardiovascu-
lar Cohort (CCCC) study, the multivariate-adjusted relative risks (95% CI) of AF were 2.90 (1.28–6.59) for stroke incidence and
2.05 (1.27–3.32) for all-cause mortality. In NIPPON DATA 80, the hazard ratios were adjusted for age, body mass index, systolic
blood pressure, blood glucose level, history of valvular disease, left ventricular hypertrophy, regular drinking, and current smoking.
In the CCCC study, marital status, education level, occupation, exercise habit, history of stroke and coronary artery disease, left
atrial diameter, and left ventricular ejection fraction measured by echocardiography were added to the confounding factors. CI,
confidence interval.
Based on these findings, the CHADS2 score has been used for III, aVF, or V1 because of a counterclockwise reentrant path-
risk stratification of stoke, and AF patients with a CHADS2 way, but are sometimes upright if the reentrant loop is clock-
score ≥2 should be treated with anticoagulation therapy. wise. AFL is less common than AF, and more prevalent in
In the Framingham Heart Study, subjects with AF had mark- patients with organic heart disease. According to an epidemio-
edly reduced survival compared with subjects without AF, logical study in the USA, the estimated prevalence of AFL
with multivariate-adjusted ORs for death of 1.5 in men and 1.9 (including patients complicated with AF) was 0.3%, and that
in women.27 Figure 1 shows the hazard ratios (HRs) of AF for of AFL alone (without AF) was 0.13%.29,30 The risk factors
cardiovascular events in Japan and Taiwan. In the Japanese associated with AFL development were advancing age, male
general population, the multivariate-adjusted relative risks sex, heart failure, and chronic obstructive pulmonary diseas-
(RRs) of AF were 2.7, 2.8, and 1.9 for stroke death, cardiovas- es.30 The patients with AFL had a 2-fold higher mortality than
cular death, and all-cause death, respectively. In the Chinese control subjects, which was almost the same as that of patients
general population, the multivariate-adjusted RRs of AF were with AF.29
2.9 for stroke and 2.1 for all-cause mortality. Taken together,
AF is significantly associated with a 2–3-fold higher risk of Supraventricular Tachyarrhythmias
stroke and a 2-fold higher risk of death,7,9 which is comparable Paroxysmal supraventricular tachycardia (PSVT) is generally
to the prognostic impact on mortality in Western populations. a regular, narrow QRS tachyarrhythmia frequently encoun-
tered in clinical practice, and is often caused by reentry cir-
Atrial Flutter (AFL) cling into the reentrant pathways with a component above the
In typical AFL, ECGs reveal identical recurring, regular saw- His bundle. The prevalence of PSVT is approximately 2–3 per
tooth flutter waves and evidence of continual electrical activ- 1,000 persons and the incidence is 35 per 100,000 person-
ity. The flutter waves for typical AFL are inverted in leads II, years in the general population.31,32 There are 2 main causes
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MURAKOSHI N et al.
Figure 2. Number of new pacemaker implantations by country (Right) and per million population(Left) in 2009.
of PSVT, namely atrioventricular nodal reentrant tachycardia Cardiac Pacing and Implantable Cardioverter-Defibrillators,
(AVNRT) and AV reentrant tachycardia (AVRT). AVNRT more than 1 million pacemakers are implanted worldwide every
accounts for approximately 50% of PSVT, and occurs by re- year, with 75% being new implants.37 Figure 2 shows the num-
entry into the dual AV nodal pathways.32 The incidence of dual bers of new pacemaker implants by country in 2009. Accord-
AV nodal pathways in an electrophysiological study (EPS) of ing to the survey, the nation implanting the most devices, with
apparently healthy adults was estimated to be approximately 235,567 new pacemakers, was the USA. In Asia, the numbers
10%.33 AVRT accounts for approximately 40% of PSVT, and of new pacemaker implants are lower than in the USA and
results from reentry between the AV node and the accessory Europe, comprising 40,728 in China, 34,813 in Japan, 3,952 in
pathway. Wolff-Parkinson-White (WPW) syndrome is the Taiwan, 1,894 in Thailand, and 1,691 in South Korea. Japan
most well-known type of AVRT. A WPW pattern ECG has had the highest number of new pacemaker implants per million
been found in 0.1–0.2% of Asian subjects,34,35 being consistent population at 272, followed by Taiwan at 172. High-degree
with a previously reported prevalence in the USA.36 Approxi- AV block and sick sinus syndrome were the major reasons for
mately half of the WPW patients were asymptomatic at diag- pacemaker implantation, and each of them accounted for 40–
nosis and had a better prognosis, although sudden cardiac 45% of pacemaker implants. AF bradycardia was responsible
death (SCD) occurred in WPW patients with USA a mortality for approximately 10% of pacemaker implants.
rate of 0.02–0.15% per year.36
Epidemiology of Sudden Cardiac Death
Bradycardias
Bradycardia is an abnormally slow heart rate of less than SCD is an unexpected death from cardiac causes occurring
60 beats/min. Apparently healthy adults often have a resting within a short time period (generally within 1 h from onset of
heart rate slower than 60 beats/min without any symptoms, symptoms if witnessed or within 24 h of having been observed
and this does not cause any problems. However, symptomatic alive if unwitnessed) in a person without any prior condition
bradycardia, such as repeated syncope or heart failure, should that would appear fatal.38 It is estimated that more than 3.7
be considered an indication for therapy. Permanent pace- million lives per year are lost to SCD worldwide, including
maker implantation is an established life-saving therapy for over 300,000 in the USA.38,39 Men have a 3-fold higher inci-
patients with symptomatic bradycardia. The number of pa- dence of SCD than women, which generally reflects the high-
tients undergoing pacemaker implantation has been increasing er incidence of coronary artery disease in men. In the USA and
with the aging of society. According to the World Survey of Europe, the annual incidence of SCD ranges from 50 to 100
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Arrhythmias and SCD in Asia
Figure 3. Causes of sudden unexpected death within 24 h in 204 cases in the Hisayama Study. Heart disease was responsible
for 49% of cases, followed by stroke (33.3%), aortic disease (11.7%), and pulmonary disease (4.5%). Coronary artery disease was
the leading cause of sudden unexpected death, accounting for approximately 30%, with unknown cardiac deaths, which were
estimated to include primary electrophysiological disorders, accounting for 10%.
Figure 4. Reasons for implantable cardioverter-defibrillator (ICD) implantation in Japan. Myocardial infarction (MI) was the lead-
ing cause, followed by cardiomyopathy (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ven-
tricular cardiomyopathy) and primary electric disorders.
per 100,000 in the general population.40 In Asia, the inci- Americans and Whites.45 Left ventricular systolic dysfunction
dence of SCD has been reported as 37 per 100,000 person- (especially, ejection fraction <30%) was a major independent
years in Japan,41 41 in China,42 38 in Thailand,43 and 43 in the predictor of SCD in patients with ischemic and nonischemic
Phillipines,44 all of which are relatively lower than in the USA cardiomyopathy.46 A general Japanese population-based co-
and Europe. According to a cohort study of residents in the hort in the town of Hisayama showed that MI was the leading
USA, Asians had a lower incidence of SCD than African- cause of SCD, similar to the USA and Europe, but accounted
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MURAKOSHI N et al.
Table 2. Genotype-Specific Prevalence and Prognosis in Subjects With Long QT Syndrome
Area/authors/year published
USA, Italy, Israel New Zealand Japan
Zareba et al56 1998 Earle et al51 2013 Horigome et al55 2010
Gene 541 (probands, family) 309 (probands, family) 58 (probands)
Cardiac SD/aborted Cardiac SD/aborted SD/aborted
n (%) n (%) n (%)
events (%) SD (%) events (%) SD (%) SD (%)
LQT1 KCNQ1 112 (20.7%) 70 (62.5%) 10 (8.9%) 120 (38.8%) 43 (35.8%) 12 (10.0%) 11 (26.8%) 1 (9.1%)　　
LQT2 KCNH2 72 (13.3%) 33 (45.8%) 4 (5.6%) 78 (25.2%) 33 (42.3%) 9 (11.5%) 11 (26.8%) 1 (9.1%)　　
LQT3 SCN5A 62 (11.5%) 11 (17.7%) 4 (6.5%) 19 (6.1%) 9 (47.4%) 6 (31.6%) 6 (14.6%) 1 (16.6%)
LQT4 ANK2
LQT5 KCNE1 1 (0.32%)
LQT6 KCNE2
LQT7 KCNJ2 2 (0.64%)
LQT8 CACNA1C 1 (2.4%) 1 (100%)　
LQT9 CAV3
LQT10 SCN4B
LQT11 AKAP9
LQT12 SNTA1
LQT13 KCNJ5
negative 295 (54.5%) 89 (28.8%) 12 (29.2%) 4
no gene test 0 0 17 5
for just 30% of SCD (Figure 3).47 Ventricular tachycardia and gene analysis are often helpful in making the diagnosis.49
(VT) degenerating first to ventricular fibrillation (VF) and later The prevalence of LQTS is reported as at least 4/10,000
to asystole appears to be the most common pathophysiological (nearly 5/10,000) apparently healthy live births in Italy,50 and
cascade involved in fatal arrhythmias recorded as the primary 2.2/10,000 in New Zealand.51 The prevalence of QT prolonga-
electrical event at the time of SCD. Primary electric disorders tion, defined as QTc ≥460 ms, was reportedly 0.02% in appar-
related to channelopathies, such as long QT syndrome (LQTS), ently healthy young Korean men,52 and among 7,961 Japanese
Brugada syndrome (BrS), catecholaminergic polymorphic school children (4,044 males), the prevalence of a high prob-
ventricular tachycardia (CPVT), short QT syndrome (SQTS), ability of LQTS, defined as LQTS score >3.5, was 0.038%.53
early repolarization syndrome (ERS), and idiopathic VF, are Taking these reports together, the prevalence of LQTS in Asia
estimated to be responsible for 10% of SCDs. Implantable ranges from 0.02% to 0.04%, which is consistent with data
cardioverter-defibrillators (ICDs) have been established as ef- from Europe and the USA.
fective secondary prevention for SCD. Figure 4 shows the Congenital LQTS is a genetically heterogeneous disorder
underlying heart diseases responsible for ICD implantation in associated with mutations in various cardiac ion channel genes.
Japan. MI accounted for approximately 30% of ICD implants, At least 13 responsible genes for LQTS have been identified,
followed by cardiomyopathy (hypertrophic cardiomyopathy, and mutations have been found in 40–70% of patients with
dilated cardiomyopathy, and arrhythmogenic right ventricular LQTS.54 Among these, more than 75% of mutations in con-
cardiomyopathy) and primary electric disorders. The numbers genital LQTS are located in the KCNQ1 (LQT1), KCNH2
of ICD implantations have grown exponentially in almost (LQT2), or SCN5A (LQT3) genes.54 The International LQTS
every surveyed country, and more than 300,000 ICDs were Registry reported that the prevalence of LQT1, LQT2, LQT3,
implanted in 2009. The USA has the world’s highest numbers, and others was 52%, 33%, 7%, and 1.2%, respectively. Ac-
with 133,262 implants or 434 new implants per million popu- cording to a nationwide survey in Japan, genetic testing was
lation. Figure 5 shows the numbers of new ICD implants (and available in 41 (71%) cases, and the genotypes were confirmed
new implants per million population) in 2009: 5,341 (42) in in 29 (71%) cases, consisting of LQT1 (n=11; 38% of geno-
Japan, 1,316 (1) in China, 1,100 (1) in India, 310 (111) in typed patients), LQT2 (n=11; 38%), LQT3 (n=6; 21%), and
Taiwan, 294 (183) in Thailand, and 277 (6) in South Korea, LQT8 (n=1; 3%).55
showing a 2-fold increase compared with the survey in 2005. Table 2 shows the genotype-specific prevalences and prog-
We will now focus on the primary electric disorders (chan- noses in patients with LQTS. The International LQTS Registry
nelopathies). reported that the incidence rates of cardiac events (syncope,
cardiac arrest, and SCD) from birth through to 40 years of age
LQTS and SQTS were 63%, 46%, and 18% for LQT1, LQT2, and LQT3, re-
LQTS is characterized by prolonged ventricular repolarization spectively.56 Although the incidence rate of cardiac events in
and susceptibility to syncope and SCD through VT (torsade de LQT3 was relatively low, the mortality rate was higher in
pointes), which can deteriorate into VF. A clinical diagnosis is LQT3 than in LQT1 and LQT2.56 Exercise such as swimming
made from a combination of suspicious history, family history, is likely to induce arrhythmic events in LQT1 patients, where-
and 12-lead ECG, which typically reveals a heart rate-correct- as emotional stress, loud noises such as alarm clocks, or partu-
ed QT interval (QT interval divided by the square root of the rition can trigger events in LQT2 patients and arrhythmic
RR interval in seconds=QTc) >0.46 seconds in women and events tend to occur during rest and sleep in LQT3 patients.49
>0.45 seconds in men.49 Exercise testing, epinephrine loading, Boys with LQTS are more susceptible than girls to fatal or
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Arrhythmias and SCD in Asia
Table 3. Prevalence and Prognosis of Subjects With Brugada-Type ECG in Population-Based Cohort Studies
Area/authors/year published
Japan Japan Japan Japan Japan
Miyasaka et al70 Matsuo et al71 Atarashi et al72 Furuhashi et al73 Sakabe et al74
2001 2001 2001 2001 2003
N 13,929 4,788 10,000 8,612 3,339
Sex, M/F 3,691/10,238 1,956/2,832 8,913/1,087 5,987/2,625 2,646/693
Age, years 58±10 (>40) NA 22–66 (42±9) 49.2 (22–84) 48±9
J-point amplitude, mV ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.2
Follow-up, years 2.6±0.3 40 3 10
Subtype Type 1 Non-type 1 Type 1 Non-type 1 Type 1 Non-type 1 Type 1 Non-type 1 Type 1 Non-type 1
Prevalence (%) 17 81 32 NA 26 41 4 8 5 25
(0.12%) (0.58%) (0.67%) (0.26%) (0.41%) (0.05%) (0.09%) (2.1%) (1.6%)
Cardiac events (%) 0 1 7 NA 1 0 0 1
(0.0%) (1.2%) (22%) (3.8%) (0.0%) (0.0%) (2.1%)
France Finland Canada USA Europe
Hermida et al75 Junttila et al76 Lee et al77 Ito et al78 Gallagher et al79
2000 2004 2005 2006 2008
N 1,000 2,479 3,983 8006 12,012
Japanese-American
Sex, M/F 632/368 2,479/0 3,983/0 8,006/0 10,901/1,111
Age, years 39±10 (17–68) 18–30 31 45–68 17–66
J-point amplitude, mV ≥0.1 ≥0.2 ≥0.2 ≥0.2 ≥0.1
Follow-up, years 49±30 19±2 55 30 10.1±5.5
Subtype Type 1 Non-type 1 Type 1 Non-type 1 Type 1 Non-type 1 Type 1 Non-type 1 Type 1 Non-type 1
Prevalence (%) 1 60 0 15 4 NA 12 11 2 29
(0.1%) (6.0%) (0.0%) (0.61%) (0.1%) (0.15%) (0.14%) (0.02) (0.1%)
Cardiac events (%) 0 0 0 0 0 NA 0 0 0 1
(0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (3.4%)
NA, not applicable.
near-fatal cardiac events during childhood, whereas cardiac amplitude or ST-segment elevation of ≥2 mm, followed by a
events are comparable between males and females after child- negative T-wave; type 2 has ≥2-mm J-point elevation, ≥1-mm
hood.57 Patients with QTc ≥500 ms or recurrent syncope have ST-segment elevation, and a saddleback appearance, followed
a higher risk of cardiac events.57 Several studies revealed inter- by a positive or biphasic T-wave; type 3 has either a saddle-
actions between genotype and clinical course. LQT1 patients back or coved appearance, but with an ST-segment elevation
with missense mutations located at the transmembrane region <1 mm.67 Type 1 is the only diagnostic ECG pattern of BrS,
and LQT2 patients with missense mutations located at the and types 2 and 3 should only be considered as suggestive of
transmembrane pore had greater risks for cardiac events.58–60 the disease. Because the BrS-like ECG patterns can fluctuate
β-blocker therapy is associated with a halving of the risk of and are often concealed, it is difficult to estimate the true preva-
cardiac events, and mexiletine is effective in LQT3 patients.57,61 lence of the disease in the general population.68
ICD implantation is recommended for resuscitated cardiac Among young and middle-aged Southeast Asian men, sud-
arrest/VF or recurrent syncope in patients on β-blockers. den unexpected nocturnal death syndrome, called ‘Lai Tai’
SQTS is a clinical entity characterized by short QT intervals (died during sleep) in Thailand and ‘Pokkuri’(sudden unex-
on ECG (generally, QTc <300 ms), high incidence of VT/VF, pected death at night) in Japan, is likely to have been endemic
absence of structural heart disease, familial history of SCD, and for a long time, and has been recognized as being mainly
resuscitated cardiac arrest.62 Among 10,984 Japanese (females: caused by BrS.69 The estimated prevalence of BrS among the
49.8%), only 3 (0.03%) subjects exhibited QTc <300 ms.63 It is general population in Southeast Asia is thought to be higher
likely that a number of the cases of idiopathic VF corresponded than in Europe and the USA.67 The results of representative
to latent or borderline SQTS, and SQTS has been found in 12% early population-based cohort studies are summarized in
of survivors of VF with no apparent cause.64 SQTS patients Table 3.70–79 The estimated prevalence of BrS ranges from
with prior history of aborted SCD or syncope have a high risk 0.02% to 0.1% in Europe and from 0.1% to 0.25% in Asia.
of recurrent arrhythmic events, including SCD.65 It has been established that 15–30% of BrS cases can be
attributed to mutations in SCN5A.80 A further 11–12% of BrS
BrS cases can be attributed to CACNA1C and CACNB2, and a
BrS is characterized by ST-segment elevation in the right pre- minor number of cases arise from mutations in other genes
cordial lead of standard ECGs, and is associated with an in- (GPD1L, SCN1B, KCNE3, and SCN3B).81
creased risk of SCD because of VF.66 Approximately 80–90% The cardiac event rates of patients with BrS in hospital-
of affected individuals are men, and the onset of symptoms based studies are summarized in Table 4. The spontaneous
typically occurs at a mean age of 40 years. Three repolariza- appearance of type 1 ECG with symptoms of aborted sudden
tion patterns have been described:67 type 1 is characterized by death or unexplained syncope are indicative of a poor progno-
a prominent coved ST-segment elevation displaying J-point sis for patients with BrS compared with patients having no
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MURAKOSHI N et al.
Table 4. Prognosis of Subjects With Brugada Syndrome in Hospital-Based Cohort Studies
Area/authors/year published
Italy Worldwide Europe
Priori et al84 Brugada et al83 FINGER registry (Probst)85
2000 2002 2010
Type 1 1 1
Proband/family Both Both Both
No. of patients 60 334 1,029
Age (years) 40±15 42±16 45 (35–55)
Sex (% of male) 75.0 76.3 72.4
Cardiac events 5 (8%) 45 (8%) 51 (5.0%)
Subgroup VF Asymptomatic VF Syncope Asymptomatic VF Syncope Asymptomatic
N 30 30 71 73 190 62 313 654
Follow-up (months) 33±38 54±54 26±36 27±29 31.9 (14–54.4)
Cardiac events (%) 5 (16%) 0 (0%) 44 (62%) 14 (19%) 16 (8%) 22 (35.5%) 19 (6.1%) 10 (1.5%)
Event rate (% per year) 5.8 0 13.7 8.8 3.6 7.7 1.9 0.5
China Japan Japan
Mok et al86 Kamakura et al87 J-IVFS (Takagi)88
2004 2009 2013
Type Both Both 1
Proband/family Both Only proband Only proband
No. of patients 50 330 460
Age (years) 53 51.4±14.8 52±14
Sex (% of male) 94.0 95.5 93.9
Cardiac events 6 (12.0%) 24 (7.2%) 38 (8.3%)
Subgroup VF Syncope Asymptomatic VF Syncope Asymptomatic VF Syncope Asymptomatic
N 8 12 30 45 46 154 84 109 267
Follow-up (months) 30±13 25±7 25±11 48.7±15.0 50±32
Cardiac events (%) 4 (50.0%) 2 (16.7%) 0 (0.0%) 15 (33%) 1 (2%) 3 (2%) 27 (32%) 8 (7%) 3 (1%)
Event rate (% per year) 20.0 8.0 0.0 10.2 0.6 0.5 8.4 1.7 0.3
clinical symptoms.82–88 Symptomatic patients with a history of was more frequent in 31% (64/206) of idiopathic VF patients
VF have a significantly higher risk of VF occurrence and SCD. than in 5% (21/412) of matched control subjects, suggesting
The annual event rates are reported as 5.8–20.0% in cardiac that the presence of this pattern might be associated with vul-
arrest survivors with spontaneous type 1 ECG. Meanwhile, nerability to VF.90 According to reports from the USA and
symptomatic patients with a history of syncope have a slightly Europe, the ER pattern was present in 243 of 3,955 partici-
higher risk of cardiac events, with an annual event rate of pants (6.1%) in the Framingham Heart Study, and 630 of
0.6–8.8%. On the other hand, the event rates are generally 10,864 (5.8%) of the Finnish population.91,92 In Asia, the
lower in asymptomatic patients without any episodes of car- prevalence of J wave (at least 0.05 mV) was 7.26% among
diac arrest or syncope compared with symptomatic patients, 1,817 healthy Chinese subjects,93 and the incidence rate was
with an annual event rate of 0–0.5% in asymptomatic patients. 715 per 100,000 person-years in Japanese.94 Although the
The event rate in Asian patients does not differ much from that prevalence of the ER pattern varies widely according to the
in European patients. reports, it ranges from approximately 6% to 13% in the gen-
In 50–80% of patients with BrS, VF or polymorphic VT can eral population.95 Male sex, younger age, lower systolic blood
be induced by ventricular extrastimuli in an EPS. Patients in pressure, higher Sokolow-Lyon index, and lower Cornell volt-
whom VT/VF is induced by the EPS have a poorer prognosis age are independently associated with the presence of the ER
than patients without EPS induction, although many studies pattern.91 The presence of ER is associated with an elevated
have reported no association between VT/VF inducibility by risk of VF occurrence in the general population or in patients
EPS and long-term prognosis.82,83,85,87 The association between with MI.92,96 In the general Finnish middle-aged population,
familial history of SCD and prognosis remains controversial. the ER pattern was present in 576 of 10,864 subjects (5.3%),
ICD implantation should be recommended for prevention of and among them, subjects with an ER ≥0.1 mV had a higher
SCD in BrS patients with a history of VF or aborted sudden risk of arrhythmic death (adjusted HR 1.43; 95% confidence
death. interval (95% CI) 1.05–1.94), and subjects with a higher am-
plitude ER (≥0.2 mV) in the inferior leads had a much higher
ERS risk than those without ER (adjusted HR 3.14; 95% CI 1.56–
ERS is characterized by elevation of the QRS-ST junction (J 6.30) during a mean follow-up of 30±11 years.97 Subjects with
point) and QRS notching or slurring (J wave) in multiple a notched J point seemed to have a worse prognosis, but the
leads, especially the inferior and/or left precordial leads.89 results were unambiguous in other comparisons. On the other
Although the finding has been considered a benign ECG man- hand, rapidly ascending ST variants and a dominant ST pat-
ifestation, Haissaguerre et al first reported that the ER pattern tern in healthy athletes seem to comprise a benign variant of
Advance Publication by-J-STAGE
Arrhythmias and SCD in Asia
Figure 5. Numbers of new implantable cardioverter-defibrillator (ICD) implants by country (Right) and per million population (Left)
in 2009.
ER. According to a long-term follow-up study of 5,976 atom- and recessive forms of CPVT, respectively.100,101 In addition,
ic-bomb survivors in Japan, the ER pattern was associated a third variant of CPVT was reported to result from a mutation
with a higher risk of sudden unexpected death (adjusted HR in KCNJ2, which encodes Kir2.1, a subunit for inward-rectifi-
1.83; 95% CI 1.12–2.97), and both slurring and notching were er potassium channels.102 In 50 Japanese CPVT probands,
related to a higher risk of sudden unexpected death (adjusted mutations in RYR2, CASQ, and KCNJ2 were identified in 28
HR: 2.09; 95% CI 1.06–4.12), as was ER pattern manifesta- (56%), 1 (2%), and 1 (2%), respectively.103 CPVT is a rare
tion in both the inferior and lateral leads (adjusted HR 2.50; disease with an estimated prevalence of 1/10,000, but has be-
95% CI 1.29–4.83).94 A meta-analysis reported from China come recognized as a significant cause of SCD in children and
revealed that the RR of the ER pattern was 1.70 (95% CI young adults.104 CPVT has a highly malignant course when
1.19–2.42) for arrhythmic death, and that the estimated abso- untreated, with estimates of mortality ranging from 30% to
lute risk difference of subjects with the ER pattern was 70 50% by the age of 20–30 years.105 Postmortem genetic tests in
cases per 100,000 person-years for arrhythmic death.98 J-point the Mayo Clinic for 173 autopsy-negative cases of sudden un-
elevation ≥0.1 mV in the inferior leads and a notching con- expected death (106 males; age: 18.4±12.9 years; 89% white)
figuration had an increased risk for arrhythmic death in sub- revealed that mutations involving the CPVT1-associated RYR2
group studies.98 gene were detected in 21 cases (12.1%), compared with 25
ERS and BrS share similar ECG characteristics, clinical cases (14.5%) hosting mutations involving LQTS-associated
outcomes, genetic basis, and risk factors, as well as a common genes, and that pathogenic mutations in RYR2 were the most
arrhythmic platform.89 Therefore, ERS and BrS may be con- common among the 6 LQTS-associated and CPVT-associated
sidered a common clinical entity under the term of J-wave genes analyzed in the study.106 A mutational screening study
syndromes. in 17 Japanese sudden unexpected death autopsy cases also
reported a high incidence (17.6%) of RYR2 mutations in the
CPVT cases.107 According to a clinical report from France, aborted
CPVT is an inherited arrhythmogenic disorder characterized cardiac arrest or SCD occurred in 13 of 101 patients (13%)
by polymorphic VT induced by physical or emotional stress during an 8-year follow-up, and absence of β-blockers and
without any detectable morphological abnormalities in the prior history of aborted cardiac arrest were independent predic-
heart.99 Mutations in genes encoding cardiac ryanodine type 2 tors for aborted cardiac arrest or SCD.104 In 29 young Japanese
receptor (RYR2) and calsequestrin 2 (CASQ2) have been iden- patients with CPVT, 7 (24%) died suddenly and 2 (7%) devel-
tified, and are recognized as causing the autosomal dominant oped anoxic brain damage during a follow-up of 6.8±4.9
Advance Publication by-J-STAGE
MURAKOSHI N et al.
Figure 6. Prognosis of 460 patients with Brugada syndrome in the Japan-Idiopathic Ventricular Fibrillation Study (J-IVFS). During
a mean follow-up of 50±32 months, cardiac events (sudden cardiac death or ventricular fibrillation) occurred in 27 of 84 (32%)
symptomatic patients with aborted sudden death or documented ventricular fibrillation (Vf), 8 of 109 (7%) patients with unex-
pected syncope, and 3 of 267 (1%) asymptomatic patients. The incidence of cardiac events per year was 8.4% in the Vf group,
1.7% in the syncope group, and 0.3% in the asymptomatic group. (Modified from reference 88 with permission.)
years.108 Moreover, male patients with RyR2 mutations and men. Although an implanted device has been established as an
patients with CASQ2 mutations are at higher risk of arrhythmic effective life-saving therapy, the growing number of implants
events.109 ICD implantation is indicated for patients with VF is becoming an emerging issue because of the burden of med-
or aborted cardiac arrest, and is a Class IIa indication for pa- ical expenses. For reduction of SCD and arrhythmic diseases,
tients with syncopal episodes, patients with CASQ2 mutations, it is important not only to prevent, or control, the progression
or male patients with RyR2 mutations. β-blockers are useful for of coronary artery disease and heart failure, but also to com-
primary prevention in CPVT patients. prehensively address public health and the development of
future risk stratification using epidemiological, clinical, and
genetic approaches.
Conclusions
We have reviewed the prevalence, incidence, risk factors, and Ackowledgements
clinical features of arrhythmic diseases and SCD. AF is the This research was partly supported by a Grant-in-Aid from the Ministry of
most common sustained arrhythmia, and is becoming a serious Health, Labour and Welfare, and Health Labour Sciences Research Grants,
public health problem in Asia, because of increasing preva- Japan (Intractable Diseases Conquest Research: H21-Nanchi-Ippan-059;
Intractable Diseases Conquest Research: H22-Nanchi-Ippan-144; and Com-
lence, high rates of morbidity and mortality, and healthcare
prehensive Research on Cardiovascular and Life-Style Related Diseases:
expenses, as in Western countries. Therefore, primary preven-
H23-Junkankitou[Seishuu]-Ippan-005; Intractable Diseases Conquest
tion, including adequate control of body weight, hypertension, Research: H24-Nanchi-Ippan-033).
and diabetes, will be of growing importance in the medical
care of AF. SCD occurs in approximately 40 cases per 100,000 References
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