**1. Introduction**

One of the most devastating life moments that may impact the whole life of a person, family and society is sudden death experience of close relative or beloved. The whole medical provision is dedicated to prevent or delay death while maintaining good quality of life (QOL). For this reason, sudden loss of human life is creating the most serious challenge for medical professionals and decision-makers.

Sudden cardiac death (SCD) is defined as death occurring unexpectedly in the first hour after symptoms commence [1]. In the United States, around 300,000 deaths are occurring every year because of SCD [2]. It is conspicuous that this huge loss in the world communities is creating a major social impact. This impact is undoubtedly more destructive with the loss of young member of the family [3]. Ion channels in the myocardial cellular membrane are responsible for creating the basic unit of the electromagnetic foundation in humans known as cardiac action potential (AP). This is the result of an elegant interplay of ions at the cellular level. Genetic mutations in these channels can predispose to wide spectrum of clinical presentations and syndromes referred collectively to channelopathies (ionopathies). The basic pathology is genetic mutations creating disturbance in the process of critical ions traffic (Na+ , Ca2+, K+ ) across the cell membrane. The delicate miraculous balance in this ion traffic is the basic unit of the normal action potential. Disturbance of this balance in terms of loss or gain of function is the source of the fatal heart rhythm. Sadly, life-threatening arrhythmias and sudden cardiac death can be the first presenting symptom. Scientists and clinicians are racing in the last two decades in a unique complementary scientific effort to reconcile the rapidly growing body of knowledge of the molecular mechanisms and clinical correlates of SCD. In this chapter, we will review the epidemiology of the sudden cardiac death (SCD), then we will discuss the basic science of cellular action potential and its anomalies. We will navigate in detail in the genetic characterization of arrhythmic phenotypes, which started in 1995 with discovery of LQTS mutations, and the subsequent characterization of the diversity of genetic and molecular derangements, which can lead to channelopathies and the fatal rhythms.

#### **2. Epidemiology of sudden cardiac death**

Incidence and prevalence calculation in any disease in medicine is inevitably underestimation of the actual figures. This is due to the fact that underdiagnosis is the role. The most common cause of sudden death (SD) is SCD. Sudden cardiac death (SCD) is defined as sudden death within 1 h of the appearance of witnessed symptom or within 24 h of unwitnessed symptom in an individual without potentially lethal diagnosis [1].

Many cases of SCD have identifiable abnormalities such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, coronary artery anomalies or myocarditis [4]. However, a significant proportion of SD (3–53%) has no identifiable cause on autopsy examination, and these are labelled sudden unexpected death (SUD). Cardiac channelopathies (used interchangeably with ionopathy) account for approximately one-third of SUD cases. Worldwide records demonstrated that around 3,700,000 death per annum are due to SCD. In the western world (the United States and Europe), 1–2 death per 2000 of the general population are lost due to SCD. SCD in male gender is 3 times higher than female [2]. Channelopathies such as long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), early repolarization syndrome (ERS) and idiopathic VF are estimated to be responsible for 10% of SCDs [5]. It is believed that about one-third of SUD cases are due to channelopathies.

#### **2.1 Epidemiology of channelopathies**

#### *2.1.1 Long QT syndrome*

Long QT syndrome (LQTS) is an inherited genetically heterogeneous group of arrhythmias characterized by a prolonged QTc interval in the 12-lead ECGs

**93**

*Inherited Ventricular Arrhythmias, the Channelopathies and SCD; Current Knowledge…*

(with QTc values >470 ms for males and >480 ms for females, representing approximate 99th percentile values). The prevalence of LQTS in what seems to be healthy live births in Italy is 1:2500 [6]. In New Zealand, the reported prevalence is 1:4500 [7]. In Korean males, they reported QT prolongation (equal or more than 460 ms) as 1:5000 [8]. In Japanese males with high likelihood of LQTS score >3.5, the preva-

In conclusion, the Asian reported prevalence is comparable to the west (1:5000– 1:2500). At least 17 genes were identified contributing to LQTS. Mutations have been found in more than half of them (40–70%) [10]. In spite of the complexity of the subject, clinicians need to know for their practice more than 75% of mutations in congenital LQTS are located in the KCNQ1 (LQT1), KCNH2 (LQT2) or SCN5A (LQT3) genes [10]. The prevalence of the different gene mutations for LQT1, LQT2, LQT3 and others is 52%, 33%, 7% and 1.2%, respectively. A Japanese survey of 41 individuals reported genotypes in 71% constituting LQT1 38%, LQT2 38%, LQT3 21% and LQT8 3% [11]. The International LQTS Registry documented cardiac events (syncope, cardiac arrest and SCD) in LQTS individuals to be 63% for LQT1, 46% for LQT2 and 18% for LQT3 [12]. Cardiac events in LQT3, although being the less frequent, were shown to be more lethal than the other two types [12]. The triggers of the different LQTS are of special diagnostic indication. LQT1 is known to be triggered by exercise (typically swimming), while LQT2 has been linked to emotional events, like startle (typically alarm clocks) and delivery [13]. LQT3 is the 'inevitable' as it occurs during periods of rest or sleep. During childhood, boys with LQTS tends to develop more fatal attacks, compared to girls. After childhood, the

SQTS was described in 2000, and it is a clinical entity characterized by short QT intervals on ECG (generally, QTc < 350 ms), high incidence of VT/VF, absence of structural heart disease, familial history of SCD and resuscitated cardiac arrest [15]. It is the severest form of the major channelopathies, with cardiac arrest/SCD being the most common presentation. Events occur during rest, sleep or exertion [4]. For this reason, high index of suspicion should be practiced in order to be able to diagnose this type of malignant channelopathies. Among 10,984 Japanese with approximately equal sex distribution, 1:3400 individuals showed QTc less than 300 ms [16]. Parts of idiopathic VF cases are likely to be borderline or latent SQTS individuals. SQTS was diagnosed in 12% of idiopathic VF survivors [17]. The course of SQTS individuals is more malignant with higher risk of recurrence of life-threat-

There is general impression that BrS incidence is underestimated. In one publication, BrS accounts for 4–12% of SCD [4]. It appears to be related to mutations

mostly autosomal dominant, affecting the SCN5A gene, leading to loss of Na+ channel function in a variety of ways (interestingly, mutations in other parts of

in BrS. BrS is characterized electrocardiographically by classical finding of coved ST-segment elevation in anterior precordial leads. Cardiac events secondary to ventricular tachycardia typically occur in young adults but have been described in children and infants [4]. Individuals with BrS develop a monomorphic ventricular tachycardia; often precipitated during sleep or rest, and during febrile illnesses [19].

this gene lead to LQTS3). Other genes affecting the Na+

channels. There are currently more than 300 mutations described,

channel are also implicated

*DOI: http://dx.doi.org/10.5772/intechopen.92073*

incidence is comparable [14].

*2.1.2 Short QT syndrome (SQTS)*

ening arrhythmias and SCDs [18].

*2.1.3 Brugada syndrome (BrS)*

affecting Na+

lence was similar to Italy (approximately 1:2500) [9].

#### *Inherited Ventricular Arrhythmias, the Channelopathies and SCD; Current Knowledge… DOI: http://dx.doi.org/10.5772/intechopen.92073*

(with QTc values >470 ms for males and >480 ms for females, representing approximate 99th percentile values). The prevalence of LQTS in what seems to be healthy live births in Italy is 1:2500 [6]. In New Zealand, the reported prevalence is 1:4500 [7]. In Korean males, they reported QT prolongation (equal or more than 460 ms) as 1:5000 [8]. In Japanese males with high likelihood of LQTS score >3.5, the prevalence was similar to Italy (approximately 1:2500) [9].

In conclusion, the Asian reported prevalence is comparable to the west (1:5000– 1:2500). At least 17 genes were identified contributing to LQTS. Mutations have been found in more than half of them (40–70%) [10]. In spite of the complexity of the subject, clinicians need to know for their practice more than 75% of mutations in congenital LQTS are located in the KCNQ1 (LQT1), KCNH2 (LQT2) or SCN5A (LQT3) genes [10]. The prevalence of the different gene mutations for LQT1, LQT2, LQT3 and others is 52%, 33%, 7% and 1.2%, respectively. A Japanese survey of 41 individuals reported genotypes in 71% constituting LQT1 38%, LQT2 38%, LQT3 21% and LQT8 3% [11]. The International LQTS Registry documented cardiac events (syncope, cardiac arrest and SCD) in LQTS individuals to be 63% for LQT1, 46% for LQT2 and 18% for LQT3 [12]. Cardiac events in LQT3, although being the less frequent, were shown to be more lethal than the other two types [12]. The triggers of the different LQTS are of special diagnostic indication. LQT1 is known to be triggered by exercise (typically swimming), while LQT2 has been linked to emotional events, like startle (typically alarm clocks) and delivery [13]. LQT3 is the 'inevitable' as it occurs during periods of rest or sleep. During childhood, boys with LQTS tends to develop more fatal attacks, compared to girls. After childhood, the incidence is comparable [14].

#### *2.1.2 Short QT syndrome (SQTS)*

*Sudden Cardiac Death*

Ca2+, K+

**2. Epidemiology of sudden cardiac death**

**2.1 Epidemiology of channelopathies**

*2.1.1 Long QT syndrome*

maintaining good quality of life (QOL). For this reason, sudden loss of human life is creating the most serious challenge for medical professionals and decision-makers. Sudden cardiac death (SCD) is defined as death occurring unexpectedly in the first hour after symptoms commence [1]. In the United States, around 300,000 deaths are occurring every year because of SCD [2]. It is conspicuous that this huge loss in the world communities is creating a major social impact. This impact is undoubtedly more destructive with the loss of young member of the family [3]. Ion channels in the myocardial cellular membrane are responsible for creating the basic unit of the electromagnetic foundation in humans known as cardiac action potential (AP). This is the result of an elegant interplay of ions at the cellular level. Genetic mutations in these channels can predispose to wide spectrum of clinical presentations and syndromes referred collectively to channelopathies (ionopathies). The basic pathology is genetic mutations creating disturbance in the process of critical ions traffic (Na+

) across the cell membrane. The delicate miraculous balance in this ion traffic is the basic unit of the normal action potential. Disturbance of this balance in terms of loss or gain of function is the source of the fatal heart rhythm. Sadly, life-threatening arrhythmias and sudden cardiac death can be the first presenting symptom. Scientists and clinicians are racing in the last two decades in a unique complementary scientific effort to reconcile the rapidly growing body of knowledge of the molecular mechanisms and clinical correlates of SCD. In this chapter, we will review the epidemiology of the sudden cardiac death (SCD), then we will discuss the basic science of cellular action potential and its anomalies. We will navigate in detail in the genetic characterization of arrhythmic phenotypes, which started in 1995 with discovery of LQTS mutations, and the subsequent characterization of the diversity of genetic and molecular derangements, which can lead to channelopathies and the fatal rhythms.

Incidence and prevalence calculation in any disease in medicine is inevitably underestimation of the actual figures. This is due to the fact that underdiagnosis is the role. The most common cause of sudden death (SD) is SCD. Sudden cardiac death (SCD) is defined as sudden death within 1 h of the appearance of witnessed symptom or within 24 h of unwitnessed symptom in an individual without potentially lethal diagnosis [1]. Many cases of SCD have identifiable abnormalities such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, coronary artery anomalies or myocarditis [4]. However, a significant proportion of SD (3–53%) has no identifiable cause on autopsy examination, and these are labelled sudden unexpected death (SUD). Cardiac channelopathies (used interchangeably with ionopathy) account for approximately one-third of SUD cases. Worldwide records demonstrated that around 3,700,000 death per annum are due to SCD. In the western world (the United States and Europe), 1–2 death per 2000 of the general population are lost due to SCD. SCD in male gender is 3 times higher than female [2]. Channelopathies such as long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), early repolarization syndrome (ERS) and idiopathic VF are estimated to be responsible for 10% of SCDs [5]. It is believed that about one-third of SUD cases are due to channelopathies.

Long QT syndrome (LQTS) is an inherited genetically heterogeneous group of

arrhythmias characterized by a prolonged QTc interval in the 12-lead ECGs

,

**92**

SQTS was described in 2000, and it is a clinical entity characterized by short QT intervals on ECG (generally, QTc < 350 ms), high incidence of VT/VF, absence of structural heart disease, familial history of SCD and resuscitated cardiac arrest [15]. It is the severest form of the major channelopathies, with cardiac arrest/SCD being the most common presentation. Events occur during rest, sleep or exertion [4]. For this reason, high index of suspicion should be practiced in order to be able to diagnose this type of malignant channelopathies. Among 10,984 Japanese with approximately equal sex distribution, 1:3400 individuals showed QTc less than 300 ms [16]. Parts of idiopathic VF cases are likely to be borderline or latent SQTS individuals. SQTS was diagnosed in 12% of idiopathic VF survivors [17]. The course of SQTS individuals is more malignant with higher risk of recurrence of life-threatening arrhythmias and SCDs [18].

#### *2.1.3 Brugada syndrome (BrS)*

There is general impression that BrS incidence is underestimated. In one publication, BrS accounts for 4–12% of SCD [4]. It appears to be related to mutations affecting Na+ channels. There are currently more than 300 mutations described, mostly autosomal dominant, affecting the SCN5A gene, leading to loss of Na+ channel function in a variety of ways (interestingly, mutations in other parts of this gene lead to LQTS3). Other genes affecting the Na+ channel are also implicated in BrS. BrS is characterized electrocardiographically by classical finding of coved ST-segment elevation in anterior precordial leads. Cardiac events secondary to ventricular tachycardia typically occur in young adults but have been described in children and infants [4]. Individuals with BrS develop a monomorphic ventricular tachycardia; often precipitated during sleep or rest, and during febrile illnesses [19]. It is thought that some SCN5A mutations alter the Na+ channel in a temperaturedependent manner. Males have arrhythmic events more frequently, and there is thought to be a gender effect on ion channel expression [20]. The estimated prevalence of BrS ranges from 0.02 to 0.1% in Europe and from 0.1 to 0.25% in Asia [5]. Lai Tai means the southern pattern (referring to the mode of death during sleep) is a famous horror term in Thailand and 'Pokkuri'. The death secret has been diagnosed as Brugada syndrome, which is thought to be endemic heart electrical disease in this part of the world [21]. Later on, Europeans were shown to have similar prevalence [5]. About one-third of cases have been attributed to SCN5A mutations [22]. Mutations attributed to CACNA1C and CACNB2 are seen in around 12% of cases. Minor percentages are due to other gene mutations like GPD1L, SCN1B, KCNE3 and SCN3B [23–27]. In 50–80% of patients with BrS, VF or VT can be induced by ventricular extra stimuli in an EPS. There is dispersion of opinions in the ionopathy literature regarding the prognostic value of VT/VF inducibility in EPS. Nobuyuki Murakoshi and colleague consider inducibility as a poor prognostic factor, while many other authors do not believe of any significant correlation [5].

## *2.1.4 Early repolarization syndrome (ERS)*

ERS is characterized by elevation of the QRS-ST junction (J point) and QRS notching or slurring (J wave) in multiple leads, especially the inferior and/or left precordial leads [28]. The slurred J point elevation which was interpreted by cardiology communities as normal electrocardiographic variant distracted Haissaguerre et al. who reported very important observation in this regard. Among 207 victims of idiopathic VF, 30% were found to have the slurred J point pattern (ER pattern) compared to 5% of controls [29].

In the Framingham Heart Study, the ER pattern was found in 6.1% of American and European persons and 5.8% in Finnish population [30, 31]. In Asia, the story seems to be more impressive. J wave elevation of at least 0.05 mV was detected in 7.26% of Chinese subjects [32]. In Japan, the incidence rate was 715 per 100,000 person-years [33].

In general, reviewing todays medical literature will reveal ERS prevalence figures which range from approximately 6 to 13% in the general population [34]. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index for LVH calculation (S in V1 + R in V5 or V6 (whichever is larger) ≥ 35 mm (≥7 large squares) or R in aVL ≥ 11 mm) and lower Cornell voltage (S in V3 + R in aVL > 28 mm (men) or S in V3 + R in aVL > 20 mm (women)) are independently associated with the presence of the ER pattern [30]. An important observation in that regard points to the proportionality of ER amplitude to the risk of arrhythmic death.

ER of 0.2 mV or more in ECG inferior leads was shown to have much increased risk than those without. This was concluded after long mean follow-up of 29–41 years [35]. Notching of the J point was found to be associated with worse prognosis [5]. The rapid rise of ST segment and dominance of ST pattern in athletes was found to be benign variant of ERS. Looking with eye of scrutiny will show the similarities of clinical, electrocardiographic and genetic aspects between BrS and ERS. Future research could prove both syndromes to be a spectrum of one pathology.

#### *2.1.5 Catecholaminergic polymorphic ventricular tachycardia (CPVT)*

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by polymorphic VT induced by physical or emotional stress without any detectable morphological abnormalities in the

**95**

*Inherited Ventricular Arrhythmias, the Channelopathies and SCD; Current Knowledge…*

heart [36]. Two important gene mutations has been described: mutations in genes encoding cardiac ryanodine type 2 receptor (RYR2) [autosomal dominant] and calsequestrin 2 (CASQ2) [autosomal recessive] [37, 38]. A subunit for inwardrectifier potassium channels called Kir2.1. Mutation in this subunit (KCNJ2) is responsible of a third variant of CPVT [39]. A Japanese report of 50 cases ranks the CPVT mutations frequency as follows: RYR2 (56%), CASQ (22%) and KCNJ2 (22%) [40]. CPVT is gaining more attention although being a rare disease compared to other channelopathies (1:10,000) because of its tendency to affect children and young adults [41]. In fact, CPVT is considered as highly malignant heart rhythm if neglected. In those situations, by the age of 20–30 years, the mortality is

Action potential is the basic unit of human body electricity. It is conceivable that ionopathic involvement of other systems is a fact. This will result in symptoms and syndromes that deserve attention for proper risk stratification of ionopathic subjects. Behere and Weindling elaborated on this in their unique review [43]. Jervell and Lange-Nielsen syndrome (JLNS) has been associated with about 4% of patients with the bilateral sensorineural loss [44]. However, Chang et al. challenged this concept. They thought that this association may have been overestimated in the era before genetic testing, and newer studies seem to reflect the similar rate of LQTS causing mutations in deaf children, as in the general population [45]. There is overlap between seizure disorders and cardiac channelopathies. Sudden unexpected death in epilepsy (SUDEP) has an incidence of 6–9/1000 person-years in epilepsy surgery programs. Channelopathy-associated mutations have been identified in 13% of patients with SUDEP [46]. Seizures triggered by exercise, emotion, sudden stimuli, seizures unresponsive to anti-seizure medications and seizures in the setting of family history of SD, syncope or obvious electrocardiographic abnormalities should all be viewed with high index of suspicion for underlying channelopathy [47]. In patients with BrS, fever is a well-known arrhythmogenic trigger because SCN5A mutations alter the temperature sensitivity

events (ALTEs)' and even SUD or sudden infant death syndrome (SIDS) in susceptible infants in the setting of febrile illnesses [48]. As many as 30% of victims of drowning-related deaths have been found to have cardiac channelopathies [49, 50]. Patients with SCN5A mutations have been found to have irritable bowel syndrome (IBS). In a recent study, 2% of patients with IBS were found to have SCN5A mutations, and in one case, mexiletine administration even caused normalization of bowel habits. It is hypothesized that channelopathies are involved in the pathogenesis of some forms of IBS [51]. There is also a co-existence of iron-deficiency anaemia, hypergastrinemia and gastric hyperplasia associated with LQT1. This suggests not only a role for the gene KCNQ1 in gastric secretion but also a role for gastrin as a marker of arrhythmia severity [52, 53]. Interestingly, in a study from the United States, 36% of patients with drug-induced LQTS possessed known

*2.1.7 Cardiac channelopathies and sudden infant death syndrome (SIDS)*

SIDS is defined as SD of seemingly healthy children of age <1 year. The incidence of SIDS varies across the world [54]. About 10–20% of SIDS cases are attributed to genetic mutations associated with channelopathies [19, 54, 55]. Mutations associated with LQTS1 and LQTS3 have been related to SIDS [54]. Mutations in the

channel. This may cause 'apparent life-threatening

*DOI: http://dx.doi.org/10.5772/intechopen.92073*

*2.1.6 Heart channelopathies and systemic involvement*

30–50% [42].

of fast inactivation of the Na<sup>+</sup>

arrhythmia-associated mutations [54].

*Inherited Ventricular Arrhythmias, the Channelopathies and SCD; Current Knowledge… DOI: http://dx.doi.org/10.5772/intechopen.92073*

heart [36]. Two important gene mutations has been described: mutations in genes encoding cardiac ryanodine type 2 receptor (RYR2) [autosomal dominant] and calsequestrin 2 (CASQ2) [autosomal recessive] [37, 38]. A subunit for inwardrectifier potassium channels called Kir2.1. Mutation in this subunit (KCNJ2) is responsible of a third variant of CPVT [39]. A Japanese report of 50 cases ranks the CPVT mutations frequency as follows: RYR2 (56%), CASQ (22%) and KCNJ2 (22%) [40]. CPVT is gaining more attention although being a rare disease compared to other channelopathies (1:10,000) because of its tendency to affect children and young adults [41]. In fact, CPVT is considered as highly malignant heart rhythm if neglected. In those situations, by the age of 20–30 years, the mortality is 30–50% [42].

#### *2.1.6 Heart channelopathies and systemic involvement*

Action potential is the basic unit of human body electricity. It is conceivable that ionopathic involvement of other systems is a fact. This will result in symptoms and syndromes that deserve attention for proper risk stratification of ionopathic subjects. Behere and Weindling elaborated on this in their unique review [43].

Jervell and Lange-Nielsen syndrome (JLNS) has been associated with about 4% of patients with the bilateral sensorineural loss [44]. However, Chang et al. challenged this concept. They thought that this association may have been overestimated in the era before genetic testing, and newer studies seem to reflect the similar rate of LQTS causing mutations in deaf children, as in the general population [45]. There is overlap between seizure disorders and cardiac channelopathies. Sudden unexpected death in epilepsy (SUDEP) has an incidence of 6–9/1000 person-years in epilepsy surgery programs. Channelopathy-associated mutations have been identified in 13% of patients with SUDEP [46]. Seizures triggered by exercise, emotion, sudden stimuli, seizures unresponsive to anti-seizure medications and seizures in the setting of family history of SD, syncope or obvious electrocardiographic abnormalities should all be viewed with high index of suspicion for underlying channelopathy [47]. In patients with BrS, fever is a well-known arrhythmogenic trigger because SCN5A mutations alter the temperature sensitivity of fast inactivation of the Na<sup>+</sup> channel. This may cause 'apparent life-threatening events (ALTEs)' and even SUD or sudden infant death syndrome (SIDS) in susceptible infants in the setting of febrile illnesses [48]. As many as 30% of victims of drowning-related deaths have been found to have cardiac channelopathies [49, 50]. Patients with SCN5A mutations have been found to have irritable bowel syndrome (IBS). In a recent study, 2% of patients with IBS were found to have SCN5A mutations, and in one case, mexiletine administration even caused normalization of bowel habits. It is hypothesized that channelopathies are involved in the pathogenesis of some forms of IBS [51]. There is also a co-existence of iron-deficiency anaemia, hypergastrinemia and gastric hyperplasia associated with LQT1. This suggests not only a role for the gene KCNQ1 in gastric secretion but also a role for gastrin as a marker of arrhythmia severity [52, 53]. Interestingly, in a study from the United States, 36% of patients with drug-induced LQTS possessed known arrhythmia-associated mutations [54].

#### *2.1.7 Cardiac channelopathies and sudden infant death syndrome (SIDS)*

SIDS is defined as SD of seemingly healthy children of age <1 year. The incidence of SIDS varies across the world [54]. About 10–20% of SIDS cases are attributed to genetic mutations associated with channelopathies [19, 54, 55]. Mutations associated with LQTS1 and LQTS3 have been related to SIDS [54]. Mutations in the

*Sudden Cardiac Death*

It is thought that some SCN5A mutations alter the Na+

dependent manner. Males have arrhythmic events more frequently, and there is thought to be a gender effect on ion channel expression [20]. The estimated prevalence of BrS ranges from 0.02 to 0.1% in Europe and from 0.1 to 0.25% in Asia [5]. Lai Tai means the southern pattern (referring to the mode of death during sleep) is a famous horror term in Thailand and 'Pokkuri'. The death secret has been diagnosed as Brugada syndrome, which is thought to be endemic heart electrical disease in this part of the world [21]. Later on, Europeans were shown to have similar prevalence [5]. About one-third of cases have been attributed to SCN5A mutations [22]. Mutations attributed to CACNA1C and CACNB2 are seen in around 12% of cases. Minor percentages are due to other gene mutations like GPD1L, SCN1B, KCNE3 and SCN3B [23–27]. In 50–80% of patients with BrS, VF or VT can be induced by ventricular extra stimuli in an EPS. There is dispersion of opinions in the ionopathy literature regarding the prognostic value of VT/VF inducibility in EPS. Nobuyuki Murakoshi and colleague consider inducibility as a poor prognostic factor, while

many other authors do not believe of any significant correlation [5].

ERS is characterized by elevation of the QRS-ST junction (J point) and QRS notching or slurring (J wave) in multiple leads, especially the inferior and/or left precordial leads [28]. The slurred J point elevation which was interpreted by cardiology communities as normal electrocardiographic variant distracted Haissaguerre et al. who reported very important observation in this regard. Among 207 victims of idiopathic VF, 30% were found to have the slurred J point pattern (ER pattern)

In the Framingham Heart Study, the ER pattern was found in 6.1% of American and European persons and 5.8% in Finnish population [30, 31]. In Asia, the story seems to be more impressive. J wave elevation of at least 0.05 mV was detected in 7.26% of Chinese subjects [32]. In Japan, the incidence rate was 715 per 100,000

In general, reviewing todays medical literature will reveal ERS prevalence figures which range from approximately 6 to 13% in the general population [34]. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index for LVH calculation (S in V1 + R in V5 or V6 (whichever is larger) ≥ 35 mm (≥7 large squares) or R in aVL ≥ 11 mm) and lower Cornell voltage (S in V3 + R in aVL > 28 mm (men) or S in V3 + R in aVL > 20 mm (women)) are independently associated with the presence of the ER pattern [30]. An important observation in that regard points to

ER of 0.2 mV or more in ECG inferior leads was shown to have much increased

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by polymorphic VT induced by physical or emotional stress without any detectable morphological abnormalities in the

the proportionality of ER amplitude to the risk of arrhythmic death.

*2.1.5 Catecholaminergic polymorphic ventricular tachycardia (CPVT)*

risk than those without. This was concluded after long mean follow-up of 29–41 years [35]. Notching of the J point was found to be associated with worse prognosis [5]. The rapid rise of ST segment and dominance of ST pattern in athletes was found to be benign variant of ERS. Looking with eye of scrutiny will show the similarities of clinical, electrocardiographic and genetic aspects between BrS and ERS. Future research could prove both syndromes to be a spectrum of one

*2.1.4 Early repolarization syndrome (ERS)*

compared to 5% of controls [29].

person-years [33].

channel in a temperature-

**94**

pathology.

genes encoding the beta sub-units of Na channels have also been implicated [56]. Interestingly, a loss of function mutation in the K+ channel encoding gene KCNJ8 has also been associated with SIDS. It is hypothesized that this mutation causes maladaptation to stress such as endotoxemia [55]. A Japanese study looking more broadly at the characteristics of all infantile LQTS found that 84% of all cases were diagnosed in the foetal or neonatal period. LQTS1 was associated with most risk of a first cardiac event, but LQTS2 and LQTS3 more exclusively caused VT or TdP [11]. QT intervals were found to be longest around 2 months of age [57]. Foetal magnetocardiography and echocardiography have been used to assess foetal LQTS. Sinus bradycardia is a common finding. Trans-placental magnesium and lidocaine, and prenatal beta-blocker therapies have been used for management [58]. While less commonly studied or identified, mutations associated with CPVT, SQTS, and BS have been linked to SIDS [54].
