This chapter represents advanced scientific exploration in the different disciplines of SCD and channelopathy. Epidemiology of SCD and channelopathy is given special attention. The essence of detailed electrophysiological bases of the different diseases of channelopathies and the diverse cellular pathways mandated detailed discussion that can open the closed doors that we faced to the next generation(s). Special sections have been devoted to spatial as well as temporal heterogeneity of the cardiac action potential. Genetic heterogeneity and allelic heterogeneity are two prominent findings of channelopathies that confirm the fact of the major overlap in the field. The way we present the clinical findings is a true call for the next generation(s) of clinicians and researchers to revolutionize the field in the near future. Detailed management plans based on the up to date basic sciences findings for the different channelopathies give better therapeutic options for the clinicians in the field. Unique to this chapter is the new directions to look for channelopathies beyond the human body. The new understanding of the psychophysiological well-being of HRV and the sympathovagal balance extending to cosmic resonances and its possible effect on cardiac ion channels carries new era of promising preventive, diagnostic and therapeutic options.
- Brugada syndrome (BrS)
- cardiac coherence (CC)
- catecholaminergic polymorphic ventricular tachycardia
- ERS early repolarization syndrome
- heart rate variability
- long QT syndrome (LQTS)
- progressive cardiac conduction disease
- sudden cardiac death
- Schumann resonance
- solar geomagnetic activity
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 . In the United States, around 300,000 deaths are occurring every year because of SCD . 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 . 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 .
Many cases of SCD have identifiable abnormalities such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, coronary artery anomalies or myocarditis . 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 . 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 . 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 (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 . In New Zealand, the reported prevalence is 1:4500 . In Korean males, they reported QT prolongation (equal or more than 460 ms) as 1:5000 . In Japanese males with high likelihood of LQTS score >3.5, the prevalence was similar to Italy (approximately 1:2500) .
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%) . 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 . 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% . 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 . Cardiac events in LQT3, although being the less frequent, were shown to be more lethal than the other two types . 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 . 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 .
2.1.2 Short QT syndrome (SQTS)
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 . 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 . 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 . Parts of idiopathic VF cases are likely to be borderline or latent SQTS individuals. SQTS was diagnosed in 12% of idiopathic VF survivors . The course of SQTS individuals is more malignant with higher risk of recurrence of life-threatening arrhythmias and SCDs .
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 . 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 . Individuals with BrS develop a monomorphic ventricular tachycardia; often precipitated during sleep or rest, and during febrile illnesses . It is thought that some SCN5A mutations alter the Na+ channel in a temperature-dependent manner. Males have arrhythmic events more frequently, and there is thought to be a gender effect on ion channel expression . The estimated prevalence of BrS ranges from 0.02 to 0.1% in Europe and from 0.1 to 0.25% in Asia . 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 . Later on, Europeans were shown to have similar prevalence . About one-third of cases have been attributed to SCN5A mutations . 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, 24, 25, 26, 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 .
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 . 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 .
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 . In Japan, the incidence rate was 715 per 100,000 person-years .
In general, reviewing todays medical literature will reveal ERS prevalence figures which range from approximately 6 to 13% in the general population . 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 . 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 . Notching of the J point was found to be associated with worse prognosis . 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 heart . 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 inward-rectifier potassium channels called Kir2.1. Mutation in this subunit (KCNJ2) is responsible of a third variant of CPVT . A Japanese report of 50 cases ranks the CPVT mutations frequency as follows: RYR2 (56%), CASQ (22%) and KCNJ2 (22%) . 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 . 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% .
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 .
Jervell and Lange-Nielsen syndrome (JLNS) has been associated with about 4% of patients with the bilateral sensorineural loss . 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 . 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 . 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 . In patients with BrS, fever is a well-known arrhythmogenic trigger because SCN5A mutations alter the temperature sensitivity of fast inactivation of the Na+ 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 . 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 . 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 .
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 . 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 . Mutations in the genes encoding the beta sub-units of Na channels have also been implicated . 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 . 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 . QT intervals were found to be longest around 2 months of age . 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 . While less commonly studied or identified, mutations associated with CPVT, SQTS, and BS have been linked to SIDS .
3. The basic electrophysiology of the myocyte and myocardium in ion channel disease
Basic understanding of the electrophysiology of cardiac cells action potential (AP) and its anomalies constitutes the corner stone to dive and disclose the secrets of ionopathies and the resultant fatal cardiac rhythm. Basic research uses molecular techniques, as well as animal models. Phases of the ventricular action potential with description of major events (Figure 1) proved extremely useful in improving the arrhythmia communities’ knowledge of inherited arrhythmogenic syndromes. The discussion of the myocyte action potential is invariably the discussion of the ion channels of the cellular membrane since the delicate trans-membrane traffic of ions is the source of cardiac action potential during normal electrophysiological function of the heart. It is critical to perceive that abnormal heart rhythms including the fatal ventricular arrhythmias are primarily due to abnormal formation or mutations of those trans-membrane pores or its regulatory subunits. Mutations in any of the genes involved in regulation of cardiac ion channels may potentially result in arrhythmias and may be classified as arising from either abnormal AP formation or abnormal AP propagation. Martin CA et al. authored unique review in this regard .
3.1 Abnormal AP formation and propagation
Aberrancy of AP formation can be interpreted through three main mechanisms: reentry, triggered activity or automaticity. Acceleration of depolarization of pacemaker tissue will end up with autonomous formation of AP called enhanced automaticity. This can be precipitated by underlying sympathovagal imbalance in favour of excessive sympathetic tone, hypokalaemia or drugs such as digitalis. Triggered activity referred to extra systole generated outside the primary pacemaker tissue . The underlying mechanism is called afterdepolarization, which is oscillations of cardiac cell membrane potential generated before the previous AP, ending up with premature new AP. If this premature AP magnitude is reaching threshold, it will produce triggered beat. According to the timing of this triggered activity, it can be early or late. Triggered activity during repolarization of the original AP is called early afterdepolarization (EAD). It occurs when AP duration is prolonged until a degree where L-type Ca2+ channels are recovered from inactivation during the time of membrane depolarization. Inward ICa-L current will initiate the new premature depolarization of the membrane and will initiate the afterdepolarization . Triggered activity after completion of repolarization or near completion is called delayed afterdepolarization (DAD). It occurs due to enhanced Ca2+ release from the cellular calcium store organelle called sarcoplasmic reticulum (SR) due to either activation of the Na+/Ca2+ exchanger or Ca2+-activated Cl-current. Classical examples of this Ca2+ overload environment is during digitalis toxicity or Catecholaminergic Polymorphic VT  (Figure 2A). The reentrant mechanism is unique. It requires an electrical obstacle around which AP is able to go around, disproportionately conducting exit pathways, one conducting fast and the other conducting slow and finally unidirectional conduction block. It is the most important mechanism as it is widely spread in much pathologies and most importantly the only type that is amenable for study and ablation in electrophysiology laboratory. The most common arrhythmias in clinical electrophysiology like atrioventricular nodal reentry tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) are both reentrant and amenable for ablation. It is the underlying mechanism in patients with ventricular scarring, usually from old myocardial infarction, cardiomyopathy and infiltrative disease (Figure 2B).
3.2 Spatial electrophysiological heterogeneity
The human heart has been created in miraculous way where the structure supports and complements the function. After initiation of the normal impulse in the sinus node, the wave of action potentials is characterized by highly sophisticated levels of gradients of depolarization and repolarizations, to maintain the normal electro-mechanical activation sequence for the pumping heart functions. The dominant determiner of these spatial gradients is the regional differences in repolarizing K+ channels. These include channel density variations, kinetics and cycling traffic between membrane and cytoplasm. The substrate for reentry is created by disturbances in these gradients, which may permit depolarized regions to reexcite polarized areas . Transmural gradients alterations correlated with arrhythmogenic tendencies in a number of both pharmacological canine and genetic murine models for LQTS and BrS. The reexcitation may occur when the epicardial action potential duration is much shorter than the endocardial, potentially leading to new AP (Figure 2C).
This new environment of electrical dispersion within the cardiac tissue was proved to be arrhythmogenic in cardiomyopathies. This spatial heterogeneity was linked to T wave alternans (TWA) and ventricular tachycardia . Reentry created by epicardial dispersion of repolarization was seen to be the trigger for ventricular tachycardia in preparation of canine right ventricular wedge  and the Scn5a+/− mouse model . Source of arrhythmia in Brugada syndrome is thought to be secondary to AP duration differences between left ventricle and right ventricle. This is reflected in Brugada patients as ST elevation in right precordial leads and right epicardial AP changes .
3.3 Temporal electrophysiological heterogeneity
Electrical dispersion may also affect activation sequence. Temporal beat-to-beat variation in the AP amplitude or duration, a phenomenon known as alternant (Figure 2D), has been associated with arrhythmogenesis in both clinical and experimental studies [66, 67]. This can have significant consequences on the spatial organization of repolarization across the ventricle, amplifying the heterogeneities of repolarization present at baseline into pathophysiological heterogeneities of sufficient magnitude to produce conduction block and reentrant excitation. Regions which alternate out of phase generate a line of block called the nodal line between them. This has the potential to act as a focus for reentrant circuits following the addition of a triggered beat.
3.4 The channelopathies
3.4.1 Long QT syndromes
LQTS constitute a group of genetic disorders distinguished by long QT interval in the electrocardiogram, representing prolongation of repolarization period associated with the risk of ventricular arrhythmias (in specific torsade de point) and sudden death. In comparison to Brugada syndrome, the genetic mutations in LQTS result in tendency for electrical disturbance, affecting depolarization rather than repolarization. An arrhythmic substrate with prolonged AP duration was implicated in several mouse models  (Figure 3). Functional block pockets are created by prolonged depolarization phase during which the impulse pathway will be refractory. This functional block will create reentry focus and myocardial excitation. In addition, repolarization potentials dispersion across the myocardium will provide a functional reentry pathway facilitating initiation of torsade de point. Prolonged depolarization may result in EAD with consequent polymorphic VT. Data from transgenic rabbits , have recently been instrumental to support a novel view on the arrhythmogenesis in LQTS by Chang et al. . These authors developed an in silico model (i.e. computational modelling, simulation and visualization of the cardiomyocyte electrophysiological behaviour and arrhythmogenesis in a virtual computerized environment) of prolonged repolarization. They were able to demonstrate that arrhythmogenesis is initiated by two types of spiral waves: short cycle and long cycle. The short cycle is mediated through INa (Figure 4A) and the long cycle is mediated through slow L-type calcium current (ICa) (Figure 4B) . The alteration of those two types of waves gives what resemble torsade de point in the ECG. Arrhythmogenesis in LQT1 was investigated by Kim et al. using transgenic rabbit models. Multiple EAD foci were demonstrated as well as AP bimodal distribution compatible with the concept of two excitation types .
3.4.2 Brugada syndrome (BrS)
BrS is clearly distinguished between other channelopathies with its electrocardiographic manifestation in the form of delayed right ventricular activation with posterior T wave manifested mainly in V1 and V2. Clinically it is characterized by episodic history of poly morphic VT and ventricular fibrillation (VF) . Genetic heterogeneity is a hall mark feature of BrS where multiple genetic mutations result in the same phenotype. All mutations end up with imbalance of the currents favouring repolarization over depolarization (in contrast to LQTS). The most famous BrS mutation is the SCN5A gene where there is loss of function encoding the alpha subunit of the Na+ voltage-gated channel. INa reduction seems to be the underlying mechanism. Experimental studies using canine hearts as well as clinical studies support this pathophysiological mechanism underlying BrS [71, 72]. Reduction of Na+ current can impose its effect represented by the deep notch of phase 1 of the epicedial AP, which is most impressive in RV. This reduction in Na+ current creates voltage gradient across RV. This state of electrical imbalance in RV epicardium facilitates participation of the proximal myocardium to reactivate RV, ending up with reentry. This type of reentry is called phase 2 reentry (Figure 5). Another perspective to interpret the ECG manifestations of BrS is based on right ventricular out flow (RVOT) conduction delay perspective . This perspective was derived from echocardiographic measurements, signal-averaged ECG (SAECG) potentials and mapping of body surface [74, 75]. An ex vivo experiment demonstrating RVOT conduction delay was published . Fractionated late potentials that was amenable for catheter ablation was documented in the anterior aspect of RVOT epicardium. This specific site ablation normalized ECG and prevented VT and VF associated with BrS .
3.4.3 Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Surge of catecholamines due to stress or exercise is the substrate fuel of bidirectional VT leading to syncope or SCD. This is creating an important category of channelopathies called CPVT. At cellular level, enhanced Ca2+ release from the cellular calcium store organelle called sarcoplasmic reticulum (SR) is the operating mechanism. This enhanced Ca2+ release is due to gain of function gene mutation encoding ryanodine receptor 2 (RyR2), which is an important regulator of Ca2+ release for myocardial cells excitation contraction coupling . The other important gene mutation results in loss of function affecting calsequestrin (CASQ2) protein, which is in normal situations functioning as SR calcium buffering protein . This Ca+ release affects AP in a way favouring DAD as in digitalis toxicity concluded in arrhythmic trigger  (Figure 6). A net inward current is generated secondary to cytosolic Ca+ overload in vitro studies with RyR2 and CASQ2 mutations [61, 80]. RyR2  or in CASQ2  genes deliberately inserted into transgenic animals (mouse in this situation) revealed abnormal Ca+ transients and bidirectional VT. This level of evidence is supporting the idea that inward current might be the underlying mechanism of DAD triggering the abnormal beat. RYR2 mutations have also been suggested to be associated with dilated cardiomyopathy , hypertrophic cardiomyopathy  and arrhythmogenic right ventricular cardiomyopathy .
3.4.4 Other syndromes
While a majority of cases of SCD in the absence of structural heart abnormalities are caused by LQTS, BrS and CVVT, other less common syndromes are of importance. Short AP and accordingly QT intervals in short QT syndrome (SQTS) is due to mutations causing gain of function handling K+ channels  or mutations causing loss of function handling Ca+ channels . An increase in repolarization gradients was seen to be the underlying mechanism . In early repolarization syndrome (ERS), J point elevation with prominent T wave is seen (early repolarization pattern). This electrocardiographic pattern is associated clinically with VT and sudden death . The exact mechanism is still obscure although AP early phase increment in transmural gradients has been suggested in canines hearts . Rarely, reduction in inward Ca+ current  or increment in outward K+ current mutations  has been described, although a majority of cases lack genetic mutations. The weight of evidence nowadays is supporting that the ER pattern is polygenic with an important contribution of epigenetic and environmental factors.
Progressive cardiac conduction disease (PCCD) also known as Lenegre’s disease is a rare progressive degenerative disease of the cardiac conduction system with autosomal dominant pattern of inheritance that may end up with widening of QRS complexes, long pauses and bradycardia. It is a cause of SCD. The first gene mutation of PCCD described was SCN5A. This mutation can be associated with complex phenotype of PCCD, Brs and LQT3, sometimes referred as (overlap syndrome) . Recently, PCCD was seen as an association with altered expressions of other gene proteins encoding impulse propagation like Ca+-activated ion channel and cytoskeletal components. The conclusive phenotype as seen in mouse experiments is thought to be an additive effect of genetic components with environmental modifiers and aging .
SCD is extreme, devastating and traumatic life event. Inherited ventricular arrhythmias, which is due to disturbed ionic traffic across cardiac cell membrane (channelopathy), comprised 1/3 of all cases of SUD and 10% of SCD as a whole. Channelopathies occupies strategic location in the basic science as well as clinical and research arenas due to its recalcitrant behaviour and complexity. The discoveries of the genetic mutations of channelopathies heralded in 1995 have expanded drastically, resulting in revolutionary understanding of the disease. The most important described channelopathies up to date are long QT syndromes (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), early repolarization syndrome (ERS) and idiopathic VF. New disease entities are expected to be discovered in the near future. LQTS is an inherited genetically heterogeneous group of arrhythmias characterized by a prolonged QTc interval in the 12-lead ECGs (with QTc values >470 ms for males and >480 ms for females, representing approximate 99th percentile values). LQTSs as a whole occurs in 1:2500 of the general population. At least 17 genes were identified contributing to LQTSs with mutations positive in about half of the affected individuals. The incidence of LQTSs in decreasing frequency illustrates LQT1 as the commonest (35%) followed by LQT2 (30%) and then LQT3 (10%). The least frequent but most lethal and more difficult to manage is LQT3. Other rare types of LQTSs account for less than 1%. It seems that the normal range of QTc interval is critical for normal AP and normal heart rhythm. Prolongation or shortening of QTc interval is arrhythmogenic. Short QT syndrome with QTc < 350 ms (reported in 1:3400) is etiologically proven cause of malignant VT and VF. Brugada syndrome diagnosed as coved ST-segment elevation in anterior precordial leads occurs in approximately 0.02% up to 0.20% in general population. It overlaps with some of the genetic and clinical features of LQT3. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is relatively a rarely inherited arrhythmogenic disorder (1;10,000) characterized by polymorphic VT induced by physical or emotional stress without any detectable morphological abnormalities in the heart. The most important mutations causing CPVT are in genes encoding cardiac ryanodine type 2 receptor (RYR2) [autosomal dominant] and calsequestrin 2 (CASQ2) [autosomal recessive]. It is considered as highly malignant heart rhythm if neglected. 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. It seems to be more frequent than ever thought with ranges from approximately 6–13% in the general population. Approaching channelopathies in its broad spectrum is an excellent example of the demand of system biology approach in medicine. Channelopathies involving the heart may overlap with manifestations in the nervous system, gastrointestinal system, hearing, infant death syndrome and others. Fatal ventricular arrhythmias are due primarily to abnormal formation or mutations of trans-membrane pores or its regulatory subunits. Aberrancy of cardiac action potential (AP) formation can be interpreted through three main mechanisms: reentry, triggered activity or automaticity. All the different mechanisms described will end up with anomalous action potential. Spatial as well as temporal electrophysiological heterogeneity are important basic electrophysiological derangements that underline cardiac action potential anomalies. Heterogeneity of AP in time and location between myocardium and epicardium are critical predisposing factors to the fatal cardiac rhythm. In comparison to Brugada syndrome, the genetic mutations in LQTS result in tendency for electrical disturbance affecting depolarization rather than repolarization. Surge of catecholamines due to stress or exercise is the substrate fuel of bidirectional VT leading to syncope or SCD in CPVT. RYR2 mutations have also been suggested to be associated with dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. ER pattern is thought to be polygenic with an important contribution of epigenetic and environmental factors. Advances in our knowledge and understanding of disease epidemiology and the basic electrophysiological derangements of channelopathies are intelligent directions that should guide all diagnostic and therapeutic approaches.
To the spirit of the later crown prince of Saudi Arabia HRH Sultan Bin Abdulaziz Al Saud, who made my dreams in establishing the prestigious Prince Sultan Cardiac Center reality and from which this science and others are introduced to the world.
Conflict of interest
I declare no conflict of interest.
Showers of mercy to the spirit of my Great Beloved Father who shocked me with his sudden agonizing absences during writing this chapter. Prayers for long peaceful life for my great mother. Both of them fed me the love to all humanity and all biology. Thanks to all my teachers who taught me that sky is not the limit.
Appendices and nomenclature
|CPVT||catecholaminergic polymorphic ventricular tachycardia|
|ERS||early repolarization syndrome|
|LQTS||long QT syndrome|
|PCCD||progressive cardiac conduction disease|
|SCD||sudden cardiac death|