*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

**101**

This Ca+

**Figure 4.**

to cytosolic Ca+

*3.4.4 Other syndromes*

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

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 [78]. 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 [79].

*In silico cardiac tissue model of prolonged repolarization. Arrhythmogenesis is initiated by two types of spiral waves: short cycle and long cycle. The short cycle is mediated through* I*Na (A) and the long cycle is mediated* 

release affects AP in a way favouring DAD as in digitalis toxicity concluded

overload in vitro studies with RyR2 and CASQ2 mutations [61, 80].

transients and bidirectional

in arrhythmic trigger [36] (**Figure 6**). A net inward current is generated secondary

RyR2 [81] or in CASQ2 [82] genes deliberately inserted into transgenic animals

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 [83], hypertrophic cardiomyopathy [84] and arrhythmogenic right ventricular cardiomyopathy [85].

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

(mouse in this situation) revealed abnormal Ca+

*through slow L-type calcium current (ICa) (B) [70].*

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

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

#### **Figure 4.**

*Sudden Cardiac Death*

**100**

**Figure 3.**

Experimental studies using canine hearts as well as clinical studies support this pathophysiological mechanism underlying BrS [71, 72]. Reduction of Na+

*LQTS mechanistic representation of arrhythmogenesis as understood from animal model. Scales showed genetic mutations can give rise to either gain of depolarization currents or loss of repolarization currents. EAD (triggered activity) will result as well as transmural gradients and refractory pockets formation. The clinical outcome as seen in ECG is represented by the trace at the bottom of the graph (torsade de pointes) [59].*

is most impressive in RV. This reduction in Na+

and prevented VT and VF associated with BrS [77].

*3.4.3 Catecholaminergic polymorphic ventricular tachycardia (CPVT)*

impose its effect represented by the deep notch of phase 1 of the epicedial AP, which

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 [73]. 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 [76]. Fractionated late potentials that was amenable for catheter ablation was documented in the anterior aspect of RVOT epicardium. This specific site ablation normalized ECG

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

current can

current creates voltage gradient across

*In silico cardiac tissue model of prolonged repolarization. Arrhythmogenesis is initiated by two types of spiral waves: short cycle and long cycle. The short cycle is mediated through* I*Na (A) and the long cycle is mediated through slow L-type calcium current (ICa) (B) [70].*

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 [78]. 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 [79]. This Ca+ release affects AP in a way favouring DAD as in digitalis toxicity concluded in arrhythmic trigger [36] (**Figure 6**). A net inward current is generated secondary to cytosolic Ca+ overload in vitro studies with RyR2 and CASQ2 mutations [61, 80]. RyR2 [81] or in CASQ2 [82] 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 [83], hypertrophic cardiomyopathy [84] and arrhythmogenic right ventricular cardiomyopathy [85].

#### *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

#### **Figure 5.**

*Brugada syndrome's mechanistic representation of arrhythmogenesis as understood from animal model. Scales showed genetic mutations can give rise to either loss of depolarization currents or gain of repolarization currents. The ultimate outcome of those AP changes is more likelihood for alternans and phase 2 reentry. The clinical outcome as seen in ECG is represented by the trace at the bottom of the graph (polymorphic VT) [59].*

importance. Short AP and accordingly QT intervals in short QT syndrome (SQTS) is due to mutations causing gain of function handling K<sup>+</sup> channels [86] or mutations causing loss of function handling Ca<sup>+</sup> channels [87]. An increase in repolarization gradients was seen to be the underlying mechanism [88]. 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 [89]. The exact mechanism is still obscure although AP early phase increment in transmural gradients has been suggested in canines hearts [90]. Rarely, reduction in inward Ca<sup>+</sup> current [91] or increment in outward K+ current mutations [92] 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.

**103**

fiers and aging [94].

**4. Summary**

**Figure 6.**

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

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) [93]. Recently, PCCD was seen as an association with altered expressions of other

*CPVT mechanistic representation of arrhythmogenesis as understood from animal model. DAD-triggered* 

cytoskeletal components. The conclusive phenotype as seen in mouse experiments is thought to be an additive effect of genetic components with environmental modi-

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


 *which in turn will result in depolarization* 

*/Ca2+ exchanger. The clinical outcome as seen in ECG is* 

gene proteins encoding impulse propagation like Ca+

*activity is due to genetic mutation causing rise in cytosolic Ca+*

*represented by the trace at the bottom of the graph (bidirectional VT) [59].*

*current obeying the electrogenic nature of the Na<sup>+</sup>*

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

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

#### **Figure 6.**

*Sudden Cardiac Death*

**102**

**Figure 5.**

importance. Short AP and accordingly QT intervals in short QT syndrome (SQTS)

*Brugada syndrome's mechanistic representation of arrhythmogenesis as understood from animal model. Scales showed genetic mutations can give rise to either loss of depolarization currents or gain of repolarization currents. The ultimate outcome of those AP changes is more likelihood for alternans and phase 2 reentry. The clinical outcome as seen in ECG is represented by the trace at the bottom of the graph (polymorphic VT) [59].*

gradients was seen to be the underlying mechanism [88]. 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 [89]. The exact mechanism is still obscure although AP early phase increment in transmural gradients has been suggested in canines hearts [90].

rent mutations [92] 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.

channels [86] or mutations

cur-

channels [87]. An increase in repolarization

current [91] or increment in outward K+

is due to mutations causing gain of function handling K<sup>+</sup>

causing loss of function handling Ca<sup>+</sup>

Rarely, reduction in inward Ca<sup>+</sup>

*CPVT mechanistic representation of arrhythmogenesis as understood from animal model. DAD-triggered activity is due to genetic mutation causing rise in cytosolic Ca+ which in turn will result in depolarization current obeying the electrogenic nature of the Na<sup>+</sup> /Ca2+ exchanger. The clinical outcome as seen in ECG is represented by the trace at the bottom of the graph (bidirectional VT) [59].*

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) [93]. 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 [94].

#### **4. Summary**

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.

**105**

**Author details**

Abdullah Abdulrhman Al Abdulgader

Cardiac Center, Alhasa, Hofuf, Saudi Arabia

provided the original work is properly cited.

\*Address all correspondence to: kidsecho@yahoo.com

Senior Congenital Cardiologist and Invasive Electrophysiologist, Prince Sultan

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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

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.

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 biol-

ogy. Thanks to all my teachers who taught me that sky is not the limit.

CPVT catecholaminergic polymorphic ventricular tachycardia

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

I declare no conflict of interest.

**Notes/thanks/other declarations**

**Appendices and nomenclature**

BrS Brugada syndrome CC cardiac coherence

LQTS long QT syndrome

SCD sudden cardiac death SQTS short-QT syndrome VF ventricular fibrillation VT ventricular tachycardia

ERS early repolarization syndrome

PCCD progressive cardiac conduction disease

**Acknowledgements**

**Conflict of interest**

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