**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 [59].

#### **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 [59]. 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 [60]. 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

**97**

**Figure 1.**

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

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

reticulum (SR) due to either activation of the Na<sup>+</sup>

*Phases of the ventricular action potential with description of major events [59].*

**3.2 Spatial electrophysiological heterogeneity**

infarction, cardiomyopathy and infiltrative disease (**Figure 2B**).

Cl-current. Classical examples of this Ca2+ overload environment is during digitalis toxicity or Catecholaminergic Polymorphic VT [61] (**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

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

/Ca2+ exchanger or Ca2+-activated

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


#### **Figure 1.**

*Sudden Cardiac Death*

**channel disease**

genes encoding the beta sub-units of Na channels have also been implicated [56].

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].

**3. The basic electrophysiology of the myocyte and myocardium in ion** 

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 [59].

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 [59]. 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 [60]. 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

Aberrancy of AP formation can be interpreted through three main mechanisms:

**3.1 Abnormal AP formation and propagation**

channel encoding gene KCNJ8 has

Interestingly, a loss of function mutation in the K+

**96**

*Phases of the ventricular action potential with description of major events [59].*

reticulum (SR) due to either activation of the Na<sup>+</sup> /Ca2+ exchanger or Ca2+-activated Cl-current. Classical examples of this Ca2+ overload environment is during digitalis toxicity or Catecholaminergic Polymorphic VT [61] (**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

#### **Figure 2.**

*Different mechanisms of arrhythmias [59]: (A) triggered activity: early after depolarization (EAD) (upper trace) and delayed after depolarization (DAD) (lower trace). Dotted lines represent formation of new AP. (B) Reentrant circuit: normal impulse propagation in two equal conduction velocities with collision in the middle and termination of the impulse (upper diagram). Presence of slow limb in the circuit (solid line) will end up with the normal impulse pass through and circulates around the other limb which is the fast limb at a time where its refractoriness is over (dotted). This will end up with excitation of the myocardium and initiation of tachycardia (lower diagram). (C) Transmural gradients due to heterogeneity of AP in different locations: shorter AP in epicardium compared to endocardium will end up with reexcitation. (D) Heterogenity of AP timing: creating duration alternans with the result of nodal line when the alternans time out creating block predisposing to reentry in the presence of triggered impulse.*

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 [59]. 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 [62]. Reentry created by epicardial dispersion of repolarization was seen to be the trigger for ventricular tachycardia in preparation of canine right ventricular wedge [63] and the Scn5a+/<sup>−</sup> mouse model [64]. 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 [65].

**99**

the Na+

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

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

Electrical dispersion may also affect activation sequence. Temporal beat-to-beat

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 [68] (**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 [69], have recently been instrumental to support a novel view on the arrhythmogenesis in LQTS by Chang et al. [70]. 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 *I*Na (**Figure 4A**) and the long cycle is mediated through slow L-type calcium current (ICa) (**Figure 4B**) [70]. 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 distri-

bution compatible with the concept of two excitation types [70].

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) [59]. 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

voltage-gated channel. INa reduction seems to be the underlying mechanism.

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

addition of a triggered beat.

**3.4 The channelopathies**

*3.4.1 Long QT syndromes*

*3.4.2 Brugada syndrome (BrS)*

**3.3 Temporal electrophysiological heterogeneity**

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

#### **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**

*Sudden Cardiac Death*

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 repo-

*block predisposing to reentry in the presence of triggered impulse.*

*Different mechanisms of arrhythmias [59]: (A) triggered activity: early after depolarization (EAD) (upper trace) and delayed after depolarization (DAD) (lower trace). Dotted lines represent formation of new AP. (B) Reentrant circuit: normal impulse propagation in two equal conduction velocities with collision in the middle and termination of the impulse (upper diagram). Presence of slow limb in the circuit (solid line) will end up with the normal impulse pass through and circulates around the other limb which is the fast limb at a time where its refractoriness is over (dotted). This will end up with excitation of the myocardium and initiation of tachycardia (lower diagram). (C) Transmural gradients due to heterogeneity of AP in different locations: shorter AP in epicardium compared to endocardium will end up with reexcitation. (D) Heterogenity of AP timing: creating duration alternans with the result of nodal line when the alternans time out creating* 

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 [59]. 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

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 [62]. Reentry created by epicardial dispersion of repolarization was seen to be the trigger for ventricular tachycardia in preparation of canine right ventricular wedge [63] and the Scn5a+/<sup>−</sup> mouse model [64]. 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

channels. These include channel density variations, kinetics and cycling

**98**

larizing K+

**Figure 2.**

AP (**Figure 2C**).

epicardial AP changes [65].

#### *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 [68] (**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 [69], have recently been instrumental to support a novel view on the arrhythmogenesis in LQTS by Chang et al. [70]. 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 *I*Na (**Figure 4A**) and the long cycle is mediated through slow L-type calcium current (ICa) (**Figure 4B**) [70]. 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 [70].

#### *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) [59]. 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.

#### **Figure 3.**

*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].*

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