**2.2 Brugada syndrome risk stratification and management plan**

Any patient that survived a VF arrest or with syncope and an ECG consistent with spontaneous type I pattern should undergo permanent cardiac defibrillator. Other high-risk factors include male gender, atrial fibrillation or a fragmented QRS. There is no consensus on the use of electrophysiologic study to risk stratify patients. Importantly, the programmed electrical stimulation predictive value (PRELUDE) registry showed that the inability to induce arrhythmias does not correlate with a negative predictive value [35]. A family history of SCD and the presence of an SCN5A mutation have proven to be high risk predictors as well. Criteria to diagnose Brugada syndrome [36] in symptomatic patients are as follows: Type I ST segment elevation via drug challenge or spontaneously in at least 1 right precordial lead (V1 or V2). In asymptomatic patients, the situation is little bit guarded. Constellation of strong and concealed electrocardiographic manifestation should be looked for. Attenuation of the ST segment during maximum exercise with subsequent coved ST segment elevation when rested is an important finding, in the setting of absent structural heart disease. StT wave alternans (TWA), development of spontaneous left bundle branch or PVCs are all relevant to alert to BrS diagnosis in the absence of symptoms. Other subtle electrical alerts are first-degree AV block and left axis deviation as well as fragmented QRS. In TWA test, late potentials are additional alerting alarm. During electrophysiological study, a ventricular effective refractory period less than 200 ms is alarming also. Other alerts are the fragmentation of QRS as well as the presence of atrial fibrillation.

BrS is well known to be triggered by febrile illness. This is why meticulous fever management should be carried out in Brugada patients and their families. Pharmaceutical agents inducing Brugada arrhythmias should be avoided. Physicians and public may refer to (www.brugadadrugs.org) for reliable information in this regard. Sympathovagal imbalance with dominant parasympathetic tone predisposes to ventricular arrhythmias in BrS patients. Isoproterenol intravenously is used with success to control VF storms in BrS patients [37]. In a limited study, quinidine was found to be of a role in asymptomatic individuals [38]. In case of frequent ICD shocks, quinidine can be used as adjunct treatment. Quinidine effectiveness was found to be 85% in a follow-up of up to 4 years with a dose of ≤600 mg per day [39]. An empirical quinidine registry for asymptomatic Brugada individuals recommended doses of 600–900 mg per day if tolerated [40]. The decision of ICD implant in asymptomatic Brugada individuals needs true contemplation in view of the rarity of the events. Annual rate of cardiac events in this group is 0.5% versus 7.7%–10.2% in VF patients and 0.6%–1.2% in syncope patients [41]. Many authorities in the field do not recommend ICD implant in asymptomatic Brugada individuals [42]. With a history of VT/VF or arrhythmia-related syncope, in Brugada individuals, ICD must be the first-line management. In contrast to what we have mentioned earlier in LQTS management, tiered therapy is recommended in BrS ICD programming. Fractionated late potentials in the anterior aspect of right ventricular out flow tract (RVOT) were detected in nine patients with VF storm due to Brugada syndrome [43]. Ablation at this site normalized the Brugada ECG findings in majority of patients (with one patient only left with amiodarone) [44]. These electrocardiographic findings and site ablation results were repeated in recent works [45, 46].

*Sudden Cardiac Death*

nadolol have similar risk reduction in LQT1 [14]. No significant scientific evidence is favoring selective beta blockers over the non-selective group [15]. It is always advised to keep beta blockers as adjunct treatment after ICD implants. The sympathetic surge after delivery of a shock is always a risk for recurrence [16]. There are experimental data supporting the use of beta blockers in LQT3 [17] and others contradicting its use [18]. Analysis of 493 LQT3 patients derived from 9 registries supports the use of beta blockers [19]. There is in the horizon an early evidence suggesting significant therapeutic role of sodium channel blockers like ranolazine, mexiletine and flecainide in LQT3 treatment [20–22]. Mexiletine was proved also of being an effective therapeutic option in LQT3 as well as LQT1 and LQT2 [23]. Rarely, cautious use of mexiletine in LQT3 is needed as it may cause QT interval prolongation [24]. Successful shortening of the QTc interval (565 ± 60 ms to 461 ± 23 ms; P < 0.04) was achieved with flecainide. With its potent sodium blockage properties, flecainide was able to normalize QTc in five patients with LQT3 with DKPQ mutation [25]. Ranolazine, a late INa blocker, was seen to be effective to shorten the QT interval as well as suppress TdP as proved by experimental models of LQT3 [26]. Dose-dependent shortening of QT interval was achieved in human patients with DKPQ mutation of LQT3 using ranolazine [27]. What seems to be a therapeutic paradox is the benefit of adrenergic stimulation in cases with acquired LQTS and low heart rate with pauses. In the absence of concomitant gene mutations, epinephrine and isoproterenol were found to be effective in acquired LQTS [28]. In addition, selective effect of β-adrenergic stimulation was reported in the different LQTSs. The effect was seen in canine models as induction of TdP in LQT1 and LQT2 but suppression in LQT3 [29]. This concludes that therapeutic paradox is evident in LQTSs, as beta blockers are therapy of LQT1 and LQT2 but beta adrenergic stimulation is therapy for LQT3. Pause-dependent TdP in case of acquired or

congenital LQT can be minimized using temporary pacing [30].

1.As secondary prevention after aborted cardiac arrest

3.Intolerance to primary pharmacotherapy (β-blockers)

ICD is indicated in the following conditions:

The implantation of an ICD is pivotal secondary prevention in LQTS and a reasonable primary prevention approach in selected cases [31]. Thoughtful ICD programming to prevent inappropriate shocks is important. In our practice, for LQTS secondary prevention, we do not incorporate tiered therapy for this type of patients but program the ICD to VF-only zone (detect rate, >220 beats per minute).

2.Failure of optimal medical therapy to control events of cardiac arrest

4.Symptomatic patients with QTc of 500 ms or greater, especially women with

Well-accepted treatment option in LQTS patients is left cardiac sympathetic denervation (LCSD). It is an exceptional therapeutic option that can be leaned on in selected cases like LQT1 and LQT2 patients with no proper response to beta blockers, intolerance to beta blockers, or after ICD implant with recurrent arrhythmias [32]. LCSD can be chosen as a primary treatment option or secondary, with what is described as excellent results in selected patients [33]. It seems that there are specific selection criteria to obtain optimal outcome of LCSD. More

**116**

LQT2

5.LQT3 genotype

#### **2.3 Catecholaminergic PMVT risk stratification and management plan**

Catecholaminergic polymorphic VT (CPVT) is a syndrome of exercise- or stressinduced PMVT in the absence of overt structural heart disease or abnormalities on the baseline ECG. CPVT should be suspected in patients with exertional presyncope/syncope and a normal resting QTc interval. The most useful diagnostic test is the stress ECG. The hallmark finding is exertional bidirectional VT, although more commonly exertional ventricular ectopy or short runs of PMVT may occur [47, 48]. The prevalence of CPVT is estimated to be 1 in 10,000, and it is often diagnosed among healthy children or young adults [49]. High doses (nadolol, 3–5 mg/kg) may be necessary to suppress exertional ectopy; doses can be titrated to effect based on inducibility of ventricular arrhythmias with stress testing [50]. Because of the high risk of recurrent events and SCD on β-blockers, adjunctive ICD implantation is recommended in all symptomatic patients.

Pharmaceutical emergency management involves intravenous beta blockers. Anesthetic measures to reduce adrenergic sympathetic surge like conscious sedation or even general anesthesia might be used in emergency situation especially with ICD shock storm. This approach still lacks scientific evidence. In spite of the pivotal role of beta blockers in CPVT management, recurrence of arrhythmic events is still high. Eleven studies have been reviewed comprising 493 patients, and 88% were on beta blockers, with follow-up periods of 20–96 months. The eight-year arrhythmic event rate was 37.2%, with a near-fatal event rate of 15.3% and a fatal event rate of 6.4% [51]. This review alerts the arrhythmia community to very important management alert, where suppression of arrhythmia induced by exercise with beta blockers does not imply long-term effectiveness.

If gene mutation is positive for CPVT, without using beta blockers, SCD may occur even if exercise test is negative [52]. Flecainide is also a promising first-line drug. It might be used as second-line treatment combined with beta blockers regardless of the presence or absence of genetic mutation [53, 54]. It was proved to target the calcium waves inducing arrhythmia as it targets RYR2 channels [55]. Flecainide was shown to be highly effective if combined with beta blockers compared to beta blockers alone (P < 0.003) [56]. The recommended daily dose of flecainide is 150–200 mg with maximum dose not exceeding 300 mg/day. In genotype-negative CPVT patients, flecainide was shown to reduce VT during exercise test [57].

Surgical option represented by left cardiac sympathetic denervation (LCSD) is an effective choice as a hybrid therapy to pharmaceutical agents. It was found to be safe and effective and requires minimal endoscopic surgery, although its availability is a problem. LCSD was found to raise the VT threshold and ventricular refractoriness [58]. In high-risk patients, it might be advisable to be done early in the treatment plan. Larger cohort studies are needed for better understanding the role of LCSD in PCVT [59].

ICD, with primary termination, was able to clear VT in 24 young patients with PCVT. In spite of its critical role in management, ICD may act as proarrhythmic due to its induction of adrenergic state [60]. In certain patients with cautious personalities, ICD may act paradoxically to increase arrhythmic events through emotionally higher adrenergic state of fear. This is why reducing negative emotions should be thought of as primary essential non-pharmaceutical measure to inhibit arrhythmic events in any adrenergic-mediated arrhythmia [61]. This should be emphasized more in younger age group and patients with higher shock frequency. It was found that patients younger than 50 years of age might be at higher risk due to life style disruption and distressing social comparisons [62]. Programming ICD in PCVT patients should be tiered therapy with three zones of management (SVT, VT and VF). This is important to avoid inappropriate shocks with its vicious cycle

**119**

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

exercise might be allowed to asymptomatic CPVT individuals.

arrhythmic effects. Symptomatic CPVT patients should avoid exercise. Guarded

**2.4 Early repolarization syndrome (ERS) risk stratification and management** 

This is a steep repolarization of transmural AP gradients that was thought to be benign and was proven to be truly arrhythmogenic in 2008 after Haïssaguerre et al.'s landmark study [64]. Because of their similar pathophysiological mechanisms, it is not surprising that the approach to therapy of ERS is similar to that of BrS. β-adrenergic activation with isoproterenol is effective in suppressing ER arrhythmias by enhancing inward calcium current [65]. As cardiac transient outward potassium current (*I*to) inhibitor, quinidine is also effective [66]. An observational cohort study of 122 patients (age 25–49, 90 male patients) with ERS who implanted ICD was done [67]. Follow-up was done through ICD interrogation. Successful suppression of VF in this cohort was demonstrated using isoproterenol (100% success) in acute cases, while quinidine was shown superior in chronic cases. Quinidine was able to abolish all VF attacks over 2 years. Quinidine success was extraordinarily confirmed as it was able to restore normal ECG. To the surprise, medications like β-blockers, amiodarone, class 1C agents, mexiletine and verapamil were found not to be effective. In another publication of five BrS and two ERS patients, a combination of cilostazol and bepridil was found to suppress VF effectively [68]. Cilostazol inhibits the activity of phosphodiesterase III in the heart. It thereby increases the inward calcium current (ICa) via elevation of the intracellular concentrations of cyclic adenosine monophosphate (cyclic AMP), which shares some pharmacological features with isoproterenol. Cilostazol can cause symptomatic palpitations and its long-term effects have not been reported. Bepridil (calcium antagonist with fast kinetic block of sodium currents) inhibits most types of potassium currents, including (Ito) and could decrease the number of sudden VF episodes in patients with idiopathic VF (including those with BrS). The addition of bepridil could attenuate cilostazol-induced palpitations without preventing the suppressive effects

If VT or VF is documented, then ICD is indicated. No available clinical strategy is present for asymptomatic individuals with ERS electrocardiographic manifestation. Syncope correlation to the arrhythmia in ESR is unusual. The presence of syncope in ERS-diagnosed individuals should warrant more investigations.

Although the exit list of primary arrhythmias from idiopathic VF circle is increasing, it still stands alone as a primary diagnosis. Acute suppression of the VF can be achieved successfully with isoproterenol or quinidine [70, 71]. The mechanism of quinidine effect in idiopathic VF is unknown [72]. The famous Ca++ channel blocker, verapamil, also proves to be successful acutely [73]. Ventricular ectopy mostly originating from the distal Purkinje system is observed in up to 30%

Promising publications report the successful ablation of the triggering PVC with cure rate of 89% [75]. After ablation rate of recurrence is low (18%), there is a possibility that the recurrence is due to another site of triggering PVC [76]. For patients

As we emphasized above, suppression of exercise-induced ventricular arrhythmias with β-blocker therapy does not necessarily translate into long-term effectiveness of

*DOI: http://dx.doi.org/10.5772/intechopen.92131*

therapy [63].

**plan**

of cilostazol on VF [69].

**2.5 Idiopathic VF management plan**

of cases of idiopathic ventricular fibrillation VF [74].

who were lucky to be retrieved after VF, ICD implant is a MUST.

*Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge… DOI: http://dx.doi.org/10.5772/intechopen.92131*

arrhythmic effects. Symptomatic CPVT patients should avoid exercise. Guarded exercise might be allowed to asymptomatic CPVT individuals.

As we emphasized above, suppression of exercise-induced ventricular arrhythmias with β-blocker therapy does not necessarily translate into long-term effectiveness of therapy [63].

#### **2.4 Early repolarization syndrome (ERS) risk stratification and management plan**

This is a steep repolarization of transmural AP gradients that was thought to be benign and was proven to be truly arrhythmogenic in 2008 after Haïssaguerre et al.'s landmark study [64]. Because of their similar pathophysiological mechanisms, it is not surprising that the approach to therapy of ERS is similar to that of BrS. β-adrenergic activation with isoproterenol is effective in suppressing ER arrhythmias by enhancing inward calcium current [65]. As cardiac transient outward potassium current (*I*to) inhibitor, quinidine is also effective [66]. An observational cohort study of 122 patients (age 25–49, 90 male patients) with ERS who implanted ICD was done [67]. Follow-up was done through ICD interrogation. Successful suppression of VF in this cohort was demonstrated using isoproterenol (100% success) in acute cases, while quinidine was shown superior in chronic cases. Quinidine was able to abolish all VF attacks over 2 years. Quinidine success was extraordinarily confirmed as it was able to restore normal ECG. To the surprise, medications like β-blockers, amiodarone, class 1C agents, mexiletine and verapamil were found not to be effective. In another publication of five BrS and two ERS patients, a combination of cilostazol and bepridil was found to suppress VF effectively [68]. Cilostazol inhibits the activity of phosphodiesterase III in the heart. It thereby increases the inward calcium current (ICa) via elevation of the intracellular concentrations of cyclic adenosine monophosphate (cyclic AMP), which shares some pharmacological features with isoproterenol. Cilostazol can cause symptomatic palpitations and its long-term effects have not been reported. Bepridil (calcium antagonist with fast kinetic block of sodium currents) inhibits most types of potassium currents, including (Ito) and could decrease the number of sudden VF episodes in patients with idiopathic VF (including those with BrS). The addition of bepridil could attenuate cilostazol-induced palpitations without preventing the suppressive effects of cilostazol on VF [69].

If VT or VF is documented, then ICD is indicated. No available clinical strategy is present for asymptomatic individuals with ERS electrocardiographic manifestation. Syncope correlation to the arrhythmia in ESR is unusual. The presence of syncope in ERS-diagnosed individuals should warrant more investigations.

#### **2.5 Idiopathic VF management plan**

Although the exit list of primary arrhythmias from idiopathic VF circle is increasing, it still stands alone as a primary diagnosis. Acute suppression of the VF can be achieved successfully with isoproterenol or quinidine [70, 71]. The mechanism of quinidine effect in idiopathic VF is unknown [72]. The famous Ca++ channel blocker, verapamil, also proves to be successful acutely [73]. Ventricular ectopy mostly originating from the distal Purkinje system is observed in up to 30% of cases of idiopathic ventricular fibrillation VF [74].

Promising publications report the successful ablation of the triggering PVC with cure rate of 89% [75]. After ablation rate of recurrence is low (18%), there is a possibility that the recurrence is due to another site of triggering PVC [76]. For patients who were lucky to be retrieved after VF, ICD implant is a MUST.

*Sudden Cardiac Death*

recommended in all symptomatic patients.

does not imply long-term effectiveness.

**2.3 Catecholaminergic PMVT risk stratification and management plan**

Catecholaminergic polymorphic VT (CPVT) is a syndrome of exercise- or stressinduced PMVT in the absence of overt structural heart disease or abnormalities on the baseline ECG. CPVT should be suspected in patients with exertional presyncope/syncope and a normal resting QTc interval. The most useful diagnostic test is the stress ECG. The hallmark finding is exertional bidirectional VT, although more commonly exertional ventricular ectopy or short runs of PMVT may occur [47, 48]. The prevalence of CPVT is estimated to be 1 in 10,000, and it is often diagnosed among healthy children or young adults [49]. High doses (nadolol, 3–5 mg/kg) may be necessary to suppress exertional ectopy; doses can be titrated to effect based on inducibility of ventricular arrhythmias with stress testing [50]. Because of the high risk of recurrent events and SCD on β-blockers, adjunctive ICD implantation is

Pharmaceutical emergency management involves intravenous beta blockers. Anesthetic measures to reduce adrenergic sympathetic surge like conscious sedation or even general anesthesia might be used in emergency situation especially with ICD shock storm. This approach still lacks scientific evidence. In spite of the pivotal role of beta blockers in CPVT management, recurrence of arrhythmic events is still high. Eleven studies have been reviewed comprising 493 patients, and 88% were on beta blockers, with follow-up periods of 20–96 months. The eight-year arrhythmic event rate was 37.2%, with a near-fatal event rate of 15.3% and a fatal event rate of 6.4% [51]. This review alerts the arrhythmia community to very important management alert, where suppression of arrhythmia induced by exercise with beta blockers

If gene mutation is positive for CPVT, without using beta blockers, SCD may occur even if exercise test is negative [52]. Flecainide is also a promising first-line drug. It might be used as second-line treatment combined with beta blockers regardless of the presence or absence of genetic mutation [53, 54]. It was proved to target the calcium waves inducing arrhythmia as it targets RYR2 channels [55]. Flecainide was shown to be highly effective if combined with beta blockers compared to beta blockers alone (P < 0.003) [56]. The recommended daily dose of flecainide is 150–200 mg with maximum dose not exceeding 300 mg/day. In genotype-negative CPVT patients, flecainide was shown to reduce VT during exercise test [57].

Surgical option represented by left cardiac sympathetic denervation (LCSD) is an effective choice as a hybrid therapy to pharmaceutical agents. It was found to be safe and effective and requires minimal endoscopic surgery, although its availability is a problem. LCSD was found to raise the VT threshold and ventricular refractoriness [58]. In high-risk patients, it might be advisable to be done early in the treatment plan. Larger cohort studies are needed for better understanding the role of

ICD, with primary termination, was able to clear VT in 24 young patients with PCVT. In spite of its critical role in management, ICD may act as proarrhythmic due to its induction of adrenergic state [60]. In certain patients with cautious personalities, ICD may act paradoxically to increase arrhythmic events through emotionally higher adrenergic state of fear. This is why reducing negative emotions should be thought of as primary essential non-pharmaceutical measure to inhibit arrhythmic events in any adrenergic-mediated arrhythmia [61]. This should be emphasized more in younger age group and patients with higher shock frequency. It was found that patients younger than 50 years of age might be at higher risk due to life style disruption and distressing social comparisons [62]. Programming ICD in PCVT patients should be tiered therapy with three zones of management (SVT, VT and VF). This is important to avoid inappropriate shocks with its vicious cycle

**118**

LCSD in PCVT [59].
