**2. Management of ventricular arrhythmias in suspected channelopathies**

#### **2.1 The long QT syndromes' risk stratification and management plan**

The yield of genetic mutations in LQTS is better than in other channelopathies but still did not exceed 50%. The cutoff numbers for QTc interval before labeling it long is 480 and 470 ms in post pubertal women and men, respectively. In the 12 leads ECG, manual measurement from limb lead 2 or chest lead V5 using Bazzet's formula (**QTc = QT/√RR**) is a must. Moss and Schwartz developed a reliable scoring system for better risk stratification of LQTS individuals (**Table 1**) [1, 2]. Goldenburg criteria for risk stratification in long QT are also useful to add in clinical practice (**Table 2**) [3]. There must be no medications affecting ECG.

Schwartz score is more commonly used. The Schwartz score was proposed in 1993 and revised in 2011 by Schwartz and Crotti [4]. Schwartz Moss scoring system comprises clinical, electrocardiographic as well as familial historical data. It is designed for use for the index case but not others. It was found to have high correlation to positive genetic testing with 75% likelihood if the score is more than 4 points. It is not of use for a family member with long QT interval but with no symptoms [5]. T-wave abnormalities are important indicators for electrical instability. The score will count 1 point for positive T-wave alternans in the TWA test and another 1 point for notched T waves that are considered as poor prognostic sign. Poor prognostic factors with more likelihood for SCD are QTc more than 500 ms, LQTS symptoms, genotype of LQT2 or LQT3 and female gender. Male gender with LQT1 refers to lower risk group. The strongest indicator for SCD is the QTc interval [6]. Survival from cardiac arrest before age 7 or development of syncope before puberty carries worse overall prognosis [7]. Risk of recurrence is very high if syncope or cardiac arrest happens in the first year of life [8]. Genetic testing carries important prognostic value as asymptomatic positive mutation individuals below 40 years of age carry 10% higher risk of life-threatening arrhythmia if not treated [9]. Placebo controlled

**115**

**Table 2.**

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

F: Low heart rate for age (resting heart rate below the second percentile for age)

B: Unexplained SCD at age < 30 years among immediate family members

*Updated Schwartz score: The same family member cannot be counted in A and B.*

**Risk factor Points**

2 1 0.5

1 0.5

randomized trials in LQTS management are lacking (except 2019 AHA editorial Published online 2019 May 29. doi: 10.1161/JAHA.119.012833, entitled "Energy Drinks: Another Cause of QT Prolongation?") The assignment of placebo group in LQTS creates difficult ethical choices. Almost all present strategic plans in LQTS management were deduced from registries with beta blockers and cardioverter defibrillator (ICD) therapy [10]. Electrolytes disturbances correction like hypokalemia and hypomagnesaemia is a critical primary step in LQTS management. Magnesium sulfate intravenously proved to be safe and effective for acquired or congenital TdP management [11]. Beta blockers are the first line and the easiest therapeutic choice for both LQT1 and LQT2. In the current medical literature, there is controversy regarding the use of beta blockers in LQT3. For LQT1 and LQT2, propranolol and nadolol seem to be more effective than metoprolol [12]. Nadolol with its longer half life (twice a day) and sustained release propranolol seem to be attractive options. There are data suggesting that propranolol is more effective than atenolol [13]. Disease-specific favorable responses are suggested with nadolol providing the sole significant risk reducer in LQT2, while metoprolol, atenolol, propranolol and

*Score ≤ 1 point: low probability of LQTS. 1.5–3 points: intermediate probability of LQTS. ≥3.5 points: high* 

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

B: QTc fourth minute of recovery from exercise

A: Family members with definite LQTS

Very high risk (secondary prevention) Postcardiopulmonary resuscitation

High risk (primary prevention)

Qtc <500 ms and no prior syncope

*Goldenburg criteria for LQTS risk stratification.*

Spontaneous TdP

QTc >500 ms Prior syncope Low risk

EKG findings A: QTc ≥480 ms 460–479 ms 450–459 (men)

Stress test ≥480 ms

D: T-wave alternans E: Notched T-wave in 3 leads

Clinical History A: Syncope With stress Without stress B: Congenital deafness

Family History

*probability of LQTS.*

**Table 1.**

C: TdP

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


#### **Table 1.**

*Sudden Cardiac Death*

on channelopathies.

affecting ECG.

or a beloved one. 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 occur 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 a young member of the family. Sadly, life-threatening arrhythmias and sudden cardiac death can be the first presenting symptom. Scientists and clinicians were 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 discuss the available risk stratification for channelopathies and detailed management steps with focus on the different trials for pharmaceutical approach of the different channelopathies. The electrical therapy in the form of ICD is a critical management step but will be prioritized according to channelopathy type and clinical settings. Future speculations of fatal ventricular rhythms are going to be discussed with special reference to solar and geomagnetic activity fluctuation and heart rate variability (HRV) correlations to SCD and the up to the moment knowledge in its impact

**2. Management of ventricular arrhythmias in suspected channelopathies**

The yield of genetic mutations in LQTS is better than in other channelopathies but still did not exceed 50%. The cutoff numbers for QTc interval before labeling it long is 480 and 470 ms in post pubertal women and men, respectively. In the 12 leads ECG, manual measurement from limb lead 2 or chest lead V5 using Bazzet's formula (**QTc = QT/√RR**) is a must. Moss and Schwartz developed a reliable scoring system for better risk stratification of LQTS individuals (**Table 1**) [1, 2]. Goldenburg criteria for risk stratification in long QT are also useful to add in clinical practice (**Table 2**) [3]. There must be no medications

Schwartz score is more commonly used. The Schwartz score was proposed in 1993 and revised in 2011 by Schwartz and Crotti [4]. Schwartz Moss scoring system comprises clinical, electrocardiographic as well as familial historical data. It is designed for use for the index case but not others. It was found to have high correlation to positive genetic testing with 75% likelihood if the score is more than 4 points. It is not of use for a family member with long QT interval but with no symptoms [5]. T-wave abnormalities are important indicators for electrical instability. The score will count 1 point for positive T-wave alternans in the TWA test and another 1 point for notched T waves that are considered as poor prognostic sign. Poor prognostic factors with more likelihood for SCD are QTc more than 500 ms, LQTS symptoms, genotype of LQT2 or LQT3 and female gender. Male gender with LQT1 refers to lower risk group. The strongest indicator for SCD is the QTc interval [6]. Survival from cardiac arrest before age 7 or development of syncope before puberty carries worse overall prognosis [7]. Risk of recurrence is very high if syncope or cardiac arrest happens in the first year of life [8]. Genetic testing carries important prognostic value as asymptomatic positive mutation individuals below 40 years of age carry 10% higher risk of life-threatening arrhythmia if not treated [9]. Placebo controlled

**2.1 The long QT syndromes' risk stratification and management plan**

**114**

*Updated Schwartz score: The same family member cannot be counted in A and B.*

randomized trials in LQTS management are lacking (except 2019 AHA editorial Published online 2019 May 29. doi: 10.1161/JAHA.119.012833, entitled "Energy Drinks: Another Cause of QT Prolongation?") The assignment of placebo group in LQTS creates difficult ethical choices. Almost all present strategic plans in LQTS management were deduced from registries with beta blockers and cardioverter defibrillator (ICD) therapy [10]. Electrolytes disturbances correction like hypokalemia and hypomagnesaemia is a critical primary step in LQTS management. Magnesium sulfate intravenously proved to be safe and effective for acquired or congenital TdP management [11]. Beta blockers are the first line and the easiest therapeutic choice for both LQT1 and LQT2. In the current medical literature, there is controversy regarding the use of beta blockers in LQT3. For LQT1 and LQT2, propranolol and nadolol seem to be more effective than metoprolol [12]. Nadolol with its longer half life (twice a day) and sustained release propranolol seem to be attractive options. There are data suggesting that propranolol is more effective than atenolol [13]. Disease-specific favorable responses are suggested with nadolol providing the sole significant risk reducer in LQT2, while metoprolol, atenolol, propranolol and

Very high risk (secondary prevention) Postcardiopulmonary resuscitation Spontaneous TdP High risk (primary prevention) QTc >500 ms Prior syncope Low risk Qtc <500 ms and no prior syncope

#### **Table 2.**

*Goldenburg criteria for LQTS risk stratification.*

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].

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). ICD is indicated in the following conditions:


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

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

tion 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].

than half of high-risk patients did not benefit from the procedure. Addition of right cardiac sympathetic denervation to LCSD might be of benefit in selected patients [34]. At all times, LCSD is not a replacement of the beta blockers and/or

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 fragmenta-

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

ICD therapy.

than half of high-risk patients did not benefit from the procedure. Addition of right cardiac sympathetic denervation to LCSD might be of benefit in selected patients [34]. At all times, LCSD is not a replacement of the beta blockers and/or ICD therapy.
