17 ICD Therapy in Channelopathies
Cardiac channelopathies, also called ion channel disorders, include long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. This group of genetically determined diseases has low prevalence in the general population, usually less than 5 per 10,000.1 Affected individuals have a structurally normal heart but an increased risk of syncope and sudden cardiac death (SCD) caused by ventricular tachycardia (VT) or ventricular fibrillation (VF). The genes affected by causative mutations encode proteins that form cardiac ion channels, regulate their function, or participate in ionic-cellular imbalance, regulating the electrical function of the heart and resulting in primary electrical diseases. The penetrance of channelopathies is variable, and individuals who show the most severe phenotype are at higher risk of presenting with life-threatening episodes of ventricular arrhythmias.
Symptoms usually begin early in life, and risk stratification is paramount because patients might present with SCD, in some cases as the first symptom. Although genetic information is entering clinical practice and being integrated in the risk stratification schemes,2,3 family history of SCD has not been identified as a reliable marker of high risk in patients with channelopathies.
There are no large, randomized trials of treatment for these diseases, and probably never will be. Current indications for risk stratification and treatment are based on information from large registries and retrospective analysis. Thus, the level of evidence for all indications is low. Patients diagnosed with channelopathies are advised to restrict exercise, even if exercise is not a recognized trigger for their arrhythmic events.4 This chapter reviews risk stratification and implantable cardioverter-defibrillator (ICD) indications for the channelopathies, as well as benefits and drawbacks of ICD implantation in these patients.
Long QT Syndrome
Described for the first time by Jervell and Lange-Nielsen5 in 1957 (autosomal recessive pattern of inheritance; associated genes: KCNQ1 and KCNE1)6 and by Romano et al. in 1963 and Ward et al.7 in 1964 (autosomal dominant inheritance; associated genes: KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, and SNTA1),6 long QT syndrome (LQTS) is the most studied cardiac channelopathy. Established in 1979, the International LQTS Registry includes more than 3000 patients and provides information about causative mutations, clinical course, risk factors, and response to treatment.8
The typical features of LQTS are prolonged corrected QT (QTc) interval in the 12-lead electrocardiogram (ECG), T-wave abnormalities, and symptoms that vary from syncope to SCD. Symptoms are secondary to torsades de pointes (TdP), a rapid polymorphic VT that may be self-limited or may degenerate into VF (mean age of onset, 12 years).9 The arrhythmic episodes are often triggered by adrenergic stimuli (e.g., exercise, emotion) but may also occur at rest.10 TdP may be pause dependent or adrenergic dependent.11,12 Pause-dependent TdP mainly follows post-extrasystolic pauses but may also appear after pauses during sinus arrhythmia or sinus arrest. These pauses enhance early afterdepolarizations (EADs), manifesting on ECG as more prolonged QT interval and U-wave augmentation in the beat immediately after the pause, and may trigger TdP. Adrenergic-dependent TdP follows sinus tachycardia during physical or emotional stress. In this case, tachycardia and high sympathetic tone increase the dispersion of repolarization by shortening it in different degrees across the myocardial layers. Also during sinus tachycardia, however, ventricular extrasystoles and the following post-extrasystolic pause are able to trigger TdP.13
Risk Stratification
Factors in risk stratification of LQTS patients include ECG, age, gender, genotype, and symptoms.
Electrocardiogram
Many studies have confirmed a direct relationship between prolonged QTc interval and risk of arrhythmia-related symptoms in patients with LQTS.3,14–19 A QTc interval of 500 msec or higher implies high risk for arrhythmic events.3 The strength of QTc interval to predict arrhythmic risk varies when dividing patients into subgroups according to age or gender, but it always maintains a strong value as an independent risk factor. Serial QTc measurements may have a role in risk stratification, because maximum QTc interval during adolescence was the strongest predictor of cardiac events.20
Age and Gender
Observation of the natural history of LQTS reveals how gender and age interact as risk factors.8,21,22 Several analyses of the probability of arrhythmic events during different decades of life showed that risk is significantly higher in boys than girls (5% vs. 1%).17 Also, the gender-related risk reverses in the final stage of adolescence, about age 17, with respect to any cardiac events, and about age 23 with SCD and sudden cardiac arrest (SCA).15–18
Genotype
Genotype testing identifies a causative mutation in up to 68% of probands of LQTS; 90% of patients are LQT1, LQT2, or LQT3.23,24 Genotype is useful for risk stratification. Patients with LQT1 and LQT2 have more cardiac events (mainly syncope) than patients with LQT3, who present a higher rate of lethal or potentially lethal events.2 Triggers for the arrhythmic events in LQTS are also associated with the genotype: exercise (especially swimming) in patients with LQT1, sudden loud noise in LQT2, and rest/sleep in LQT3 patients.10 Furthermore, the response to β-blocker therapy for prevention of cardiac events is significantly better in LQT1 than in LQT2 or LQT3 patients.9 A given type of mutation or its location in the affected gene can influence risk.25–27
Symptoms
Syncope is the strongest predictor of cardiac events and SCD in the patient with LQTS. In all age groups, recent or remote syncope is associated with a 2.7- to 18-fold increased risk of SCD.15–18
Unrelated Factors
Electrophysiologic study (EPS)1,28 and family history of SCD29 have proved not to influence risk stratification in LQTS.
Aborted Cardiac Arrest
A simplified scheme for risk stratification of aborted cardiac arrest (ACA) or SCD in LQTS patients divides patients in three groups: (1) high risk (history of ACA or documented TdP), with an estimated rate of ACA or SCD of 14% at 5-year follow-up; (2) intermediate risk (QTc >500 msec and/or time-dependent syncopal history), with an estimated rate of ACA or SCD at 5-year follow up of 3%; and (3) low risk (QTc ≤500 msec and/or no history of prior syncope), with 0.5% estimated rate of ACA or SCD at 5-year follow-up.30
Current Therapeutic Recommendations
Current guidelines suggest that all patients diagnosed with LQTS should avoid triggers of arrhythmias (exercise, emotional stress, loud noises) as well as drugs that prolong the QTc interval. Patients should receive β-blockers (class I indication in clinical diagnosis, i.e., prolonged QTc interval; class IIa indication in molecular diagnosis and normal QTc interval). Beta-adrenergic blockers should be given at the highest dose tolerated by the patient, and the dose may be titrated by exercise testing.1
Torsades de pointes in patients with congenital LQTS is often pause dependent (up to 74%),31 and cardiac pacing at lower rate limit (LRL) >70 bpm has proved helpful for preventing TdP development in acquired LQTS,32 in which TdP is almost always pause dependent. Therefore, strategies to avoid “short-long-short” sequences were proposed in these patients as a complement to pharmacologic treatment. However, patients undergoing pacemaker implantation and β-blocker therapy still presented unacceptably high rates of aborted SCD (aSCD) and SCD, leading to further indication for ICDs in high-risk patients with LQTS.33 Even though this is currently the preferred approach, LQTS patients can still obtain additional benefits from their ICD if antibradycardia therapy is correctly programmed, in combination with pharmacologic treatment and antitachycardia settings (see later Antibradycardia Therapy in Long QT Syndrome).
The LQTS patients with aSCD are at high risk of repeating a fatal or near-fatal arrhythmic event and thus are candidates for ICD implantation. Patients who continue to experience syncope or TdP while taking maximally tolerated β-blockers also are candidates. These two groups of LQTS patients are also candidates for left sympathetic cardiac denervation.34 Genotype information may help guide the decision about ICD implantation. However, it is also important to consider other clinical markers of high risk, which have proved very useful and simple to evaluate, such as QTc duration, symptoms, presence of sinus pauses, T-wave alternans, and 2 : 1 atrioventricular (AV) block.35
Several studies support a role for ICDs in preventing or reducing SCD in high-risk patients with LQTS. However, most patients do not belong to this subgroup and remain at a relatively low risk of cardiac events; these patients may be appropriately protected from arrhythmic events by a combination of noninvasive and simple measures. Moss et al.14 reported a 5%/yr incidence of syncope and 0.9%/yr incidence of SCD in probands. In affected family members, incidence of cardiac events was even lower: 0.5%/yr for syncope and 0.2%/yr for SCD.
Some studies may have overestimated the benefits of ICD implantation, comparing ICD patients with non-ICD patients who were not adequately treated with drugs,22 or by making “appropriate ICD therapy” synonymous with SCD. Considering that TdP is often nonsustained, and that the rates of “lifesaving therapies” in several studies were higher than the expected mortality in LQTS, some “appropriate ICD shocks” likely were inappropriate, delivered for ventricular arrhythmia that otherwise would have terminated spontaneously.36–39
Short QT Syndrome
Initially described in 2000, short QT syndrome (SQTS) is characterized by an abnormally short QT interval, often followed by morphologic T-wave abnormalities (tall, narrow), and increased susceptibility to atrial fibrillation (AF) and VF.40,41 To date, mutations in five genes have been found in almost 25% of SQTS patients. Mutations in KCNH2, KCNQ1, and KCNJ242–44 result in gain of function in the encoded potassium ion (K+) channels and lead to shortening of the ventricular repolarization phase. Mutations in CACNA1C and CACNB2 cause loss of function in the cardiac L-type calcium ion (Ca2+) channel and produce an overlap between Brugada syndrome and SQTS.45 At present, it is still unclear whether diagnosis of SQTS should be based on QT or QTc interval; sensitivity and specificity of different QT/QTc cutoff values also remain undefined.1
Age of onset of symptoms varies from 4 months to 62 years, and incidence of SQTS is higher among males. Atrial and ventricular effective refractory periods are shortened and AF/VF easily induced in patients undergoing EPS (up to 60%).46 The risk for arrhythmic events is high in SQTS patients. Cardiac arrest is frequently the first manifestation of disease and may occur during the first year of life. Patients also present with syncope and AF (up to 30%) at any age (even intrauterine), making SQTS a differential diagnosis to rule out in young patients with lone AF. The use of quinidine in a group of patients with SQT1 proved useful in making VT noninducible by prolonging ventricular refractory periods.47
Risk Stratification
Up to 2008, only 51 patients with SQTS had been diagnosed worldwide.48 Thus, risk stratification is based on limited data; currently, symptoms are the only tool available to evaluate risk of arrhythmic events. Patients with SQTS and SCA and those with syncope of unknown origin should have an ICD for secondary and primary prevention, respectively, even if no data exist on the usefulness of syncope to predict cardiac events.49 Although ECG helps diagnose the disease, its role in risk stratification is still undefined (e.g., it is unknown if degree of QT shortening identifies patients at higher risk of arrhythmic events). Age, gender, genotype, and inducibility of ventricular tachyarrhythmias during EPS have not yet proved to have a predictive value for cardiac events in this group of patients.
Current Therapeutic Recommendations
Management of patients with SQTS is poorly established. Although limited data show that quinidine may suppress inducibility of ventricular arrhythmias during EPS,50,51 whether it confers long-term protection for malignant arrhythmias remains unknown. Most SQTS patients receive an ICD, with a high rate of complications reported, mostly inappropriate shocks caused by T-wave oversensing.52
Brugada Syndrome
The Brugada syndrome (BS) is one of the leading causes of SCD in patients with structurally normal hearts.53 A characteristic electrocardiographic pattern (“type 1 ECG”) in at least two right precordial leads, spontaneously or after pharmacologic challenge with a class I antiarrhythmic agent confirms the diagnosis, in conjunction with at least one clinical diagnostic criterion reflecting documented ventricular arrhythmias, a positive family history of SCD or BS, or arrhythmia-related symptoms.54 The disease has autosomal dominant inheritance; to date, mutations in eight genes have been linked to BS,55–60 identified in up to 30% of patients, most affecting SCN5A.53 Patients are predominantly male, up to 83% in most series.61–67 Diagnosis is made and cardiac events occur mainly in the fourth decade of life,3,53,63–65 although cardiac arrest has been reported in neonates and children.62,63,68 Fever is a predisposing factor for cardiac arrest in the BS patient.68–72
Risk Stratification
There is an ongoing controversy about risk stratification in BS. All groups agree that patients who recover from an episode of SCD are at high risk of repeating a fatal or near-fatal arrhythmic event (17%-62% at follow-up of 24-40 months)62,63,65 and should receive an ICD.1 However, the best management of patients without a history of SCD remains unclear, specifically asymptomatic patients. Brugada et al.63,64 described a high rate of events in patients with previous syncope (19%) and even in asymptomatic patients (8%) after mean follow-up of 24 months, and inducibility during EPS and previous syncope were independent predictors of cardiac events. Giustteto et al.66 emphasized the role of symptoms as predictors of future cardiac events in 136 consecutive BS patients, supporting the role of EPS as a valuable tool for risk stratification. However, Priori et al.,62 Eckardt et al.,65 and more recently Probst et al.67 found that the incidence of cardiac events was much lower, and inducibility in EPS did not prove useful as a predictor of future arrhythmic events.
Current Therapeutic Recommendations
Quinidine has proved useful in BS patients with ICD and frequent shocks.73 It is also effective in episodes of electrical storm,74 a class IIb indication.1 Some studies show that quinidine in BS patients with inducible VF may render the EPS noninducible for sustained ventricular arrhythmias.75–77 Isoproterenol is also indicated in patients with BS and electrical storm74,78 (class IIa indication).1 Other pharmacologic options are currently being investigated.79–82
Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is considered one of the most malignant channelopathies. Clinical manifestations include syncope and SCD triggered by adrenergic stimuli (exercise, emotion) from ventricular arrhythmias: bidirectional VT (35% of cases) and polymorphic VT (PVT), which sometimes degenerate into VF. Symptoms often begin early in life (age 7-9 years), and by age 40, up to 80% of patients have developed symptoms.83 Overall mortality without treatment is 30% to 50%.84
To date, mutations in two genes have been linked to CPVT. RyR2 (encoding cardiac receptor of ryanodine)85 and CASQ2 (calsequestrin 2)86 are involved in intracellular management of Ca2+ in the myocardium.87,88 Mutations in both genes result in a cytosolic Ca2+ overload from the sarcoplasmic reticulum in the myocytes, giving rise to delayed afterdepolarizations (DADs). During β-adrenergic stimulation, DADs increase in number and magnitude and may trigger multiple action potentials, resulting in symptomatic ventricular arrhythmias. Mutations in RyR2 account for 50% to 55% of genotyped CPVT patients,89 with autosomal dominant inheritance and mean penetrance of 83%.90 Mutations in CASQ2 represent only 5% to 10% of patients, with autosomal recessive inheritance.
