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.
Risk Stratification
Current risk stratification is based on limited data because the number of patients identified with CPVT is low. The largest published series includes 101 patients,83 estimated prevalence of CPVT is 1 : 10,000, and available follow-up periods are short. As in other channelopathies, family history of SCD has not proved a predictive factor for cardiac events in CPVT. The baseline ECG is not useful as a diagnostic or prognostic tool. The natural history does not differ among CPVT patients with or without identified mutations or among patients with RyR2– and CASQ2-related mutations. Silent mutation carriers (asymptomatic, with no arrhythmias at exercise testing or on Holter monitoring) present a similar event rate to symptomatic patients.83 Neither gender seems to have a higher risk of cardiac events or SCD. EPS is not useful to diagnose or evaluate risk of cardiac events, because arrhythmias in CPVT patients are usually not inducible. Young age at diagnosis, history of ACA, and absence of β-blocker therapy have been identified as independent predictors of fatal or near-fatal cardiac events. Syncope before diagnosis did not identify patients at higher risk for cardiac events; however, these results may be biased because most patients with a diagnosis of CPVT and syncope were receiving β-blockers, resulting in a significant reduction of cardiac events and SCD.83
Current Therapeutic Recommendations
Exercise testing is the most useful tool for diagnosis of CPVT because the ventricular arrhythmias are highly reproducible with exercise. It is also of value to titrate the dose of β-blockers. All patients diagnosed with CPVT must be treated with β-blockers; asymptomatic gene carriers show a similar rate of arrhythmic events to symptomatic patients.83 Patients who recovered from an episode of SCD are considered at high risk of cardiac events, and ICD implantation plus β-blockers for secondary prevention are mandatory. Patients with complex ventricular arrhythmias or symptoms despite full doses of β-blockers are also candidates for ICD (class IIa indication). Some reports suggest that the use of Ca2+ antagonists (in combination with β-blockers)91 and left cardiac sympathetic denervation may be useful in patients with recurrent ventricular arrhythmias despite full-dose β-blockers and in those with ICD and electrical storm.92
General Considerations
Correct risk stratification and treatment in patients with cardiac channelopathies is challenging. Some patients are at risk of fatal or near-fatal arrhythmias at a very young age, and all efforts should be directed to avoid these events. Table 17-1 summarizes current indications for ICD implantation, according to the American College of Cardiology/American Heart Association (ACC/AHA) Task Force and the European Society of Cardiology (ESC) guidelines.1 ICD therapy has proved the most effective tool to prevent arrhythmic SCD,22 and its indication in high-risk patients is clearly justified (Fig. 17-1), especially considering the cumulative increased risk of very young patients who present for primary or secondary prevention. However, it is important to highlight that ICD therapy does have associated complications.
Some series of BS patients with an ICD reported low rates of appropriate shocks (8%-15%; median follow-up, 45 months; annual appropriate discharge rate, 2.6%) and high rates of complications (28%), including inappropriate shocks (20%-36%), which often greatly exceeded (2-2.5 times) the rate of appropriate shocks.93–95 However, some studies of LQTS patients may have promoted ICD use based on incidence of ICD shock delivery, considering “appropriate ICD therapy” equivalent to SCD, with resulting rates of “livesaving therapies” higher than the expected mortality for the disease. In randomized trials for primary and secondary prevention of SCD in LQTS patients, the number of appropriate shocks consistently exceeded the sudden death rate in the control group by 2 : 1. Because most TdP episodes terminate spontaneously, some of those “appropriate ICD shocks” may have been inappropriate, treating a ventricular arrhythmia that would have terminated spontaneously.36–39 Other studies also showed excellent response to β-blocker therapy (especially in LQT1) when patients were fully compliant and avoided QT-prolonging medications.96
Antibradycardia Therapy in Long QT Syndrome
Most episodes of TdP in congenital LQTS are preceded by “short-long-short” sequences. Therefore, antibradycardia therapy was proposed in these patients to avoid sudden increases in R-R intervals, which may be arrhythmogenic. The simplest way to avoid pauses when the patient carries a pacemaker or ICD is to increase the lower rate limit. Different groups suggest programming LRL above 70 bpm,32 between 70 and 80 bpm,13 or at 80 bpm or higher97 in adults diagnosed with LQTS, increasing this value for short periods when the patient is known to be at increased risk for developing TdP (e.g., postpartum period, surgical procedures). Maintenance of higher LRL for long periods, however, may lead to tachycardia-induced cardiomyopathy.
To prevent pauses in LQTS patients through pacing, other antibradycardia parameters of the ICD should be correctly programmed, as follows98:
Complications
Implantation
The reported overall risk of any early complication after device implant was 6.7%, with 4.9% of patients requiring an invasive treatment; rate of late procedure-related complications was 3.1%.99 Diagnosis of implant complications requires a high index of suspicion. Routine examination after implantation should include physical examination, chest radiograph, and device interrogation.
Infection
Pocket infection and device infection are some of the most severe complications related to ICD implantation, requiring aggressive and expensive treatment: prolonged in-hospital antibiotic administration and usually surgical explantation of the device. Identified risk factors for device infections in patients with channelopathies include multiple implant procedures (up to fivefold increased risk)100,101 and young age at implantation,102 especially during childhood. Lead and infection complications were more prevalent in children, doubling the incidence of device infection in patients under 40 versus over age 40.103 Evidence also indicates that ICDs become infected more frequently than pacemakers.104,105
Inappropriate Shocks
Inappropriate shocks are defined as shocks delivered by the ICD for a non-VT/VF rhythm. Identified causes of inappropriate shocks are common in patients with channelopathies, including sinus tachycardia (Fig. 17-2); atrial tachyarrhythmias (Fig. 17-3), found in up to 30% of BS patients,53 in 70% of SQTS patients, and in CPVT patients; and T-wave oversensing, especially in SQTS. Young patients may lead more active physical lives and inadvertently damage their leads, causing inappropriate shocks by sensing artifacts (“noise”) or myopotentials. Lead failures, which cause one third to one half of inappropriate shocks in younger patients, are more frequent in children than adults.102,106–108 In adults, the lead failure rate reaches 2% to 3% in short-term follow-up, versus a 10-fold rate among the pediatric population. There have been reports of a high rate of lead failure beyond 10 years after implantation (up to 20% cumulative risk), which is relevant in this population, who have a long survival expectation (especially after ICD implantation).109
The incidence of inappropriate shocks in young patients is high: 25% after 16-month follow-up.106 Reported rate of inappropriate shocks in BS patients is 20% at 38 months and 36% at 54 months.94 Inappropriate shocks leading to cardiac arrest or SCD by triggering VT or VF are extremely rare. Even if these do not trigger fatal or near-fatal arrhythmias, inappropriate shocks have negative consequences on the quality of life of these patients.95,110 In CPVT patients, an important concern is electrical storms, which may lead to death secondary to exhaustion of therapies by the ICD after shocks (appropriate and inappropriate).111 Inappropriate shocks after sinus tachycardia or supraventricular arrhythmias cause increased release of endogenous catecholamines, leading to polymorphic VT and more shocks.112 The patient also may receive an inadequate shock for nonsustained ventricular tachycardia (NSVT), which is common in patients with channelopathies (Fig. 17-4). Special care must be taken during programming the ICD to avoid treating NSVT (see Strategies to Avoid Complications).
Risk of Never Using Device
In patients with no myocardial disease, the percentage of surviving patients in the “never used device” category may remain high, because death from heart failure is low or completely unexpected.53,94 In patients with BS and LQTS, mortality was near or at 0%, and survival without appropriate discharge was 85% to 93%.39,94 In young patients, this poses a special problem; besides being exposed for decades to the risk of sudden death, they will also be exposed to the risks of ICD implantation, but accrue none of the benefit, which may fade over time.113
Strategies to Avoid Complications
Table 17-2 summarizes suggested strategies to avoid complications with ICD therapy. Other recommendations include the following:
TABLE 17-2 Tips to Avoid Complications with ICD Therapy in Patients with Channelopathies
| Tips at Implantation | Programming Tips |
|---|---|
| 1. IV antibiotic prophylaxis ≥30 min before surgery. | 1. Only one therapy zone (VF). |
ATP, Antitachycardia pacing; IV, intravenous; LQTS; long QT syndrome; NID, number of intervals to detect; NSVT, nonsustained ventricular tachycardia; VF, ventricular fibrillation.
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