Implantable Cardioverter-Defibrillators in Inherited Arrhythmia Syndromes

Disease Description

Hypertrophic cardiomyopathy (HCM) is a cardiac disorder characterized by myocardial hypertrophy in the absence of abnormal loading conditions. It is a genetically heterogeneous disease with mainly variants in genes encoding for sarcomeric proteins involved as the causal substrate. Disease expression is highly variable and the main complications of the disease are heart failure, stroke, and SCD. In the early years the latter was considered a significant problem, but data from more contemporary studies suggest that the overall risk is relatively small, with annual SCD rates of 1% or less in most series. Clearly, the challenge for the clinician is to identify the individual patient who is at risk for life-threatening arrhythmias in order to provide timely ICD treatment.

Risk Stratification

Risk stratification has for a long time been based on a number of classic risk factors. Documented malignant ventricular arrhythmias (ventricular fibrillation [VF] and fast ventricular tachycardia [VT]) have never been disputed as indicative for a high risk, and patients with these arrhythmias (with or without actual cardiac arrest) qualify for an ICD (secondary prevention). Primary prevention, on the other hand, was based, in the past two decades, on the presence of one of the following risk factors: a family history of sudden death (at young age), a history of syncope, a septum thickness ≥30 mm, an abnormal blood pressure response during exercise (<25 mm Hg rise in blood pressure), and nonsustained VT on 24-hour Holter monitoring. The definition of almost every risk factor proved to be variable, however. For example, the definition of a positive family history at young age includes different degrees of relationship (1st or 2nd degree), the number of deceased individuals (1 or 2) and different ages (40 and 50 years of age). For all these risk factors, it can be concluded that the negative predictive value is reasonably high and useful, but the positive predictive value is insufficient. Additional risk factors with equal problems are the presence of atrial fibrillation, myocardial ischemia, and/or an outflow track gradient. Recently, it has been proposed that a quantitative analysis of the presence of fibrosis may significantly contribute to accurate risk stratification. Finally, the number of these risk factors required for primary prevention has been and is disputed across the Atlantic Ocean, with two or more required in Europe and one or more in the United States. The latter is mainly based on studies with a few hundred patients, but a considerable number of those patients have incomplete descriptions of these risk factors. Very recently, a new risk stratification scheme has been proposed. This attempt includes eight risk factors and, importantly, several of them are included as continuous variables (age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient), which intuitively makes a lot of sense. The others (family history of SCD, nonsustained ventricular tachycardia, and unexplained syncope) are binary. This new strategy, leading to 5-year risk estimates for SCD, has been adopted by the EU guidelines. A 5-year risk of ≥6% is considered a class I indication for ICD implant; a 5-year risk of ≥4% and <6%, a class IIa indication ( Fig. 21-1 ).

Therapeutic Recommendations

In the last 20 years, it is evident that HCM is frequently compatible with normal life expectancy, often without functional disability or disease-related events or the necessity for major therapeutic interventions. Nevertheless, subgroups at risk for important disease complications, such as atrial fibrillation and heart failure and SCD, reside within the overall HCM population. In general, symptomatic patients with HCM with mild heart failure symptoms can be treated with β-blockers, calcium channel antagonists such as verapamil, or disopyramide. Severely symptomatic patients who are drug refractory can be treated by surgical myectomy (or alcohol septal ablation) in case of obstructive HCM or heart transplantation in case of nonobstructive HCM.

The risk of SCD is not mitigated by pharmacologic or surgical strategies, including rhythm-modulating drugs such as amiodarone. Patients at risk for SCD can be protected with an ICD. There is no dispute of the use of defibrillators for secondary prevention, that is, implants after cardiac arrest or sustained VT. The use of risk factors for primary prevention has been discussed above. The decision to implant also needs to be individualized with regard to patient age, because SCD occurs at the highest rate in young patients <30 years of age, but at a very low rate in patients >60 years, even among those with acknowledged risk factors. Age is included in the most recent risk stratification algorithm, as discussed above. Moreover, participation in intense competitive sports can represent a potential risk factor in athletes with HCM, even when conventional risk factors are absent, and disqualification can reduce this risk.

Specific Aspects of Implantable Cardioverter-Defibrillator Therapy in Hypertrophic Cardiomyopathy

Safety and outcome of ICD therapy in HCM may be influenced by the unique clinical features, such as increased left ventricular mass and dynamic outflow obstruction. Single-chamber ICDs are nowadays often implanted in patients with HCM, as well as in cases of concomitant atrial fibrillation ( Table 21-1 ). The atrial lead in dual-chamber ICDs has not proven to be beneficial for supraventricular tachycardia (SVT) discrimination in order to reduce inappropriate shocks, whereas placing an additional atrial lead is associated with more lead-related complications. Moreover, the benefit of dual-chamber pacing to reduce left ventricular outflow tract obstruction has been a matter of debate. Multiple studies demonstrated that dual-chamber pacing indeed decreases outflow tract gradient in the great majority of patients with HCM, but these improvements are generally not accompanied by improvements in objective exercise capacity. Randomized trials additionally indicated that symptomatic improvement is not greater when the pacemakers are programmed to dual-chamber pacing than when they are programmed to atrial pacing, suggesting a placebo effect. Cardiac resynchronization therapy (CRT) may be considered in patients with HCM with symptomatic heart failure and left bundle branch block.

The entirely subcutaneous ICD (S-ICD) may also be a viable alternative in patients with HCM whose long-term survival and often active lifestyle may put them at increased risk for lead fractures and other lead-related complications. The design of the S-ICD may overcome these problems. If an S-ICD is considered in a patient with HCM, special attention should be paid on the morphology-based sensing algorithm before and after S-ICD implant. However, the S-ICD cannot provide antitachycardia pacing (ATP), which is a reasonable treatment to terminate (monomorphic) ventricular arrhythmias in patients with HCM. ATP potentially reduces the number of appropriate shocks, which are known to decrease quality of life and possibly shorten ICD pulse-generator longevity.

Defibrillation threshold (DFT) may be elevated due to the increased left ventricular mass in HCM or concomitant amiodarone therapy in the past or present, although more than 95% of the patients with HCM undergoing ICD implantation have uneventful DFTs using standard transvenous leads, without significant complications or difficulties in achieving a defibrillation safety margin. This notwithstanding, DFTs should be routinely checked in order to document the safety margin and thereby identify the small subset of patients who encounter DFT issues. In cases where transvenous defibrillation has proven to be difficult, epicardial lead placement using thoracotomy, or a subcutaneous array patch electrode positioned over the postero­lateral chest wall may be used to achieve an adequate safety margin ≥10 J for defibrillation of induced VF.

Dual-coil leads might be considered because of the potential to decrease DFTs. However, should lead removal be required, such as in case of lead fractures or infections, extraction of a dual-coil lead is usually more difficult given the tight adherence of the proximal coil to the thin walls of the right atrium or vena cava. As patients with HCM are expected to survive long and with the subsequent increased risk of future lead problems, single-coil leads may be preferable in young patients with HCM with DFTs in the normal range.

Disease Description

Arrhythmogenic right ventricular cardiomyopathy (ARVC) was originally described as arrhythmogenic right ventricular dysplasia. Nowadays ARVC is used, and because the left ventricle (LV) is frequently involved as well, even arrhythmogenic cardiomyopathy (AC) has been suggested. The disease is most significantly expressed in the right ventricle (RV) with fibrofatty displacement of cardiac myocytes. Frequently, the LV is involved as well. The diagnosis is based on a clinical scoring system, which includes clinical, electrocardiographic, imaging, and pathoanatomic data and nowadays also includes genetic information. Patients have a significant risk for malignant ventricular arrhythmias, and some develop heart failure during the course of their life.

The genetic basis is identified in genes encoding for proteins that are involved in the desmosomes. However, in recent years, genes encoding for nondesmosomal proteins also involved in the pathophysiology of dilated cardiomyopathy have been shown to be involved in ARVC as well.

Risk Stratification

Risk stratification in ARVC is still controversial, in particular for individuals tested before the development of symptoms. In patients with ARVC who survived a cardiac arrest or sustained VT, ICD therapy is unequivocally mandatory for prevention of SCD. Indications for prophylactic ICD implantation, however, are less clear, because the majority of data available on management strategies in patients with ARVC rely on retrospective analyses in single centers with relatively small patient cohorts. Patients with ARVC with prior syncope deemed to be of arrhythmic origin are thought to be appropriate candidates for ICD therapy ( Fig. 21-2 ). Moreover, patients with young age at presentation (<5 years) and patients with early and severe right ventricular dysfunction or advanced disease with biventricular involvement are also assumed to be at increased risk of SCD irrespective of warning arrhythmic events. In the most recent evaluation of the North American ARVC Registry, the only independent predictor for life-threatening arrhythmias was a younger age at enrollment.

Asymptomatic patients with ARVC with no or minimal manifestations of the disease have a low risk for arrhythmias irrespective of familial SCD and/or inducibility during programmed electrical stimulation. They should undergo regular cardiac follow-up for early identification of warning symptoms, new onset or worsening of morphologic or functional right ventricular abnormalities, and ventricular arrhythmias.

As in other disease entities, patients with “multiple hits” (i.e., two or more mutations in the desmosomal genes) are at increased risk for developing symptoms. Patients with “ARVC5,” that is, based on a TMEM43 mutation (in particular, a founder mutation in New Foundland, Canada), are at particular high risk.

Therapeutic Recommendations

All patients with ARVC are advised to refrain from competitive/professional sport, strenuous exercise, and vigorous training, which have been alleged to augment the risk of fatal ventricular arrhythmias and of accelerating disease progression. In patients with heart failure, treatment consists of adequate heart-failure drugs such as diuretics and angiotensin-converting-enzyme inhibitors. Patients initially presenting with hemodynamically stable nonsustained VTs accompanying antiarrhythmic drug therapy with class III agents (especially with sotalol) could provide a relatively long stable period without recurrences of ventricular tachyarrhythmias. Also, catheter ablation may be an alternative in patients with localized ARVC and a single morphology of a hemodynamically well-tolerated VT, but relapses are frequent with a VT recurrence rate up to 90% during a 3-year follow-up because of the progressive nature of the disease.

Although antiarrhythmic drug therapy and catheter ablation may reduce VT relapses, ICD therapy is the only treatment strategy that has proven to be effective in the prevention of SCD. In ICD patients with drug-refractory frequent or incessant VT with appropriate shocks, catheter ablation may be an additional treatment option to reduce VT episodes. Attempts to prevent (further) RV dilation should be undertaken. In case of untreatable VTs or refractory congestive heart failure, heart transplantation is the final therapeutic option.

Specific Aspects of Implantable Cardioverter-Defibrillator Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy

ICD therapy in patients with ARVC might present some specific challenges. Concerns have been raised about the potential risk of right ventricle perforation, adequate placement, and long-term performance of transvenous leads in the diseased and potentially thinned right ventricle myocardium in ARVC. The frequency of a low R-wave amplitude and high pacing threshold at ICD implantation is high in patients with ARVC, and multiple endocardial positions are often tested before appropriate sensing is found. Also during follow-up, significant decreases in R-wave amplitudes or increases in pacing thresholds are frequently reported due to the progressive myocardial atrophy with fibrofatty replacement. A low R wave can cause undersensing of VT/VF and also inappropriate sensing due to T-wave oversensing because of the automatic algorithm of the ICD for sensing. Sensing failure due to an extremely delayed depolarization has also been reported in an ICD programmed in DDD mode. Meticulous placement and regular observation of transvenous lead performance with a focus on sensing function are required for the prevention of lead-related morbidity during long-term follow-up. Moreover, it has been suggested that apical lead placement should be avoided because the ventricular apex is one of the areas most frequently involved in ARVC and might prevent good sensing. In case of sensing dysfunction, lead repositioning in the right ventricle, placement of an additional sensing lead, surgical lead revision, or the implantation of a coronary sinus lead for sensing and pacing can be considered to secure adequate device function.

Despite lower R waves and higher pacing threshold, DFTs have only sporadically been reported to be significantly increased. Patients with markedly enlarged hypokinetic and myopathic right ventricles might be particularly at risk for high DFTs. Standard testing might identify patients with high a DFT and high voltage devices are therefore recommended.

Furthermore, in most patients with ARVC, a single-chamber ICD with ATP function enabled is recommended (see Table 21-1 ). Although theoretically, patients with thin myocardial walls are at risk for RV perforation, this was not observed in multiple studies. In patients with symptomatic heart failure and a left bundle branch block a CRT-D is recommended. The S-ICD might be less suitable for patients with ARVC, because this device is not able to provide ATP.

Disease Description

Long QT syndrome (LQTS) is the most frequent disease entity within the group of pure “electrical” disorders. As the name implies, the disease is characterized by prolongation of the QT _c interval (the QT interval corrected for heart rate) in the absence of secondary causes, such as the use of QTc-prolonging drugs. The recent consensus document endorsed by the three main electrophysiologic societies worldwide defines LQTS as the presence of an LQTS risk score ≥3.5 (a clinical risk score including a variety of clinical markers) in the absence of a secondary cause for QT prolongation and/or in the presence of an unequivocally pathogenic mutation in one of the LQTS genes or in the presence of a QT _c ≥500 msec in repeated 12-lead electrocardiogram (ECG) and in the absence of a secondary cause for QT prolongation. The prevalence is approximately 1 : 2000. In general, LQTS is a disease of the pediatric age group, with most symptomatic patients in their young years.

LQTS was the first electrical disease in which the underlying molecular genetic substrate was unraveled. This development in the past two decades has led to a tremendous increase in knowledge and a far more sophisticated approach to patients with LQTS than in the past. To date, there are at least 14 genes involved in the pathophysiology of LQTS. The first three subtypes of LQTS (i.e., LQT1, 2, and 3, involving the two main potassium channels I _Ks and I _Kr and the cardiac sodium channel SCN5a, respectively) are the most important, with 90% of successfully genotyped patients involved.

Risk Stratification

The risk for lethal arrhythmias is determined by the baseline QT _c interval and the presence of symptoms. The genotype carries a gene specific age- and gender-related risk with LQT1 males most at risk at young age (well before puberty) and LQT2 females most at risk during and after puberty. Patients carrying double mutations are often more severely affected, and that includes patients with the Jervell and Lange-Nielsen syndrome. Because the Long QT registry, established in the late seventies, has not sampled exercise tests or 24-hour ECG/rhythm monitoring, these potentially very relevant data are not used in the current risk stratification schemes.

In LQTS, genetics play an increasing role in determining the risk. Specific mutations carry a very high risk (e.g., KCNQ1 A341V ), and these patients could qualify for prophylactic ICD implantation. KCNQ1 mutations with an autosomal dominant negative functional effects are associated with increased risk compared with mutations with a haploinsufficient effect (most often nonsense mutations), and the same holds for specific mutation sides in the KCNQ1 gene (i.e., “the cytoplasmatic loop”). In LQT2, KCNH2 mutations in the pore region are associated with increased risk. Data for LQT3 are lacking. In the meantime, modifying genes have also been identified, and these variants could increase risk. A well-known example is NOS1AP and variants in the 3′ untranslated region (UTR) area of the KCNQ1 gene.

Therapeutic Recommendations

Avoidance of QT-prolonging drugs ( www.qtdrugs.org ) is recommended in all patients with LQTS. Other lifestyle modifications that should be routine are restriction of strenuous exercise, especially swimming without supervision in LQT1 patients, and avoidance of nightly or sudden noise in LQT2 patients, such as alarm clock, phone ringing, and so on. Participation of patients with LQTS in competitive sports is still under discussion among the experts. Recently available retrospective data suggest that participation in competitive sports of some patients with LQTS is safe.

β-Adrenergic blocking agents are the cornerstone of therapy in symptomatic patients with LQTS, unless a contraindication such as active asthma is present. Also, patients with a genetic diagnosis of LQTS and a near-to-normal or normal QT _c are demonstrated to benefit from β-blockers. The success of β-blockers is not equal among the different LQTS subtypes. The occurrence of cardiac events is clearly reduced in LQT1 patients who are on β-blocker therapy. However, LQT2 and LQT3 patients still experience a significant rate of cardiac events of 7% and 15%, respectively, under β-blocker therapy, although it is a misconception that β-blockers are of limited or no value. Moreover, not all β-blockers are equally effective. Propranolol and nadolol have been demonstrated to be most effective, whereas metoprolol is less effective. β-Blockers seldom result in excessive bradycardia, especially if the dosage is gradually increased over several weeks.

Patients refractory to β-blockers may be treated with left-sided cardiac sympathetic denervation or ICDs. A collection of small studies in the early 2000s and larger studies more recently have begun to clarify the role of ICDs in LQTS. There is an overall consensus for immediately implanting an ICD in cases in which there has been a documented cardiac arrest, either on or off therapy. Some exceptions exist, such as in a clear case of a drug-induced event in an otherwise asymptomatic (LQTS1) patient with modest QT prolongation. In contrast, opinions differ strongly regarding the use of ICDs in patients without cardiac arrest ( Table 21-2 ). Prophylactic ICD therapy should be considered in very high-risk patients. Syncope is the strongest predictor of cardiac events and SCD, with a 4- to 18-fold increased risk of SCD in all age groups while on β-blocker therapy. Therefore an ICD is advised in patients with recurrent syncope events despite adequate β-blocker therapy ( Fig. 21-3 ). Moreover, appropriate ICD therapies were predicted by age <20 years and a QT _c >500 msec, and patients with LQTS with these baseline characteristics should be carefully monitored for prophylactic ICD therapy. For patients with Jervell and Lange-Nielsen syndrome and Timothy syndrome who appear incompletely protected by antiadrenergic therapy, a case-by-case approach regarding the best therapeutic management is needed. An ICD is not indicated in asymptomatic ICD patients with LQTS who have not been tried on β-blocker therapy.

Specific Aspects of Implantable Cardioverter-Defibrillator Therapy in Long QT Syndrome

Whenever ICD therapy is chosen, permanent pacing can be considered to reduce bradycardia-dependent QT prolongation and short-long-short sequences, which often precede torsade de pointes (TdP, Fig. 21-4 ). Additionally, pacing reduces the dispersion of repolarization. A dual-chamber ICD programmed in DDD pacing mode with a long AV interval is preferred to allow for atrial pacing with conduction to the ventricle by the normal conduction system (see Table 21-1 ). A lower rate limit (LRL) of 70 to 80 bpm and higher postshock pacing rates have been optioned by several studies, with higher rates when patients are at increased risk for developing TdP (e.g., postpartum period, surgical procedures). However, maintenance of a high LRL for long periods may lead to tachycardia-induced cardiomyopathy, and the maximal LRL that can safely be used for long periods is unknown. Also features that allow slowing of the heart rate below the programmed LRL (e.g., hysteresis and sleep function) should be programmed off.

Further optimal device programming has not been studied extensively, but most experts recognize the need to program a higher detection rate, such as a cutoff rate >220 bpm, in particular to prevent inappropriate shocks. Whether one or more zones of detection are best is unknown. Whether the programming of ATP is useful to convert some VTs is unknown, but this is thought to be unlikely because of the electrophysiologic basis of the TdP arrhythmia (and the rapid rate and suspected disorganization compared with monomorphic VTs). It is preferable to set a long detection duration to prevent intervention for nonsustained TdP episodes that would have terminated spontaneously. There should be specific attention to the possible occurrence of T-wave oversensing in some patients with LQTS because of the relatively large and/or late T wave. Concomitant β-blockade should be prescribed to minimize the incidence of shocks and especially electrical storm due to enhanced catecholamine levels after syncope or from the pain of a first ICD shock.