I mplantable Def ibr illat o r s i n L o ng QT Syndrom e, Br u g ada Sy ndrome, Hyper t rop h ic C a rdi o m y o p a t h y, an d Arrhythmogenic Right Ven t r i c u l a r Ca rd i o m y o p a t h y Mustafa Dohadwala, MD, Mark S. Link, MD* KEYWORDS  Long QT syndrome  Hypertrophic cardiomyopathy  Brugada syndrome  Arrhythmogenic right ventricular cardiomyopathy  Channelopathy  Sudden death  Genetic syndrome

KEY POINTS  Sudden death is often the first manifestation in inherited cardiac arrhythmia syndromes.  Patients with long QT syndrome who have an episode of syncope while on beta-blockade should be offered an implantable cardioverter-defibrillator (ICD).  In Brugada syndrome and hypertrophic cardiomyopathy, ICDs are often the most effective treatment of primary and secondary prevention of cardiac arrest.  Risk stratification is crucial in identifying those at greatest risk to provide lifesaving therapy while avoiding complications in those unlikely to receive benefit.

Sudden cardiac death (SCD) has an overall incidence of 0.1% to 0.2% per year with 300,000 to 350,000 deaths annually in the United States. Depending on the patient population, up to 20% of SCDs are attributable to primary genetic disorders. Prevention of SCD in these inherited syndromes often requires implantable cardioverterdefibrillators (ICDs). However, implantation of ICDs has short-term and long-term risks, especially in a young person. This article reviews the role of ICDs and adjunctive treatments in 4 major inherited syndromes that lead to sudden death;

namely long QT syndrome (LQTS), Brugada syndrome (BrS), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC).

LQTS Overview, Clinical Presentation, and Pathophysiology Since the initial description of the LQTS, 13 genetic LQTSs have been delineated.1,2 Because of variable penetrance and geographic differences, the prevalence ranges from 1 in 2000 to 1 in 10,0003,4 with a slight female preponderance.5,6 The initial presentation in LQTS may include

Department of Medicine, The Cardiac Arrhythmia Center, Tufts Medical Center, 800 Washington Street, Box #197, Boston, MA 02111, USA * Corresponding author. Tufts Medical Center, 800 Washington Street, Box #197, Boston, MA 02111. E-mail address: [email protected] Cardiol Clin 32 (2014) 305–318 http://dx.doi.org/10.1016/j.ccl.2013.11.003 0733-8651/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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Dohadwala & Link palpitations, presyncope, syncope, or even cardiac arrest. LQTS type 1 (LQT1), LQTS type 2 (LQT2), and LQTS type 3 (LQT3) account for approximately 75% of LQTS. In an observational study of 193 consecutive genotype-proven families with more than 600 patients over almost 3 decades, 13% (n 5 81) had cardiac arrest or death before 40 years of age.7 LQT1 is caused by a mutation (KCNQ1) of the IKs channel. Although cardiac events are more frequent, the risk of sudden death remains similar to that with LQT2 and LQT3. Emotional and physical stress and activities such as swimming and diving classically trigger events. LQT2 is caused by a mutation (KCNH2) of the IKr channel. Common triggers include emotional stress, sudden arousal, and auditory stimulation. LQT3, unlike LQT1 and LQT2, is characterized by the SCN5A mutation in the INa channel. Events are less frequent in this group, but events tend to be more dangerous.8 Early afterdepolarizations (EADs) caused by reactivation of L-type calcium channels and, less frequently, from late INa or Na-Ca exchange trigger polymorphic ventricular tachycardia (VT). Transmural heterogeneity in repolarization, particularly in the M cells, provides substrate for block and reentry leading to perpetuation of torsades de pointes (TDP).9

Diagnosis Diagnosis of LQTS relies on a combination of clinical presentation, personal history, family history, and electrocardiogram (ECG). Coexistent factors, such as congenital deafness, can be a clue for syndromic LQTS. Depending on clinical suspicion, the ECG should be repeated frequently because the QT interval can be dynamic.10,11 The 2 clinical scoring systems, Schwartz and Keating, combine ECG and clinical findings for diagnosis. Both are hindered by a high false-negative rate. In response, it has been suggested to use a QTc cutoff of 430 milliseconds with gene testing to provide better sensitivity.2,12–14 The recently published expert consensus recommendations from the Heart Rhythm Society (HRS)/European Heart Rhythm Association (EHRA)/Asia Pacific Heart Rhythm Society (APHRS) for diagnosis of LQTS are available (Box 1).15

Risk Stratification QTc is a strong predictor for cardiac events and sudden death. A QTc greater than 470 milliseconds is a risk predictor for symptoms, whereas QTc greater than 500 milliseconds is a risk predictor for life-threatening events.2,7,8 In the

Box 1 Diagnosis of LQTS 1. LQTS is diagnosed: a. In the presence of an LQTS risk score greater than or equal to 3.5 in the absence of a secondary cause for QT prolongation, and/or b. In the presence of an unequivocally pathogenic mutation in one of the LQTS genes, or c. In the presence of a corrected QT interval for heart rate using the Bazett formula (QTc) greater than or equal to 500 milliseconds in repeated 12-lead ECG and in the absence of a secondary cause for QT prolongation 2. LQTS can be diagnosed in the presence of a QTc between 480 and 499 milliseconds in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation. From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Expert consensus statement on inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013:e75–106; with permission.

second decade of life, a QTc greater than 530 milliseconds increases risk for an event by a hazard ratio of 2.3 (95% confidence interval, 1.6–3.3).16 Because the QTc can change by 47  40 milliseconds on repeated ECGs,17 it should be repeated and interpreted cautiously for risk stratification. The strongest clinical predictor for cardiac arrest remains recent syncope. Recent syncope in children, adolescents, and young adults can increase the likelihood of sudden death or cardiac arrest by 10-fold to 20-fold.17–19 Even a remote syncopal episode increases the likelihood by 2.7.16 If syncope is present while on b-blockers, the risk of death is the same as if not on a b-blocker.19 In childhood, boys, especially with LQT1, are at a higher risk of sudden death and cardiac arrest.20 By adolescence, the risk of lifethreatening events equalizes between the genders. After the second decade of life, women, especially with LQT2, have higher risk of cardiac arrest and sudden death.21–23 Gender differences are less exaggerated with LQT3. Programmed electrical stimulation24 and family history25 do not predict events.

Implantable Defibrillators Beta-Blockade and Adjunctive Therapies for Sudden Death Prevention Beta-blockade is most effective in LQT1 and b-blockers decrease the sudden cardiac arrest rate to 1% over the course of 5 years.26,27 Patients with LQTS1 who are compliant with b-blockers and are off all QT-prolonging drugs did not have recurrent events in one study.28 The response to b-blockers is not as assured with LQT2 and LQT3.26,27 Even with beta-blockade, the aborted cardiac arrest rate has been reported to be 6.6% over 5 years and 14% over 5 years.27

Defibrillator Therapy for Sudden Death Prevention A collection of small studies in the early 2000s and larger studies more recently have began to clarify the role of ICD in the LQTS. In 27 patients with LQTS who received ICD for aborted arrest (n 5 17), syncope on b-blockers (n 5 9), and family history of SCD (n 5 1), 10 of 17 patients with history of cardiac arrest had a total of 169 appropriate shocks. None of the 9 patients with syncope on b-blockers required a shock. Those with prior cardiac arrest have a particularly malignant course, because 19% of patients had appropriate shocks despite being started on b-blockers.29 In a study of 459 patients with LQTS; 51 had an ICD. Of these, 24% had appropriate, ventricular fibrillation (VF)–terminating therapy during follow-up of 7.3 years. Women with LQTS2 were most likely to receive appropriate therapy. The likelihood of appropriate ICD therapy correlated with secondary prevention indication, non-LQT3 genotype, QTc greater than 500 milliseconds, syncope, history of Torsades, and negative family history. None of the patients without an ICD implanted died.30 The largest experience of ICDs in LQTS was the European LQTS registry. Of 233 patients followed for 4.6  3.2 years, 28% of patients had an appropriate shock. Predictors of appropriate therapy included age less than 20 years at implantation, QTc greater than 500 milliseconds, prior arrest, and cardiac events despite b-blocker therapy. No patients without an aforementioned risk factor had an appropriate shock. Risk factors were additive; if a patient had all of the risk factors, 70% had a shock.31 Thus, ICD implantation seems reasonable in the following patients: (1) those who have survived a cardiac arrest, (2) patients with syncope despite b-blocker, and (3) asymptomatic patients with QTc greater than or equal to 550 milliseconds with electrical instability (ie, T-wave alternans) or other long sinus pauses that may favor early afterdepolarizations.32 ICD implantation may be

considered in women with LQT2 with QTc greater than 500 milliseconds who either have symptoms or cannot tolerate b-blockers. Routine use of ICDs in LQT3 does not seem to be appropriate. The recently published expert consensus recommendations from the HRS/EHRA/APHRS for therapeutic interventions in LQTS are available (Box 2).15

ICD Considerations Specific to LQTS If an ICD is implanted, permanent pacing can be considered to reduce bradycardia-dependent QT prolongation and short-long-short sequences. Beta-blockade should be prescribed to prevent events.

BRS Overview, Clinical Presentation, and Pathophysiology BrS is an autosomal dominant condition that disproportionately affects men with an 8:1 ratio. Prevalence of Brugada, from ECG, varies markedly based on population studied. In the United States 0.012% to 0.43% of individuals show the ECG pattern, whereas in endemic areas of southeast Asia the pattern may be present in up to 3% of patients.33,34 In the seminal article by Brugada and colleagues,35 547 patients with either spontaneous (n 5 408) or antiarrhythmic-induced (n 5 156) Brugada pattern ECG were followed over 24  32 months. None had preceding cardiac arrest, the mean age of patients was 41  15 years, and 408 were men. During the follow-up period, 45 patients (8%) sustained SCD or VF. In endemic areas, it is the leading cause of death in men less than 40 years of age and frequently is the cause of sudden infant death syndrome. Sudden death is the initial manifestation of Brugada in 30%, so diagnosis and primary prevention are paramount. The first mutation linked to BrS was the SCN5A, accounting for 15% to 30% of genotyped Brugada, which is a loss-of-function mutation leading to diminished Na inward current. Over time, other mutations in the Na channel, along with mutations that reduce Ca current or enhance transient inward K current, have been discovered. Patients with BrS have arrhythmic events and death in the early morning hours during sleep and bradycardia. Other triggers include fevers, large meals, alcohol, and cocaine.36 In children, BrS can be mistaken for febrile seizures.37 In addition to ventricular arrhythmias, 20% of patients have paroxysmal supraventricular arrhythmia (SVT) and atrial fibrillation,38,39 which can trigger ventricular arrhythmias.

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Box 2 Treatment of LQTS Class I 1. The following lifestyle changes are recommended in all patients with a diagnosis of LQTS: a. Avoidance of QT-prolonging drugs (www.qtdrugs.org) b. Identification and correction of electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss 2. b-Blockers are recommended in patients with a diagnosis of LQTS who are: a. Asymptomatic with QTc greater than or equal to 470 milliseconds, and/or b. Symptomatic for syncope or documented VT/VF 3. Left cardiac sympathetic denervation (LCSD) is recommended in high-risk patients with a diagnosis of LQTS in whom: a. ICD therapy is contraindicated or refused, and/or b. b-Blockers are either not effective in preventing syncope/arrhythmias, not tolerated, not accepted, or contraindicated 4. ICD implantation is recommended in patients with a diagnosis of LQTS who are survivors of a cardiac arrest. 5. All patients with LQTS who wish to engage in competitive sports should be referred to a clinical expert for the evaluation of risk. Class IIa 6. b-Blockers can be useful in patients with a diagnosis of LQTS who are asymptomatic with QTc less than or equal to 470 milliseconds. 7. ICD implantation can be useful in patients with a diagnosis of LQTS who experience recurrent syncopal events while on b-blocker therapy. 8. LCSD can be useful in patients with a diagnosis of LQTS who experience breakthrough events while on therapy with b-blockers/ICD. 9. Sodium channel blockers can be useful as add-on therapy for patients with LQT3 with a QTc of 450 milliseconds who shorten their QTc by 440 milliseconds following an acute oral drug test with one of these compounds. Class III 10. Except under special circumstances, ICD implantation is not indicated in asymptomatic patients with LQTS who have not been tried on b-blocker therapy. From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Expert consensus statement on inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013:e75–106; with permission.

Patients may also have conduction disease with PR and HV prolongation.

Diagnosis Electrocardiographic abnormalities in right precordial leads form the basis for diagnosis of BrS. ECG findings have been categorized into 3 types. Type 1, the most specific and diagnostic for BrS, represents ST elevation of greater than or equal to 2 mm with a coved (or downward convex) morphology associated with either incomplete or complete right bundle branch pattern followed by

descending negative T wave with little or no isoelectric separation. Type II and III patterns are characterized by saddleback appearance of the ST segment, with type II having greater ST elevation than type III. Both are nonspecific.40 The ECG pattern may be dynamic and/or elicited by Na channel blocking antiarrhythmics. A more cephalad placement of the right precordial leads (up to the second intercostal space above normal) increases the sensitivity without decreasing specificity.41 Other strategies to unmask the ECG pattern include nighttime monitoring of ST segments and documenting ECG at times of any stress.33

Implantable Defibrillators Aside from the classic findings, QT interval prolongation and QRS fragmentation along the right precordium may be present.42,43 Signal average ECG may show late potentials in 60% to 70% of patients with Brugada.33,40 Particularly with SCN5A mutation, patients may have depolarization abnormalities with increased P-wave duration, prolonged PR interval, and increased QRS duration. To make BrS diagnosis, a patient should have spontaneous or pharmacologically inducible type 1 pattern in greater than or equal to 1 right precordial lead (ie, V1–V3) with 1 of the following: (1) history of VF, (2) history of polymorphic VT, (3) family history of SCD at less than 45 years of age, (4) coved-type ECG in another family member, (5) inducibility of VT with programmed electrical stimulation, (6) history of syncope, or (7) nocturnal agonal respirations. Despite low sensitivity, genetic testing for SCN5A is a useful adjunct with type I ECG pattern for family members.14 The recently published expert consensus recommendations from the HRS/EHRA/APHRS for diagnosis of BrS are available (Box 3).15

Risk Stratification There has been controversy regarding risk predictors for cardiac arrest. Patients with aborted

Box 3 Diagnosis of BrS 1. BrS is diagnosed in patients with ST-segment elevation with type I morphology greater than or equal to 2 mm in greater than or equal to 1 lead among the right precordial leads V1 and V2 positioned in the second, third, or fourth intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of class I antiarrhythmic drugs. 2. BrS is diagnosed in patients with type 2 or type 3 ST-segment elevation in greater than or equal to 1 lead among the right precordial leads V1 and V2 positioned in the second, third, or fourth intercostal space when a provocative drug test with intravenous administration of class I antiarrhythmic drugs induces a type I ECG morphology. From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Expert consensus statement on inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013:e75–106; with permission.

sudden death have a recurrence rate of up to 11%/y.44 For asymptomatic patients and those with syncope, the event rate is lower.35,45 Finding higher risk patients within this group becomes crucial. Brugada and colleagues35 suggested electrophysiological (EP) study, but recent data have caused this to be questioned.37,45–48 Although controversial,35,45,49 a spontaneous type I ECG pattern seems to confer risk compared with a drug-induced pattern.35,37,45,46,50,51 In a meta-analysis of 1545 patients with Brugada ECG, the overall event rate (sudden cardiac arrest, syncope, or ICD shock) at 32 months was 10%. Predictors included previous cardiac arrest or syncope (relative risk [RR], 3.24), male gender (RR, 3.47), and spontaneous type I pattern (RR, 4.65). Family history, SCN5A mutation, and inducibility during programmed electrical stimulation were not predictors of risk.46 In the more recently published European FINGER registry, 1029 consecutive patients (72% male, median age 42 years, range 35–55 years) with spontaneous or inducible BrS were followed over 31.9 months (range, 14– 54.4 months). The ICD event rate was 7.7%, 1.9%, and 0.5% in patients with history of aborted sudden death, syncope, and without symptoms, respectively. Presence of spontaneous type 1 ECG predicted events, whereas gender, family history, inducibility via EP study, and SCN5A mutation were not predictive.52 In another study of 320 (54% spontaneous, 46% inducible) patients with BrS with prior syncope or no symptoms, major events occurred in patients with 2 or more of prior syncope, family history of sudden death, or a positive EP study. Those with 2 or more risk factors and spontaneous type I ECG had a 30% event rate.51 From these data, major risk predictors include prior cardiac arrest, prior syncope, and spontaneous type I ECG. Inducibility on programmed electrical stimulation remains controversial.

Defibrillator and Adjunctive Therapies for Sudden Death Prevention Medications (ie, b-blocker) have not proved useful for either primary or secondary prevention; an ICD is the only proven therapy for Brugada. Thus, patients with type I Brugada who have history of cardiac arrest or syncope should receive an ICD. There is no consensus for asymptomatic patients. Experts argue for (1) close follow-up; (2) ICD implantation in those with positive EP study, especially if there is a family history of sudden death; and (3) ICD implantation in all spontaneous type 1 patterns. Pharmacologic therapies in Brugada are adjunctive, to decrease risk of recurrent events and ICD storm. These therapies include Ito

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Dohadwala & Link blockers or ICaL augmenting agents that can restore the right ventricular (RV) epicardial action potential dome and normalize ST segments.40 Such medications include quinidine, denopamine, cilostazol, bepridil, tedisamil, mexiletine, disopyramide, and isoproterenol. More recently, there has been success in ablating areas within the RV outflow tract (RVOT) that could be responsible for phase 2 reentry and initiation of VT/VF in BrS.53 The recently published expert consensus recommendations from the HRS/EHRA/APHRS for therapeutic interventions in BrS are available (Box 4).15

HCM Overview, Clinical Presentation, and Pathophysiology HCM is the most common genetic cardiac disease, affecting 1 in 500 people. It is an autosomal dominant disease with variable clinical penetrance; half of the cases are familial and the remaining sporadic. More than 900 mutations in 24 genes encoding sarcomeric proteins have been reported, leading to thickening of the left ventricle with myocyte disarray. There are several forms, including asymmetric hypertrophy of the septum, symmetric hypertrophy, and apical hypertrophy. Between 5%

Box 4 Treatment of BrS Class I 1. The following lifestyle changes are recommended in all patients with diagnosis of BrS: a. Avoidance of drugs that may induce or aggravate ST-segment elevation in right precordial leads (eg, Brugadadrugs.org) b. Avoidance of excessive alcohol intake c. Immediate treatment of fever with antipyretic drugs 2. ICD implantation is recommended in patients with a diagnosis of BrS who: a. Are survivors of a cardiac arrest, and/or b. Have documented spontaneous sustained VT with or without syncope Class IIa 3. ICD implantation can be useful in patients with a spontaneous diagnostic type I ECG who have a history of syncope judged likely to be caused by ventricular arrhythmias. 4. Quinidine can be useful in patients with a diagnosis of BrS and history of arrhythmic storms defined as more than 2 episodes of VT/VF in 24 hours. 5. Quinidine can be useful in patients with a diagnosis of BrS who: a. Qualify for an ICD but present a contraindication to the ICD or refuse it, and/or b. Have a history of documented supraventricular arrhythmias that require treatment 6. Isoproterenol infusion can be useful in suppressing arrhythmic storms in patients with BrS. Class IIb 7. ICD implantation may be considered in patients with a diagnosis of BrS who develop VF during programmed electrical stimulation (inducible patients). 8. Quinidine may be considered in asymptomatic patients with a diagnosis of BrS with a spontaneous type I ECG. 9. Catheter ablation may be considered in patients with a diagnosis of BrS and history of arrhythmic storms or repeated appropriate ICD shocks. Class III 10. ICD implantation is not indicated in asymptomatic patients with BrS with a drug-induced type I ECG and a family history of SCD alone. From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Expert consensus statement on inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013:e75–106; with permission.

Implantable Defibrillators and 10% may progress to end-stage or burnt-out HCM with left ventricular (LV) dysfunction. HCM manifests in a myriad of ways including dyspnea, chest pain, palpitations, dizziness, presyncope, syncope, and cardiac arrest. These symptoms are related to diastolic dysfunction, LV outflow tract (LVOT) obstruction, LV dysfunction, atrial fibrillation, and ventricular arrhythmias. In the United States, HCM is the leading cause of sudden death in athletes. Early studies overestimated the rate of SCD in HCM,54 because more recent studies show sudden death to be closer to 1% per year in the general HCM population.55,56 The seemingly low 1% per year rate of sudden death is significant when viewed in the context of accumulated risk in a young patient with HCM. The cumulative lifetime increased risk for sudden death from VT/VF may be 10% to 20%, and, for high-risk patients, risk may be up to 5% per year.55–57 Aborted cardiac arrest and sudden death in HCM is classically attributed to polymorphic VT or VF. However, monomorphic VT occurs more frequently than has been appreciated based on intracardiac electrogram data in patients with ICDs.57 This is not surprising given that myofibrillar disarray, interstitial fibrosis, and perhaps focal ischemia provide arrhythmogenic substrate leading to reentrant ventricular arrhythmias.58

Risk Stratification Over the past 2 decades, 5 clinical markers for sudden death in the primary prevention population have been identified: (1) family history of premature sudden death in at least 1 relative, (2) unexplained syncope (in young patients and/or on exertion), (3) nonsustained ventricular arrhythmias (NSVT) on Holter, (4) massive LV hypertrophy greater than or equal to 30 mm, and (5) hypotensive response to exercise. In the 2011 ACCF/ AHA HCM guidelines, family history, syncope, and massive LV hypertrophy are major risk factors. However, NSVT and hypotensive blood pressure should be considered significant only if associated with one of the emerging risk factors.59 Data from the Maron ICD registries showed an 11% per year risk of appropriate ICD therapy for those patients previously resuscitated from SCD.60,61 The yearly risk of appropriate ICD therapy in those patients without a prior cardiac arrest was 3.6%. In these studies there was no difference in risk of appropriate ICD therapy in those with a single risk factor compared with multiple risk factors. In a pediatric population, similar results were observed. There was a 14%/y risk of appropriate ICD therapy for those resuscitated

from SCD, and a 3.1%/y risk in those implanted for primary prophylaxis.62 In this population it was also observed that there was no difference in the occurrence of appropriate ICD intervention between those with a single risk factor or multiple risk factors. In contrast, data from the United Kingdom suggest that a single risk factor may not place an patient with HCM at greater risk of an event.63 Emerging risk factors, such as presence and extent of late gadolinium enhancement on magnetic resonance imaging, may prove useful.64,65 Other less validated risk factors include ischemia, atrial fibrillation, LVOT obstruction, competitive sports, and certain genetic mutations. Those with end-stage HCM awaiting heart transplant or LV apical aneurysm have up to a 10%/y risk of death.66,67 Because older patients are at low risk for sudden death even with risk factors, they should not be stratified in the same manner as younger patients.68

Defibrillator and Adjunctive Therapy for Sudden Death Prevention Antiarrhythmics such as amiodarone and sotalol have not proved to be effective in preventing sudden death or VT.61,69,70 Thus, ICDs are central for sudden death prevention. The 5-year cumulative appropriate discharge rate in HCM is almost 39% in the secondary population and 17% in the primary prevention population.61 ICDs are thus indicated for patients with HCM with prior cardiac arrest and high-risk primary prevention patients. High-risk primary prevention patients should be selected by having at least one risk factor from the 2011 ACCF/AHA guidelines (Box 5)59 because 35% of appropriate ICD interventions for VT/VF occur in patients with a single risk factor.61

ICD Considerations Specific to HCM In the late 1990s, dual-chamber pacing to decrease LVOT gradient was promising based on observational trials. However, randomized trials have not proved long-term benefit but individuals more than 65 years of age may have some benefit.71–73 Thus, older individuals with LVOT obstruction and heart failure symptoms may benefit from a dual-chamber system. Moreover, when implanting an ICD, clinicians must be mindful that defibrillation thresholds (DFTs) are on average higher compared with a non-HCM population.74 Thus, DFTs should be routinely checked and, if a safety margin greater than or equal to 10 J is not present, adding an superior vena cava coil or subcutaneous array may be necessary.

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Box 5 Defibrillator treatment of HCM Class I 1. The decision to place an ICD in patients with HCM should include application of individual clinical judgment, as well as a thorough discussion of the strength of evidence, benefits, and risks to allow the informed patient’s active participation in decision making. 2. ICD placement is recommended for patients with HCM with prior documented cardiac arrest, VF, or hemodynamically significant VT. Class IIa 1. It is reasonable to recommend an ICD for patients with HCM with: a. Sudden death presumably caused by HCM in 1 or more first-degree relatives b. A maximum LV wall thickness greater than or equal to 30 mm c. One or more recent, unexplained syncopal episodes 2. An ICD can be useful in select patients with NSVT (particularly those 560 years of age. Circulation 2013;127(5):585–93. Melacini P, Maron BJ, Bobbo F, et al. Evidence that pharmacological strategies lack efficacy for the prevention of sudden death in hypertrophic cardiomyopathy. Heart 2007;93(6):708–10. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2008; 19(10):1118–26. Nishimura RA, Trusty JM, Hayes DL, et al. Dualchamber pacing for hypertrophic cardiomyopathy: a randomized, double-blind, crossover trial. J Am Coll Cardiol 1997;29(2):435–41. Gadler F, Linde C, Daubert C, et al. Significant improvement of quality of life following atrioventricular synchronous pacing in patients with hypertrophic obstructive cardiomyopathy. Data from 1 year of follow-up. PIC Study Group. Pacing in cardiomyopathy. Eur Heart J 1999;20(14):1044–50. Maron BJ, Nishimura RA, McKenna WJ, et al. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation 1999;99(22):2927–33. Roberts BD, Hood RE, Saba MM, et al. Defibrillation threshold testing in patients with hypertrophic cardiomyopathy. Pacing Clin Electrophysiol 2010; 33(11):1342–6. Cha YM, Gersh BJ, Maron BJ, et al. Electrophysiologic manifestations of ventricular tachyarrhythmias provoking appropriate defibrillator interventions in high-risk patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2007;18(5):483–7. Rogers DP, Marazia S, Chow AW, et al. Effect of biventricular pacing on symptoms and cardiac remodelling in patients with end-stage hypertrophic cardiomyopathy. Eur J Heart Fail 2008; 10(5):507–13. Lenarczyk R, Wozniak A, Kowalski O, et al. Effect of cardiac resynchronization on gradient reduction in patients with obstructive hypertrophic

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