In a subgroup analysis of SCD-HeFT that included 472 patients, the ICD did not reduce either recurrent syncope or the increased risk of mortality associated A subgroup analysis of the MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy) trial found syncope to be arrhythmic only in 39% These studies suggest that syncope in some HF patients may be an indica- tor of an end-stage cardiomyopathy associated with a poor prognosis.S7.2.1-11 In a substudy of DEFINITE, inducible sustained VT/VF was found in a minority of patients, but it was associated with appropriate ICD therapy.S7.2.1-14 Another study of electrophysiological testing in NICM found inducible VT/VF in 27.8% of patients, which was associated with future ICD events.S7.2.1-15 In a study of patients with NICM, cardiac mortality correlated with LVEF but not with inducibility on Based on these data, many experts are uncomfortable withhold- ing an ICD from patients with NICM who expe- rience syncope potentially due to a VA even if the electrophysiological study shows no inducible sustained VT. 3. Access to ICDs may be limited by financial, medi- cal, or personal considerations. In addition, not all patients at high risk of SCD meet ICD indica- tions, such as those with class IV HF without CRT possibility or with a life expectancy <1 year. A meta-analysis of RCTs, which examined the use of amiodarone for the prevention of SCD, included 15 studies with 8522 patients assigned to amio- darone or placebo/control.S7.2.1-12 Amiodarone reduced the risk of SCD by 29%; however, it did not reduce all-cause mortality and was asso- ciated with an increased risk of pulmonary and thyroid toxicity. In a subgroup analysis, the ben- efit of amiodarone appeared similar in patients with ischemic cardiomyopathy and those with In a separate meta-analysis,S7.2.1-13 the evidence was insufficent to support amioda- rone s efficacy for reduction of SCD and all-cause mortality in survivors of cardiac arrest or those with syncope due to VA. A subgroup analysis of the VALIANT (Valsartan in Acute Myocardial Infarction) trial found that amiodarone was asso- ciated with increased mortality in patients with NYHA class III HF.S7.2.1-17 These data call for a care- ful and nuanced approach to using amiodarone for the secondary prevention of SCD in patients with NICM. 7.2.2. Primary Prevention of SCD in Patients With NICM Recommendations for Primary Prevention of SCD in Patients With NICM References that support the recommendations are summarized in Online Data Supplements 27 and 28. COR LOE Recommendations I A In patients with NICM, HF with NYHA class II III symptoms and an LVEF of 35% or less, despite GDMT, an ICD is recommended if meaningful survival of greater than 1 year is IIa B-NR In patients with NICM due to a Lamin A/C mutation who have 2 or more risk factors (NSVT, LVEF <45%, nonmissense mutation, and male sex), an ICD can be beneficial if meaningful survival of greater than 1 year is IIb B-R In patients with NICM, HF with NYHA class I symptoms and an LVEF of 35% or less, despite GDMT, an ICD may be considered if meaningful survival of greater than 1 year is III: No Benefit C-EO In patients with medication-refractory NYHA class IV HF who are not also candidates for cardiac transplantation, an LVAD, or a CRT defibrillator that incorporates both pacing and defibrillation capabilities, an ICD should not be implanted. Recommendation-Specific Supportive Text 1. For all patients with NICM, it is imperative that patients be on GDMT for HF for at least 3 months before a primary prevention ICD is offered. Four initially evaluated ICDs for primary prevention of SCD in patients with NICM. TwoS7.2.2-2,S7.2.2-6 were small studies that were terminated early due to a low event rate. In DEFINITE,S7.2.2-5 an ICD reduced the risk of SCD, with a trend toward reduced all- cause mortality. SCD-HeFT included 792 NICM Total mortality at 5 years was 27% in the placebo group and 21% in the ICD group (P=0.06). A pooled analysis of these studies dem- onstrated a significant 31% reduction in all-cause mortality for ICD relative to medical therapy.S7.2.2-4 The DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality) trialS7.2.2-11 raised ques- tions about the role of primary pevention ICDs in patients with NICM. This trial randomized 1116 patients with NICM LVEF <35% and class II, III, or IV (if CRT was planned) HF to an ICD or no ICD. CRT (either ICD or pacemaker) was pres- ent in 58% of patients in the ICD and medical CLINICAL STATEMENTS AND GUIDELINES therapy arms. Therefore, the results of DANISH should not be generalized to patients with NICM who are ineligible for CRT. During a median follow-up of 5.6 years, ICD reduced SCD from 8.4% to 4.3%, but there was no difference in Several meta-analyses have been published.S7.2.2-12,S7.2.2-13 One provided data on ICDs with and without CRT and showed survival benefit from the ICD.S7.2.2-13 The second used patient level data from 2 trials and adopted a more robust approach to reducing heterogene- ity by excluding patients with CRT and those ran- domized to antiarrhythmic medications; a 25% relative risk reduction in mortality with an ICD 2. Laminopathies are diseases caused by mutations mainly in the Lamin A/C gene that produce various inherited diseases including subtypes of muscular dystrophy and progeria. Isolated cardiac involve- ment is also observed and is an important cause of familial cardiomyopathy.S7.2.2-9 The disease is highly penetrant such that all affected individu- als have evidence of disease by 60 years of age. Cardiac manifestations may include atrial fibril- lation, conduction disturbances, VA, and NICM. A number of observational studies reported a high risk of SCD when cardiac involvement is One study reported SCD as the most frequent mode of death (46%) in both the isolated cardiac and the neuromuscular phe- notypes of Lamin diseases.S7.2.2-9 In a cohort of 269 LMNA mutation positive individuals,S7.2.2-10 NSVT during ambulatory electrocardiographic monitor- ing, LVEF <45% at first evaluation, male sex, and nonmissense mutations were independent risk factors for VA. Malignant VA were observed only in persons with 2 of these risk factors.S7.2.2-10 No studies have tested the effect of the ICD on long- term survival. 3. Patients with NICM and class I HF symptoms were not included in SCD-HeFT or DANISH.S7.2.2-1,S7.2.2-11 Although such patients were included in the DEFINITE trial, only 99 (21.6%) of 458 patients in the DEFINITE trial had class I HF.S7.2.2-5 Therefore, it is uncertain whether a primary prevention ICD in such patients improves survival. 4. There are insufficient data from RCTs regarding the value of the ICD in patients with NYHA class IV. Ambulatory class IV HF patients were included in the COMPANION trial that, overall, showed improved functional status and survival with a Unless such a patient is a candidate for CRT or advanced HF therapies such as heart transplantation or an LVAD, an ICD is not expected to meaningfully prolong survival.S7.2.2-3 7.2.3. Treatment of Recurrent VA in Patients With NICM Recommendations for Treatment of Recurrent VA in Patients With NICM References that support the recommendations are summarized in Online Data Supplement 29. COR LOE Recommendations IIa B-R In patients with NICM and an ICD who experience spontaneous VA or recurrent appropriate shocks despite optimal device programming and treatment with a beta blocker, amiodarone or sotalol can be IIa B-NR In patients with NICM and recurrent sustained monomorphic VT who fail or are intolerant of antiarrhythmic medications, catheter ablation can be useful for reducing recurrent VT and ICD Recommendation-Specific Supportive Text 1. ICDs reduce mortality from VA, yet ICD shocks are painful and associated with significant morbidity and poor QoL. Although ICDs are highly programmable and provide antitachy- cardia pacing therapy that can terminate most VT episodes without the need for a shock, pre- vention of shocks, both appropriate and inap- propriate, remains an important concern. In the OPTIC (Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients) study, 412 patients with documented VT and VF who received an ICD within 21 days of the docu- were randomized to amiodarone plus beta blocker, sotalol alone, or beta blocker alone. Over 1 year, shocks occurred in 38.5% assigned to beta blocker alone, 24.3% assigned to sotalol, and 10.3% assigned to amiodarone plus beta blocker. The rates of study medication discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for beta blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycar- dia were more common among patients ran- domized to amiodarone. Thus, amiodarone plus beta blocker were more effective than sotalol in preventing ICD shocks but at the expense of increased risk of medication-related adverse Sotalol should not be used in patients with an LVEF <20% due to its negative inotropic effects. 2. Sustained monomorphic VT due to NICM is most often due to scar-related reentry. Cardiac MRI often indicates scar location, which tends to be basal along the mitral annulus or in the The VT substrate can be CLINICAL STATEMENTS AND GUIDELINES Figure 6. Secondary and primary prevention of SCD in patients with NICM. Colors correspond to Class of Recommendation in Table 1. See Section 7.2 for discussion. *ICD candidacy as determined by functional status, life expectancy or patient preference. 2 indicates secondary; EP, electrophysiological; GDMT, guideline-directed management and therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; NICM, nonischemic cardiomyopathy; SCA, sudden cardiac arrest; SCD, sudden cardiac death; VA, ventricular arrhythmia; and WCD, wearable cardioverter-defibrillator. subendocardial, subepicardial, or intramyo- cardial, and all locations may be affected and require endocardial and epicardial ablation. In the HELP-VT (Heart Center of Leipzig VT) successful ablation of all VT mor- phologies was achieved in 66.7% of patients with NICM, compared with the 77.4% suc- cess rate in ischemic cardiomyopathy. An epi- cardial approach to ablation was required in 30.2% of NICM patients, compared with only 1.2% with ischemic cardiomyopathy. Epicardial ablation was an independent predictor of suc- cessful ablation. Acute and long-term success of ablation is lower for NICM, compared with post-MI patients. The long-term survival-free of VT recurrence after catheter ablation appears to be better for patients with ischemic than Risks are similar to those observed for post-MI VT ablation, with additional risks of epicardial access and ablation when required. Although any NICM can produce scar-related VT, cardiac sarcoidosis (see Section 7.6) and Lamin muta- tions are particularly associated with sustained 7.3. Arrhythmogenic Right Ventricular Cardiomyopathy Recommendations for Arrhythmogenic Right Ventricular Cardiomyopathy References that support the recommendations are summarized in Online Data Supplement 30. COR LOE Recommendations I B-NR In selected first-degree relatives of patients with arrhythmogenic right ventricular cardiomyopathy, clinical screening for the disease is recommended along with genetic counseling and genetic testing, if the proband has a disease causing mutation.S7.3-1 S7.3-4 I B-NR In patients with suspected arrhythmogenic right ventricular cardiomyopathy and VA or electrocardiographic abnormalities, cardiac MRI is useful for establishing a diagnosis and for risk stratification.S7.3-5 S7.3-8 I B-NR In patients with arrhythmogenic right ventricular cardiomyopathy and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT, significant ventricular dysfunction with RVEF or LVEF 35%), an ICD is recommended if meaningful survival greater than 1 year is I B-NR In patients with arrhythmogenic right ventricular cardiomyopathy and VA, a beta blocker is recommended.S7.3-11,S7.3-14,S7.3-15 CLINICAL STATEMENTS AND GUIDELINES I B-NR In patients with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy, avoiding intensive exercise is IIa B-NR In patients with clinically diagnosed or suspected arrhythmogenic right ventricular cardiomyopathy, genetic counseling and genetic testing can be useful for diagnosis and for gene-specific targeted family IIa B-NR In patients with arrhythmogenic right ventricular cardiomyopathy and syncope presumed due to VA, an ICD can be useful if meaningful survival greater than 1 year is IIa B-NR In patients with clinical evidence of arrhythmogenic right ventricular cardiomyopathy but not VA, a beta blocker can be useful.S7.3-14,S7.3-15 IIa B-NR In patients with arrhythmogenic right ventricular cardiomyopathy and recurrent symptomatic sustained VT in whom a beta blocker is ineffective or not tolerated, catheter ablation with availability of a combined endocardial/epicardial approach can be beneficial.S7.3-27 S7.3-33 IIa B-NR In patients with suspected arrhythmogenic right ventricular cardiomyopathy, a signal averaged ECG can be useful for diagnosis and risk stratification.S7.3-14,S7.3-34,S7.3-35 IIb B-NR In asymptomatic patients with clinical evidence of arrhythmogenic right ventricular cardiomyopathy, an electrophysiological study may be considered for risk Synopsis Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy that predominantly af- fects the right ventricle but can affect the left ven- tricle causing areas of myocardial replacement with fibrosis and adipose tissue that frequently causes VA and SCD. Recommendation-Specific Supportive Text 1. Selected first-degree relatives refers to rela- tives who are willing to undergo further testing and who could benefit from further screening and testing (and not the terminally ill patients or those who do not want to be screened and tested). Arrhythmogenic right ventricular cardio- myopathy is often due to a mutation involving a desmosomal protein, and it usually has auto- somal dominant inheritance with variable pen- etrance. SCD can be the initial manifestation of arrhythmogenic right ventricular cardiomyopathy. Clinical screening with ECG, cardiac imaging, and ambulatory rhythm monitoring and/or exer- cise testing may identify family members at risk for arrhythmogenic right ventricular cardiomy- opathy. Arrhythmogenic right ventricular cardio- myopathy is detected clinically in approximately most commonly in siblings or symptomatic first- When a proband is identi- fied with a disease-causing mutation, targeted genotype screening can identify mutation positive with approximately 35% of muta- tion positive individuals ultimately developing progressive disease expression.S7.3-1,S7.3-4 In stud- ies of arrhythmogenic right ventricular cardiomy- opathy mutation-positive individuals who do not initially manifest the disease, 8% to 16% have a major arrhythmic event over the next 7 to 39 Early identification of affected or potentially affected family members can allow lifestyle modifications in sports participation and serial monitoring for development of electrocar- diographic abnormalities, symptoms, ventricular dysfunction, or arrhythmia. As genetic testing for arrhythmogenic right ventricular cardiomyopathy has subtle complexities, the decision to proceed with family screening is facilitated by informed genetic counseling to discuss the cost of test- ing, the potential lack of a single gene as the determinant for disease expression, psychological implications of uncertain disease progression, and implications for lifestyle modification, screening, and potential treatment. 2. Cardiac MRI provides high-quality assess- ment of ventricular function, size, regional wall motion abnormalities, and extent of scar and fibrosis (late gadolinium enhancement) that are seen in 30% to 95% of patients with the clini- cal diagnosis of arrhythmogenic right ventricu- Cardiac MRI detects biventricular involvement in 34% to 56% of patients, with isolated LV involve- ment noted in 4% to 9% of patients.S7.3-37 S7.3-40 Cardiac MRI should include assessment of late gadolinium enhancement with quantification of fibrosis. Application of the 2010 Task Force Criteria to cardiac MRI criteria for diagnosis of arrhythmogenic right ventricular cardiomyopa- thy has improved the specificity of this test.S7.3- Electrocardiographic and Holter findings precede detectable cardiac MRI abnormalities in arrhythmogenic right ventricular cardiomyopa- thy mutation-positive individuals, with only 4% of patients with normal electrocardiographic and Holter results having cardiac MRI abnormalities, Recommendations for Arrhythmogenic Right Ventricular Cardiomyopathy (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES suggesting that evaluation of cardiac structure and function using cardiac MRI may be unnecessary in mutation-positive individuals who do not have The presence of both electrocardiographic abnormalities and abnor- mal cardiac MRI findings may identify patients at an increased risk for developing sustained Areas of scar identified on cardiac MRI have correlated with the location of VT sub- strate identified by endocardial and epicardial During early stages of disease, a baseline cardiac MRI may provide useful informa- tion along with electrocardiographic and rhythm abnormalities to monitor disease progression over time. Experience and expertise in interpretation of cardiac MRI are important.S7.3-5,S7.3-8 3. Arrhythmogenic right ventricular cardiomy- opathy is characterized by progressive ven- tricular myocyte loss with replacement by fatty or fibrous tissue, and is associated with progressive ventricular dysfunction that may involve both ventricles. VA, syncope, and SCD may occur at a relatively young age, particularly in the second and third decades of life and often occurring during physical Sustained VT is an important predictor of SCA and SCD or appropri- ate ICD shocks in patients with arrhythmogenic right ventricular cardiomyopathy.S7.3-10,S7.3-13 In patients receiving an ICD for primary prevention, appropriate ICD shocks are reported in 24% to As sustained VT in arrhythmogenic right ventricular cardiomy- opathy patients is monomorphic in 55% to 90% of episodes based on ICD interrogation or elec- antitachycardia pacing algorithms are used to terminate VT. 4. Frequent PVCs, >760 to 1000 per 24 hours dur- ing ambulatory rhythm monitoring, correlate with The presence of NSVT or sustained VT is an important predictor of adverse The increased arrhythmia risk conferred by intense exercise is consistent with beta-adrenergic modu- lation of disease expression.S7.3-17,S7.3-20,S7.3-21 An observational registry reported that treatment with atenolol or amiodarone was associated with less clinically relevant VA, while sotalol was associ- ated with no effect or increased arrhythmia.S7.3-15 Ambulatory monitoring to assess VA burden and adequacy of beta-blocker therapy is usually 5. Patients with arrhythmogenic right ventricular cardiomyopathy have a significantly increased risk of SCD during exertion.S7.3-16,S7.3-17,S7.3-20,S7.3-21 Vigorous exercise in patients with arrhythmogenic right ventricular cardiomyopathy has been shown to impair myocardial function by echocardiogra- phy and cardiac MRI.S7.3-19 Participation in high intensity/duration or endurance physical activity accelerates the penetrance/disease progression and arrhythmic risk for arrhythmogenic right ventricular cardiomyopathy patients and muta- tion positive individuals, as well as mutation positive family members.S7.3-17,S7.3-19 S7.3-21 Patients with arrhythmogenic right ventricular cardiomy- opathy who participate in competitive sports are at increased risk for VT or SCD, compared with those who participate in recreational sports or Exercise influences disease progression in a linear manner; family members who limited activity to less than the AHA recommended minimum for activity guide- lines (<650 metabolic equivalent hours per year [MET-Hr/year]) were less likely to develop VA or In a study of arrhyth- mogenic right ventricular cardiomyopathy pro- bands and exercise, athletes (defined as subjects with 4h vigorous exercise/week) were found to have reduced biventricular function compared with nonathletes in arrhythmogenic right ven- tricular cardiomyopathy patients and in muta- tion-positive family members.S7.3-19 Many advise limiting exercise intensity and duration to <650 6. The proband with arrhythmogenic right ven- tricular cardiomyopathy is usually diagnosed by the presence of clinical symptoms along with the presence of arrhythmogenic right ventricu- lar cardiomyopathy Task Force criteria including: abnormalities on ECG, structural and functional changes of either ventricle, arrhythmias, and arrhythmogenic right ventricular cardiomyopathy in first-degree relatives.S7.3-6 A pathogenic genetic mutation was added to the major Task Force criteria in 2010.S7.3-44 The yield of genetic test- ing in probands with suspected arrhythmogenic right ventricular cardiomyopathy is generally 30% to 54%, and is up to 58% among patients with a strong family history of SCD in multiple A negative genetic test for arrhythmogenic right ventricular cardiomyop- athy does not exclude the disease, and a positive genetic test currently does not guide therapy.S7.3-22 For the proband with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy, identification of pathogenic mutations provides limited prognostic information relative to the risk or development of HF.S7.3-22 In a large multicenter study, the presence of posi- tive mutations among probands was not asso- ciated with a difference in mortality or cardiac CLINICAL STATEMENTS AND GUIDELINES However, the identification of a pathogenic mutation facilitates targeted genetic screening for that mutation in first- degree relatives, that may identify approximately highest among siblings, and those with symptoms.S7.3-4 Screening for the specific mutation can identify some gene positive family members prior to disease expres- sion, while relieving others from the need for life- style changes and long-term monitoring.S7.3-2,S7.3-3 7. Syncope is reported in 16% to 39% of arrhythmo- genic right ventricular cardiomyopathy patients at the time of diagnosis,S7.3-13,S7.3-14,S7.3-16,S7.3-41,S7.3-43 is frequently exercise-related, and has been associated with high arrhythmic risk in some Among patients with arrhyth- mogenic right ventricular cardiomyopathy and implanted ICDs, syncope was an important pre- dictor of appropriate shocks in 1 study,S7.3-10 but not in other studies.S7.3-9,S7.3-12,S7.3-13,S7.3-43 Studies have not provided information about ventricular function or abnormalities on ECG in patients with syncope, limiting its assessment as an indepen- dent risk factor. Syncope may be a harbinger of progression of underlying disease and should be integrated into the decision-making process for ICD implantation with the patient. 8. Asymptomatic patients with arrhythmogenic right ventricular cardiomyopathy and no VA or ventric- ular dysfunction are generally observed without antiarrhythmic therapy other than beta-blocker therapy, with ongoing periodic reassessment for the development of arrhythmias or ventricular Atenolol was shown to reduce VA in 1 study.S7.3-15 Ambulatory monitor- ing and/or exercise testing can be performed to assess adequacy of beta-blocking dosing. 9. Interrogation of ICDs shows that >90% of sponta- neous sustained VTs in arrhythmogenic right ven- tricular cardiomyopathy are monomorphic,S7.3-12 while sustained monomorphic VT is induc- ible at electrophysiological study in 55% of VT is usually related to scar-related reentry, and the subepicardium usually has more extensive scar than the endocardium.S7.3-27 In experienced centers, use of epicardial map- ping and ablation is associated with better Important complications including pericardial tamponade, MI, and death occur in 2.3% to 3.3% of abla- emphasizing the need for performance in centers with specialized expertise in epicardial procedures. Ablation reduces the fre- quency of recurrent VT, although 27% to 55% have at least 1 recurrence; ablation of VT in arrhythmogenic right ventricular cardiomyopathy patients does not eliminate the need for an ICD in appropriate candidates. The potential risk of VT recurrence due to disease pro- gression should be reviewed with patients when considering ablation. There are no randomized comparisons of antiarrhythmic therapy to sup- press recurrent VT. Beta blockers, sotalol and ami- odarone have been used.S7.3-15 In an observational series, sotalol suppressed inducible VT in 58% of patients with <10% of patients experienc- ing arrhythmia recurrence during follow-up.S7.3-48 Effectiveness of the different medications appears to be variable, and so more studies are needed. 10. In arrhythmogenic right ventricular cardiomyop- athy, areas of fibrofatty scar in the RV free wall create areas of delayed ventricular activation causing fractionated deflections following the QRS, known as epsilon waves on the surface ECG (a major criterion) and late potentials in the signal averaged ECG (minor criterion) in the 2010 Task Force Criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy.S7.3-6 When the standard ECG QRS duration is 110 ms, criteria for abnormal signal-averaged ECG include any 1 of the following: filtered QRS duration 114 ms, duration of the terminal QRS <40 uV exceeding 37 ms, or a root mean square voltage in the terminal Abnormal findings on sig- nal averaged ECG correlated with disease severity on cardiac MRI,S7.3-35 and increased adverse events In an assessment of the diagnostic use of testing for arrhythmogenic right ventricu- lar cardiomyopathy, signal averaged ECG was of greater value than cardiac MRI or biopsy.S7.3-14 11. The value of an electrophysiological study is uncer- tain in asymptomatic arrhythmogenic right ven- tricular cardiomyopathy patients with preserved ventricular function in predicting subsequent risk for SCD. Studies of programmed ventricular stimulation in patients with definite or probable arrhythmogenic right ventricular cardiomyopathy include most symptomatic patients, making rec- ommendations on asymptomatic patients difficult. Electrophysiological studies induce sustained VT in ; many of whom have had prior spontaneous episodes of sustained VT. In patients with primary prevention ICDs, inducible sustained VT did not predict sub- sequent appropriate ICD shocks.S7.3-13 In 1 study including symptomatic patients, patients without inducible VT were less likely to receive appropriate In asymptomatic patients without evidence of VA on ambulatory monitoring, a neg- ative electrophysiological study may have limited value in decision-making for an ICD. CLINICAL STATEMENTS AND GUIDELINES 7.4. Hypertrophic Cardiomyopathy Recommendations for HCM References that support the recommendations are summarized in Online Data Supplement 31. COR LOE Recommendations I B-NR In patients with HCM, SCD risk stratification should be performed at the time of initial evaluation and periodically I B-NR In patients with HCM who have survived an SCA due to VT or VF, or have spontaneous sustained VT causing syncope or hemodynamic compromise, an ICD is recommended if meaningful survival greater than 1 year is expected.S7.4-1,S7.4-6,S7.4-9,S7.4-10 I B-NR In first-degree relatives of patients with HCM, an ECG and echocardiogram should be I B-NR In first-degree relatives of patients with HCM due to a known causative mutation, genetic counseling and mutation-specific genetic testing are IIa B-NR In patients with clinically suspected or diagnosed HCM, genetic counseling and genetic testing IIa B-NR In patients with HCM and 1 or more of the following risk factors, an ICD is reasonable if meaningful survival of greater than 1 year is expected: a. Maximum LV wall thickness 30 mm b. SCD in 1 or more first-degree relatives presumably caused by HCM c. 1 or more episodes of unexplained syncope within the preceding 6 months C-LD C-LD IIa B-NR In patients with HCM who have spontaneous NSVT (LOE: C-LD) S7.4-2,S7.4-26,S7.4-27 or an abnormal blood pressure response with exercise (LOE: B-NR) S7.4-5,S7.4-28,S7.4-29 , who also have additional SCD risk modifiers or high-risk features, an ICD is reasonable if meaningful survival greater than 1 year is expected. C-LD IIb B-NR In patients with HCM who have NSVT or an abnormal blood pressure response with exercise (LOE: but do not have any other SCD risk modifiers, an ICD may be considered, but its benefit is uncertain. B-NR IIb C-LD In patients with HCM and a history of sustained VT or VF, amiodarone may be considered when an ICD is not feasible or not preferred by the patient.S7.4-30,S7.4-31 III: No Benefit B-NR In patients with HCM, an invasive electrophysiological study with programmed ventricular stimulation should not be performed for risk stratification.S7.4-32,S7.4-33 III: No Benefit B-NR In patients with an identified HCM genotype in the absence of SCD risk factors, an ICD should not be implanted.S7.4-7,S7.4-34,S7.4-35 Refer to the ACCF/AHA HCM guideline for the defi- nition of HCM.S7.4-36 Recommendation-Specific Supportive Text 1. Patients with HCM have approximately a 1% risk of SCD per year.S7.4-1,S7.4-6 Selection of patients who are appropriate candidates for implanta- tion of an ICD can be a difficult clinical decision because of the individuality of each patient and family, variable definitions of risk factors and risk modifiers, sparse clinical data, the relative infre- quency of both HCM and SCD in most clinical practices, and the potential complications of liv- ing with an ICD. Table 8 lists risk factors and risk modifiers associated with SCD in patients with HCM. ICD risk stratification should be performed every 1 to 3 years in patients with HCM. There is increasing evidence supporting the association of late gadolinium enhancement on cardiac MRI with the risk of sudden death and it is included as a risk modifier.S7.4-37 S7.4-39 LV aneurysm may be Table 8. Major Clinical Features Associated With Increased Risk of SCD in Patients With HCM Established risk factors* Survival from a cardiac arrest due to VT or VF S7.4-1,S7.4 5,S7.4 6 Spontaneous sustained VT causing syncope or hemodynamic Family history of SCD associated with HCM S7.4 25,S7.4 26 LV wall thickness 30 mm S7.4-2,S7.4-3,S7.4 23,S7.4 24 Unexplained syncope within 6 mo S7.4 8,S7.4 26 Abnormal blood pressure response during exercise S7.4 5,S7.4 28,S7.4 29 Potential risk modifiers Delayed hyperenhancement on cardiac MRI S7.4 37 S7.4 39,S7.4 54 LVOT obstruction S7.4-2,S7.4-4 Syncope >5 y ago S7.4 8,S7.4 26 High-risk subsets LV aneurysm S7.4 40,S7.4 55,S7.4 56 *There is general agreement in the literature that these factors independently convey an increased risk for SCD in patients with HCM. Decrease in blood pressure of 20 mmHg or failure to increase systolic blood pressure >20 mmHg during exertion. There is a lack of agreement in the literature that these modifiers independently convey an increased risk of SCD in patients with HCM; however, a risk modifier when combined with a risk factor often identifies a patient with HCM at increased risk for SCD beyond the risk conveyed by the risk factor alone. A small subset of patients with an LVEF <50% (end-stage disease) or an LV aneurysm warrant consideration for ICD implantation.S7.4-52 HCM indicates hypertrophic cardiomyopathy; ICD, implantable cardioverter- defibrillator; LV, left ventricular; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; NSVT, nonsustained ventricular tachycardia; SCD, sudden cardiac death; VT, ventricular tachycardia; and VF, ventricular fibrillation. CLINICAL STATEMENTS AND GUIDELINES associated with a risk of sustained monomorphic Age is also an important consideration, as sudden death risk is greater in those <30 years of age, and low in patients whose initial presenta- tion is after the age of 60 years,S7.4-5,S7.4-26 2. HCM is the most common cause of SCD in individuals <40 years of age.S7.4-26 Individuals who have survived an episode of SCD, VF, or sustained VT resulting in syncope or hemodynamic compromise warrant ICD Although there are no RCTs assessing the use of the ICD in patients with HCM who have survived SCD, 1 study reported that 54% of patients with an ICD placed for secondary prevention received appro- priate ICD therapy during an average follow-up of Select patients with HCM may be candidates for implantation of the subcutaneous ; how- ever, more data on this group are needed especially given their higher risk of T wave oversensing that may increase the risk of inappropriate ICD shocks. 3. Clinical and/or genetic screening of first- and second-degree family members of patients with HCM is important to identify those with unrec- ognized disease. Genetic counseling should precede genetic testing of family members to enhance their understanding of the useful- ness and cost of testing.S7.4-18,S7.4-20,S7.4-43 On the basis of family history, clinical screening, and pedigree analyses, the pattern of inheri- tance is ascertained to identify and manage relatives at risk.S7.4-13,S7.4-14,S7.4-18,S7.4-19,S7.4-43 S7.4-45 Because familial HCM is a dominant disorder, the risk that an affected patient will transmit disease to each offspring is 50%. When a pathogenic mutation is identified in an index patient, the genetic status of each family member can be readily ascertained. Relatives with overt HCM will have the same patho- genicHCMmutationastheindexpatient.Pathogenic mutations may also be identified in other relatives with unknown clinical status. These mutation- positive individuals should be evaluated by physi- cal examination, electrocardiography,S7.4-11,S7.4-17 and, if HCM is identified, these individuals should undergo risk stratification. Gene-positive subjects with- out evidence of HCM may be at risk for future development of HCM and benefit from ongoing If the proband s implicated mutation is the bona fide disease causing mutation, then mutation-negative fam- ily members and their descendants are not at an increased risk for developing HCM and do not need further evaluation. However, such muta- tion-negative family members must have an echocardiogram to ensure genotype and pheno- type concordance. 4. In a study of 1053 unrelated patients with clini- cally manifest HCM, 359 patients (34%) were genotype positive for an HCM-associated muta- tion in 1 HCM-associated genes.S7.4-22 Whether the results of genetic testing in the proband improve outcomes is uncertain, but identification Figure 7. Prevention of SCD in patients with HCM. Colors correspond to Class of Recommendation in Table 1. See Section 7.4 for discussion. *ICD candidacy as determined by functional status, life expectancy, or patient preference. Risk modifiers: Age <30 y, late gadolinium enhancement on cardiac MRI, LVOT obstruction, LV aneurysm, syncope >5 y. BP indicates blood pressure; HCM, hypertrophic cardiomyopathy; Hx, history; ICD, implantable cardioverter-defibrillator; LVOT, left ventricular outflow tract; LVWT, left ventricular wall thickness; MRI, magnetic resonance imaging; NSVT, nonsustained ventricular tachycardia; SCD, sudden cardiac death; and VT, ventricular tachycardia. CLINICAL STATEMENTS AND GUIDELINES of a mutation can help inform screening of relatives. 5. Genetic counseling is important in patients with HCM, and genetic screening of relatives is also important unless there are no living first- or second-degree relatives. Most HCM is caused by an autosomal dominant mutation in genes that encode sarcomere proteins or sarcomere- associated proteins. Presence of a pathogenic sarcomere protein gene mutation in patients with HCM identifies risk of LV dysfunction and adverse outcome irrespective of the myofilament A single muta- tion in 1 of the 2 alleles (or copies) of a gene is sufficient to cause HCM; however, 5% of patients with HCM have 2 mutations in the same gene or different genes, which can be a marker for worse When genetic testing reveals a mutation in the index patient, ascertain- ment of genetic status in first- and second-degree relatives can be predictive of risk for developing Relatives with overt HCM will have the same pathogenic HCM mutation as the index patient. 6. Several studies have described an indepen- dent relationship between hypertrophy and SCD when the magnitude of hypertrophy is Risk does not abruptly increase for patients with a 30 mm wall thick- ness, but it rather increases in a linear mannerS7.4-24 and appears to carry more prognostic significance in younger patients. A young adult with hypertro- phy that approaches 30 mm may have similar or greater SCD risk than an older patient with maxi- mum wall thickness 30 mm.S7.4-23,S7.4-50 Patients with HCM are at an increased risk for SCD if they have a first-degree relative who expe- rienced SCD presumably caused by HCM. Family history appears to be an independent predictor of SCD although the supportive studies are small Syncope can be neu- rally mediated or medication-related as well as due to VA and requires a careful evaluation be- fore considering it a risk factor for SCD.S7.4-8,S7.4-26 In an analysis, syncope that was unexplained or thought not to be neurally mediated was associ- ated with SCD risk only when it occurred within the past 6 months but not if the most episode 7. Although sustained VT is clearly associated with SCD, the data for NSVT are less robust. Most studies do not support NSVT as an inde- pendent risk factor for SCD in patients with but the risk increases if risk modifiers are present, especially in patients <30 years of age.S7.4-27 Up to one third of patients with HCM have an abnormal blood pressure response during exercise testing (defined variably as either a 20 mm Hg decrease in blood pressure or a failure to increase systolic blood pressure by at least 20 mm Hg during effort).S7.4-28,S7.4-29 This finding has been postulated to be a risk factor for SCD; how- ever, it is unclear how this relates to the increase in dynamic LV outflow tract obstruction that occurs with exertion, a hemodynamic condition that is readily modifiable with medication or mechanical procedures. The significance of an abnormal blood pressure response with exercise predicting SCD risk increases in the presence of risk modifiers (Table 8). 8. Most studies have found that NSVT alone has a low positive predictive value for SCDS7.4-2,S7.4-26, ; therefore, use of an ICD is more appropriate if risk modifiers are also present. An abnormal blood pressure response to exercise has also been associ- ated with the risk of sudden death,S7.4-5,S7.4-28,S7.4-29 but it is unclear how this relates to the increase in dynamic LV outflow tract obstruction that occurs with effort, which is often treatable. The signifi- cance of an abnormal blood pressure response with exercise for predicting SCD risk increases when risk modifiers are present (Table 8). 9. The ICD is recommended for the prevention of SCD in patients with HCM who have survived sustained VT or VF as antiarrhythmic medications have limited effectiveness.S7.4-31 Amiodarone has been associated with improved survival in obser- vational studies and is an option for patients for whom an ICD is not feasible due to limited expec- tation for survival or patient preference.S7.4-30,S7.4-31 10. Approximately one third of consecutive patients with HCM undergoing an electrophysiologi- cal study have polymorphic VT or VF induced by programmed ventricular stimulation, but the results of programmed stimulation do not predict SCD risk. Programmed ventricular stimulation in patients with HCM has low predictive value and a nontrivial risk of complications.S7.4-32,S7.4-33,S7.4-51 Electrophysiological studies can help to clarify the diagnosis of wide complex tachycardia or guide therapy for supraventricular tachycardia or bun- dle branch reentry. 11. SCD may cluster in certain families with HCM, and the possibility that specific sarcomere muta- tions may confer SCD risk has been hypothe- sized. However, subsequent studies of selected patients with HCMS7.4-34,S7.4-35 were unable to establish a clinically useful relation between genotype and SCD risk. In some cases, the rate of adverse events (and prevalence of associated SCD risk factors) was lower in patients with mutations initially felt to be malignant than it was in those with mutations believed to be CLINICAL STATEMENTS AND GUIDELINES Data from series of unselected consecutive outpatients suggest that most mutations are novel and limited to particular Therefore, routine mutation screening would appear to be of little prognostic value in HCM.S7.4-52 The short-term risk of sud- den death in patients who are genotype positive but have no other manifestations of the disease appears to be low.S7.4-53 Therefore, an ICD is not indicated in these individuals. Recommendations for Myocarditis References that support the recommendations are summarized in Online Data Supplement 32. COR LOE Recommendations I C-LD In patients with life-threatening VT or VF associated with confirmed or clinically suspected myocarditis, referral to centers with mechanical hemodynamic support and advanced arrhythmia management is IIb C-LD In patients with giant cell myocarditis with VF or hemodynamically unstable VT treated according to GDMT, an ICD and/or an antiarrhythmic medication may be considered if meaningful survival of greater than 1 year Recommendation-Specific Supportive Text 1. Myocarditis is an inflammatory process often related to infection.S7.5-1,S7.5-5 S7.5-9 When patients are treated in centers with the availability of mechanical hemodynamic support proce- dures, cardiac catheterization, endomyocardial biopsy, advanced cardiac imaging procedures, and arrhythmia management including ICD implantation, outcomes appear improved.S7.5-1 The acute course of myocarditis varies ranging from an asymptomatic finding of transient ST-T changes noted on ECG to cardiogenic shock and recurrent VA.S7.5-10 S7.5-12 Acute management is largely supportive and can rapidly advance to requiring mechanical support.S7.5-13,S7.5-14 Cardiac arrhythmias range from conduction abnormali- ties to life-threatening VT and VF.S7.5-15 S7.5-17 Arrhythmias may require antiarrhythmic medi- cations and/or device therapy.S7.5-18 Giant cell myocarditis is fairly uncommon, but it is of particular importance because it typically affects young individuals and is usually fatal if VT may require antiar- rhythmic medications such as amiodarone and/ or an ICD that in some instances can be used as a bridge to more advanced HF therapies such as LVAD or transplant. Myocarditis and SCD have been reported with HIV infection.S7.5- Systemic lupus erythematous can cause myocarditis but only rarely VT or VF.S7.5-8,S7.5-22 In patients with Chagas disease, acute myocardi- tis is rare but more than one third of affected patients develop late myocardial damage with progressive HF. Conduction defects with pro- gression to complete heart block and VT or VF are common. Amiodarone appears to be effec- tive in treating VA.S7.5-23 An ICD is frequently used in the late phase of myocarditis,S7.5-24 and radiofrequency catheter ablation has been suc- cessfully used to control recurrent VA in some 2. Giant cell myocarditis is fairly uncommon, but it is of particular importance as it typically affects young individuals and is usually fatal if untreated. The diagnosis is confirmed by endo- myocardial biopsy. Patients may develop heart block, requiring a temporary or a permanent pacemakers. An ICD and antiarrhythmic medica- tions, such as amiodarone are often used in the acute phase to treat VT or VF and reduce the risk 7.6. Cardiac Sarcoidosis Recommendations for Cardiac Sarcoidosis References that support the recommendations are summarized in Online Data Supplement 33. COR LOE Recommendations I B-NR In patients with cardiac sarcoidosis who have sustained VT or are survivors of SCA or have an LVEF of 35% or less, an ICD is recommended, if meaningful survival of greater than 1 year is expected.S7.6-1 S7.6-5 IIa B-NR In patients with cardiac sarcoidosis and LVEF greater than 35% who have syncope and/ or evidence of myocardial scar by cardiac MRI or positron emission tomographic (PET) scan, and/or have an indication for permanent pacing, implantation of an ICD is reasonable, provided that meaningful survival of greater than 1 year is IIa C-LD In patients with cardiac sarcoidosis and LVEF greater than 35%, it is reasonable to perform an electrophysiological study and to implant an ICD, if sustained VA is inducible, provided that meaningful survival of greater than 1 year is expected.S7.6-11,S7.6-12 IIa C-LD In patients with cardiac sarcoidosis who have an indication for permanent pacing, implantation of an ICD can be IIa C-LD In patients with cardiac sarcoidosis with frequent symptomatic VA and evidence of myocardial inflammation, immunosuppression in combination with antiarrhythmic medication therapy can be useful to reduce VA burden.S7.6-14 S7.6-16 CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. Sarcoidosis is a systemic granulomatous disease of unknown cause. Pulmonary involvement is most frequent but any organ can be affected. Cardiac involvement, diagnosed by cardiac MRI or positron emission tomography (PET), has been reported in up to 55% of patients with extra- cardiac disease, while isolated cardiac sarcoidosis was seen in most patients diagnosed with cardiac Cardiac manifesta- tions include conduction abnormalities, VA, and depressed ventricular function with or without HF, and these contribute greatly to a higher mortality in cardiac sarcoidosis compared with sarcoidosis without cardiac involvement.S7.6-2 In a 25-year study of 110 patients with cardiac sarcoidosis in Finland with HF at presentation, marked LV dysfunction at diagnosis (LVEF <35%), and iso- lated cardiac sarcoidosis predicted an adverse VA can also occur in patients with relatively normal LV function, some of whom have RV involvement that can mimic arrhythmo- genic right ventricular cardiomyopathy. Several reports of patients with cardiac sarcoidosis and ICDs implanted for either primary or secondary prevention of SCD show a high frequency of appropriate ICD therapies,S7.6-3 S7.6-5 supporting use of ICDs for primary and secondary prevention of SCD according to the indications applied for other cardiomyopathies. The frequency of con- duction abnormalities often warrants a device that provides bradycardia pacing as well. 2. Patients with cardiac sarcoidosis can experience VA and SCD, even if the LVEF is normal, and approaches to identification of patients at risk of SCD despite preserved LV function are not well defined. A number of studies have evaluated the role of cardiac MRI for predicting VA and SCD. A which included 760 patients in 10 studies, found that late gadolinium enhance- ment was associated with increased all-cause mortality and more VA compared with those with- out late gadolinium enhancement. Applicability is limited by the lack of precise quantification of late gadolinium enhancement burden that may allow for more nuanced risk stratification. Some stud- ies suggested that a threshold effect exists, with extensive LV and RV involvement being a particu- larly high-risk feature.S7.6-7,S7.6-8 However, late gad- olinium enhancement can be present even if the LVEF is >50% and was associated with a risk of death or VT of 4.9% per year compared to 0.24% per year when late gadolinium enhancement was absent in 1 observational study.S7.6-7 PET for assess- ing inflammation and scar is also being increas- ingly used, but data are limited. In 1 report, the Figure 8. prevention of SCD in patients with cardiac sarcoidosis. Colors correspond to Class of Recommendation in Table 1. See Section 7.6 for discussion. *ICD candidacy as determined by functional status, life expectancy, or patient preference. For recurrent sustained monomorphic VT, refer to Figure 2. CEP indicates electrophysiological; GDMT, guideline-directed management and therapy; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; PET, positron emission tomography; SCA, sudden cardiac arrest; SCD, sudden cardiac death; VA, ventricular arrhythmia; and VT, ventricular tachycardia. CLINICAL STATEMENTS AND GUIDELINES presence of inflammation and RV involvement on PET scanning was associated with increased risk of death or e g of relatives.S7.6-10 Electrophysiological studies in a series of 76 patients with evidence of cardiac sarcoid found that 11% had inducible VT. During a median follow-up of 5 years, 75% of patients with inducible VT had spontaneous VT or death compared with 1.5% of those who did not have inducible VT.S7.6-18 3. Electrophysiological study has been proposed as a potential tool for risk stratification of VA and SCD in patients who had demonstrable evidence of cardiac sarcoidosis based on imaging studies or biopsy, but do not have documented arrhythmias or arrhythmic symptoms nor meet standard pri- mary prevention criteria for ICD implantation. One study evaluated 76 patients with document- ed cardiac sarcoidosis by PET or cardiac MRI who underwent electrophysiological study.S7.6-12 Eight (11%) were inducible for sustained VAs and re- ceived an ICD, while the rest did not receive an ICD because they were not inducible. LVEF was lower in patients with inducible VA (36.4 + 4.2% versus 55.8 + 1.5%). Over a median follow-up of 5 years, 6 of 8 patients in the group with inducible VA had VA or died, compared with 1 death in the negative An important caveat is that it remains unclear if electrophysiological study is more predic- tive than LVEF alone, because inducibility appears to reversely correlate with LVEF. Furthermore, in this study the average LVEF of the inducible patients de- clined further during the followup period.S7.6-12 4. In addition to VA and LV dysfunction, conduction abnormalities, including heart block, can also be a common manifestation of cardiac sarcoidosis. Patients with documented VA and LV dysfunction are at increased risk of cardiac events including cardiac death. One study compared outcomes in 22 patients with high-degree atrioventricular block as the initial manifestation of cardiac sar- coidosis, to 31 patients who initially presented with VT and/or HF. After a median follow up of 34 months, the patients who presented with heart block had fewer HF hospitalization, yet fatal car- diac events, including sustained VAs, were similar to those with VT and/or HF, suggesting that the risk of fatal cardiac events is high regardless of the initial clinical presentation.S7.6-13 In the same study, administration of steroids led to some clini- cal improvement, with some patients recovering conduction, yet steroid effectiveness was not uni- versal and did not seem to be protective against adverse cardiac events.S7.6-13 5. Several studies have attempted to evaluate the role of immunosuppression for reducing VA in patients with cardiac sarcoidosis, but results have been inconsistent.S7.6-14 S7.6-16 Furthermore, a worsening of VA has been reported with immunosuppressive therapy (usually glucocorti- coids) in a number of patients, including electri- cal storm developing in some within 12 months of initiating therapy.S7.6-15 One study reported a decrease of arrhythmia burden with steroid ther- apy but only when given in the early stages of the disease; those with advanced LV dysfunction did not experience benefit.S7.6-16 A systematic combined treatment approach was successful in 63% of patient in a series in which medical ther- apy included both steroids and antiarrhythmic medications, followed by radiofrequency cath- eter ablation if needed.S7.6-14 Immunosuppressive therapy may serve a dual purpose beyond arrhythmia effects as it may help stabilize dis- ease progression and prevent further deteriora- tion of LV function, although this has yet to be demonstrated in RCTs. Steroids do not appear to reverse advanced ventricular dysfunction once present, which supports the importance of early diagnosis and intervention.S7.6-1 PET scanning for assessing inflammation and scar is being increas- ingly used in sarcoidosis as well, but data sup- porting its use for guiding therapy of arrhythmias are limited. 7.6.1. Other Infiltrative Cardiomyopathies Infiltrative cardiomyopathies are a heterogeneous group of uncommon systemic diseases with associat- ed cardiac involvement. In some infiltrative cardiomy- opathies, such as Fabry s disease, VAs are uncommon. Some, such as hemochromatosis, are highly treatable especially when diagnosed early. In all cases, treat- ment of the underlying condition must accompany management of cardiac arrhythmias. Most studies of infiltrative cardiomyopathies and arrhythmias are small and observationalS7.6.1-1 but, in general, unless contraindications are present, VAs should be treated as in any other cardiomyopathy. See Section 7.6 for sarcoidosis. Until recently, cardiac amyloidosis was associated with a very poor prognosis with patients ultimately succumbing to progressive HF.S7.6.1-2 This perception is changing with advances in medical therapy for light-chain amyloidosis, which have led to improved outcomes.S7.6.1-3 Yet, decisions must be individualized because data remain too limited to al- low formal recommendations as published reports on ICD effectiveness in amyloidosis are small, observa- tional and with limited follow up.S7.6.1-4 Whether there is greater benefit to ICD placement in light chain amyloidosis versus transthyreitin-related amyloidosis remains uncertain, because most studies included mainly patients with amyloid light-chain amyloidosis for which the rate of VA may be greater and prog- CLINICAL STATEMENTS AND GUIDELINES nosis is generally worse. Whether ICDs are effective for primary prevention of SCD is uncertain, but many deaths in patients with cardiac amyloidosis do not ap- pear to be preventable by an ICD.S7.6.1-2 7.7. Heart Failure 7.7.1. HF With Reduced Ejection Fraction Recommendation for HFrEF References that support the recommendation are summarized in Online Data Supplement 35. COR LOE Recommendation IIa B-NR In patients with HFrEF who are awaiting heart transplant and who otherwise would not qualify for an ICD (eg, NYHA class IV and/ or use of inotropes) with a plan to discharge home, an ICD is reasonable.S7.7.1-1 S7.7.1-5 Synopsis Patients with HFrEF are at an increased risk for VA and SCD. The risk is increased irrespective of HFrEF SCD makes up a greater proportion of deaths in patients with milder HF symptoms and lesser proportion in those with moderate/severe HF The reported incidence of SCD varies depending on the definition used and the population studied. Although many deaths, classified as sudden, are indeed due to lethal VA, others may be due to bradyarrhythmias, pulseless electrical activity, and sud- den hemodynamic deterioration.S7.7.1-7 S7.7.1-9 Medical therapy with neurohormonal agents de- creases the risk of SCD by reducing both the incidence of VA and disease progression.S7.7.1-7,S7.7.1-10 S7.7.1-12 De- spite GDMT for HFrEF, some patients remain at risk for SCD, and an ICD may be helpful. See Sections 7.1 and 7.2 for the indications on ICDs in patients with reduced LVEF. CRT, in appropriate patients, has also been shown to reduce the incidence of SCD.S7.7.1-13 The pathophysiology of SCD in HF is complex, re- sulting from interactions between both functional and structural changes that occur in patients with HFrEF that result in increased susceptibility to SCD.S7.7.1-14 Although many of the risk factors are shared among HFrEF patients, the reason that SCD strikes a particular individual is usually unknown; however, some individu- als may have a genetic susceptibility.S7.7.1-15 Varying de- grees of myocardial fibrosis, neurohormonal activation, and increased wall stress alter the electrophysiological properties with changes in cell coupling, ionic currents (electrical remodeling), and calcium handling that likely contribute to the development of lethal VA.S7.7.1-16 Con- tributing factors extrinsic to the heart include electro- lyte abnormalities related to volume shifts and diuretic use, sympathetic activation, hemodynamic stress, and hypoxia. Recommendation-Specific Supportive Text 1. Many patients with advanced HF listed for heart transplant would not otherwise qualify for ICD given the severity of illness including NYHA class IV status and/or use of inotropic infusion. Although no randomized data on ICD use in this popula- tion exist, data from observational and large registry studies of patients awaiting heart trans- plant suggest improved survival in patients with One alternative to ICD in this population is the wearable cardioverter- The recommendation in this section is relevant to those patients without an ICD where there is a plan to discharge the patient to home to await cardiac transplant and not, for example, to those patients who remain hospitalized with no intention to discharge home until transplant occurs. For those patients with an LVAD, the decision to place an ICD is gener- ally independent of whether they are awaiting heart transplant but rather the indication in those patients is generally based on the need to treat 7.7.2. HF With Preserved Ejection Fraction Nearly half of the patients with HF have a preserved These patients tend to be older and have more comorbidities than patients with HFrEF. Howev- er, although the rate of SCD is lower in patients with HF with preserved ejection fraction (HFpEF) than in patients with HFrEF,S7.7.2-2 nearly a quarter of all deaths among patients with HFpEF are sudden.S7.7.2-3 S7.7.2-5 The challenge in preventing SCD in patients with HF- pEF is identifying which patients are at a high enough risk to benefit from preventive therapies. Studies ex- ploring noninvasive risk factors for SCD in patients with HFpEF do not identify consistent factors with the exception of ischemic heart disease.S7.7.2-2,S7.7.2-6 Consequently, there is no accepted noninvasive test to identify high-risk patients with HFpEF. Invasive risk stratification with an electrophysiological study shows promise in this population.S7.7.2-7,S7.7.2-8 This topic is cur- rently being studied in the PRESERVE-EF (Risk Strati- fication in Patients With Preserved Ejection Fraction) trial (NCT02124018). Whether to include a recommendation related to an electrophysiological study in patients with HFpEF and ischemic heart disease was carefully considered by the writing committee. However, evidence was deemed insufficient to support a formal recommendation. Still, the pros and cons of an electrophysiological study can reasonably be considered in select patients with HFpEF and ischemic heart disease who are experiencing symp- toms suggestive of a VA. CLINICAL STATEMENTS AND GUIDELINES 7.7.3. Left Ventricular Assist Device Recommendation for Patients With an LVAD References that support the recommendation are summarized in Online Data Supplement 36. COR LOE Recommendation IIa C-LD In patients with an LVAD and sustained VA, an ICD can be beneficial.S7.7.3-1 Recommendation-Specific Supportive Text 1. Patients with an LVAD have a high risk of VA, particularly those with a history of The increased risk of VA may be due to myocardial irritation from insertion of the LVAD inflow cannula, LV compression due to a suctioning effect from the LVAD, inotropic support frequently needed by some patients, and repolar- ization changes that can occur after LVAD place- ment. Although VT/VF is tolerated by some patients with an LVAD, others experience a decrease in flow as the RV is unsupported; syncope and hypoperfu- sion can result. Having an ICD can allow for prompt termination of VA before significant hemodynamic consequences occur. Data on ICDs in patients with an LVAD are from observational series. A system- atic review of 6 observational studies observed that within 7 months, 26% of patients with an LVAD The death rate was lower among patients who previously had an ICD (16% versus 32%), suggesting a 39% relative-risk reduction in all-cause mortality in an adjusted analysis.S7.7.3-1 Patients with a history of pre-LVAD VA have nearly a 10-fold risk of post-LVAD VA.S7.7.3-2 S7.7.3-4 In many of the initial studies demonstrating ICD benefit, older pulsatile LVAD devices were in use.S7.7.3-2,S7.7.3-5 Studies of ICD use with the newer, continuous flow LVADs have inconsistently shown benefit.S7.7.3-1,S7.7.3- Of note, approximately 2 of 10 patients with an LVAD develop an LVAD related infection in the first year.S7.7.3-8,S7.7.3-9 7.7.4. ICD Use After Heart Transplantation Recommendation for ICD Use After Heart Transplantation References that support the recommendation are summarized in Online Data Supplement 37. COR LOE Recommendation IIb B-NR In patients with a heart transplant and severe allograft vasculopathy with LV dysfunction, an ICD may be reasonable if meaningful survival of greater than 1 year is expected.S7.7.4-1 S7.7.4-3 Recommendation-Specific Supportive Text 1. Development of disease in the transplanted heart places some patients at an increased risk of SCD that has ranged from 10% to 35% in Both rejection and a decreased LVEF are predictors of SCD. The mechanisms underlying SCD in patients with a heart transplant include damage to the conduc- tion system itself and VA due to coronary vas- culopathy or during episodes of acute rejection. Several small case series observing appropriate ICD termination of VA suggest that an ICD can be beneficial in selected patients, particularly those with severe allograft vasculopathy, unex- plained syncope, a history of SCA, and severe LV Additionally, a patient with severe allograft vasculopathy who is being consid- ered for retransplant may be appropriate for an ICD as a bridging device. Secondary prevention indications for an ICD in patients with a heart transplant are identical to those in other patients. 7.8. Neuromuscular Disorders Recommendations for Neuromuscular Disorders References that support the recommendations are summarized in Online Data Supplement 38. COR LOE Recommendations I B-NR In patients with neuromuscular disorders, primary and secondary prevention ICDs are recommended for the same indications as for patients with NICM if meaningful survival of greater than 1 year is expected.S7.8-1,S7.8-2 IIa B-NR In patients with Emery-Dreifuss and limb- girdle type IB muscular dystrophies with progressive cardiac involvement, an ICD is reasonable if meaningful survival of greater than 1 year is expected.S7.8-3 S7.8-8 IIa B-NR In patients with muscular dystrophy, follow- up for development of cardiac involvement is reasonable, even if the patient is asymptomatic at presentation.S7.8-9 S7.8-12 IIb B-NR In patients with myotonic dystrophy type 1 with an indication for a permanent pacemaker, an ICD may be considered to minimize the risk of SCA from VT if meaningful survival of greater than 1 year is expected.S7.8-9,S7.8-13,S7.8-14 Synopsis The muscular dystrophies are a group of inherited diseas- es affecting skeletal and cardiac muscle. Some present primarily as a NICM (eg, Duchenne, Becker, and limb-gir- dle types 2C, 2F, and 2I), while others present primarily as conduction system degeneration with a variable associa- tion with cardiomyopathy (eg, myotonic dystrophy types 1 and 2, Emery-Dreifuss, limb-girdle type 1B; summa- rized in Table 9).S7.8-15 Because SCD can occur either due to VA or due to bradyarrhythmias from rapid and unpre- dictable progression of conduction system disease, the clinician is faced with the challenge of identifying those patients who would benefit from prophylactic pacemak- CLINICAL STATEMENTS AND GUIDELINES er or ICD implantation. There should be a high level of concern for those patients with muscular dystrophy who present with arrhythmia symptoms.S7.8-15 The current guideline focuses on VA and indications for implantation of an ICD. The indications for permanent pacemaker are discussed in another ACC/AHA/HRS guideline.S7.8-16 Recommendation-Specific Supportive Text 1. In general, the indications for an ICD in patients with muscular dystrophy should follow standard ICD recommendations for patients with NICM (see Section 7.2.1 on Secondary Prevention and Section 7.2.2 on Primary Prevention of SCD with NICM). A high index of suspicion for bundle- branch reentrant tachycardia is warranted in patients with myotonic dystrophy who exhibit wide QRS complex tachycardia or tachycardia- 2. In patients with Emery-Dreifuss and limb-girdle type 1B muscular dystrophies associated with Lamin A/C mutations, SCD accounts for about one third of all deaths.S7.8-4 Observational studies show a significant rate of appropriate ICD therapy in patients with cardiac conduction disorders who are gene positive for Lamin A/C mutation even if LV function is preserved.S7.8-3,S7.8-5,S7.8-17 In an obser- vational study in which 38% had isolated skeletal muscular involvement but included patients with conduction defects and other risk factors (includ- ing PR interval >240 ms, left bundle-branch block, NSVT, or bradycardia requiring a permanent pace- maker) life-threatening VAs were relatively com- mon; with 52% of patients receiving appropriate ICD therapy including approximately 40% of those patients with an LVEF 45%.S7.8-3 A study of patients who had Lamin A/C mutation, in which approximately 21% had a skeletal muscular dys- trophy phenotype, SCD and appropriate ICD ther- apy were associated with NSVT, LVEF <45%, male sex, and Lamin A/C nonmissense mutations.S7.8-4 These observational studies support the use of an ICD when a pacing indication is present and likely also when evidence of progressive cardiac involvement such as cardiac conduction defects, NSVT or reduced LVEF is present.S7.8-8 There is a paucity of data regarding the rare form of x-linked recessive Emery-Dreifuss muscular dystrophy (related to the Emerin gene mutation), but arrhythmias may be less frequent than for the Lamin A/C mutations.S7.8-15 3. Cardiac involvement can occur in a number of neuromuscular dystrophies (Table 9). To determine cardiac involvement, a 12-lead ECG and echocar- diogram are important for the initial clinical assess- ment, independent of symptom status. In general, the more extensive the cardiac involvement, includ- ing evidence of distal conduction disease, ven- tricular dysfunction, and atrial arrhythmias, the more likely a VA will occur. The initial evaluation for myotonic dystrophy patients includes ambula- tory monitoring. In asymptomatic patients, some experts advocate for annual follow-up during the concealed phase of the disease with an annual Table 9. Neuromuscular Disorders Associated With Heart Disease Muscular Dystrophy Inheritance Gene/Protein Affected Primary Cardiac Pathology Frequency of Cardiac Involvement Causes of Death Associated With Sudden Death? 