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Circulation. 2018;138:e272–e391. DOI: 10.1161/CIR.0000000000000549 September 25, 2018 e317 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 sarcomereassociated 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 involved.S7.4-13–S7.4-15,S7.4-18,S7.4-19,S7.4-22 A single mutation 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 outcomes.S7.4-13,S7.4-34,S7.4-48 When genetic testing reveals a mutation in the index patient, ascertainment of genetic status in first- and second-degree relatives can be predictive of risk for developing HCM.S7.4-14,S7.4-49 Relatives with overt HCM will have the same pathogenic HCM mutation as the index patient. 6.	 Several studies have described an independent relationship between hypertrophy and SCD when the magnitude of hypertrophy is ≥30 mm.S7.4-2,S7.4-3,S7.4-23,S7.4-24 Risk does not abruptly increase for patients with a ≥30 mm wall thickness, but it rather increases in a linear mannerS7.4-24 and appears to carry more prognostic significance in younger patients. A young adult with hypertrophy that approaches 30 mm may have similar or greater SCD risk than an older patient with maximum 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 experienced SCD presumably caused by HCM. Family history appears to be an independent predictor of SCD although the supportive studies are small and observational.S7.4-25,S7.4-26 Syncope can be neurally mediated or medication-related as well as due to VA and requires a careful evaluation before 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 associated with SCD risk only when it occurred within the past 6 months but not if the most episode occurred >5 years previously.S7.4-8 7.	 Although sustained VT is clearly associated with SCD, the data for NSVT are less robust. Most studies do not support NSVT as an independent risk factor for SCD in patients with HCM,S7.4-2,S7.4-26,S7.4-27 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; however, 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,

S7.4-27; therefore, use of an ICD is more appropriate if risk modifiers are also present. An abnormal blood pressure response to exercise has also been associated 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 significance 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 observational studies and is an option for patients for whom an ICD is not feasible due to limited expectation for survival or patient preference.S7.4-30,S7.4-31 10.	 Approximately one third of consecutive patients with HCM undergoing an electrophysiological 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 bundle branch reentry. 11.	 SCD may cluster in certain families with HCM, and the possibility that specific sarcomere mutations may confer SCD risk has been hypothesized. 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

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