model (HCM Risk-SCD) and classic risk factors for sudden death in patients with hypertrophic cardiomyopathy and defibrillator. Europace 2016; 18:773. 69. Fern ndez A, Quiroga A, Ochoa JP, et al. Validation of the 2014 European Society of Cardiology Sudden Cardiac Death Risk Prediction Model in Hypertrophic Cardiomyopathy in a Reference Center in South America. Am J Cardiol 2016; 118:121. 70. O'Mahony C, Jichi F, Ommen SR, et al. International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM). Circulation 2018; 137:1015. 71. Leong KMW, Chow JJ, Ng FS, et al. Comparison of the Prognostic Usefulness of the European Society of Cardiology and American Heart Association/American College of Cardiology Foundation Risk Stratification Systems for Patients With Hypertrophic Cardiomyopathy. Am J Cardiol 2018; 121:349. 72. Todiere G, Nugara C, Gentile G, et al. Prognostic Role of Late Gadolinium Enhancement in Patients With Hypertrophic Cardiomyopathy and Low-to-Intermediate Sudden Cardiac Death Risk Score. Am J Cardiol 2019; 124:1286. 73. O'Mahony C, Akhtar MM, Anastasiou Z, et al. Effectiveness of the 2014 European Society of Cardiology guideline on sudden cardiac death in hypertrophic cardiomyopathy: a systematic review and meta-analysis. Heart 2019; 105:623. Topic 4952 Version 37.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 24/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate GRAPHICS Morphologic variants of hypertrophic cardiomyopathy HCM typically presents with asymmetric or localized areas of LV hypertrophy, which are diagrammed in B to J. (A) Normal LV wall thickness. (B) ASH. (C) Sigmoid septum, which is more common in older adults. (D) Midcavity hypertrophy associated with midcavity obstruction. (E) Predominantly free wall hypertrophy, an unusual pattern in HCM. (F) LV wall thinning (associated with low LV ejection fraction) and biatrial enlargement. (G) Predominantly apical LV hypertrophy. (H) Severe concentric hypertrophy with cavity obliteration. (I) Biventricular hypertrophy. (J) Mild to moderate symmetric hypertrophy. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 25/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate HCM: hypertrophic cardiomyopathy; LV: left ventricular; ASH: asymmetrical septal hypertrophy. Graphic 58156 Version 6.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 26/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical activity does not cause angina. Angina with strenuous or rapid carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational anginal pain. activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional stress, or only during pain. the few hours after awakening. Walking more than 2 blocks on on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in Marked limitation of ordinary physical Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip marked limitation of activity. Walking 1 to 2 physical activity. They are comfortable at rest. blocks on the level and climbing 1 flight in Less-than-ordinary physical activity causes normal conditions. and make bed, clean windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 27/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate dyspnea, or anginal dress without stopping) pain. but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac Inability to carry on any Patients cannot or do disease resulting in physical activity not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the anginal syndrome may listed above (specific activity scale III). be present even at rest. If any physical activity is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 28/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Myocyte disarray in hypertrophic cardiomyopathy Microscopic appearance of the myocardium in hypertrophic cardiomyopathy, stained with hematoxylin and eosin, shows myocyte disarray with an irregular arrangement of abnormal shaped myocytes that contain bizarre nuclei and surrounding areas of increased connective tissue. Courtesy of Professor Michael Davies, St. George's Hospital, London. Graphic 55914 Version 2.0 Normal endomyocardial biopsy Normal endomyocardial biopsy in longitudinal section. Courtesy of Helmut Rennke, MD. Graphic 61625 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 29/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Pyramid profile of risk stratification model currently used to identify patients a sudden cardiac death (SCD) risk who may be candidates for an implantable card defibrillator (ICD) Major and minor risk markers appear in boxes at the left. At the right are the results of ICD therapy in 730 ch adolescents, and adults assembled from two registry studies. BP: blood pressure; CAD: coronary artery disease; EF: ejection fraction; ICD: implantable cardioverter-defibril ventricular; LGE: late gadolinium enhancement; LVH: left ventricular hypertrophy; NSVT: nonsustained ventri tachycardia; SD: sudden death; VT/VF: ventricular tachycardia/ventricular fibrillation. Extensive LGE is a novel primary risk marker that can also be used as an arbitrator when conventional risk a ambiguous. SD events are uncommon after 60 years of age, even with conventional risk factors. Reproduced from: Maron B, Ommen S, Semsarian C. Hypertrophic cardiomyopathy: Present and future, with translation into contempo medicine. J Am Coll Cardiol 2014; 64:83. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 99534 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 30/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate The recognized markers of risk in HCM and their sensitivity, specificity, and positive and negative predictive accuracy (PPA and NPA) Sensitivity, Specificity, PPA, NPA, Risk factor percent percent percent percent Abnormal blood pressure [1] response: <40 years old 75 66 15 97 [2] NSVT: adult <45 years old 69 80 22 97 [3] NSVT: 21 years old <10 89 <10 85 Inducible VT/VF: high risk [4] population 82 68 17 98 [5] Syncope: <45 years old* 35 82 25 86 Family history: at least one unexplained sudden death HCM* 42 79 28 88 [5] [6] LVH 3 cm 26 88 13 95 [7] Two or more risk factors 45 90 23 96 HCM: hypertrophic cardiomyopathy; LVH: left ventricular hypertrophy; ICD: implantable cardioverter- defibrillator; NPA: negative predictive accuracy; NSVT: nonsustained ventricular tachycardia; PPA: positive predictive accuracy; VF: ventricular fibrillation; VT: ventricular tachycardia. Figures provided are for the risk of death from all causes rather than sudden death only. Figures provided are for risk of sudden death and/or appropriate ICD discharge. In this data set from Elliott and colleagues, family history and syncope were combined in order to achieve statistical significance of relative risk. 1. McKenna WJ, Franklin RC, Nihoyannopoulos P, et al. Arrhythmia and prognosis in infants, children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 1988; 11:147. 2. Maron BJ, Savage DD, Wolfson JK, et al. Prognostic signi cance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 1981; 48:252. 3. McKenna WJ, Oakley CM, Krikler DM, et al. Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J 1985; 53:412. 4. Fananapazir L, Chang AC, Epstein SE, McAreavey D. Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological ndings. Circulation 1992; 86:730. 5. McKenna W, Dean eld J, Faruqui A, et al. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol 1981; 47:532. 6. Elliott PM, Gimeno BJ, Mahon NG, et al. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001; 357:420. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 31/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate 7. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identi cation of high risk patients. J Am Coll Cardiol 2000; 36:2212. Reproduced with permission from: McKenna, WJ, Behr, ER. Hypertrophic cardiomyopathy: management, risk strati cation, and prevention of sudden death. Heart 2002; 87:169. Copyright 2002 BMJ Publishing Group, Ltd. Graphic 80617 Version 3.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 32/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Established major risk markers and risk modifiers associated with increased risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) Risk factor Comment Major risk factors Family history of HCM- SCD due to HCM in a close relative, particularly if <40 years of age, related SCD should be considered evidence for increased risk of SCD in other related family members. Syncope Unexplained syncope that, based on clinical history, appears to be due to arrhythmia (and not neurally mediated) is associated with increased SCD risk, particularly in young patients and when the event occurred close to the time of evaluation (<6 months). Massive LV hypertrophy An increased risk of SCD in patients with HCM is seen in patients with echocardiographic evidence of 30 mm wall thickness anywhere in the LV chamber. If maximal wall thickness is not clearly defined using echocardiography, additional evaluation with CMR to clarify the extent of LV wall thickening may be warranted. LV apical aneurysm Uncommon subgroup with thin-walled dyskinetic LV apex with regional scarring. LV apical aneurysm is associated with increased risk for sustained monomorphic VT and warrants consideration for ICD. End-stage HCM (LVEF <50 percent) Higher incidence of life-threatening VT associated with this uncommon phase of HCM. These patients often develop advanced heart failure at a young age and therefore are often considered for ICD as a bridge to definitive therapy with heart transplant. Risk Modifiers Extensive LGE (ie, myocardial fibrosis) occupying 15 percent of LV mass is associated with markers of disease severity and adverse outcomes including increased risk for SCD and should be considered Extensive LGE by contrast-enhanced CMR an important arbitrator to resolving ICD decision-making when uncertain following assessment with established major risk markers. Age at time of SCD risk assessment Risk of SCD is greatest in young patients <30 years old and lessens through mid-life. In patients who have achieved advanced age ( 60 years), risk of SCD is low, even in the presence of other risk factors. Defined as 3 consecutive ventricular beats at >120 beats per minute, lasting less than 30 seconds. Multiple bursts identified on ambulatory NSVT on ambulatory monitoring monitoring are associated with increased risk, particularly in younger patients. Although the data relating characteristics of NSVT to SCD risk remain poorly defined, it would be reasonable to give greater weight to increased SCD risk in those patients with HCM with NSVT that is https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 33/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate frequent (>1 burst), of long duration (>7 beats), or particularly fast (>200 beats per minute). LVEF: left ventricular ejection fraction; CMR: cardiovascular magnetic resonance; NSVT: nonsustained ventricular tachycardia; BP: blood pressure; ICD: implantable cardioverter-defibrillator; LGE: late gadolinium enhancement; LVOT: left ventricular outflow tract obstruction. Graphic 102357 Version 9.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 34/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Left ventricular wall thickness predicts sudden death in HCM In a study of 480 patients with an HCM, the incidence of sudden death during a 6.5-year follow-up was directly related to maximal wall thickness. The incidence of sudden death almost doubled for each 5 mm increase in wall thickness. HCM: hypertrophic cardiomyopathy. Data from Spirito P, Bellone P, Harris KM, et al. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000; 342:1778. Graphic 75913 Version 4.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 35/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Sudden cardiac death and risk factors in hypertrophic cardiomyopathy Kaplan-Meier estimates of the proportions of patients surviving from sudden cardiac death, appropriate ICD discharge, or resuscitated ventricular fibrillation in relation to number of risk factors in patients with obstruction. ICD: implantable cardioverter-defibrillator. Reproduced with permission from: Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular out ow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006; 27:1933. Copyright 2006 Oxford University Press. Graphic 65115 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 36/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Risk of sudden death in HCM A set of four predictors of sudden death were analyzed to develop a risk stratification algorithm in a study of 368 patients with HCM. The predictors included a history of syncope and/or a family history of sudden death, a left ventricular wall thickness 30 mm, nonsustained ventricular tachycardia on ambulatory monitoring, and an abnormal blood pressure response to exercise (refer to text). This bar graph shows the percentage of each risk factor group (zero, one, two, and three risk factors) in which patients died during follow-up (black bars = sudden death; hatched bars = congestive cardiac failure or transplant; white = all deaths). The majority of deaths were sudden, and the greatest proportion occurred in patients with multiple risk factors. HCM: hypertrophic cardiomyopathy. Data from Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identi cation of high risk patients. J Am Coll Cardiol 2000; 36:2212. Graphic 75731 Version 3.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 37/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Contributor Disclosures Martin S Maron, MD Grant/Research/Clinical Trial Support: iRhythm [Hypertrophic cardiomyopathy]. Consultant/Advisory Boards: Cytokinetics [Steering committee, REDWOOD-HCM]; Edgewise Pharmaceuticals [Myosin inhibitor for treatment of symptomatic hypertrophic cardiomyopathy]; Imbria Pharmaceuticals [Hypertrophic cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. William J McKenna, MD Consultant/Advisory Boards: Bristol Meyers Squibb [Novel pharmacological treatments for HCM]; Cytokinetics [Novel pharmacological treatments for HCM]; Health in Code [Genetic testing in inherited cardiac disease]; Tenaya Therapeutics [Gene therapy in cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. 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