reason, clinical decisions about risk for sudden death and need for primary prevention ICD are not made based on the results of genetic testing. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) LV outflow tract (LVOT) gradient The majority of natural history studies involving patients with HCM have failed to show an association between LVOT gradient and adverse prognosis [20,44,46,47,53]. Two large studies, however, have shown a weak association of LVOT gradients with overall disease-related mortality and sudden death [54,55]. The impact of LVOT obstruction on overall morbidity (ie, HF symptoms and risk for atrial fibrillation) is discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.) In a multicenter, multinational study of 1101 patients (273 [25 percent] with resting LVOT gradient 30 mmHg) followed for a mean of six years, the probability of HCM- related death and of SCD was slightly greater in those with LVOT gradient of at least 30 mmHg (relative risk [RR] 2) [55]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 12/38 7/6/23, 3:40 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate In a single-center study of 917 patients (288 [31 percent] with resting LVOT gradient 30 mmHg) followed for a median of 61 months, survival free from mortality/transplant was significantly lower in patients with LVOT gradients (87 versus 90 percent), as was survival free from sudden death/ICD discharge (91 versus 96 percent) [54]. LVOT obstruction was independently associated with SCD, and there was a significant trend towards lower sudden death/ICD survival in patients with increasing LVOT obstruction. The incidence of SCD in patients with obstruction also varies substantially based upon the number of additional risk factors ( figure 4) [54]. For patients with an outflow gradient 30 mmHg but no additional risk factors, the annual incidence of SCD or ICD discharge was low. There are also a number of practical limitations to using LVOT gradient as a clinical risk factor for sudden death. Gradients are present in large numbers of patients, which would ultimately lead to significant overtreatment with ICDs in this disease. Additionally, gradients can be abolished and/or significantly mitigated with drugs or invasive septal reduction therapy. Nonrandomized retrospective cohort studies suggest that risk of SCD or appropriate ICD shocks is very low following septal myectomy [56,57]. However, surgical myectomy in asymptomatic or mildly symptomatic patients is not indicated solely as a therapy to decrease sudden death risk. In contrast, septal ablation has not been demonstrated to reduce SCD or ICD discharge rates. However, for those patients in whom risk remains ambiguous after assessment with the conventional sudden death risk factors, the presence of a high LVOT gradient can be used as a potential arbitrator to help resolve difficult ICD decision-making. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Nonpharmacologic treatment of LV outflow tract obstruction'.) Impact of number of risk factors It is reasonable to consider ICD in patients with one major risk factor, since SCD risk is increased. Decisions about high-risk status in patients with one risk factor should be individualized based on the strength of the specific risk factor and the individual patient situation. The presence of two or more risk factors for SCD is associated with even greater SCD risk. In patients in whom sudden death risk remains uncertain after assessment with the major risk markers or who are uncertain about pursuing ICD therapy, the presence of a risk modifier may be associated with additional sudden death risk and therefore may help resolve ICD decision-making. Identification of high-risk patients may be improved by using multiple factors [6,54,58,59]. In a study of 368 patients (mean age 37 years) who were followed for a mean of 3.6 years, estimated https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 13/38 7/6/23, 3:40 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate six-year SCD-free survival was associated with the number of risk factors ( figure 5) [6]: Zero risk factors (55 percent of the cohort) 95 percent survival One risk factor (33 percent of the cohort) 93 percent survival Two or three risk factors (12 percent of the cohort) 72 percent survival Data from a multicenter registry of ICDs in patients with HCM published in 2007 suggested that a single risk factor may be sufficient justification for consideration of ICD implantation [60]. Subsequently, in a 2019 single-center study of 2094 consecutive patients evaluated over a 17- year period at a tertiary HCM referral center, 527 patients were implanted with a primary prevention ICD based on clinical evaluation and the presence of one or more high-risk markers [61]. Cumulative five-year likelihood of appropriate ICD intervention was 10.5 percent, with 82 primary prevention ICD recipients (15.6 percent) experiencing VT or VF requiring ICD therapy, whereas only five patients (0.3 percent) without an ICD experienced SCD (including two patients in whom primary prevention ICD was declined by the patient). Data in low-risk patients are limited, but those meeting the following profile probably have an incidence of SCD of <0.5 percent per year [14,16,62]: None of the five major risk factors No or only mild symptoms of HF Left atrium 45 mm LV wall thickness <20 mm LV outflow gradient <50 mmHg Risk prediction model While the risk of SCD in patients with HCM can be estimated from large populations, individualized risk prediction offers the hope of the most accurate risk assessment and appropriate interventions. Given the complexity of SCD risk assessment in patients with HCM and the mixed data on the HCM Risk-SCD calculator, we feel that additional studies are warranted to further validate and refine this risk model in other HCM populations, along with the need for additional comparisons with the current United States guideline-based approach using a number of noninvasive risk markers [63,64]. As with risk prediction in any situation, the ability to discriminate patients with HCM at risk of SCD has been most successful in patients deemed at higher risk. In a retrospective cohort study involving 3675 patients from six European centers (2082 in the development cohort and 1593 in the validation cohort) with a median follow-up of 5.7 years, the primary outcome of SCD or appropriate ICD shock occurred in 198 patients (118 patients with SCD, 27 with aborted SCD, and 53 with appropriate ICD shock) [65]. Using the derived model (which incorporated parameters of age, maximal LV wall thickness, left atrial diameter, LVOT https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 14/38 7/6/23, 3:40 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate gradient, family history of SCD, NSVT, and unexplained syncope), which can be accessed online, investigators predicted that for every 16 ICDs implanted, one patient would be saved from SCD every five years. Subsequent studies looking at validation of the HCM Risk-SCD calculator have reported widely varying results in terms of the accuracy of the score for predicting SCD [66-69]. In the largest reported validation cohort (International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy [EVIDENCE-HCM] cohort), which included 2147 patients with HCM and no prior history of SCD from 14 centers in the United States, Europe, the Middle East, and Asia, 44 patients experienced an SCD event (defined as SCD, successful resuscitation from SCA, or appropriate ICD intervention for VT/VF) over the five-year follow- up (0.5 percent per year) [70]. Among patients with high predicted risk ( 6 percent, n = 297), the five-year incidence of SCD was significantly higher (8.9 percent) compared with patients with intermediate (4 to 6 percent, n = 326) or low (<4 percent, n = 1524) predicted risk (five-year incidence 1.8 and 1.4 percent, respectively). In a cohort of 706 patients with HCM and no prior history of SCD who were seen at two European referral centers, 42 patients (5.9 percent) experienced an SCD event (defined as SCD, successful resuscitation from SCA, or appropriate ICD intervention for VT/VF) over the five-year follow-up (1.2 percent per year) [66]. Patients with an SCD event had significantly greater estimated five-year risk of SCD using the HCM Risk-SCD calculator (4.9 versus 2.8 percent in patients without SCD), with the calculator resulting in improved risk assessment compared with 2003 and 2011 society guidelines. The HCM Risk-SCD calculator has also been retrospectively applied to a cohort of 2094 patients with HCM seen at a large United States referral center [61]. The HCM Risk-SCD calculator accurately predicted patients at low risk without SCD events (92 percent specificity), but the sensitivity of a high-risk classification was only 34 percent for predicting SCD events, suggesting that the majority of patients at risk for SCD would have been missed using only the calculator to quantify risk. In contrast, the enhanced 2011 ACC/AHA guideline criteria had sensitivity and specificity of 87 and 78 percent, respectively, suggesting greater likelihood of preventing SCD with an ICD at the expense of slightly higher use of ICDs in patients without SCD events. The HCM Risk-SCD model and the conventional risk factors from the American College of Cardiology/American Heart Association (ACC/AHA) guidelines were compared in a cohort of 288 patients (mean age 52 years, 66 percent male, 25 percent with LVOT obstruction 30 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 15/38 7/6/23, 3:40 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate mmHg) with HCM from a single referral center in the United Kingdom, among whom 14 patients experienced SCD or equivalent (resuscitation from cardiac arrest or appropriate ICD shock for VF or VT >200 beats per minute) over a mean follow-up of 5.6 years [71]. Compared with the conventional ACC/AHA risk factors, the HCM Risk-SCD model more accurately predicted low-risk patients who did not require an ICD (220 of 274 patients [82 percent] compared with 157 of 274 patients [57 percent]) but also failed to identify a significantly greater number of high-risk patients who experienced SCD or equivalent (6 of 14 patients [43 percent] compared with 1 of 14 patients [7 percent]). The presence of LGE identified on CMR may aid in further risk stratifying patients following calculation of the HCM Risk-SCD score. Among 354 patients with HCM and calculated HCM Risk SCD score suggesting low to intermediate five-year risk (<6 percent), patients with LGE extent 10 percent had much higher five-year rates of hard cardiac events including SCD, resuscitated cardiac arrest, appropriate ICD therapies, and sustained VT (23 versus 3 percent) [72]. (See 'Risk modifiers' above.) In a 2019 meta-analysis which included 7291 patients with HCM (including the original HCM Risk- SCD cohort and five subsequent cohorts), 70 percent of patients were identified as low risk, 15 percent as intermediate risk, and 15 percent as high risk [73]. In total, 184 SCD events occurred, with 68 percent occurring in the intermediate and high risk (prevalence of SCD events 1, 2.4, and 8.4 percent in low, intermediate, and high risk groups, respectively). The majority of patients with HCM are stratified as low risk for SCD, but the greatest number of appropriate ICD therapies occur in this low-risk group. Conversely, patients identified as being at high risk of SCD are more likely to receive an appropriate ICD shock, but overall this group receives the lowest number of appropriate ICD therapies. However, proportionally, since the denominator is much larger in low-risk patients, the percentage of patients with ICD shocks is greatest in the high-risk group. This essentially means that, similar to other risk prediction scenarios, the risk score discriminates best those patients with HCM at highest risk for sudden death, but may fail to identify a significant number of patients who have low-risk scores but who are at high risk for sudden death. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 16/38 7/6/23, 3:40 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)") Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Patients with hypertrophic cardiomyopathy (HCM) are prone to ventricular arrhythmias. Ventricular arrhythmias can range from isolated ventricular premature beats (VPBs) to nonsustained ventricular tachycardia (NSVT) to sustained VT and ventricular fibrillation (VF). While the frequency of ventricular arrhythmias is highly variable, the annual incidence of sudden cardiac death (SCD) in the clinically identified general HCM patient population is approximately 1 percent. (See 'Introduction' above and 'Epidemiology' above.) The presentation of ventricular arrhythmias in patients with HCM is highly variable, ranging from an absence of symptoms to palpitations to SCD. Most patients with VPBs or NSVT will be asymptomatic or have intermittent palpitations, while on rare occasions SCD can be the initial presentation of sustained VT or VF. (See 'Clinical manifestations' above.) Since the underlying abnormal myocardial substrate in HCM can evolve over time, all patients with known or suspected HCM should undergo serial evaluations for SCD risk stratification, including history and physical examination, interim family history, echocardiography, ambulatory electrocardiographic (ECG) monitoring, and exercise testing (on a case-by-case basis). With the emerging role of extensive late gadolinium https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 17/38 7/6/23, 3:40 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate enhancement (LGE) informing risk assessment, contrast-enhanced cardiac magnetic resonance (CMR) should also be considered. It is reasonable to repeat SCD risk assessment every 12 to 24 months in patients who remain at risk and potentially eligible for an implantable cardioverter-defibrillator (ICD) for primary prevention of SCD. (See 'Evaluation' above.) Major risk factors and risk modifiers associated with an increased risk of SCD in patients with HCM include (see 'Risk stratification' above): Prior or sustained ventricular arrhythmias. Family history of close relative with SCD due to HCM. Syncope suspected to be arrhythmic in origin, particularly when occurring relatively recently to time of evaluation and in younger patients. Multiple bursts of NSVT on ambulatory ECG monitoring. Massive LV hypertrophy 30 mm anywhere in LV wall. LV apical aneurysm. End-stage HCM with LV ejection fraction <50 percent. The results of contrast-enhanced CMR with extensive LGE (ie, myocardial scarring) can be used to help arbitrate ICD decision-making if risk remains ambiguous or uncertain following conventional risk stratification assessment. Age at time of sudden death risk assessment ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Perry Elliott, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Adabag AS, Casey SA, Kuskowski MA, et al. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. 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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, 3:40 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, 3:40 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, 3:40 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, 3:40 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, 3:40 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, 3:40 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.