JACC State-of-the-Art Review: Management of Hypertrophic Cardiomyopathy 2022 PDF

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 79, NO. 4, 2022 ª 2022 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY F...

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 79, NO. 4, 2022 ª 2022 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). JACC STATE-OF-THE-ART REVIEW Management of Hypertrophic Cardiomyopathy JACC State-of-the-Art Review Barry J. Maron, MD,a Milind Y. Desai, MD,b Rick A. Nishimura, MD,c Paolo Spirito, MD,d Harry Rakowski, MD,e Jeffrey A. Towbin, MD,f Joseph A. Dearani, MD,g Ethan J. Rowin, MD,a Martin S. Maron, MD,a Mark V. Sherrid, MDh ABSTRACT Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited primary cardiac disease, has now transformed into a contemporary highly treatable condition with effective options that alter natural history along specific personalized adverse pathways at all ages. HCM patients with disease-related complications benefit from: matured risk stratification in which major markers reliably select patients for prophylactic defibrillators and pre- vention of arrhythmic sudden death; low risk to high benefit surgical myectomy (with percutaneous alcohol ablation a selective alternative) that reverses progressive heart failure caused by outflow obstruction; anticoagulation prophylaxis that prevents atrial fibrillation-related embolic stroke and ablation techniques that decrease the frequency of paroxysmal episodes; and occasionally, heart transplant for end-stage nonobstructive patients. Those innovations have substantially improved outcomes by significantly reducing morbidity and HCM-related mortality to 0.5%/y. Palliative pharmacological strategies with currently available negative inotropic drugs can control symptoms over the short-term in some patients, but generally do not alter long-term clinical course. Notably, a substantial proportion of HCM patients (largely those identified without outflow obstruction) experience a stable/benign course without major interventions. The expert panel has critically appraised all available data and presented management insights and recommendations with concise prin- ciples for clinical decision-making. (J Am Coll Cardiol 2022;79:390–414) © 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Hypertrophic cardiomyopathy (HCM) is now recog- expression and clinical course, worldwide in its dis- nized as a relatively common contemporary and tribution, affecting both sexes and many races, cul- treatable disease, not inevitably progressive, with tures, and ethnicities. 1,2 HCM is now 60 years old potential for low mortality, and compatible with since the original pathologic description by Teare 1 normal or extended life expectancy. and the first comprehensive clinical description by INTRODUCTION the Braunwald group in the early 1960s.3 It is now diagnosed with increasing frequency at virtually any HCM is a relatively common inherited heart disease time in life from infancy to advanced age. 4-6 Esti- with diverse and complex phenotypic and genetic mated prevalence is 1:500 7 in the general population Listen to this manuscript’s From the aHCM Institute, Tufts Medical Center, Boston, Massachusetts, USA; bHCM Center, Department of Cardiovascular audio summary by Medicine, Cleveland Clinic, Cleveland, Ohio, USA; cCardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA; dPoliclinico Editor-in-Chief di Monza, Monza, Italy; ePeter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada; fHeart Institute at Dr Valentin Fuster on LeBonheur Children’s Hospital, St. Jude Children’s Research Hospital and University of Tennessee Health Science Center, JACC.org. Memphis, Tennessee, USA; gDepartment of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA; and the hHCM Program, New York University Langone Health, New York, New York, USA. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. Manuscript received September 1, 2021; revised manuscript received October 28, 2021, accepted November 2, 2021. ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2021.11.021 JACC VOL. 79, NO. 4, 2022 Maron et al 391 FEBRUARY 1, 2022:390–414 JACC Guide to HCM as rapidly and completely into consciousness ABBREVIATIONS HIGHLIGHTS AND ACRONYMS of the physician and patient communities.
Contemporary treatments have effec- Therefore, the enhanced understanding of AF = atrial fibrillation tively transformed HCM into a highly this complex disease, often mired in contro- ASA = alcohol septal ablation treatable condition with relatively low versy, represents the impetus and justification EF = ejection fraction morbidity/mortality. for assembling this consortium of experts to promote the most contemporary diagnostic HCM = hypertrophic
Sudden death in patients with HCM can cardiomyopathy and clinical management principles for HCM. be prevented through risk stratification HF = heart failure and use of ICDs. THE JACC EXPERT PANEL ICD = implantable cardioverter-defibrillator
Surgical myectomy has become a highly LGE = late gadolinium effective, low-risk operation in experi- The Expert Panel is comprised solely of cli- enhancement enced centers to relieve outflow tract nicians and thought leaders, each with high- LV = left ventricular obstruction and symptoms. est level of personal experience with HCM NYHA = New York Heart from major centers dedicated to this disease. Association This unique consensus document was the based on the disease phenotype, and higher (1:200) 8 product of a systematic overview approach producing accounting for familial transmission, subclinical evidence-based recommendations and insights that cases, and pathogenic sarcomere mutations, inferring reflect extensive practice experience (cumulative, 250 that 750,000 or more Americans may be affected by years), derived from direct interactions with HCM HCM. However, only about 100,000 patients are patients over decades, as well as knowledge acquired identified clinically, 9 suggesting that HCM is under- from personal research and the peer-reviewed diagnosed, and cardiologists may be exposed to only literature. a small proportion of patients within the broad dis- It is our goal to create a concise but comprehensive ease spectrum (“tip of the iceberg” phenomenon). best care model emphasizing decision-pathways for Not long ago considered a grim, unrelenting, and HCM scenarios commonly encountered in clinical malignant disease entity with few effective treatment practice, with reliance on the most up-to-date litera- options, the clinical narrative of HCM has evolved ture (including 2021), emphasizing the progress made substantially, 10 Over the last 20 years, in combination in diagnosis and treatment. We also wish to under- with increased clinical recognition including benign score that an often nuanced disease such as HCM may low-risk subgroups without significant symptoms or not lend itself readily to adherence with rigid disability, 1,5,6,10 effective management strategies for guideline-type categorizations that sometimes major HCM complications have emerged which cannot adequately capture disease complexity or the improve clinical course, resulting in substantially realities of clinical practice.4-6 Therefore, we have lower mortality and morbidity rates, with enhanced expressed key principles for HCM decision-making in likelihood of achieving normal longevity with good “real world” clinical language. The flexibility afforded quality of life for both adults and children with sur- by the present state-of-the-art format represents a vival possible to age 70s to 90s 1,4-6,11-19 (Central distinct advantage in this regard. Illustration, Figures 1 and 2). The present expert recommendations offer ease of Contemporary treatments and interventions, interrogation to identify decision-making principles, personalized to target adverse pathways, have signif- while not restraining the diagnosis or management of icantly reduced HCM mortality >10-fold from 6%/y individual patients. Although panel members support reported early on to 0.5%/y,1,11,15,17 currently one of the (and promote) the advantages of specialized and lowest of all major disease-related risks to living (eg, dedicated multidisciplinary HCM referral center pro- cancer, neurological disorders, and congestive heart grams as models of care,1,4-6,13 an equally important 14 failure [HF]) (Figure 3). With currently available objective is to more expansively inform cardiovas- management options, mortality specifically attribut- cular practitioners caring for most HCM patients in able to HCM is now distinctly uncommon and largely general cardiology environments outside of referral limited to a minority of nonobstructive patients with centers. progressive refractory HF.20-22 Furthermore, we recognize that no set of recom- Recognition of such clinical advances in HCM, a mendations can fully embrace all conceivable clinical condition less common in cardiovascular practice than scenarios and management decisions encountered in ischemic or valvular heart disease, may not penetrate a disease such as HCM, and implementation of 392 Maron et al JACC VOL. 79, NO. 4, 2022 JACC Guide to HCM FEBRUARY 1, 2022:390–414 C E NT R AL IL L U STR AT IO N Management Guidelines for Hypertrophic Cardiomyopathy Benign/ Stable Personalized Profiles of Prognosis in Hypertrophic Cardiomyopathy (HCM) Sudden Progressive Progressive Atrial Death Heart Failure Heart Failure Fibrillation Prevention (Obstruction) (Nonobstructive) Risk Negative Stratification Inotropes Reduced Rhythm Anticoagulation (Myosin- Preserved EF 1 of these disease pathways. ASA ¼ alcohol septal ablation; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; ICD ¼ implantable cardioverter-defibrillator; NYHA ¼ New York Heart Association. effective contemporary strategies may not yet be intuition) to resolve ambiguities by medical reasoning available for each and every patient or in all venues. that inevitably surround treatment decisions for a Indeed, HCM is a heterogeneous and relatively low nuanced disease like HCM, which unavoidably relies event rate condition comprised of numerous patient largely on nonrandomized data from observational subgroups,1 some of which may not lend itself easily registries. to available data, particularly considering the often bewildering volume of information encountered in SUDDEN DEATH PREVENTION the literature, sometimes encumbered by contradic- tory messages.1 Once considered the most common cause of sudden Our recommendations allow for personal prefer- death in the young, prevention of these events is now ences and active participation of fully informed pa- a reality by virtue of a mature risk algorithm with tients, in conjunction with physician judgment predictive markers and penetration of ICDs into this (based on knowledge, experience, acumen, and patient population. JACC VOL. 79, NO. 4, 2022 Maron et al 393 FEBRUARY 1, 2022:390–414 JACC Guide to HCM F I G U R E 1 Management Strategies for HCM A Management of Heart Failure Obstructive HCM Nonobstructive HCM Exertional dyspnea/ Exertional dyspnea/ Asymptomatic Asymptomatic fatigue fatigue Drugs Preserved EF Reduced EF 3-fold less pertrophy, diastolic dysfunction, and microvascular prevalent than progressive HF or atrial fibrillation ischemia 1 (Figure 4). 1,11,15,23,24 (AF) in HCM cohorts. Notably, implantable Subsequently, dissemination of ICDs to thou- cardioverter-defibrillators (ICDs) were introduced to sands of HCM patients resulted in a management HCM for primary prevention 20 years ago after a paradigm 11 in which there is general agreement that 25 landmark clinical study demonstrated that device these devices are highly effective in preventing therapy was effective in terminating sustained ven- sudden death in high-risk patients and have tricular tachyarrhythmias likely triggered by re-entry reduced the number of these events, thereby 394 Maron et al JACC VOL. 79, NO. 4, 2022 JACC Guide to HCM FEBRUARY 1, 2022:390–414 F I G U R E 1 Continued B Risk Stratification of SD in HCM Cardiac arrest/ sustained VT Assessment of AHA/ACC risk factors in individual patients ≥1 major No risk Grey area risk factors factors Secondary prevention ICD Shared Patient Agreement on Physician decision- perspective high risk judgement making on risk Possible Repeat risk Primary primary stratification prevention prevention annually* ICD ICD Continued on the next page significantly decreasing the HCM mortality rate [ESC], 2011 ACC/American Heart Association [AHA] (now to 0.5%/y), which also includes benign and and 2020 AHA/ACC, 2017 AHA/ACC/Heart Rhythm stable low-risk patient subsets.1,10,13-15,17 Effective- Society [HRS], 2019 enhanced ACC/AHA algorithm, ness of ICDs in hospital-based HCM populations and 2020 AHA/ACC guidelines) 4-6,27 (Table 1): coupled with apparent rarity of events in the com- including recent unexplained syncope with or munity without prior diagnosis26 suggests that without outflow obstruction; family history of HCM- HCM-related sudden death may not be as common related sudden death in a close relative; thin-walled as previously considered. akinetic-dyskinetic LV apical aneurysm with RISK STRATIFICATION. Studies of risk stratification regional scarring28 ; repetitive and/or prolonged epi- have been carried out in diverse cohorts in several sodes of nonsustained ventricular tachycardia on parts of the world, using the AHA/ACC individual risk ambulatory monitoring; extensive late gadolinium marker strategy, ie, identification of $1 conventional enhancement (LGE) (fibrosis) 29 including end-stage risk marker regarded as relevant and major within the progression; and massive left ventricular hypertro- individual patient clinical profile and sufficient to phy (LVH) (wall thickness $30 mm) (Figure 5), justify strong consideration for a primary prevention although individual patterns of LV wall thickness ICD implant (Central Illustration, Figure 1B, Tables 1 distribution do not per se predict sudden death (or and 2). Sudden death risk markers most commonly HF). No single risk marker applies to all patients associated with ICD therapy in adult HCM patients susceptible to sudden death. have been repeatedly recommended in the HCM Not uncommonly, risk stratification scenarios literature and guidelines (2003 American College of can involve a measure of ambiguity when data are Cardiology [ACC]/European Society of Cardiology insufficient to allow definitive recommendations. In JACC VOL. 79, NO. 4, 2022 Maron et al 395 FEBRUARY 1, 2022:390–414 JACC Guide to HCM F I G U R E 1 Continued C Risk for Mechanism Future AF Atrial Obstruction/mitral Diastolic HCM patients fibrosis regurgitation dysfunction without history of AF Obesity/ Primary atrial size/ Imputed clinical variables: pressure obstructive sleep myopathy Age at clinical evaluation apnea HCM-AF Age at initial HCM diagnosis Left atrial dimension score* Heart failure symptoms Quantifies individual patient Atrial Fibrillation risk of future AF in HCM Anticoagulation† Symptom burden Evaluate/treat non-HCM factors Asymptomatic or Moderate to severely minimally symptomatic symptomatic AF paroxysmal or persistent AF Obesity/ Other potential Infrequent paroxysmal Frequent paroxysmal obstructive contributors episodes episodes or persistent AF sleep apnea Rate control with Rate control with Rhythm control Ablation‡ beta-blockers beta-blockers and/or calcium and/or calcium with Either: Weight loss Hypertension, channel blockers channel blockers amiodarone CPAP hyperthyroid, disopyramide alcohol/drugs Catheter Maze procedure sotalol ablation (if myectomy dofetilide planned) Treatment such inevitable “gray zones,” ICD decision-making third of patients (Figure 6, Table 2). 1,15,16,25,32 In can rely on arbitrators including extensive LGE, contrast to ischemic heart disease, device in- coexistent ischemic heart disease, prior alcohol terventions in HCM are not associated with later septal ablation (ASA), or marked resting outflow disease-related morbidity/mortality such as HF, gradient1,11,13,15,17,29,30 (Table 1). Predictive power of multiple hospitalizations, sudden death, psychologi- individual sudden death risk factors is also influenced by cal dysfunction. 33 age, ie, with risk markers most relevant in young and Of note, timing of appropriate ICD therapy is highly middle-aged patients, but substantially less so in stable unpredictable likely attributable to the unique un- adults surviving >60 years (0.2%/y sudden death rate),31 derlying HCM electrophysiologic substrate (Figure 4), for whom prophylactic ICDs are discouraged or recom- ie, the time elapsed from implant (recognition of high mended on a case-by-case basis.11 risk status) to first ICD treatment is variable, ICD DECISIONS AND THERAPY. Notably, in studies including prolonged periods $10 years in more than from multiple centers in many countries, primary one-third of patients (range to 17 years), and without prevention ICD interventions terminating sustained objective evidence of increasing risk over that time malignant tachyarrhythmias (rapid VT/VF) occur at a interval.32 rate of 3-4%/y (at mean age 45 years), and 10%/y for A 17-year clinical practice initiative carried out in a secondary prevention (after resuscitated cardiac ar- large cohort of >2,000 consecutive patients13 used rest), with multiple interventions occurring in one- risk markers (in concert with 2020 AHA/ACC 396 Maron et al JACC VOL. 79, NO. 4, 2022 JACC Guide to HCM FEBRUARY 1, 2022:390–414 F I G U R E 2 Progress in the Management of HCM Early HCM referral cohorts 6 HCM cohorts: prior to evolution of current effective treatment 3-6%/y strategies/ interventions ICD intervention HCM-Related Mortality/Year 1.5 myectomy heart transplant OHCA/defibrillation/ hypothermia 1 1.5- 2.0%/y Present HCM cohort: contemporary treatments 0.80%/y 0.5 0.50%/y 0 General U.S. HCM-Related Mortality Population Decrease in HCM mortality over 60 years from the early studies in the 1960s and 1970s, to those before introduction of the ICD in 200025 to the present (2022). OHCA ¼ out-of-hospital cardiac arrest; other abbreviations as in Figure 1. guidelines)6 to make prospective ICD decisions for death risk in HCM does not differ by sex or race, individual patients. With a sensitivity of 95%, this although ICDs are less frequently implanted in strategy reliably identified a high proportion of at-risk minorities.35,36 ICD candidates who subsequently benefited from For primary prevention, single-chamber devices are prophylactic device therapy by terminating lethal preferred to decrease likelihood of long-term lead ventricular tachyarrhythmias at a rate 50-fold greater problems. Indeed, ICD considerations should always than the small subset who died suddenly without be weighed against the possibility of device-related ICDs,13 of whom 40% had received an ICD recom- complications, including inappropriate shocks usu- mendation with risk markers, but declined (Figure 6). ally triggered by supraventricular or sinus tachycar- The number of ICD implants needed to terminate VT/ dias, and most common in younger patients.11,15 VF in 1 patient was 6:1, similar to that from random- However, inappropriate shocks have decreased in ized defibrillator trials in compromised patients with frequency (now 1%/y) because of standardized con- ischemic heart disease. 15 servative adjustments in device programming after Decisions to implant ICDs can be challenging, 2012 based on higher rate cutoffs/thresholds and particularly when available evidence is insufficient to longer detection intervals in accord with consensus confidently assign risk level. Resolution of ambiguity recommendations.11,15,32 About 10% of patients expe- may benefit from comprehensive physician clinical rience other significant device complications, judgment/intuition and medical reasoning, as well as including lead fractures and dislodgement, pocket or transparent interactions with fully informed patients lead infections, or from lead extractions (rate, 1%/y). 32 and families weighing benefits and limitations of risk Despite potential device complications, net benefit stratification and ICDs.34 This process accounts for of prophylactic ICDs favors sudden death prevention varying personal attitudes of patients toward sudden strategies for preservation of life.1,11,15-17,28,32,37 Po- death risk and implanted devices, including per- tential adverse consequences to the venous system spectives in different countries and cultures. Sudden from indwelling leads in young high-risk HCM patients JACC VOL. 79, NO. 4, 2022 Maron et al 397 FEBRUARY 1, 2022:390–414 JACC Guide to HCM F I G U R E 3 HCM and the Risks of Living 0 10 20 30 40 50 60 70 80 90 100 Lung cancer 16.4 81.9 ALS 16.0 80.0 ESRD on hemodialysis 11.2 56.2 Ovarian cancer 10.5 52.4 Congestive heart failure 10.0 50.0 Multiple myeloma 10.1 49.5 Leukemia 7.9 39.4 AIDS 7.0 35.0 Colon/rectal cancer 7.0 34.9 Cervical cancer 6.6 33.2 All cancer (men) 6.6 33.1 All cancer (women) 6.5 32.0 Acute myocardial infarction 6.2 30.8 Dilated cardiomyopathy 6.0 30.0 Lymphoma (non-Hodgkin's) 5.7 28.6 Kidney cancer 5.2 26.0 Heart transplant 4.6 23.1 Urinary/bladder cancer 4.6 22.8 Hodgkin's disease 2.7/13.5 Breast cancer 2.0/10.2 Scleroderma 2.0/10.0 Melanoma 1.7/8.4 Cystic fibrosis 1.4/7.0 Testicular cancer 0.9/4.6 HCM 0.5/2.5 Annual Mortality Rate 5-Year Mortality Rate Annual and 5-year mortality rates for the most common chronic diseases that impact survival of the general population as of 2017. Reproduced with permission from Maron et al.14 ALS ¼ amyotrophic lateral sclerosis; ESRD ¼ end-stage renal disease; HCM ¼ hypertrophic cardiomyopathy. has created interest in the subcutaneous ICD. prevention of sudden death.5,13,39,40 As in adults with This system has now been shown to be reliable in a HCM, appropriate therapy in children occurs at 3.5%- small group of HCM patients with diverse disease 5%/y,11,15,39-42 including 1 study reporting particularly 38 phenotypes (interventions, 5%/y). Limitations high sensitivity and zero sudden deaths with ICDs. 40 include: absence of pacing function, which would In this age group, the predominant predictive sud- make transvenous implants more advisable in some den death markers reported have been: unexplained subgroups such as LV apical aneurysm, and not un- syncope, family history of HCM-related sudden common inappropriate shocks caused by T-wave death, massive LVH, and possibly nonsustained oversensing. VT.39-46 Notably, however, ESC risk scoring cannot be ICDs IN CHILDREN. Risk stratification in children used below age 16 years to identify high-risk patients, with HCM has been encumbered by lack of general even though sudden deaths not uncommonly occur in consensus for risk marker definitions and reports this age group. 4,47 from relatively small heterogeneous patient pop- Due to the paucity of relevant outcome data in ulations that may include other diseases with LVH. young rapidly growing patients with small body size, The AHA/ACC $1 individual risk marker approach has caution is advised in using the Z-score as a primary also been most effective for selection of young pa- strategy instead of absolute wall thickness to define tients for primary prevention implants and effective extreme LVH as a sudden death marker, as it could 398 Maron et al JACC VOL. 79, NO. 4, 2022 JACC Guide to HCM FEBRUARY 1, 2022:390–414 F I G U R E 4 Histopathology Underlying HCM-myocardial substrate. (A) Disorganized architecture with myocytes arranged at oblique and perpendicular angles, possibly responsible for arrhythmogenicity. (B) Interstitial (matrix) fibrosis (stained blue) responsible in part for LV thickness. (C) Vasculopathy: thick-walled narrow-lumen intramural coronary arteriole (small-vessel disease), probably the basis for microvascular ischemia. (D) Intramural arterioles within and in close proximity to replacement fibrosis shown at lower power (arrows). lead to excessive implants in young low-risk patients, and Korea), with low sensitivity, consistently failing given that therapeutic interventions in children/ad- to identify most patients who experience arrhythmic olescents most often occur at the absolute LV wall events.15,45 40 thickness threshold of $30 mm. Limitations of the ESC statistical risk score ESC RISK SCORE. The ESC has promoted an online emanate from difficulty applying a rigid mathematical decision-making risk score derived from a multivari- model to predicting sudden death for individual pa- able logistic regression model that estimates sudden tients affected by a heterogeneous heart disease, with death risk, based on a complex formula comprising 7 the inevitability of restricting physician judgment, or clinical continuous or binary variables (only 4 of which without the flexibility to evolve as new information are associated with sudden death in the literature).4,47 emerges.34 Absence of CMR data from the ESC for- Relying on the C-(concordance) statistic, the ESC mula is a major determinant of the low sensitivity of risk score attempts to distinguish high-risk vs low-risk the score, given that CMR-based markers are associ- patients who will (or will not) experience sudden ated with 20% of appropriate device therapies.15 death events over 5 years. However, this risk tool is The panel also questions the value of ESC scores associated with low sensitivity for predicting sudden for estimating risk level quantitatively in patient in- death events in both adults and children (ie, sensi- teractions,6 given the imprecision in annual mortality tivity only 33%, compared with 95% for the AHA/ACC estimates and difficulty patients have understanding individual risk marker strategy), theoretically leaving and incorporating such numerical values into their many patients unprotected without ICDs. 11,13,15,45 personal clinical circumstance. The ESC risk score has not been tested prospec- Nevertheless, the specificity attributable to the ESC tively on an external independent HCM population score suggests it could modestly reduce the number for individual patient outcome and ICD efficacy. of implants in low-risk patients mitigating excessive However, it has been repeatedly applied retrospec- ICD use, albeit at the cost of lower sensitivity for tively to adult and childhood populations of known identifying high-risk patients eligible for ICDs.4,47 It is clinical outcome (in the United States, Canada, China, impractical to combine ESC scores with an individual JACC VOL. 79, NO. 4, 2022 Maron et al 399 FEBRUARY 1, 2022:390–414 JACC Guide to HCM T A B L E 1 Major Clinical Markers Recommended for Current HCM Risk Stratification a Family history of sudden deathb Sudden death judged definitively or likely caused by HCM, generally considered when occurring in $1 first-degree, or other close relatives, 130/min, usually over 24-48 h of continuous ambulatory ECG monitoring. LGE (fibrosis) Diffuse and extensive LGE distribution representing fibrosis, either quantified or estimated by visual inspection as comprising about $ 15% of LV mass, either alone or in association with other risk markers, and a likely source of ventricular tachyarrhythmias.f End-stage HCM Systolic dysfunction with ejection fraction