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Abstract Hypertrophic cardiomyopathy (HCM) is characterized by substantial genetic and phenotypic heterogeneity, leading to considerable diversity in clinical course including the most common cause of sudden death in young people and a determinant of heart failure symptoms in patients of any age. Traditionally, two-dimensional echocardiography has been the most reliable method for establishing a clinical diagnosis of HCM. However, cardiovascular magnetic resonance (CMR), with its high spatial resolution and tomographic imaging capability, has emerged as a technique particularly well suited to characterize the diverse phenotypic expression of this complex disease. For example, CMR is often superior to echocardiography for HCM diagnosis, by identifying areas of segmental hypertrophy (ie., anterolateral wall or apex) not reliably visualized by echocardiography (or underestimated in terms of extent). High-risk HCM patient subgroups identified with CMR include those with thin-walled scarred LV apical aneurysms (which prior to CMR imaging in HCM remained largely undetected), end-stage systolic dysfunction, and massive LV hypertrophy. CMR observations also suggest that the cardiomyopathic process in HCM is more diffuse than previously regarded, extending beyond the LV myocardium to include thickening of the right ventricular wall as well as substantial morphologic diversity with regard to papillary muscles and mitral valve. These findings have implications for management strategies in patients undergoing invasive septal reduction therapy. Among HCM family members, CMR has identified unique phenotypic markers of affected genetic status in the absence of LV hypertrophy including: myocardial crypts, elongated mitral valve leaflets and late gadolinium enhancement. The unique capability of contrast-enhanced CMR with late gadolinium enhancement to identify myocardial fibrosis has raised the expectation that this may represent a novel marker, which may enhance risk stratification. At this time, late gadolinium enhancement appears to be an important determinant of adverse LV remodeling associated with systolic dysfunction. However, the predictive significance of LGE for sudden death is incompletely resolved and ultimately future large prospective studies may provide greater insights into this issue. These observations underscore an important role for CMR in the contemporary assessment of patients with HCM, providing important information impacting diagnosis and clinical management strategies.

Background: In hypertrophic cardiomyopathy (HCM), 48-hour ambulatory monitoring has been standard practice to detect nonsustained ventricular tachycardia (NSVT), a sudden death risk marker. Extended-wear ambulatory electrocardiographic (ECG) devices have more recently used for monitoring patients with HCM., Objective: We aimed to evaluate NSVT burden identified with continuous ambulatory monitoring for up to 2 weeks compared with initial 48 hours., Methods: 236 consecutive patients with HCM (49 ± 12 years) underwent 14-day continuous ambulatory monitoring (Zio XT, iRhythm Technologies, San Francisco, CA); diagnostic yield of NSVT compared for initial 48 hours vs extended for 14 days., Results: Of the 236 patients, 114 (48%) had ≥ 1 runs of NSVT (median 2) over 14 days. Median length of NSVT was 7 beats (range: 3 to 67) at rates of 120 to 240 beats per minute (bpm) (median, 167 bpm). In 42 of the 114 patients (37%), initial NSVT occurred ≤ 48 hours and in 72 (63%) only during the extended monitoring period (3 to 14 days). Diagnostic yield for detecting NSVT over 14 days was 2.7-fold greater than ≤ 48 hours (P < .001). NSVT judged at higher risk (≥ 8 beats, > 200 bpm, ≥ 2 runs in consecutive 2-day period) was identified more frequently during extended monitoring, diagnostic yield over 14 days was 3-fold greater than ≤ 48 hours (P < .001)., Conclusion: In HCM, NSVT episodes are frequent; however, in most patients, both NSVT and higher-risk NSVT were not detected during initial 48 hours and were confined solely to extended monitoring period. These data support additional clinical studies to evaluate the significance of NSVT on extended monitoring on sudden death risk in HCM., Competing Interests: Disclosures Dr Maron has served as consultant for Cytokinetics, iRhythm (with grant), Imbria Pharmaceuticals, and TAKEDA Pharmaceuticals (with grant). Dr Rowin has received research funding from Pfizer and iRhythm. Dr Hsu and Dr Crosson are employees of iRhythm Technologies. Dr Turakhia has received research grants from Bristol Myers Squibb, American Heart Association, Bayer, Gilead Sciences, and the Food and Drug Administration and has received equity from iRhythm, Connect America, Forward, Evidently, PocketRN, AliveCor, and Hippocratic.ai. Dr Turakhia is an employee and corporate officer of iRhythm Technologies Inc. The other authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Percutaneous left atrial appendage closure (LAAC) is an effective alternative strategy for stroke prevention in patients with atrial fibrillation (AF) at high risk for bleeding with anticoagulation (AC). Efficacy of this strategy in hypertrophic cardiomyopathy (HCM) remains uncertain., Objective: The study aimed to compare risk of stroke in HCM-AF patients treated with LAAC with those treated with AC., Methods: By use of the TriNetX Global Research Network, HCM-AF patients from 2015 to 2024 were assigned to categories of treatment with LAAC and treatment solely with AC and observed for 3 years for ischemic stroke, systemic embolism, and all-cause mortality. Propensity score matching was used to limit confounders., Results: Of 14,867 HCM-AF patients identified, 364 (2.5%) were treated with LAAC vs 14,503 (97.5%) treated with AC. HCM LAAC patients were older (72 vs 67 years; P < .001) and had more comorbidities and more prior bleeding events, including higher rate of prior gastrointestinal bleeding (68% vs 18%; P < .001), compared with HCM patients treated solely with AC. After propensity score matching, there was no baseline difference between groups including prior bleeding events (P > .05). During follow-up, HCM patients treated with LAAC had higher rates of ischemic stroke (13% vs 8%; hazard ratio, 1.9; P = .006) and systemic embolism (14% vs 9%; hazard ratio, 1.8; P = .006) but no difference in mortality compared with matched HCM patients receiving AC., Conclusion: These real-world data do not support percutaneous LAAC in HCM-AF patients as the primary treatment strategy during long-term AC to reduce stroke risk. However, LAAC may remain a reasonable option for HCM-AF patients who are unable to tolerate AC because of prohibitive bleeding risk., Competing Interests: Disclosures Martin S. Maron: consultant for Cytokinetics, iRhythm (with grant), Imbria Pharmaceuticals, Takeda Pharmaceuticals (with grant). Ethan J. Rowin: research funding from Pfizer, iRhythm. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with hypertrophic cardiomyopathy (HCM) are at risk of sudden death, and individuals with ≥1 major risk markers are considered for primary prevention implantable cardioverter-defibrillators. Guidelines recommend cardiac magnetic resonance (CMR) imaging to identify high-risk imaging features. However, CMR imaging is resource intensive and is not widely accessible worldwide., Objective: The purpose of this study was to develop electrocardiogram (ECG) deep-learning (DL) models for the identification of patients with HCM and high-risk imaging features., Methods: Patients with HCM evaluated at Tufts Medical Center (N = 1930; Boston, MA) were used to develop ECG-DL models for the prediction of high-risk imaging features: systolic dysfunction, massive hypertrophy (≥30 mm), apical aneurysm, and extensive late gadolinium enhancement. ECG-DL models were externally validated in a cohort of patients with HCM from the Amrita Hospital HCM Center (N = 233; Kochi, India)., Results: ECG-DL models reliably identified high-risk features (systolic dysfunction, massive hypertrophy, apical aneurysm, and extensive late gadolinium enhancement) during holdout testing (c-statistic 0.72, 0.83, 0.93, and 0.76) and external validation (c-statistic 0.71, 0.76, 0.91, and 0.68). A hypothetical screening strategy using echocardiography combined with ECG-DL-guided selective CMR use demonstrated a sensitivity of 97% for identifying patients with high-risk features while reducing the number of recommended CMRs by 61%. The negative predictive value with this screening strategy for the absence of high-risk features in patients without ECG-DL recommendation for CMR was 99.5%., Conclusion: In HCM, novel ECG-DL models reliably identified patients with high-risk imaging features while offering the potential to reduce CMR testing requirements in underresourced areas., Competing Interests: Disclosures Dr Maron is a consultant for Cytokinetics, iRhythm, Imbria Pharmaceuticals, and Takeda Pharmaceuticals. Dr Rowin has received research funding from Pfizer and iRhythm. The remaining authors have nothing to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818)., Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM trial is funded by Cytokinetics, Incorporated. Representatives of Cytokinetics have been involved in the design and conduct of the study reported in this manuscript. Dr Coats has received speaker fees from Alnylam and Roche, and advisory fees from Cytokinetics. Dr Maron has received consultant/advisor fees from Imbria and Takeda, and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Dr Olivotto has received Speakers Bureau fees from Boston Scientific, Amicus, and Novartis; consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, and Rocket Pharma; and research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Lee has received research grants to his institution from AstraZeneca and Boehringer Ingelheim, and Clinical Endpoint Committee fees from Bayer. Dr Arad has received consultant and lecture fees from Bristol Myers Squibb. Dr Cardim is on the advisory boards for Bristol Myers Squibb and Cytokinetics. Dr Düngen has received grants from Novartis, CSL Behring, and Cytokinetics. Dr Garcia-Pavia has received Speakers Bureau fees from Pfizer, AstraZeneca, NovoNordisk, Bristol Myers Squibb, BridgeBio, Ionis, and Alnylam; consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neurimmune, BridgeBio, Attralus, Intellia, Rocket Pharma, Lexeo Therapeutics, and AstraZeneca; and research/educational grants to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, and Alnylam. Dr Hagège has received consultant/advisor fees from Alnylam, Amicus Therapeutics, Bayer, MyoKardia/Bristol Myers Squibb, Pfizer, and Sanofi Genzyme; and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, and R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; honoraria for advisory boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Michels’ institution has received a research grant from Bristol Myers Squibb. Dr Michels has received consultant/advisor fees from Cytokinetics and Bristol Myers Squibb/Myokardia; and Speakers Bureau fees from Bristol Myers Squibb and Pfizer. Dr Oreziak has received investigator fees from Bristol Myers Squibb/MyoKardia; consultant/advisor fees from Biotronik Polska, Abbott Polska; and traveling fees from Hammermed. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. Dr Tfelt-Hansen is a consultant for Leo Pharma, MicroPort, and Johnson and Johnson. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Dr Heitner, Dr Jacoby, Dr Kupfer, Dr Malik, Dr Meng, and Ms Wohltman are employees of Cytokinetics, Incorporated and hold stock in Cytokinetics, Incorporated. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Lexicon, Alnylam, Haya, Intellia, and Ionis; and research grants from Ionis, Akcea, Pfizer, Cytokinetics, Ultromics, and the Wheeler Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The optimal management of hypertrophic cardiomyopathy (HCM) patients with postoperative atrial fibrillation (POAF) after surgical myectomy remains unknown. We sought to investigate the association between POAF and atrial fibrillation (AF) or cardioembolic events during follow-up to bridge this gap., Methods: Patients undergoing surgical myectomy at 2 HCM referral centres in North America from 2002 to 2020 were included in this study. Patients with preoperative AF were excluded. POAF was defined as any episode of AF within 30 days after surgery., Results: Of 1176 patients, 375 (31.9%) had POAF. Age (adjusted hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.03-1.06; P < 0.001), premyectomy left atrial diameter (LAD; adjusted HR 1.6, 95% CI 1.32-2.02; P < 0.001), and smoking (adjusted HR 1.60, 95% CI 1.17-2.20; P = 0.001) were associated with POAF on multivariable analysis. Of 934 patients with follow-up data, of duration 4.3 ± 4.1 years, AF was detected in 86 (9.2%). Only POAF (HR 4.20, 95% CI 2.44-7.23; P < 0.001), previous history of stroke (HR 4.81, 95% CI 1.63-14.17; P = 0.01), and postmyectomy LAD (HR 1.80, 95% CI 1.21-2.70; P = 0.004) were associated with AF incidence during follow-up. Cardioembolic events occurred in only 15 patients (1.6%). POAF was not associated with increased cardioembolic risk, with only 3 patients with POAF suffering such an event, all more than 4 years after surgery., Conclusions: POAF is common in HCM patients undergoing myectomy and is a predictor of AF during follow-up. Over long-term follow-up, cardioembolic events are uncommon. These findings suggest that routine long-term anticoagulation for all HCM patients with postmyectomy AF is not justified after the initial postoperative period., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is a heterogeneous albeit treatable cardiac disease of variable severity, with the potential for heart failure, atrial fibrillation and arrhythmic sudden death, characterized by otherwise unexplained left ventricular (LV) hypertrophy and affecting all ages and races. Over the last 30 years, several studies have estimated the prevalence of HCM in the general population, employing echocardiography and cardiac magnetic resonance imaging (CMR), as well electronic health records and billing databases for clinical diagnosis. The estimated prevalence in the general population based on the disease phenotype of LV hypertrophy by imaging is 1:500 (0.2%). This prevalence was initially proposed in 1995 in the population-based CARDIA study employing echocardiography, and more recently confirmed by automated CMR analysis in the large UK Biobank cohort. The 1:500 prevalence appears most relevant to clinical assessment and management of HCM. These available data suggest that HCM is not a rare condition but likely underdiagnosed clinically and by extrapolation potentially affects about 700,000 Americans and possibly 15 million people worldwide., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiologic features in HCM when relying on resting invasive hemodynamic data alone., Research Question: Do structural changes to the lung vasculature clarify PH pathophysiologic features in patients with HCM with progressive heart failure?, Study Design and Methods: Clinical data and ultrarare lung autopsy specimens were acquired retrospectively from the National Institutes of Health (1975-1992). Patients were included based on the availability of lung tissue and recorded mPAP. Discarded tissue from rejected lung donors served as control specimens. Histomorphology was performed on pulmonary arterioles and veins. Comparisons were calculated using the Student t test and Mann-Whitney U test; Pearson correlation was used to assess association between morphometric measurements and HCM cardiac and hemodynamic measurements., Results: The HCM cohort (n = 7; mean ± SD age, 43 ± 18 years; 71% men) showed maximum mean ± SD LV wall thickness of 25 ± 2.8 mm, mean ± SD outflow tract gradient of 90 ± 30 mm Hg, median mPAP of 25 mm Hg (interquartile range [IQR], 6 mm Hg), median pulmonary artery wedge pressure (PAWP) of 16 mm Hg (IQR, 4 mm Hg), and median pulmonary vascular resistance of 1.8 Wood units (WU; IQR, 2.4 WU). Compared with control samples (n = 5), patients with HCM showed greater indexed pulmonary arterial hypertrophy (20.7 ± 7.2% vs 49.7 ± 12%; P < .001) and arterial wall fibrosis (11.5 ± 3.4 mm vs 21.0 ± 4.7 mm; P < .0001), which correlated with mPAP (r = 0.84; P = .018), PAWP (r = 0.74; P = .05), and LV outflow tract gradient (r = 0.78; P = .035). Compared with control samples, pulmonary vein thickness was increased by 2.9-fold (P = .008) in the HCM group, which correlated with mPAP (r = 0.81; P = .03) and LV outflow tract gradient (r = 0.83; P = .02)., Interpretation: To the best of our knowledge, these data demonstrate for the first time that in patients with obstructive HCM, heart failure is associated with pathogenic pulmonary vascular remodeling even when mPAP is elevated only mildly. These observations clarify PH pathophysiologic features in HCM, with future implications for clinical strategies that mitigate outflow tract obstruction., (Published by Elsevier Inc.)

Syncopal events in patients with hypertrophic cardiomyopathy (HCM) are of concern as they are a vital consideration in algorithms for risk stratification for sudden cardiac death (SCD) and ICD implantation. However, the cause of syncope is often under-investigated and/or unexplained. Current syncope guidelines do not provide a detailed definition of unexplained syncope. To address this important gap, an international panel of experts in the field of both syncope and HCM wrote a consensus document with the aim of providing practical guidance for the diagnosis and management of syncope in patients with HCM., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The sudden death (SD) risk stratification algorithm in hypertrophic cardiomyopathy (HCM) has evolved, underscored recently by novel cardiac magnetic resonance (CMR)-based risk markers (left ventricular apical aneurysm, extensive late gadolinium enhancement, and end-stage disease with systolic dysfunction) incorporated into the 2020 American Heart Association (AHA)/American College of Cardiology (ACC) HCM guidelines., Objective: The purpose of this study was to assess the specific impact of newer, predominantly CMR-based risk markers in a large multicenter HCM population that underwent primary prevention implantable cardioverter-defibrillator (ICD) implants., Methods: Longitudinal study of 1149 consecutive HCM patients from 6 North American and European HCM centers prospectively judged to be at high SD risk based on ≥1 AHA/ACC individual risk markers and prophylactically implanted with an ICD was performed. European Society of Cardiology (ESC) risk score was retrospectively analyzed with respect to the known clinical outcome., Results: Of 1149 patients with an ICD, 162 (14%) experienced device therapy terminating ventricular tachycardia/ventricular fibrillation 4.6 ± 4.2 years after implant. CMR-based markers solely or in combination led to ICD implantation in 49 of the 162 patients (30%) experiencing device therapy. Particularly low ESC scores (<4%/5 years) would have excluded an ESC ICD recommendation for 67 patients who nevertheless experienced appropriate ICD therapy, including 26 with the CMR-based risk markers not part of the ESC formula., Conclusion: Identification and incorporation of novel guideline-supported CMR-based risk markers enhance selection of HCM patients for SD prevention with ICDs. Absence of CMR-based markers from the ESC risk score accounts, in part, for it not identifying many HCM patients with SD events. These data support inclusion of CMR as a routine part of HCM patient evaluation and risk stratification., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited myocardial disorder, once regarded as largely untreatable with ominous prognosis and most visibly as a common cause of sudden death (SD) in the young. Over the last several years, HCM has been transformed into a contemporary treatable disease with management options that significantly alter clinical course. With the use of implantable cardioverter-defibrillators (ICDs) in the HCM patient population, a new paradigm has emerged, with primary prevention device therapy reliably terminating potentially lethal ventricular tachyarrhythmias (3%-4% per year) and being largely responsible for a >10-fold decrease in disease-related mortality (to 0.5% per year), independent of age. An evidenced-based and guideline directed clinical risk stratification algorithm has evolved, including variables identified with cardiac magnetic resonance. One or more risk markers judged major and relevant within a patient's clinical profile can be considered sufficient to recommend a primary prevention implant (associated with a measure of physician judgment and shared decision-making). ICD decisions using the prospective individual risk marker strategy have been associated with 95% sensitivity for identifying patients who subsequently experienced appropriate ICD therapy, (albeit often delayed substantially for >5 or >10 years after implant), but without heart failure deterioration or HCM death following device intervention. A rigid mathematically derived statistical risk model proposed by the European Society of Cardiology is associated with low sensitivity (ie, 33%) for predicting SD events. Introduction of prophylactically inserted ICDs to HCM 20 years ago has significantly altered the clinical course and landscape of this disease. SD prevention has reduced HCM mortality significantly, making preservation of life and the potential for normal longevity a reality for most patients., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to systematically review and quantitatively synthesize existing evidence about the prognostic value of LV apical aneurysm in patients with HCM., Background: Hypertrophic cardiomyopathy (HCM) represents a common inherited heart disease associated with enormous diversity in morphologic expression and clinical course. With the increasing penetration of advanced high resolution cardiovascular imaging into routine HCM practice, a subset of HCM patients with left ventricular (LV) apical aneurysm have become more widely recognized., Methods: Medline was searched for studies describing the prognostic implication of LV apical aneurysm in patients with HCM. In the main analysis the combined endpoint of major HCM-related outcomes was assessed. Separate analyses for sudden cardiac death (SCD) events and thromboembolic events were also performed., Results: Six studies comprising of 2382 patients met the inclusion criteria. In the pooled analysis, the presence of LV apical aneurysm was significantly associated with major adverse outcomes (pooled OR: 5.13, 95 CI: 2.85 to 9.23, I 2 :31%), increased risk of SCD arrhythmic events (pooled OR: 4.67, 95% CI: 2.30 to 9.48, I 2 : 38%) and thromboembolic events (pooled OR: 6.30, 95% CI: 1.52 to 26.19, I 2 : 66%)., Conclusions: These data demonstrate that LV apical aneurysm in HCM patients is associated with an increased risk for SCD events and thromboembolism. This finding might encourage the inclusion of LV apical aneurysm into the HCM SCD risk stratification algorithm as a novel risk marker that supports consideration for primary prevention implantable cardioverter defibrillator and anticoagulation for stroke prophylaxis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: This study examined fibrosis progression in hypertrophic cardiomyopathy (HCM) patients, as well as its relationship to patient characteristics, clinical outcomes, and its effect on clinical decision making., Background: Myocardial fibrosis, as quantified by late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR), provides valuable prognostic information in patients with HCM., Methods: A total of 157 patients with HCM were enrolled in this study, with 2 sequential CMR scans separated by an interval of 4.7 ± 1.9 years., Results: At the first CMR session (CMR-1), 70% of patients had LGE compared with 85% at CMR-2 (p = 0.001). The extent of LGE extent increased between the 2 CMR procedures, from 4.0 ± 5.6% to 6.3 ± 7.4% (p < 0.0001), with an average LGE progression rate of 0.5 ± 1.0%/year. LGE mass progression was correlated with higher LGE mass and extent on CMR-1 (p = 0.0017 and p = 0.007, respectively), greater indexed left ventricular (LV) mass (p < 0.0001), greater LV maximal wall thickness (p < 0.0001), apical aneurysm at CMR-1 (p < 0.0001), and lower LV ejection fraction (EF) (p = 0.029). Patients who were more likely to have a higher rate of LGE progression presented with more severe disease at baseline, characterized by LGE extent >8% of LV mass, indexed LV mass >100 g/m 2 , maximal wall thickness ≥20 mm, LVEF ≤60%, and apical aneurysm. There was a significant correlation between the magnitude of LGE progression and future implantation of insertable cardioverter-defibrillators (p = 0.004), EF deterioration to ≤50% (p < 0.0001), and admission for heart failure (p = 0.0006)., Conclusions: Myocardial fibrosis in patients with HCM is a slowly progressive process. Progression of LGE is significantly correlated with a number of clinical outcomes such as progression to EF ≤50% and heart failure admission. Judicious use of serial CMR with LGE can provide valuable information to help patient management., Competing Interests: Funding Support and Author Disclosures Dr. Habib was funded by the Richard and Edith Strauss Canada Foundation and the Halpern HCM Research Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Noninvasive contemporary imaging with echocardiography and cardiovascular magnetic resonance (CMR) provide comprehensive characterization of the hypertrophic cardiomyopathy (HCM) heart including precise definition of left ventricle (LV) wall thickness and reliable identification of morphologic abnormalities of the mitral valve, LV chamber, and myocardial tissue characterization with late gadolinium enhancement (LGE) (fibrosis). Imaging also contributes to identification of patients at risk for sudden death including novel high-risk features such as LV apical aneurysm and extensive LGE. Exercise (stress) echocardiography should be considered to demonstrate physiologic provocation of LV outflow gradients and to distinguish from patients with nonobstructive HCM. Multimodality imaging identifies patients who are optimal candidates for invasive septal reduction therapy and directs preoperative planning for extended myectomy and to optimize alcohol septal ablation. Contemporary imaging interwoven with current management strategies have resulted in a low HCM-related mortality rate., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF), characterized by excessive exertional dyspnea, is a common complication within the broad clinical spectrum of hypertrophic cardiomyopathy (HCM). HF has become an increasingly prominent management issue with the reduction in sudden deaths due to use of implantable defibrillators in this disease. Exertional dyspnea ranges in severity from mild to severe (New York Heart Association functional classes II to IV) and not uncommonly becomes refractory to medical management, leading to progressive disability, but largely in the absence of pulmonary congestion and volume overload requiring hospitalization. HCM-related HF is most commonly due to dynamic mechanical impedance to left ventricular outflow produced by mitral valve systolic anterior motion, leading to high intracavity pressures. Surgical septal myectomy with low operative mortality (<1%) produces HF reversal and symptom relief in 90% to 95% of patients, while also conveying a survival benefit. Exercise echocardiography has assumed an important role in the evaluation of patients with HCM, i.e., by identifying candidates for septal reduction therapy with refractory HF when outflow gradients are present only with physiological exercise, distinguishing highly symptomatic nonobstructive patients as heart transplant candidates, and predicting future development of progressive HF. Notably, mortality directly attributable to HF has become exceedingly uncommon in HCM (<0.5%/year) in contrast with HF in non-HCM diseases (by 20-fold). In conclusion, HF in HCM is associated with diverse and complex pathophysiology, but a substantially more favorable prognosis than conventional non-HCM HF, and highly amenable to effective treatment options in the vast majority of patients., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Over the last 25 years, patients with hypertrophic cardiomyopathy (HCM) have been studied with a variety of methods employing physiological exercise that have made major contributions to disease management and are performed without increased risk. Previously under-utilized in HCM, exercise (stress) echocardiography has become incorporated into the standard clinical assessment and diagnostic armamentarium of HCM using upright or supine symptom-limited treadmill or bicycle modalities. In patients without outflow gradients at rest, exercise echocardiography is the most appropriate method for provoking obstruction, with the capability of predicting future development of progressive heart failure symptoms, and differentiating patients with provocable obstruction from those without obstruction, with major implications for dictating treatment options, that is, surgical myectomy (alternatively, alcohol septal ablation) versus heart transplant. Reduced myocardial oxygen consumption with metabolic (cardiopulmonary) exercise testing provides an independent and quantitative assessment of functional limitation for individual patients when the personal history is ambiguous, and also guides eligibility for heart transplant. Hypotensive blood pressure response to exercise can be an arbitrator in risk stratification decisions. Exercise testing with a variety of methods has become an integral and powerful component of the noninvasive evaluation of HCM, and in some patients can determine treatment strategy., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The almost 50-year odyssey of cardiac imaging in hypertrophic cardiomyopathy (HCM), revisited and described here, has been remarkable, particularly when viewed in the timeline of advances that occurred during a single generation of investigators. At each step along the way, from M-mode to 2-dimensional echocardiography to Doppler imaging, and finally over the last 10 years with the emergence of high-resolution tomographic cardiac magnetic resonance (CMR), evolution of the images generated by each new technology constituted a paradigm change over what was previously available. Together, these advances have transformed the noninvasive diagnosis and management of HCM in a number of important clinical respects. These changes include a more complete definition of the phenotype, resulting in more reliable clinical identification of patients and family members, defining mechanisms (and magnitude) of left ventricular outflow obstruction, and novel myocardial tissue characterization (including in vivo detection of fibrosis/scarring); notably, these advances afford more precise recognition of at-risk patients who are potential candidates for life-saving primary prevention defibrillator therapy. This evolution in imaging as applied to HCM has indelibly changed cardiovascular practice for this morphologically and clinically complex genetic disease., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is regarded as the most common nontraumatic cause of sudden death (SD) in young people (including trained athletes). Introduction of implantable cardioverter-defibrillators (ICD) to HCM 15 years ago represented a new paradigm for clinical practice and probably the most significant advance in management of this disease. ICDs offer protection against SD by terminating potentially lethal ventricular tachyarrhythmias (11%/year secondary and 4%/year primary prevention), although implant decisions are weighed against the possibility of device-related complications (5%/year). ICDs have altered the natural history of HCM, creating the opportunity for extended or normal longevity for many patients. However, assessing SD risk and targeting appropriate candidates for prophylactic device therapy can be compounded by unpredictability of the underlying arrhythmogenic substrate, evident by delays ≥10 years between implant and first ICD intervention. Multiple or a single strong risk marker within the clinical profile of an individual HCM patient can justify consideration for a primary-prevention ICD when combined with physician judgment and shared decision making. The role of the mathematical SD risk score proposed by the European Society of Cardiology to identify patients who benefit from ICD therapy is incompletely resolved. Contemporary treatment interventions and advanced risk stratification using ≥1 conventional markers have served the HCM patient population well, with reduced disease-related mortality rates across all age groups to <1%/year, due largely to the penetration of ICDs into HCM practice. Prevention of SD has now become an integral, albeit challenging, component of HCM management, contributing importantly to its emergence as a contemporary treatable cardiac disease., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in young patients. A number of noninvasive clinical markers, including family history, have formed the basis for a risk stratification strategy aimed at identifying high-risk patients with HCM. The observation that sudden death can occur in multiple relatives of the same family, and clinical studies in which a family history of HCM-related sudden death emerges as an independent predictor of sudden death, support the principle that family history should be considered a risk factor which, in the appropriate clinical scenario, can form the basis for recommending prophylactic implantable cardioverter defibrillator therapy., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Implantable cardioverter-defibrillator (ICD) studies in patients with coronary artery disease report higher risk of ventricular tachycardia/fibrillation (VT/VF) early post-implant, potentially related to local proarrhythmic effects of ICD leads., Objective: To characterize early and long-term risk of ICD discharge for VT/VF in a large hypertrophic cardiomyopathy (HCM) cohort., Methods: By using HCM multicenter registry data, we compared long-term risk of VT/VF subsequent to an early post-implant period (a priori defined as within 3 months of implant) between patients with or without VT/VF within 3 months after ICD implantation., Results: Over a median follow-up of 4.3 years, 109 of 506 (22%) patients with HCM who received ICDs received at least 1 ICD discharge for VT/VF. Risk of first ICD discharge for VT/VF was highest in the first year post-implant (10.8% per person-year; 95% confidence interval 7.9-13.8) and particularly in the first 3 months (17.0% per person-year; 95% confidence interval 9.8-24.3). Patients with early VT/VF (≤3 months post-implant) were older, and more commonly had secondary prevention ICDs following cardiac arrest or systolic dysfunction (end-stage HCM with ejection fraction<50%). Only 2 of 247 (0.7%) patients with primary prevention ICDs and preserved systolic function had early VT/VF. Patients with VT/VF early post-implant (≤3 months) had more than 5-fold higher risk for future VT/VF during long-term follow-up compared with patients without early VT/VF (adjusted hazard ratio 5.4; 95% confidence interval 2.3-12.6)., Conclusions: High-risk patients with HCM and VT/VF early after ICD implantation are particularly prone to subsequent VT/VF throughout follow-up. Early ICD interventions for VT/VF are largely confined to patients with prior cardiac arrest or systolic dysfunction and therefore more likely driven by higher arrhythmic risk rather than lead-related proarrhythmia., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy is a common inherited cardiovascular disease present in one in 500 of the general population. It is caused by more than 1400 mutations in 11 or more genes encoding proteins of the cardiac sarcomere. Although hypertrophic cardiomyopathy is the most frequent cause of sudden death in young people (including trained athletes), and can lead to functional disability from heart failure and stroke, the majority of affected individuals probably remain undiagnosed and many do not experience greatly reduced life expectancy or substantial symptoms. Clinical diagnosis is based on otherwise unexplained left-ventricular hypertrophy identified by echocardiography or cardiovascular MRI. While presenting with a heterogeneous clinical profile and complex pathophysiology, effective treatment strategies are available, including implantable defibrillators to prevent sudden death, drugs and surgical myectomy (or, alternatively, alcohol septal ablation) for relief of outflow obstruction and symptoms of heart failure, and pharmacological strategies (and possibly radiofrequency ablation) to control atrial fibrillation and prevent embolic stroke. A subgroup of patients with genetic mutations but without left-ventricular hypertrophy has emerged, with unresolved natural history. Now, after more than 50 years, hypertrophic cardiomyopathy has been transformed from a rare and largely untreatable disorder to a common genetic disease with management strategies that permit realistic aspirations for restored quality of life and advanced longevity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high-risk patients with hypertrophic cardiomyopathy (HCM). Therefore, additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed., Objective: The objective of this study was to determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors., Methods: Databases of 3 HCM centers were accessed, and 18 probands with 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere were identified., Results: Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, and 57 years) who experienced sudden cardiac arrest but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and 1 died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited 1 mutation independently from each of his parents with HCM)-that is, double MYBPC3 and TNNI3 mutations and compound MYBPC3 mutations-as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event., Conclusions: These observations support the emerging hypothesis that double (or compound) mutations detected by genetic testing may confer a gene dosage effect in HCM, thereby predisposing patients to adverse disease progression. In 3 families, multiple sarcomere mutations were associated with a risk of sudden death, even in the absence of conventional risk factors., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)