Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Evolving Contemporary Management of Atrial Fibrillation in Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with clinical and subclinical episodes occurring in nearly one-half of patients. AF in HCM historically has been characterized as a decisive disease complication associated with substantial risk for thromboembolic stroke and increased morbidity and mortality. However, there have been many advances in treatment strategy resulting in improved outcomes for this patient group. For example, stroke risk in HCM has been greatly reduced by using systemic oral anticoagulation initiated after the first clinical (symptomatic) AF episode, usually with preference given to direct anticoagulants over warfarin. In contrast, stroke risk scoring systems (such as CHA2DS2-VASc score) are not informative in HCM given the substantial potential for stroke events in patients with low scores, and therefore should not be used for anticoagulation decisions in this disease. A novel risk score specifically designed for HCM (HCM-AF score) can reliably identify most patients with HCM at risk for future AF. Although a strategy focused on controlling ventricular rate is effective in asymptomatic (or minimally symptomatic) patients with AF, restoring and maintaining sinus rhythm is required for most patients with marked AF symptom burden and impaired quality of life. Several antiarrhythmic drugs such as sotalol, disopyramide, and amiodarone, can be effective in suppressing AF episodes; albeit safe, long-term efficacy is supported by only limited data. Catheter AF ablation has emerged as an important treatment option for some patients, although freedom from AF after a single ablation is relatively low (35% at 3 years), multiple ablations and the concomitant use of antiarrhythmic drugs can control AF with more than two-thirds of patients maintaining sinus rhythm at 5 years. Surgical AF ablation with biatrial Cox-Maze IV performed as an adjunctive procedure during myectomy can reduce symptomatic AF episodes (70% of patients free from AF at 5 years). For the vast majority of patients who have HCM with AF, the implementation of contemporary therapies has allowed for improved quality of life and low HCM-related mortality.

Hypertrophic Cardiomyopathy: New Concepts and Therapies.

Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited myocardial disorder, transformed over the last several years into a treatable condition with the emergence of effective management options that alter natural history at all ages. Now available are a matured risk stratification algorithm selecting patients for prophylactic implantable defibrillators that prevent arrhythmic sudden death; low-risk, high-benefit surgical myectomy to reverse progressive heart failure symptoms due to left ventricular outflow obstruction; anticoagulation prophylaxis to prevent atrial fibrillation-mediated embolic stroke; and heart transplant for refractory end-stage disease in the absence of obstruction. Those strategies have resulted in reduction of HCM-related morbidity and reduction of mortality to 0.5% per year.

Assessing the impact of atrial fibrillation on symptoms and quality of life in hypertrophic cardiomyopathy.

INTRODUCTION: In hypertrophic cardiomyopathy (HCM), atrial fibrillation (AF) has historically been regarded to have a deleterious impact on clinical course, strongly associated with progressive heart failure (HF) symptoms. However, there is a paucity of information regarding the impact of AF on HCM employing validated quality of life (QoL) surveys. Therefore, we evaluated the impact of AF on QoL utilizing patient reported outcome measures (PROMs). METHODS: 218 consecutive HCM patients with or without AF at the Lahey HCM center in 2022 completed PROMs at their most recent visit evaluating HF (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and AF symptoms (AF Effect on QoL [AFEQT]). RESULTS: Among the 218 patients, 50 (23%) had a history of AF and comprise the primary study cohort. AF was diagnosed at 55 ± 10 years of age, median of 5.5 years before PROM, with 66% of patients treated with a rhythm control strategy with antiarrhythmic drug and/or AF ablation. AFEQT indicated that 52% of patients experienced no or minimal AF-related disability, mild to moderate in 22%, and severe in 26%. There was no substantial difference in HCM phenotype in patients with no or minimal AF disability compared to those with severe disability. HF symptoms for most HCM patients with prior AF history was consistent with no or minimal (59%) or only mild (27%) disability as measured by KCCQ overall summary scores. In addition, with multivariate analysis, AF history was associated with less HF symptoms and improved QoL (OR 0.4, p = 0.02). CONCLUSION: In contrast to prior perceptions, HCM patients with prior AF history were less likely to incur HF symptoms impairing QoL compared to HCM patients without AF. After treatment, prior history of AF did not substantially impact current QoL. These data provide a realistic appraisal for the impact that AF has on HCM patients and also offers a measure of reassurance for this patient subgroup.

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Impact of comorbidities on atrial fibrillation and sudden cardiac death in hypertrophic cardiomyopathy.

BACKGROUND: The impact of comorbid disease states on the development of atrial and ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) remains unresolved. OBJECTIVE: Evaluate the association of comorbidities linked to arrhythmias in other cardiovascular diseases (e.g., obesity, systemic hypertension, diabetes, obstructive sleep apnea, renal disorders, tobacco, and alcohol use) to atrial fibrillation (AF) and sudden cardiac death (SCD) events in a large cohort of HCM patients. METHODS: A total  of 2269 patients, 54 ± 15 years of age, 1392 males, were evaluated at the Tufts HCM Institute between 2004 and 2018 and followed for an average of 4 ± 3 years for new-onset clinical AF and SCD events (appropriate defibrillation for ventricular tachyarrhythmias, resuscitated cardiac arrest, or SCD). RESULTS: One or more comorbidity was present in 75% of HCM patients, including 50% with ≥2 comorbidities, most commonly obesity (body mass index [BMI] ≥ 30 kg/m2 ) in 43%. New-onset atrial fibrillation developed in 11% of our cohort (2.6%/year). On univariate analysis, obesity was associated with a 1.7-fold increased risk for AF (p = .03) with 12% of obese patients developing AF (3.3%/year) as compared to 7% of patients with BMI < 25 kg/m2 (1.6%/year; p = .006). On multivariate analysis, age and LA transverse dimension emerged as the only variables predictive of AF. Comorbidities, including obesity, were not independently associated with AF development (p > .10 for each). SCD events occurred in 3.3% of patients (0.8%/year) and neither obesity nor other comorbidities were associated with increased risk for SCD (p > .10 for each). CONCLUSIONS: In adult HCM patients comorbidities do not appear to impact AF or SCD risk. Therefore, for most patients with HCM, adverse disease related events of AF and SCD appear to be primarily driven by underlying left ventricular and atrial myopathy as opposed to comorbidities.

Radiomics and deep learning for myocardial scar screening in hypertrophic cardiomyopathy.

BACKGROUND: Myocardial scar burden quantified using late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR), has important prognostic value in hypertrophic cardiomyopathy (HCM). However, nearly 50% of HCM patients have no scar but undergo repeated gadolinium-based CMR over their life span. We sought to develop an artificial intelligence (AI)-based screening model using radiomics and deep learning (DL) features extracted from balanced steady state free precession (bSSFP) cine sequences to identify HCM patients without scar. METHODS: We evaluated three AI-based screening models using bSSFP cine image features extracted by radiomics, DL, or combined DL-Radiomics. Images for 759 HCM patients (50 ± 16 years, 66% men) in a multi-center/vendor study were used to develop and test model performance. An external dataset of 100 HCM patients (53 ± 14 years, 70% men) was used to assess model generalizability. Model performance was evaluated using area-under-receiver-operating curve (AUC). RESULTS: The DL-Radiomics model demonstrated higher AUC compared to DL and Radiomics in the internal (0.83 vs 0.77, p = 0.006 and 0.78, p = 0.05; n = 159) and external (0.74 vs 0.64, p = 0.006 and 0.71, p = 0.27; n = 100) datasets. The DL-Radiomics model correctly identified 43% and 28% of patients without scar in the internal and external datasets compared to 42% and 16% by Radiomics model and 42% and 23% by DL model, respectively. CONCLUSIONS: A DL-Radiomics AI model using bSSFP cine images outperforms DL or Radiomics models alone as a scar screening tool prior to gadolinium administration. Despite its potential, the clinical utility of the model remains limited and further investigation is needed to improve the accuracy and generalizability.

2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Aim This executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in adult and pediatric patients as well as supporting documentation to encourage their use. Methods A comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Structure Many recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.

Improved Quantification of Myocardium Scar in Late Gadolinium Enhancement Images: Deep Learning Based Image Fusion Approach.

BACKGROUND: Quantification of myocardium scarring in late gadolinium enhanced (LGE) cardiac magnetic resonance imaging can be challenging due to low scar-to-background contrast and low image quality. To resolve ambiguous LGE regions, experienced readers often use conventional cine sequences to accurately identify the myocardium borders. PURPOSE: To develop a deep learning model for combining LGE and cine images to improve the robustness and accuracy of LGE scar quantification. STUDY TYPE: Retrospective. POPULATION: A total of 191 hypertrophic cardiomyopathy patients: 1) 162 patients from two sites randomly split into training (50%; 81 patients), validation (25%, 40 patients), and testing (25%; 41 patients); and 2) an external testing dataset (29 patients) from a third site. FIELD STRENGTH/SEQUENCE: 1.5T, inversion-recovery segmented gradient-echo LGE and balanced steady-state free-precession cine sequences ASSESSMENT: Two convolutional neural networks (CNN) were trained for myocardium and scar segmentation, one with and one without LGE-Cine fusion. For CNN with fusion, the input was two aligned LGE and cine images at matched cardiac phase and anatomical location. For CNN without fusion, only LGE images were used as input. Manual segmentation of the datasets was used as reference standard. STATISTICAL TESTS: Manual and CNN-based quantifications of LGE scar burden and of myocardial volume were assessed using Pearson linear correlation coefficients (r) and Bland-Altman analysis. RESULTS: Both CNN models showed strong agreement with manual quantification of LGE scar burden and myocardium volume. CNN with LGE-Cine fusion was more robust than CNN without LGE-Cine fusion, allowing for successful segmentation of significantly more slices (603 [95%] vs. 562 (89%) of 635 slices; P < 0.001). Also, CNN with LGE-Cine fusion showed better agreement with manual quantification of LGE scar burden than CNN without LGE-Cine fusion (%ScarLGE-cine = 0.82 × %Scarmanual , r = 0.84 vs. %ScarLGE = 0.47 × %Scarmanual , r = 0.81) and myocardium volume (VolumeLGE-cine = 1.03 × Volumemanual , r = 0.96 vs. VolumeLGE = 0.91 × Volumemanual , r = 0.91). DATA CONCLUSION: CNN based LGE-Cine fusion can improve the robustness and accuracy of automated scar quantification. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: 1.

Paradigm of Sudden Death Prevention in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a worldwide genetic heart disease and a common cause of sudden death in the young. Penetration of the implantable cardioverter-defibrillator (ICD) into this patient population over the past 20 years has made accurate selection of patients for primary prevention ICDs a priority. Consequently, a new paradigm has emerged in the management of this complex disease with ICD therapy responsible for a substantial decrease in overall HCM-related mortality (to 0.5%/y) and independent of patient age. Selection of candidates for ICDs has matured substantially with the formulation of an enhanced risk stratification algorithm. One or more contemporary risk markers judged major within a given patient's clinical profile, in association with physician judgment and shared decision-making, is sufficient to consider a primary prevention ICD implant. An enhanced American College of Cardiology/American Heart Association risk factor model (including new contrast-magnetic resonance-based markers, such as left ventricular apical aneurysm) used prospectively to make ICD decisions proved to be 95% sensitive for identifying patients who would experience ≥1 appropriate device therapies terminating ventricular tachycardia/fibrillation. The number of HCM patients required to treat with ICDs to save 1 patient with abolition of lethal ventricular tachyarrhythmias was 6:1, similar to randomized defibrillator trials in other cardiomyopathies. In contrast to patients with ischemic heart disease, after ICD shock HCM patients rarely experience transformation to heart failure deterioration or sudden arrhythmic death. The mathematically derived risk score model proposed by the European Society of Cardiology was inferior for identifying high-risk patients susceptible to arrhythmic sudden death with a sensitivity of only 33%, leaving many patients exposed to the possibility of sudden death without ICDs. In conclusion, introduction of the ICD associated with a matured risk stratification algorithm has altered management strategy and clinical course of many HCM patients, making the likelihood of sudden death prevention a reality and fulfilling the aspiration of preservation of life and reduced mortality for this vulnerable patient population.

Plasma Proteomic Profiling in Hypertrophic Cardiomyopathy Patients before and after Surgical Myectomy Reveals Post-Procedural Reduction in Systemic Inflammation.

Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction, referred for surgical myectomy. Plasma was collected at the surgical preoperative visit, approximately one month prior to surgery and then at the post-surgical visit, approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p-value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of differentially expressed proteins, such as interferon-γ, TGF-ß1, and TNF. Biological pathways affected by surgery included organ inflammation, migration, and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis, and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function.

Three-dimensional Deep Convolutional Neural Networks for Automated Myocardial Scar Quantification in Hypertrophic Cardiomyopathy: A Multicenter Multivendor Study.

Background Cardiac MRI late gadolinium enhancement (LGE) scar volume is an important marker for outcome prediction in patients with hypertrophic cardiomyopathy (HCM); however, its clinical application is hindered by a lack of measurement standardization. Purpose To develop and evaluate a three-dimensional (3D) convolutional neural network (CNN)-based method for automated LGE scar quantification in patients with HCM. Materials and Methods We retrospectively identified LGE MRI data in a multicenter (n = 7) and multivendor (n = 3) HCM study obtained between November 2001 and November 2011. A deep 3D CNN based on U-Net architecture was used for LGE scar quantification. Independent CNN training and testing data sets were maintained with a 4:1 ratio. Stacks of short-axis MRI slices were split into overlapping substacks that were segmented and then merged into one volume. The 3D CNN per-site and per-vendor performances were evaluated with respect to manual scar quantification performed in a core laboratory setting using Dice similarity coefficient (DSC), Pearson correlation, and Bland-Altman analyses. Furthermore, the performance of 3D CNN was compared with that of two-dimensional (2D) CNN. Results This study included 1073 patients with HCM (733 men; mean age, 49 years ± 17 [standard deviation]). The 3D CNN-based quantification was fast (0.15 second per image) and demonstrated excellent correlation with manual scar volume quantification (r = 0.88, P < .001) and ratio of scar volume to total left ventricle myocardial volume (%LGE) (r = 0.91, P < .001). The 3D CNN-based quantification strongly correlated with manual quantification of scar volume (r = 0.82-0.99, P < .001) and %LGE (r = 0.90-0.97, P < .001) for all sites and vendors. The 3D CNN identified patients with a large scar burden (>15%) with 98% accuracy (202 of 207) (95% confidence interval [CI]: 95%, 99%). When compared with 3D CNN, 2D CNN underestimated scar volume (r = 0.85, P < .001) and %LGE (r = 0.83, P < .001). The DSC of 3D CNN segmentation was comparable among different vendors (P = .07) and higher than that of 2D CNN (DSC, 0.54 ± 0.26 vs 0.48 ± 0.29; P = .02). Conclusion In the hypertrophic cardiomyopathy population, a three-dimensional convolutional neural network enables fast and accurate quantification of myocardial scar volume, outperforms a two-dimensional convolutional neural network, and demonstrates comparable performance across different vendors. © RSNA, 2019 Online supplemental material is available for this article.

Coexistence of acute takotsubo syndrome and acute coronary syndrome.

BACKGROUND: Takotsubo syndrome (TS) is an acute cardiac condition with presentation indistinguishable from acute coronary syndrome (ACS), and mechanism independent of epicardial coronary obstruction. Acute coronary artery plaque rupture/occlusion is not expected in TS. Nonetheless, the physiologic stress of ACS might itself trigger TS, leading to coexistence of both conditions, and diagnostic uncertainty. METHODS: From 2011 to 2014, we encountered 137 consecutive patients with typical TS (without acute coronary plaque rupture/occlusion). During this time, among a population of 3,506 consecutive ACS patients, nine (0.3%) presented with features of both ACS and TS, that is, acute onset, troponin elevation, acute plaque rupture/occlusion, and reversible LV ballooning not corresponding to culprit coronary distribution. RESULTS: The nine patients (seven female) with TS-ACS coexistence, average age 70 ± 13 years, presented with chest pain (n = 6), nausea/vomiting (n = 2), or cardiac arrest (n = 1), ST-elevation (n = 5), all with troponin elevation (peak 1.3 ± 1.2 ng/ml). Each had single vessel coronary disease; right coronary (n = 3), circumflex (n = 3), mid-LAD (n = 2), ramus intermedius (n = 1), with percutaneous coronary intervention in seven patients (78%). Initial ejection fraction was 26 ± 7%, with apical ballooning in eight patients and mid-LV ballooning in one patient. Each patient had LV ballooning resolution and ejection fraction normalization to 57 ± 3%, hospital survival was 89%. CONCLUSIONS: Among patients with ACS, a subset have evidence of coexisting TS, findings which further expand the clinical profile of both conditions, raising the possibility that ACS itself may trigger TS.

Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF), the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), is capable of producing symptoms that impact quality of life and is associated with risk for embolic stroke. However, the influence of AF on clinical course and outcome in HCM remains incompletely resolved. METHODS: Records of 1558 consecutive patients followed at the Tufts Medical Center Hypertrophic Cardiomyopathy Institute for 4.8±3.4 years (from 2004 to 2014) were accessed. RESULTS: Of the 1558 patients with HCM, 304 (20%) had episodes of AF, of which 226 (74%) were confined to symptomatic paroxysmal AF (average, 5±5; range, 1 to >20), whereas 78 (26%) developed permanent AF, preceded by 7±6 paroxysmal AF episodes. At last evaluation, 277 patients (91%) are alive at 62±13 years of age, including 89% in New York Heart Association class I or II. No difference was found in outcome measures for patients with AF and age- and sex-matched patients with HCM without AF. Four percent of patients with AF died of HCM-related causes (n=11), with annual mortality 0.7%; mortality directly attributable to AF (thromboembolism without prophylactic anticoagulation) was 0.1% per year (n=2 patients). Patients were treated with antiarrhythmic drugs (most commonly amiodarone [n=103] or sotalol [n=78]) and AF catheter ablation (n=49) or the Maze procedure at surgical myectomy (n=72). Freedom from AF recurrence at 1 year was 44% for ablation patients and 75% with the Maze procedure (P<0.001). Embolic events were less common with anticoagulation prophylaxis (4/233, 2%) than without (9/66, 14%) (P<0.001). CONCLUSIONS: Transient symptomatic episodes of AF, often responsible for impaired quality of life, are unpredictable in frequency and timing, but amenable to effective contemporary treatments, and infrequently progress to permanent AF. AF is not a major contributor to heart failure morbidity or a cause of arrhythmic sudden death; when treated, it is associated with low disease-related mortality, no different than for patients without AF. AF is an uncommon primary cause of death in HCM virtually limited to embolic stroke, supporting a low threshold for initiating anticoagulation therapy.

Left ventricular apical aneurysm in hypertrophic cardiomyopathy as a risk factor for sudden death at any age.

In hypertrophic cardiomyopathy (HCM) aging has proved protective against sudden death (SD) risk and aggressive recommendations for prophylactic ICDs are uncommon in patients ≥60 years. Nevertheless, we present a patient with an unexpected but aborted sudden death event at the advanced age of 71 years due to a left ventricular apical aneurysm (LVAA) which has emerged as a novel SD marker. Subsequent reappraisal of the Tufts HCM database, specifically the 118 LVAA patients, showed that 36% of SD events occurred at ≥60 years. Of HCM patients ≥ 60 years, SD was 8-fold more common with aneurysm than without aneurysms (16% vs 2%; P < 0.001). Risk in HCM with LVAA persists throughout life and senior LVAA patients should also be considered for primary prevention of SD with the ICD.

Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies.

BACKGROUND: Youthful age has been considered the time of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely because of the possibility of sudden death. The last 2 decades have witnessed more reliable identification of at-risk patients and utilization of implantable cardioverter-defibrillators for prevention of sudden death, and other contemporary treatment options. Whether such management advances have significantly altered the considerable mortality rate for young HCM patients remains unresolved. METHODS AND RESULTS: We studied long-term outcome in 474 consecutive HCM patients between 7 and 29 years of age presenting at 2 referral institutions. Over 7.1±5.1 years of follow-up (6.0 [3.0, 10.0]), 452 patients (95%) survived, with 95% experiencing no or mild symptoms. HCM-related death occurred in 18 patients (3%; 0.54%/y): arrhythmic sudden death (n=12), progressive heart failure and heart transplant complications (n=5), or postoperatively (n=1). In contrast, aborted life-threatening events occurred in 63 other high-risk patients (13%) with implantable cardioverter-defibrillator interventions for ventricular tachyarrhythmias (n=31), resuscitated out-of-hospital cardiac arrest (n=20), or heart transplant for advanced heart failure (n=12), 1.8%/y, 3-fold higher than HCM mortality. Five- and 10-year survival (considering only HCM deaths) was high (97% and 94%, respectively), virtually identical to that reported in middle-aged adult HCM patients (98% and 94%, P=0.23). CONCLUSIONS: In a large hospital-based cohort of young HCM patients, representing an age group considered at greatest risk, low mortality rates can be achieved with the application of contemporary cardiovascular treatment strategies, largely because of reliable identification of high-risk patients who benefited from implantable cardioverter-defibrillators for sudden death prevention, thereby creating the opportunity for extended longevity and good quality of life.

Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy and Defibrillators: Triggers, Treatment, and Implications.

INTRODUCTION: Triggers and ICD interventions of ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) offer insight into mechanisms and treatment. METHODS AND RESULTS: Intracardiac ICD electrograms from 71 HCM patients in the HCM I and II studies were analyzed by three individuals. Rhythms were defined as VF (polymorphic ventricular arrhythmia), VT (monomorphic ventricular tachycardia), and ventricular flutter (VFL; VT ≥ 240 bpm). Physical activity and rhythm preceding the arrhythmia were ascertained. Of 149 arrhythmias, VF was present in 74, VT in 57, and VFL in 18. In those whose activity was known, moderate or intense physical activity was associated with over 50% of the tachycardias (57 of 111). Rhythms preceding ventricular arrhythmias were often sinus tachycardia (49 of 149; 33%) or rapid atrial fibrillation (7 of 149; 5%). VF and VFL were more likely preceded by supraventricular rhythms >100 bpm (30 of 68 with VF; 44%; 12 of 16 with VFL 75%, vs. 14 of 50 with VT 28%; P = 0.001). Antitachycardia pacing (ATP) was successful in 39 of 53 (74%). Multiple shocks were more often required to terminate VFL (10 of 18; 56%) compared to VF (10 of 72; 14%) and VT (2 of 25; 8%; P < 0.0001). Of arrhythmias requiring more than one shock to terminate, 16 of 22 were preceded by sinus tachycardia and/or moderate or extreme physical activity. CONCLUSIONS: Rapid supraventricular rhythms, and at least moderate activity, frequently precede VT and VF, and when they occur in these situations often require multiple ICD shocks to restore sinus rhythm. ATP is successful in terminating VT and VFL, and should be a programmed in all HCM patients with ICDs.

Underappreciated occurrence of discrete subaortic membranes producing left ventricular outflow obstruction in hypertrophic cardiomyopathy.

Subaortic obstruction due to systolic anterior motion (SAM) of the mitral valve with ventricular septal contact is a major cause of progressive heart failure symptoms in patients with hypertrophic cardiomyopathy (HCM). However, we have recently observed a unique, but not uncommon subgroup of HCM patients with outflow tract obstruction due only to discrete subaortic membrane or who have a membrane in addition to SAM-septal contact. HCM patients with subaortic membranes may be at increased risk for developing progressive heart failure symptoms. Identification requires a high index of suspicion and raises important management considerations, including need for surgical myectomy for definitive relief of obstruction with associated excellent outcomes, as the alternative invasive treatment option with percutaneous alcohol septal ablation would be ineffective.