ABSTRACT
BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.
Subject(s)
Cardiomyopathy, Hypertrophic , Stroke Volume , Ventricular Function, Left , Humans , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/diagnosis , Male , Female , Middle Aged , Aged , Ventricular Function, Left/drug effects , Stroke Volume/drug effects , Treatment Outcome , Double-Blind Method , Dose-Response Relationship, Drug , Adult , Atrial Fibrillation/drug therapy , Atrial Fibrillation/diagnosis , Atrial Fibrillation/physiopathology , Benzylamines , Uracil/analogs & derivativesABSTRACT
Purpose To develop a deep learning model for increasing cardiac cine frame rate while maintaining spatial resolution and scan time. Materials and Methods A transformer-based model was trained and tested on a retrospective sample of cine images from 5840 patients (mean age, 55 years ± 19 [SD]; 3527 male patients) referred for clinical cardiac MRI from 2003 to 2021 at nine centers; images were acquired using 1.5- and 3-T scanners from three vendors. Data from three centers were used for training and testing (4:1 ratio). The remaining data were used for external testing. Cines with downsampled frame rates were restored using linear, bicubic, and model-based interpolation. The root mean square error between interpolated and original cine images was modeled using ordinary least squares regression. In a prospective study of 49 participants referred for clinical cardiac MRI (mean age, 56 years ± 13; 25 male participants) and 12 healthy participants (mean age, 51 years ± 16; eight male participants), the model was applied to cines acquired at 25 frames per second (fps), thereby doubling the frame rate, and these interpolated cines were compared with actual 50-fps cines. The preference of two readers based on perceived temporal smoothness and image quality was evaluated using a noninferiority margin of 10%. Results The model generated artifact-free interpolated images. Ordinary least squares regression analysis accounting for vendor and field strength showed lower error (P < .001) with model-based interpolation compared with linear and bicubic interpolation in internal and external test sets. The highest proportion of reader choices was "no preference" (84 of 122) between actual and interpolated 50-fps cines. The 90% CI for the difference between reader proportions favoring collected (15 of 122) and interpolated (23 of 122) high-frame-rate cines was -0.01 to 0.14, indicating noninferiority. Conclusion A transformer-based deep learning model increased cardiac cine frame rates while preserving both spatial resolution and scan time, resulting in images with quality comparable to that of images obtained at actual high frame rates. Keywords: Functional MRI, Heart, Cardiac, Deep Learning, High Frame Rate Supplemental material is available for this article. © RSNA, 2024.
Subject(s)
Deep Learning , Magnetic Resonance Imaging, Cine , Humans , Male , Magnetic Resonance Imaging, Cine/methods , Middle Aged , Female , Prospective Studies , Retrospective Studies , Heart/diagnostic imaging , Image Interpretation, Computer-Assisted/methodsABSTRACT
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.
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BACKGROUND: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.
Subject(s)
Cardiomyopathy, Hypertrophic , Genotype , Humans , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/mortality , Cardiomyopathy, Hypertrophic/diagnosis , Male , Female , Middle Aged , Adult , Mutation , Phenotype , Disease Progression , Risk Factors , Genetic Predisposition to Disease , Aged , Genetic Testing/methods , Prognosis , Time Factors , Heart Failure/genetics , Heart Failure/mortality , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/epidemiology , Heart TransplantationABSTRACT
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.).
Subject(s)
Cardiomyopathy, Hypertrophic , Cardiovascular Agents , Exercise Test , Aged , Female , Humans , Male , Middle Aged , Benzylamines , Cardiac Myosins/antagonists & inhibitors , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/physiopathology , Double-Blind Method , Exercise Tolerance/drug effects , Oxygen Consumption/drug effects , Uracil/analogs & derivatives , Valsalva Maneuver , Ventricular Outflow Obstruction/drug therapy , Ventricular Outflow Obstruction/physiopathology , Ventricular Outflow Obstruction/etiology , Cardiovascular Agents/pharmacology , Cardiovascular Agents/therapeutic use , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Administration, OralABSTRACT
BACKGROUND: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. OBJECTIVES: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. METHODS: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. RESULTS: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). CONCLUSIONS: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.
Subject(s)
Cardiomyopathy, Hypertrophic , Humans , Cardiomyopathy, Hypertrophic/drug therapy , Female , Male , Middle Aged , Double-Blind Method , Treatment Outcome , Aged , Oxygen Consumption/drug effectsABSTRACT
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.
ABSTRACT
Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited heart disease encumbered throughout much of its almost 60-year history by the expectation of an unfavorable outcome with shortened longevity. However, it is notable that in 2023, most patients affected with HCM can now achieve normal or extended life expectancy without major disability because of a comprehensive constellation of management strategies that have evolved largely over the last 20 years. Distinct adverse disease pathways dictate high-benefit low-risk personalized treatments, without reliance on genomics and sarcomere mutations, including: primary prevention implantable defibrillators for sudden cardiac death prevention, surgical myectomy and percutaneous alcohol septal ablation to reverse heart failure symptoms, anticoagulation to prevent embolic stroke associated with concomitant atrial fibrillation, external defibrillation and hypothermia for out-of-hospital cardiac arrest, and heart transplant in a small patient subgroup with end-stage disease. Large cohort studies using these contemporary management strategies achieved remarkably low HCM-related mortality (0.5%/year) across all age groups, which is lower than in the other cardiac or noncardiac risks of living, and largely confined to nonobstructive patients with progressive heart failure, including those awaiting heart transplant.
Subject(s)
Atrial Fibrillation , Cardiomyopathy, Hypertrophic , Heart Failure , Heart Transplantation , Vascular Diseases , Humans , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/therapy , Cardiomyopathy, Hypertrophic/diagnosis , Cohort Studies , Heart Failure/complications , Heart Transplantation/adverse effects , Atrial Fibrillation/complications , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Vascular Diseases/complicationsABSTRACT
Hypertrophic cardiomyopathy (HCM) is a relatively common and, often, inherited cardiac disease, once regarded as largely untreatable with ominous prognosis and, perhaps, most visibly as a common cause of sudden cardiac death (SCD) in the young. However, HCM is now more accurately considered a treatable disease with management options that significantly alter its clinical course. This is particularly true for SCD because the penetration of implantable cardioverter-defibrillators into HCM practice enables primary prevention device therapy that reliably terminates potentially lethal ventricular tachyarrhythmias (3% to 4%/year). This therapeutic advance is largely responsible for >10-fold decrease in the overall disease-related mortality to 0.5%/year, independent of patient age. A guideline-based clinical risk stratification algorithm has evolved, which included variables identifiable with cardiac magnetic resonance: ≥1 risk markers judged major within the clinical profile of an individual patient, associated with a measure of physician judgment and shared decision-making, can be sufficient to consider the recommendation of a prophylactic defibrillator implant. Implantable cardioverter-defibrillator decisions using the American College of Cardiology and the American Heart Association traditional major risk marker strategy are associated with a 95% sensitivity for identifying those patients who subsequently experience appropriate therapy, albeit often 5 to 10+ years after implant but without heart failure deterioration or death after a device intervention. A mathematical SCD risk score proposed by European Society of Cardiology is associated with a relatively low sensitivity (33%) for predicting and preventing SCD events but with potential for less device overtreatment.
Subject(s)
Cardiomyopathy, Hypertrophic , Defibrillators, Implantable , Humans , Risk Factors , Defibrillators, Implantable/adverse effects , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Prognosis , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/therapy , Risk AssessmentABSTRACT
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.
Subject(s)
Cardiomyopathy, Hypertrophic , Deep Learning , Electrocardiography , Magnetic Resonance Imaging, Cine , Humans , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/diagnostic imaging , Male , Female , Middle Aged , Magnetic Resonance Imaging, Cine/methods , Risk Assessment/methods , Retrospective Studies , Death, Sudden, Cardiac/prevention & control , Death, Sudden, Cardiac/etiology , Risk FactorsABSTRACT
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.
Subject(s)
Atrial Fibrillation , Cardiomyopathy, Hypertrophic , Vascular Diseases , Humans , Quality of Life , Anti-Arrhythmia Agents/therapeutic use , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/therapy , Vascular Diseases/complicationsABSTRACT
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).