BACKGROUND:Atrial fibrillation (AF) is common among patients with obstructive hypertrophic cardiomyopathy (oHCM), although the impact of AF on health care resource use and costs is not well defined. METHODS:We performed a retrospective analysis of claims data from 2016 to 2021 and used International Classification of Diseases, Tenth Revision (ICD-10) codes to identify adult patients with symptomatic oHCM and classify their status with respect to AF as follows: (1) prevalent AF, (2) incident AF, and (3) no AF. Health care resource use and costs for each cohort were analyzed and expressed as per person per year (PPPY). RESULTS:Of 22 216 patients with symptomatic oHCM, 6677 had prevalent AF (30.1%), 2879 had incident AF (13.0%), and 12 660 were without AF (57.0%). Patients with incident AF incurred mean total health care costs that were similar to those with prevalent AF but substantially greater than those without AF (mean, $66 619 [95% CI, $59 702-$74 336] versus $63 937 [95% CI, $59 803-$68 356] versus $46 686 [95% CI, $43 901-$49 648] per person per year, P<0.0001). After adjusting for age, sex, major comorbidities, and septal reduction therapy, mean total health care costs remained greater in the groups with incident and prevalent AF than the group without AF, with trends toward even greater relative costs in the group with incident AF. Similar trends were present in adjusted costs related to hospitalizations, surgeries, and urgent care. CONCLUSIONS:The diagnosis of AF in the setting of symptomatic oHCM not only has important implications for patient management but also substantial economic impacts, as it is associated with significantly greater health care costs and resource use relative to patients with symptomatic oHCM and no AF.

Background: Women with obstructive hypertrophic cardiomyopathy (oHCM) may present with a greater burden of disease and carry a worse prognosis. Whether there are sex-related differences in response to aficamten is unknown. Research Question: To assess the change in clinical and echocardiographic characteristics in response to aficamten in male and female participants of the SEQUOIA-HCM trial. Methods: A post-hoc analysis of sex differences in the double-blind, randomized-controlled SEQUOIA-HCM trial of aficamten versus placebo in patients with oHCM was performed. Baseline clinical and echocardiographic characteristics were compared using t-test for continuous variables and C 2 test for categorical variables. Prespecified primary (change in peak oxygen uptake, pVO 2 ) and secondary endpoints from baseline to end of treatment (week 24) were analyzed using linear regression models, adjusted for baseline values, beta-blocker use, and exercise mode. Results: Of the 282 participants in SEQUOIA-HCM, women (n=115, 41%) were older, had lower Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, higher NT-proBNP levels, and lower pVO 2 at baseline (Table 1). Women had smaller left ventricular (LV) chamber sizes, higher E/e’ ratios, and higher LV outflow tract (LVOT) gradients at rest and with Valsalva. At 24 weeks, there was a significant treatment-related increase in pVO 2 in men (+2.0 [+0.9 to +3.0]) and women (+1.5, [+0.7 to +2.4]), with no significant interaction by sex (p-interaction = 0.51). Both men and women had a significant treatment-related decrease in LVOT gradients at rest and with Valsalva (Figure 1) with no sex-by-treatment interaction (p-interaction ≥ 0.13). Women had a trend towards greater improvement in KCCQ-CSS (Table 1, p-interaction = 0.08) and a greater reduction in lateral E/e’ ratio (Figure 1, p-interaction = 0.01). Women had similar geometric mean proportional reduction in NT-proBNP (women: 0.16 [0.13 to 0.21]; men: 0.22 [0.18 to 0.27], P-interaction = 0.10). Conclusions: Women enrolled in SEQUOIA-HCM were older with worse baseline health status, higher NT-proBNP, higher LV filling pressure, and higher LVOT gradients compared to men. Despite these differences, both men and women derived similar benefits in the primary and most secondary endpoints following treatment with aficamten, with a greater improvement in health status in women.

Background: A hallmark feature of obstructive hypertrophic cardiomyopathy (oHCM) is impaired exercise capacity, which impacts quality of life and is a determinant of clinical outcomes. Understanding the mechanisms of exercise intolerance in oHCM remains essential to optimizing patient care. Research Question: This study addresses the relationships between changes in echocardiographic parameters and cardiopulmonary exercise testing (CPET) metrics in patients with oHCM from the SEQUOIA-HCM trial (NCT05186818). Methods: Patients enrolled in SEQUOIA-HCM with CPET data available at baseline and 24 weeks (w24) were included. Linear regression models were used to assess associations between changes in echo parameters and CPET metrics (peak oxygen uptake [pVO 2 ], minute ventilation [VE]/carbon dioxide output [VCO 2 ], composite z score, and anerobic threshold [AT]) from baseline to w24, adjusting for baseline values and clinical covariates. The composite z score was defined as the mean of standardized changes in pVO 2 and inverse VE/VCO 2 slope, with equal weighting for each component, and higher scores indicating favorable exercise performance. Cubic spline regression was used to model the relationship between changes in echo parameters and changes in CPET metrics. Results: A total of 282 patients (age 59±13years, 59% male, baseline pVO 2 18.5±4.5 mL/kg/min) were included. After adjustment, per each 5 mL/m 2 decrease in left atrial volume index (LAVi), there was a 0.3 mL/kg/min increase in pVO 2 (p=0.02), a 0.5 unit decrease in VE/VCO 2 slope (p=0.005), a 0.07 unit increase in the composite z score (p=0.001), and a 9.5 mL/min increase in AT (p=0.05) ( Table 1 ). Improvement in measures of diastolic function (lateral e’ and E/e’) demonstrated highly significant association with improvements in both pVO 2 and the composite z score (p<0.001 for both), and modest correlation with improved AT. Decreases in inferolateral wall thickness were associated with improvements in all CPET measures except AT. Cubic spline curves illustrate the relationships between changes in LAVi, lateral E/e’, and pVO 2 ( Fig 1 ). Conclusions: Aficamten treatment resulted in the improvement of measures of diastolic function, including E/e’, along with evidence of LA remodeling, both of which were associated with enhanced exercise capacity. These findings highlight diastolic dysfunction as a key pathophysiologic feature in oHCM and identify modifiable metrics that may aid in monitoring therapeutic response.

Background: Aficamten treatment over 24 weeks in SEQUOIA-HCM (NCT05186818) improved left ventricular (LV) outflow tract gradients (LVOT-G), showed evidence of favorable cardiac remodeling, and improved measures of LV diastolic function in patients with obstructive hypertrophic cardiomyopathy (oHCM). Whether longer-term treatment over 48 weeks results in further cardiac remodeling is unknown. Research Question: This study evaluates the effect of chronic treatment with aficamten on echocardiographic measures of cardiac structure and function in FOREST-HCM (NCT04848506), an open-label extension study that enrolled patients who completed a parent study with aficamten. Methods: Serial echocardiograms were performed in patients receiving open-label aficamten (5–20 mg daily) titrated to relieve LVOT obstruction (Valsalva LVOT <30 mmHg) while maintaining LV ejection fraction (LVEF) 50%. Results: As of August 31, 2024, 169 patients (mean±SD age 60±13 years; 45.6% female, 95.6% White, 2.4% Black, 1.2% Asian) completed 48 weeks of follow-up. Aficamten treatment resulted in sustained improvement in Valsalva and resting LVOT-G, LV wall thickness, left atrial volume index, and lateral and septal E/e' ( Figure 1 ). LVEF decreased mildly (-7±8%) and remained stable within a normal range between weeks 24 and 48. After 48 weeks, 74 patients demonstrated improvement in the total number of normal LV diastolic function measures ( Figure 2 ). Conclusion: Treatment with aficamten for 48 weeks in patients with oHCM resulted in significant improvement in important measures of cardiac structure and function, with continued benefit after 24 weeks and no meaningful adverse effects on LV systolic function, indicating sustained and favorable long-term cardiac remodeling.

Introduction/Background: Obesity, hypertension, and diabetes commonly coexist with obstructive hypertrophic cardiomyopathy (oHCM), potentially influencing symptom burden and functional limitation. It is not known if aficamten provides similar benefit across comorbidity subgroups. Research Questions/Hypothesis: Efficacy of aficamten in patients with oHCM and comorbidities. Methods/Approach: SEQUOIA-HCM (NCT05186818) randomized 282 adults with symptomatic oHCM to aficamten or placebo for 24 weeks. Participants were grouped by obesity (body mass index [BMI] ≥30 kg/m 2 ), hypertension (history or average screening/baseline systolic blood pressure ≥140 or diastolic blood pressure ≥90 mmHg), and diabetes (type 1, type 2, or unspecified per history). Baseline characteristics and treatment effects on peak oxygen uptake (pVO 2 ) and secondary endpoints were compared across comorbidity groups. Results/Data: At baseline, 32% had obesity, 55% had hypertension, and 8% had diabetes; 24% had 2 comorbidities, and 3% had all 3 comorbidities. At baseline, obesity was associated with lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), N-terminal pro-B-type natriuretic peptide (NT-proBNP), pVO 2 , and resting left ventricular outflow tract gradient (LVOT-G), and higher use of beta-blockers and disopyramide ( Table 1 ). At baseline, hypertension was associated with lower NT-proBNP, pVO 2 , and resting LVOT-G; older age; more atrial fibrillation and diabetes; and more use of non-dihydropyridine calcium-channel blockers and renin angiotensin system blockers. At baseline, diabetes was associated with older age, hypertension, higher KCCQ-CSS, lower NT-proBNP, and pVO 2 , and more use of renin angiotensin system blockers. Despite baseline differences, aficamten treatment compared to placebo consistently improved pVO 2 , KCCQ-CSS, Valsalva LVOT-G, and NT-proBNP independent of comorbid status (all interaction p-values >0.05) ( Figure 1; Table 2 ). The incidence of serious adverse events and left ventricular ejection fraction <50% were similar across subgroups, including when grouped by treatment arm. Conclusion(s): Comorbidities, particularly obesity and hypertension, are common in patients with oHCM. Aficamten treatment showed consistent clinical efficacy regardless of comorbidity status, supporting its use across a broad patient population.

Beta-blockers and nondihydropyridine calcium-channel blockers have been standard-of-care (SOC) medications for patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), even though these agents do not directly affect the underlying pathophysiology of the disease. Cardiac myosin inhibitors act by decreasing the number of myosin heads binding to actin, reducing the pathologic hypercontractility of HCM, and have been shown to improve exercise capacity and alleviate symptoms in oHCM when added to SOC medications. Cardiac myosin inhibitors are currently considered as second-line therapy in the absence of head-to-head comparison studies vs SOC medications. The aim of the ongoing phase 3 study MAPLE-HCM (Metoprolol vs Aficamten in Patients With LVOT Obstruction on Exercise Capacity in HCM) is to fill this evidence gap by evaluating aficamten as both first-line therapy for newly diagnosed oHCM and as a monotherapy alternative for patients currently on SOC drugs. The authors describe the rationale, design, and baseline characteristics of patients in this study. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM [MAPLE-HCM]; NCT05767346) (JACC Heart Fail. 2025;13:346-357) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND AND AIMS:Patients with obstructive hypertrophic cardiomyopathy (oHCM) treated with aficamten in SEQUOIA-HCM (NCT05186818) demonstrated marked improvement in symptoms and functional capacity. This analysis explores whether oHCM and mild symptoms patients experience similar clinical benefits with aficamten as patients with more advanced limitations. METHODS:Patients in SEQUOIA-HCM (N = 282) were grouped at baseline according to symptom severity. Mild symptoms (n = 118) were defined as New York Heart Association (NYHA) class II and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) ≥ 80, and moderate to severe symptoms (n = 150) as NYHA class II/III/IV and KCCQ-CSS <80. Primary endpoint was change in peak oxygen uptake (pVO2) from baseline to Week 24; secondary endpoints included change in NYHA class, KCCQ-CSS, outflow tract gradients, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). RESULTS:In aficamten-treated patients, change at Week 24 was not different between moderate to severe (1.8 mL/kg/min; n = 71) and mild (1.6 mL/kg/min; n = 62) symptom groups (P = .8). Likewise, the change in secondary endpoints (NYHA class, resting or Valsalva gradients, and NT-proBNP) did not differ significantly between the two symptom groups. Both groups experienced statistically significant improvements in KCCQ-CSS, but the extent of improvement was greater in the advanced symptom group (P = .02 for interaction). Treatment-emergent serious adverse events were infrequent in both groups. CONCLUSIONS:Patients with oHCM and mild symptoms treated with aficamten achieved significant improvement across a range of clinically relevant outcomes and generally similar to patients with more advanced symptoms. Less severely symptomatic patients could be considered for aficamten treatment.

Introduction: Treatment with aficamten in patients with obstructive HCM (oHCM) led to significant improvements in patient-reported outcomes (PROs) over 24 weeks in the pivotal SEQUOIA-HCM trial. The aim of this analysis was to provide a comprehensive evaluation of the long-term effects of aficamten across multiple PROs in the open-label extension trial FOREST-HCM (NCT04848506). Methods: Patients completing an aficamten parent study were offered participation in FOREST-HCM. Patients completing ≥48 weeks in FOREST-HCM as of August 31, 2024 were included. The Kansas City Cardiomyopathy Questionnaire (KCCQ), Seattle Angina Questionnaire 7-item (SAQ-7), and EuroQol Five-Dimensional Questionnaire (EQ-5D-5L) index and visual analog scale (VAS) were administered at baseline and at Weeks 12, 24, 36, and 48. The patient global impression of change (PGI-C) survey was administered at Weeks 12, 24, 36, and 48. Mixed models for repeated measures were used to analyze changes in mean KCCQ summary scores (including the Clinical Summary Score [CSS] and Overall Summary Score [OSS]), SAQ-7 summary scores, and EQ-5D-5L index and VAS scores from baseline to 48 weeks. Associations among PROs and between PROs and clinical measures of HCM severity were evaluated using Spearman correlation coefficients. Results: As of August 2024, 182 patients (mean age 60.2 [SD ±13.1] years, 56% were male) had reached 48 weeks of follow-up. Significant improvements in all PROs were observed by Week 12 and sustained through Week 48 ( Figure ). Least-squares mean differences (95% CI) between the KCCQ-CSS and -OSS from baseline to 48 weeks were 16.1 (14.4–17.7) and 19.1 (17.3–21.0), respectively (P<0.0001), with the largest gains in the quality-of-life (QoL) domain (26.0 [23.3–28.6]; P<0.0001). The SAQ-7 summary score increased by 17.7 (15.5–19.8; P<0.0001), with a 22.4-point gain (19.1–25.6; P<0.0001) in the QoL domain. EQ-5D-5L index and VAS scores improved by 0.12 (0.10–0.14) and 13.4 (11.6–15.2), respectively (P<0.0001). At 48 weeks, 77% of patients reported feeling “Much Improved” or “Very Much Improved” on the PGI-C. Improvements in PROs were significantly correlated with important clinical measures of oHCM severity ( Table ). Conclusions: Aficamten led to significant and sustained improvements in PROs in patients with oHCM. The improvement was seen across all symptom domains, particularly QoL, and correlated with important clinical measures of disease severity.

Beta-blockers and nondihydropyridine calcium-channel blockers have been standard-of-care (SOC) medications for patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), even though these agents do not directly affect the underlying pathophysiology of the disease. Cardiac myosin inhibitors act by decreasing the number of myosin heads binding to actin, reducing the pathologic hypercontractility of HCM, and have been shown to improve exercise capacity and alleviate symptoms in oHCM when added to SOC medications. Cardiac myosin inhibitors are currently considered as second-line therapy in the absence of head-to-head comparison studies vs SOC medications. The aim of the ongoing phase 3 study MAPLE-HCM (Metoprolol vs Aficamten in Patients With LVOT Obstruction on Exercise Capacity in HCM) is to fill this evidence gap by evaluating aficamten as both first-line therapy for newly diagnosed oHCM and as a monotherapy alternative for patients currently on SOC drugs. The authors describe the rationale, design, and baseline characteristics of patients in this study. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM [MAPLE-HCM]; NCT05767346).

Background Septal myectomy (SM) outcomes in patients with obstructive hypertrophic cardiomyopathy (oHCM) are derived from experienced centers' reports or survey data. In this study, we report the characteristics and procedural outcomes of SM in an all-payer oHCM cohort. Methods An observational study using individual-level healthcare claims data (Symphony Health, covers ˃280 million enrollees). Adult patients with oHCM diagnosis who underwent SM (2016-2021) were included. Patients had to have ≥ 1 diagnosis claim (continuous enrollment) in the 120 days prior to SM. Baseline characteristics were derived from claims codes in the 90 days prior to SM. Inpatient complications (within 30 days post-SM) included a composite of: repeat SM, cardiac arrest, CPR, TIA/stroke, anoxic brain damage, hemothorax, tracheotomy, emergency intubation, ECMO, new dialysis, and ventricular septal defect. Results We identified 5,324 patients who underwent SM for oHCM (median age 62.0, 53.5% female, 70% with commercial insurance). Baseline characteristics are shown (Table 1). Concomitant mitral valve repair occurred in 33.4%, mitral valve replacement in 13.2%, papillary muscle intervention in 11.8%, and left atrial appendage clipping/excision in 11.8%. There were 48 (0.9%) patients without claims following SM. Inpatients events occurred in 627 (11.8%) patients. New atrial fibrillation/flutter occurred in 1498 (28.1%) patients and heart block requiring pacemaker implantation occurred in 526 (9.9%) patients. Repeat septal myectomy within 30 days was required in 43 (0.8%) patients. Predictors of inpatients complications are shown in Table 2. Conclusions In a large cohort of patients with oHCM undergoing SM, morbidity resulting from SM complications was substantial. Further representative nationwide studies are needed to understand the long-term non-fatal outcomes of HCM patients post-SM.