Ko JM, Kutty S, Van Bulck L
… +7 more, Jackson JL, Caruana M, Jameson SM, Mahadevan VS, Moons P, Cedars AM, APPROACH-IS II consortium, on behalf of the International Society for Adults Congenital Heart Disease (ISACHD)
BACKGROUND: Although disease-specific patient-reported outcomes (PROs) are well accepted as direct and indirect clinical outcomes in various diseases, data on PRO performance in adult congenital heart disease (ACHD) are...BACKGROUND: Although disease-specific patient-reported outcomes (PROs) are well accepted as direct and indirect clinical outcomes in various diseases, data on PRO performance in adult congenital heart disease (ACHD) are limited to nondisease-specific metrics. We, therefore, investigated the association between responses to a novel ACHD-specific PRO metric and both clinical variables and gold standard PROs. METHODS: We assessed the association between patient-perceived health status as assessed by the summary score of the Adult Congenital Heart Disease Patient-Reported Outcome Version 1 (ACHD PRO V.1) and hospital admission within the preceding 5 years in the English-speaking subgroup of an international cohort of patients with ACHD enrolled in APPROACH IS-II between February 10, 2019, and December 14, 2022. We also examined the relationship between ACHD PRO V.1 domain scores and domain-relevant clinical variables, the Linear Analog Scale Quality of Life, the Patient Health Questionnaire-8, and the Generalized Anxiety Disorder-7. RESULTS: The analysis includes 333 patients. Both unadjusted and adjusted models revealed that worse patient-perceived health status was associated with unplanned hospital admission (adjusted β, -5.7 [95% CI, -9.9 to -1.6]; =0.007). Univariate analysis indicated a strong association between ACHD PRO V.1 domains and relevant clinical variables. A moderate correlation was found between the QOL and anxiety/depression domains and their corresponding gold standard (=0.467, <0.001 with the Linear Analog Scale Quality of Life; =-0.581, <0.001 with the Patient Health Questionnaire-8; and =-0.540, <0.001 with the Generalized Anxiety Disorder-7). CONCLUSIONS: A lower ACHD PRO V.1 summary score is associated with a history of unplanned cardiac admission. In addition, the ACHD PRO V.1 domains show good content validity by comparison with relevant clinical conditions and gold standard PROs. These data support the use of the ACHD PRO V.1 as a direct and surrogate clinical outcome in ACHD.
Aguado B, Ruffenach G, Lacoste-Palasset T
… +9 more, Görlach A, Riou M, Gourmelon M, Bauer F, Humbert M, Schini-Kerth V, Vachiéry JL, Montani D, Antigny F
Circ Heart Fail
· 2026 Feb · PMID 41347317
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Inhibiting SGLT2 (sodium-glucose cotransporter 2) has recently transformed the medical care of patients with left heart disease. Right ventricular failure is a major predictor for patients suffering from pulmonary hypert...Inhibiting SGLT2 (sodium-glucose cotransporter 2) has recently transformed the medical care of patients with left heart disease. Right ventricular failure is a major predictor for patients suffering from pulmonary hypertension of various causes, including those with postcapillary pulmonary hypertension due to left heart disease. Similar to how SGLT2 inhibition benefits patients with left heart failure, recent studies have suggested utilizing these molecules to enhance right ventricular function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of SGLT2is (SGLT2 inhibitors) in pulmonary hypertension. Further dedicated trials are necessary to establish their role in right ventricular pulmonary vascular disease.
BACKGROUND: Studies have demonstrated that patients with myocarditis may have a higher burden of cardiomyopathy-associated genetic variants than the general population. However, data on children are limited. We compared...BACKGROUND: Studies have demonstrated that patients with myocarditis may have a higher burden of cardiomyopathy-associated genetic variants than the general population. However, data on children are limited. We compared the prevalence of rare predicted-damaging variants and clinically pathogenic variants in children with dilated cardiomyopathy (DCM) secondary to myocarditis with that in children with DCM alone and in heart-healthy controls. METHODS: Children with DCM secondary to myocarditis and children with DCM alone who underwent exome sequencing as part of a prior cross-sectional study were identified in the Pediatric Cardiomyopathy Registry, a large multicenter registry of children with cardiomyopathy. Controls from the Indiana University Biobank were matched 4:1 with myocarditis cases on genomic similarity. Rare predicted-damaging variants in cardiomyopathy-associated genes were identified using a bioinformatics approach. Clinical guidelines were used to determine clinical pathogenicity. The prevalence of variants was compared across the 3 groups. RESULTS: There were 32 patients with DCM secondary to myocarditis. The prevalence of rare predicted-damaging variants was 34.4% (11/32 [95% CI, 18.6%-53.2%]) in cases compared with 6.3% (8/128 [95% CI, 2.7%-11.9%]) in controls (<0.001). Clinical review indicated all rare predicted-damaging variants in cases were pathogenic (1/12), likely pathogenic (3/12), or variants of uncertain significance (8/12), whereas most variants in controls were benign (2/8) or likely benign (4/8). The prevalence of pathogenic/likely pathogenic variants in cases was 12.5% (95% CI, 3.5%-29.0%) compared with 0% (95% CI, 0%-2.3%) in controls (<0.01). Rare predicted-damaging and clinically pathogenic/likely pathogenic variant prevalence was not significantly different in children with DCM secondary to myocarditis and DCM without myocarditis (=0.17 and =1.00, respectively). CONCLUSIONS: Children with DCM secondary to myocarditis had a higher burden of variants in cardiomyopathy-associated genes than that of heart-healthy controls. Larger studies will be needed to determine the utility of routine genetic testing in this population.
Kaski JP, Kantor PF, Nakano SJ
… +17 more, Olivotto I, Russell MW, Godown J, Chiu M, German P, Heitner SB, Jacoby DL, Kupfer S, Lutz J, Maharao N, Malik FI, Melloni C, Nieto Morales PF, Simkins T, Wei J, Ho CY, CEDAR-HCM Investigators
Circ Heart Fail
· 2026 Feb · PMID 41347307
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BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality in children, but treatment options are limited. Aficamten, a next-in-class cardiac myosin inhibitor, directly targets the hyp...BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality in children, but treatment options are limited. Aficamten, a next-in-class cardiac myosin inhibitor, directly targets the hypercontractility underlying HCM. Aficamten improved exercise capacity, health status, and symptoms in adults with obstructive HCM in the pivotal, phase 3 SEQUOIA-HCM trial (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM; NCT05186818). METHODS: CEDAR-HCM (Clinical Evaluation of dosing With Aficamten to Reduce Obstruction in Pediatric Population With HCM) is an international, multicenter, randomized, double-blind, placebo-controlled trial followed by an open-label extension to evaluate the efficacy, safety, and pharmacokinetics of aficamten in pediatric participants with symptomatic obstructive HCM. The trial will enroll ≈55 adolescents (12 to <18 years) and subsequently expand to include at least 10 children (6 to <12 years) with nonsyndromic obstructive HCM, left ventricular ejection fraction ≥60%, Valsalva left ventricular outflow tract gradient ≥50 mm Hg, and New York Heart Association functional class ≥II. Participants will be randomized 2:1 to aficamten or placebo in addition to standard of care therapy or as monotherapy, with echocardiogram-guided dose adjustments targeting a Valsalva left ventricular outflow tract gradient <30 mm Hg while maintaining left ventricular ejection fraction ≥50%. The primary end point is the change in Valsalva left ventricular outflow tract gradient from baseline to week 12. Secondary end points include change in resting left ventricular outflow tract gradient, cardiac biomarkers, New York Heart Association functional class, and assessment of pharmacokinetics. After completing the 12-week randomized period, eligible participants will continue into a long-term open-label extension. RESULTS: The trial is currently enrolling. CONCLUSIONS: Results of CEDAR-HCM will provide insight into the safety and efficacy of aficamten in adolescents and in children as young as 6 years of age. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06412666.
Air pollution is a major global environmental health threat and the leading environmental risk factor contributing to cardiovascular morbidity and mortality. Emerging evidence increasingly implicates air pollution as a c...Air pollution is a major global environmental health threat and the leading environmental risk factor contributing to cardiovascular morbidity and mortality. Emerging evidence increasingly implicates air pollution as a critical, modifiable driver in the pathogenesis, progression, and prognosis of heart failure. Air pollution is increasingly recognized as part of the exposome-a complex interplay of environmental, social, and behavioral exposures accumulated across the life course. In this review, we synthesize experimental data demonstrating mechanistic links between air pollution and heart failure, along with growing experimental, clinical, and epidemiological evidence connecting both short- and long-term air pollution exposure with increased risk of heart failure progression across heart failure stages. We further examine how air pollution interacts with other exposomic risk domains-such as the social exposome, built environment, and access to greenery-compounding vulnerability in marginalized and underserved populations. The review will also summarize current approaches to communicate air pollution risk and propose practical strategies for both individuals and healthcare systems to mitigate its cardiovascular impact. Finally, we present a clinical framework for assessing and managing air pollution exposure in patients with heart failure, emphasizing the need for targeted risk stratification and the development of context-specific mitigation interventions.
BACKGROUND: Less than 1 in 3 patients in the United States with heart failure (HF) with reduced ejection fraction are receiving guideline-recommended medical therapy. Remote titration programs outside of structured episo...BACKGROUND: Less than 1 in 3 patients in the United States with heart failure (HF) with reduced ejection fraction are receiving guideline-recommended medical therapy. Remote titration programs outside of structured episodes of care may address this issue and improve the implementation of guideline-recommended care. METHODS: AIM-POWER (Artificial Intelligence Mobile Health Trial of a Digital Platform to Optimize Guideline-Directed Heart Failure Therapy Using Wearable Sensors) was a multicenter, open-label, clinical trial of participants with HF with reduced ejection fraction who were not optimized on medical therapy designed to evaluate the safety and efficacy of a digital intervention to guide optimal initiation and titration of pharmacological therapy. Participants were randomized 1:1 to a BiovitalsHF intervention or usual care and followed for 90 days. Participants receiving the intervention assessed their weight daily, and blood pressure and heart rate twice daily. These data were collected remotely and used to create outpatient medication titration recommendations from the BiovitalsHF platform to site clinicians every 2 weeks. The primary outcome was the between-group difference in the change in an HF optimal therapy score. RESULTS: We randomized 122 participants at 21 sites in the United States. The mean (±SD) age of the participants was 61.6±12.4 years, and 69% were male. The mean left ventricular ejection fraction was 29±6.7%, and the mean baseline HF optimal therapy score was 3.8±1.8 (range, 0-8). At 90 days after randomization, the change in the score was significantly greater in the intervention group than usual care group (1.72 ±1.75 intervention versus 0.44 ±1.18 usual care; <0.001). CONCLUSIONS: In participants with HF with reduced ejection fraction who were not yet optimized on medical therapy, a digital intervention that focused on the optimization of HF pharmacological therapy resulted in a significantly greater change in an HF optimal therapy score at 90 days than usual care. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04191330.
Gamble DT, Ross J, Khan H
… +10 more, Cheyne L, Rudd A, Srivanasan J, Horgan G, Hogg D, Myint PK, Newby DE, Williams C, Gray SR, Dawson D
Circ Heart Fail
· 2026 Mar · PMID 41332388
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BACKGROUND: Takotsubo cardiomyopathy is an acute cardiac emergency presenting with severe left ventricular dysfunction. Physical exercise training or cognitive behavioral therapy may enhance myocardial recovery after tak...BACKGROUND: Takotsubo cardiomyopathy is an acute cardiac emergency presenting with severe left ventricular dysfunction. Physical exercise training or cognitive behavioral therapy may enhance myocardial recovery after takotsubo cardiomyopathy. METHODS: In a prospective multicenter clinical trial conducted between February 2020 and August 2023, patients with acute takotsubo cardiomyopathy were randomized 1:1:1 to physical exercise training, cognitive behavioral therapy, or standard care for 12 weeks after index presentation. The primary end point was resting phosphocreatine/gamma-ATP ratio assessed by P-magnetic resonance spectroscopy. Secondary end points were the rate of oxygen consumption at peak exercise on cardiopulmonary exercise testing, 6-minute walk distance, left ventricular global longitudinal strain, and the Minnesota Living With Heart Failure Questionnaire. Twelve-week changes in outcome were compared between allocated trial interventions. RESULTS: Seventy-six participants were recruited: the median age was 66 years, and 91% were women. Compared with standard care, the primary end point of myocardial phosphocreatine/gamma-ATP ratio was improved by physical exercise training (0.4 [95% CI, 0.1-0.8]; =0.016) and cognitive behavioral therapy (0.3 [0.01-0.7]; =0.043). Both physical exercise training and cognitive behavioral therapy improved rate of oxygen consumption at peak exercise (4.7 [1.4-8.0] and 4.0 [1.5-6.4] mL/min per kg; =0.001 and 0.004, respectively) and 6-minute walk distance (92.6 [24.7-160.6] and 73.3 [7.9-138.8] m; =0.004 and 0.029, respectively) compared with standard care. There were no differences in global longitudinal strain or symptom burden. CONCLUSIONS: In patients with acute takotsubo cardiomyopathy, a 12-week intervention with exercise training or cognitive behavioral therapy improved left ventricular myocardial energetics and exercise performance without demonstrable effects on symptoms of heart failure. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04425785.
BACKGROUND: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the i...BACKGROUND: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH. METHODS: Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models. RESULTS: Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output (<0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; <0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16-3.47]; =0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10-2.46]; =0.01) was associated with worse survival. CONCLUSIONS: Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.
Golbus JR, Basu T, Luff E
… +6 more, Hu Y, Zeng D, Gesierich C, Resnicow K, Klasnja P, Nallamothu BK
Circ Heart Fail
· 2026 Jan · PMID 41332378
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BACKGROUND: Anecdotal evidence suggests that symptoms and physical activity levels in patients with heart failure (HF) fluctuate considerably, though empirical data to support this claim are sparse. We examined how stabl...BACKGROUND: Anecdotal evidence suggests that symptoms and physical activity levels in patients with heart failure (HF) fluctuate considerably, though empirical data to support this claim are sparse. We examined how stable psychosocial traits (eg, intrinsic motivation), situational psychosocial states (eg, vitality), and HF symptoms vary in stable patients with HF and their association with physical activity. METHODS: The MOVIN-HF study (Mobile Health Intervention to Increase Activity in Heart Failure) was a prospective, observational study of patients with symptomatic HF. We collected data on (1) psychosocial traits at baseline and (2) twice daily ecological momentary assessments for 28 days of participants' symptoms and current psychosocial states. Physical activity was measured by smartwatch step counts. We evaluated the association between baseline psychosocial states and mean daily step counts and between ecological momentary assessments of symptoms and psychosocial states and short-term step counts (12 hours after ecological momentary assessments). Mixed effects models quantified associations. RESULTS: Between February and June 2024, 30 participants enrolled in the study; the mean age was 59.7 (SD, 13.6) years, 53% were female, and most (63%) had New York Heart Association class 2 HF symptoms. Baseline psychosocial traits like motivational quality were significantly associated with daily step count. For example, each 1-point increase in intrinsic motivation was associated with 39% higher daily step count (95% CI, 3%-87%). There was also significant variability in ecological momentary assessment scores of symptoms and psychosocial states: 10 (33%) participants experienced a 50% or greater change in HF symptoms, and 18 (60%) a 50% or greater change in vitality. HF symptoms and psychosocial states (eg, vitality, competence) were significantly associated with 12-hour step count. CONCLUSIONS: Baseline psychosocial traits are associated with daily physical activity. In addition, symptoms and psychosocial states fluctuate frequently among patients with HF and are associated with short term physical activity. These findings suggest tailored interventions may improve physical activity levels.
Park A, Andargie TE, Tian X
… +15 more, Keller M, Cavagna I, Redekar N, Hill T, Kong H, Park W, Zhao X, Balasubramanian P, Tang D, Karaba A, Jang M, Solomon MA, Valantine H, Shah P, Agbor-Enoh S
Circ Heart Fail
· 2026 Jan · PMID 41307146
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BACKGROUND: Adverse events after durable left ventricular assist devices (LVADs) pose a challenge to survival. However, there are limited risk stratification approaches. Plasma cell-free DNA (cfDNA) offers potential as a...BACKGROUND: Adverse events after durable left ventricular assist devices (LVADs) pose a challenge to survival. However, there are limited risk stratification approaches. Plasma cell-free DNA (cfDNA) offers potential as a biomarker for assessing end-organ injury and risk stratification. METHODS: The study included a multicenter prospective cohort of patients with heart failure with and without LVAD (cohort 1), a separate cohort of patients with heart failure with paired samples before and after LVAD (cohort 2) implantation, and a comparator group of healthy controls. Nuclear cfDNA (ncfDNA) and mitochondrial cfDNA were quantified by digital droplet polymerase chain reaction. Tissue-specific cfDNA was identified using whole-genome bisulfite sequencing. Differences in cfDNA levels by LVAD use were assessed with the Wilcoxon rank-sum test or the paired test. Outcomes (hemocompatibility-related adverse event-free survival and infection-free survival) by cfDNA tertiles were compared by log-rank tests. RESULTS: Cohort 1 had 76 patients with LVAD and 144 without LVAD. Cohort 2 had 40 patients with LVAD with samples before and after LVAD. ncfDNA levels were 4-fold higher (9794 versus 2386 copies/mL; <0.001), and mtDNA was 1.5-fold higher (134 707 versus 82 054 copies/mL; =0.01) in cohort 1 compared with healthy controls (n=48). Patients without LVAD had higher ncfDNA levels compared with those with LVAD in cohort 1 (11 423 versus 7912 copies/mL; =0.019). After LVAD placement in cohort 2, ncfDNA nearly halved (18 980 versus 10 228 copies/mL; <0.001), with significant reductions in innate immune, vascular endothelium, gastrointestinal, and liver cfDNA levels. The highest pre-LVAD tertile of ncfDNA was associated with worse infection-free (hazard ratio, 2.94 [95% CI, 1.31-6.56]; =0.006) and hemocompatibility-related adverse event-free (hazard ratio, 3.24 [95% CI, 1.03-10.3]; =0.034) survival. CONCLUSIONS: LVAD implantation was associated with reductions in systemic and tissue-specific cfDNA levels. cfDNA levels offer promise for improving risk stratification of LVAD candidates for post-LVAD outcomes.
Gao Z, Rossler KJ, Rogers HT
… +12 more, Gregorich ZR, Aballo TJ, Chapman EA, Price SJ, Hermsen J, de Lange WJ, Zhu Y, Zhang B, Chen J, Ralphe JC, Kamp TJ, Ge Y
Circ Heart Fail
· 2025 Dec · PMID 41277423
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BACKGROUND: Hypertrophic cardiomyopathy (HCM) has traditionally been regarded as a disease of the sarcomere; however, it is in the midst of a paradigm shift with growing recognition of contributions beyond the sarcomere...BACKGROUND: Hypertrophic cardiomyopathy (HCM) has traditionally been regarded as a disease of the sarcomere; however, it is in the midst of a paradigm shift with growing recognition of contributions beyond the sarcomere to the heterogeneity of HCM phenotypes. Innovative approaches are essential to uncover novel determinants and mechanisms underlying this heterogeneity. Top-down proteomics has emerged as a powerful method for analysis of proteoforms-the myriad protein products arising from genetic variants, posttranslational modifications, and splicing isoforms from a single gene-offering a more precise lens to understand the disease heterogeneity in HCM. Yet, how proteoforms are altered on a global scale in HCM has not been investigated. METHODS: Global top-down proteomics was performed on myocardial samples from patients with advanced obstructive HCM and nonfailing controls. Specifically, serial protein extraction enabled by the photocleavable surfactant, 4-hexylphenylazosulfonate (Azo), was utilized to solubilize diverse categories of proteins from minimal tissue, including membrane proteins. Subsequently, high-sensitivity top-down mass spectrometry was used to detect and quantify proteoforms across various cellular compartments. RESULTS: Using this global top-down proteomics approach, we have detected ≈2000 proteoforms across disparate cellular compartments, including the sarcoplasmic reticulum, cytoskeleton, mitochondria, and nucleus, in advanced obstructive HCM tissues. Quantitative analysis uncovered significant alterations not only in sarcomeric but also cytoskeletal, mitochondrial, nucleosome, and sarcoplasmic reticulum proteoforms in HCM as compared with nonfailing controls. Notably, we have discovered a significant proteoform crosstalk among the sarcomere, sarcoplasmic reticulum, and cytoskeleton. Moreover, we have identified a previously unrecognized decrease in succinylated mitochondrial proteoforms as a critical feature of the advanced obstructive HCM proteoform landscape, alongside a marked reduction in acetylation of nucleosome proteins. CONCLUSIONS: This study represents the most comprehensive analysis of the proteoform landscape in HCM to date, uncovering pathways beyond the sarcomere that may contribute to HCM pathophysiology and identifying potential targets for development of therapeutic interventions.
BACKGROUND: Women with obstructive hypertrophic cardiomyopathy often present with a greater burden of disease and worse prognosis. Whether there are sex-related differences in response to aficamten is unknown. METHODS: W...BACKGROUND: Women with obstructive hypertrophic cardiomyopathy often present with a greater burden of disease and worse prognosis. Whether there are sex-related differences in response to aficamten is unknown. METHODS: We performed a prespecified subgroup analysis of sex differences in the double-blind, randomized-controlled SEQUOIA-HCM trial (Safety, Efficacy and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) of aficamten versus placebo in patients with obstructive hypertrophic cardiomyopathy. Baseline characteristics were compared using the test for continuous variables and the χ test for categorical variables. Prespecified primary (change in peak oxygen uptake) and secondary end points from baseline to end of treatment (week 24) were analyzed using linear regression models, adjusted for baseline values, β-blocker use, and exercise mode. RESULTS: Of the 282 participants, women (n=115) were older (64 years in women versus 56 years in men) and had lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and lower peak oxygen uptake at baseline. Women had smaller left ventricular chamber sizes, higher E/e' ratios, and higher left ventricular outflow tract gradients. At 24 weeks, there was a significant treatment-related increase in peak oxygen uptake in women (+1.5 [+0.7 to +2.4]) and men (+2.0 [+0.9 to +3.0]). Both women and men had significant treatment-related decreases in left ventricular outflow tract gradients at rest and with Valsalva, with no sex-by-treatment interaction at week 24 (≥0.13). There was a significant improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score in women (11 [6-15]) and men (6 [2-9]; =0.08). Women had a greater reduction in lateral E/e' ratio (=0.01). The geometric mean proportional reduction in NT-proBNP was similar in women and men (=0.10). CONCLUSIONS: Women enrolled in SEQUOIA-HCM were older with worse baseline health status, higher NT-proBNP, and higher left ventricular outflow tract gradients compared with men. Despite these differences, both men and women derived significant benefits in the primary and secondary end points following treatment with aficamten.