Abstract Body (Do not enter title and authors here): 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 C² test for categorical variables. Prespecified primary (change in peak oxygen uptake, pVO₂) 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 pVO₂ 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 pVO₂ 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.