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: The comparative effect of cardiac myosin inhibitor therapy in obstructive hypertrophic cardiomyopathy (oHCM) patients with high vs. lesser left ventricular outflow tract gradients (LVOT-G) has not been described previously. : Patients in SEQUOIA-HCM (NCT5186818), the pivotal phase 3 placebo-controlled trial of aficamten in symptomatic oHCM, were grouped according to baseline peak Valsalva LVOT-G of < 100 mmHg (Group 1; n=209; 74%) or ≥100 mmHg (Group 2, n=73; 26%). The prespecified primary endpoint was proportional change from baseline to Week 24 in Valsalva LVOT-G. All echocardiographic data were core lab reported. Secondary endpoints included symptoms, cardiac biomarkers, and exercise capacity. : Baseline characteristics were generally similar with important differences seen in NT-proBNP (median 644 vs. 1148 pg/mL; p < 0.001) and pVO 2 (mean 18.8 vs. 17.5 mL/kg/min; p = 0.031) in Groups 1 vs. 2, respectively. Baseline Valsalva LVOT-G was 69 ± 21 mmHg vs 123 ± 25 mmHg in Groups 1 and 2, respectively. While the absolute reductions in Valsalva LVOT-G at week 24 in Group 2 demonstrated a significantly larger treatment effect (-43 vs -68 mmHg in Groups 1 vs 2, p = 0.002), the proportional reductions were similar between groups (-64% vs -71% in Group 1 vs 2; interaction p = 0.21). Secondary endpoints (rest LVOT-G, symptom burden, cardiac biomarkers, and exercise capacity) improved significantly from baseline with no significant between-group differences (Table). Post-titration doses by group were similar, with 81% and 88% in each cohort receiving 15mg or 20mg dose (p = 0.21), respectively. Treatment emergent adverse events (TEAE's) were similar (any TEAE 77 [71%] vs. 28 [85%] p = 0.60). There were no per protocol down titrations in Group 2. : Patients in SEQUOIA-HCM with LVOT gradients ≥100 mmHg demonstrated similar efficacy and safety to those with LVOT gradients < 100 mmHg. Specifically, treatment with aficamten resulted in significant improvements in proportional hemodynamic response, symptom relief, exercise capacity, and reduction in cardiac biomarkers, independent of the severity of baseline obstruction. These results suggest that aficamten is a safe and effective treatment option for oHCM regardless of baseline LVOT-G. [ABSTRACT FROM AUTHOR]