Abstract Body (Do not enter title and authors here): Background
Recent heart failure studies show that post-exercise VO₂ recovery (VO₂Rec) patterns track closely with exercise cardiac output and outcomes, but not with peripheral oxygen (O₂) extraction. In patients with obstructive hypertrophic cardiomyopathy (oHCM), studies of VO₂Rec changes with effective cardio-specific interventions are lacking. We hypothesized that treatment with aficamten, a next-in-class cardiac myosin inhibitor, would shorten VO₂Rec in patients with oHCM.

Methods
SEQUOIA-HCM is the pivotal phase 3 trial of aficamten in symptomatic patients with oHCM (New York Heart Association functional class [NYHA FC] II-III, peak VO₂ [pVO₂] ≤90% predicted, respiratory exchange ratio ≥1.05). Patients were randomized 1:1 to aficamten or placebo for 24 weeks with the primary endpoint of change from baseline (BL) in pVO₂. For this analysis, VO₂Rec was measured as the time taken after exercise cessation for VO₂ to decline by 12.5% (t_12.5%), 25%, or 50% of pVO₂. Response rates for achieving clinically meaningful threshold reductions (>15 seconds) in t_12.5%, and correlations with changes in cardiac function (echocardiographic parameters/cardiac biomarkers) were assessed.

Results
Among 282 randomized patients (mean age 59.1±12.9 years, 115 female [41%]), 263 (93%) had CPETs at BL and W24 with VO₂Rec values as shown (Table). At W24, t_12.5% improved by 8sec (95% CI, -12, -5sec, p<0.001) in the aficamten group compared to the placebo group. Those treated with aficamten were more likely to improve t_12.5% by ≥15sec (OR 3.7 95% CI 1.9-6.9, NNT=4.8) than those on placebo. Shortening of t_12.5% correlated with reduced NT-proBNP, high-sensitivity cardiac troponin I, left ventricular outflow tract gradient, and improved NYHA FC and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (all p<0.005).

Conclusion
This is the first study to establish that VO₂Rec is modifiable in response to cardio-specific intervention (aficamten) in patients with oHCM. VO₂Rec (t_12.5%) shortened proportionally and in parallel with other metrics of improved cardiac function, underscoring the benefits of aficamten for oHCM, and supporting inclusion of VO₂Rec as a routine metric for evaluating cardio-specific interventions for oHCM.