Abstract Body (Do not enter title and authors here): 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 [pVO₂], minute ventilation [VE]/carbon dioxide output [VCO₂], 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 pVO₂ and inverse VE/VCO₂ 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 pVO₂ 18.5±4.5 mL/kg/min) were included. After adjustment, per each 5 mL/m² decrease in left atrial volume index (LAVi), there was a 0.3 mL/kg/min increase in pVO₂ (p=0.02), a 0.5 unit decrease in VE/VCO₂ 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 pVO₂ 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 pVO₂ (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.