Characterization and Application of Novel Exercise Recovery Patterns That Reflect Cardiac Performance: A Substudy of the SEQUOIA-HCM Trial

Circulation. 2025 Sep 5. doi: 10.1161/CIRCULATIONAHA.124.073585. Online ahead of print.

ABSTRACT

BACKGROUND: Post-exercise oxygen uptake recovery (VO₂Rec) is slow in advanced heart failure. We sought to establish easily derived VO₂Rec measures and evaluate their cardiospecificity and prognostic relevance in patients with dyspnea on exertion. We further sought to determine VO₂Rec modifiability proportional to changes in cardiac function with disease-specific treatment of obstructive hypertrophic cardiomyopathy.

METHODS: VO₂Rec patterns were evaluated in relation to cardiac performance and the primary outcome of heart failure hospitalization death in a referral cohort with dyspnea on exertion undergoing cardiopulmonary exercise testing with hemodynamic monitoring (MGH-ExS [Massachusetts General Hospital Exercise Study]). We then investigated longitudinal measures of VO₂Rec in the pivotal phase 3 randomized controlled trial SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in Hypertrophic Cardiomyopathy) of aficamten versus placebo for 24 weeks in participants with symptomatic obstructive hypertrophic cardiomyopathy. For both cohorts, VO₂Rec was uniformly measured as time for VO₂ to decline by >0%, 12.5% (VO₂T_12.5%), 25%, and 50% of peak VO₂.

RESULTS: Among 814 MGH-ExS patients (58±16 years of age, 58% women), those with a longer VO₂T_12.5% (≥35 versus <35 seconds) demonstrated elevated exercise pulmonary capillary wedge pressure to cardiac output slope (P<0.0001) with no difference in peripheral oxygen extraction (P=0.11). For each 15-second increase in VO₂T_12.5%, the hazard ratio for heart failure hospitalization and all-cause death was 1.54 (95% CI, 1.35-1.76; P<0.001). In SEQUOIA-HCM participants with cardiopulmonary exercise testing at baseline and week 24 (n=263, 59.1±2.9 years of age, 41% women), baseline VO₂T_12.5% was 45±20 seconds and improved 8 seconds (95% CI, -12 to -5 seconds; P<0.001) with aficamten treatment compared with placebo at 24 weeks. Participants treated with aficamten versus placebo were more likely to improve VO₂T_12.5% by ≥15 seconds (odds ratio [OR], 3.7 [95% CI, 1.9-6.9]; number needed to treat=4.8). Shortening of VO₂T_12.5% correlated with reduced NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin I, and left ventricular outflow tract gradient (all P<0.005).

CONCLUSIONS: This study established VO₂T_12.5% as a new measure that reflects cardiac performance during exercise and predicted heart failure event-free survival. Furthermore, VO₂T_12.5% improved proportional to improvements in left ventricular outflow tract gradient and cardiac biomarkers in response to aficamten treatment, a cardiospecific therapy for obstructive hypertrophic cardiomyopathy. The simplicity and physiological relevance of VO₂T_12.5% support its regular inclusion in cardiopulmonary exercise testing protocols evaluating cardiac function during exercise.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05186818.

PMID:40910168 | DOI:10.1161/CIRCULATIONAHA.124.073585