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

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

Methods: VORec 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 VORec 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, VORec was uniformly measured as time for VO to decline by >0%, 12.5% (VOT), 25%, and 50% of peak VO.

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

Conclusions: This study established VOT as a new measure that reflects cardiac performance during exercise and predicted heart failure event-free survival. Furthermore, VOT 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 VOT support its regular inclusion in cardiopulmonary exercise testing protocols evaluating cardiac function during exercise.

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