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

Campain, J; Griskowitz, C; Newlands, C; Claggett, BL; Kulac, IJ; McGinnis, S; Giverts, I; Moreno, F; Minasian, A; Prasad, C; Rupert, L; Landsteiner, I; Iskenderian, N; Coats, CJ; Lee, MMY; Maron, MS; Owens, AT; Jacoby, DL; Heitner, SB; Kupfer, S; Malik, FI; Wohltman, A; Malhotra, R; Lewis, GD

doi:10.1161/circulationaha.124.073585

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

CirculationPublished 5 Sep 2025Secondary analysis of the SEQUOIA-HCM randomised trial, with a derivation referral cohort

Primary resultResultHazard ratio 1.54 95% CI 1.35–1.76

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Authors' conclusion

This study established VO2T12.5% as a new measure that reflects cardiac performance during exercise and predicted heart failure event-free survival. Furthermore, VO2T12.5% 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.

Study context

Population: Referral cohort with dyspnea on exertion undergoing CPET with hemodynamic monitoring (MGH-ExS); participants with symptomatic obstructive hypertrophic cardiomyopathy (SEQUOIA-HCM)814 MGH-ExS

Comparison: Aficamten vs placebo; VO2T12.5% ≥35 vs <35 seconds
Primary endpoint: HF hospitalization or death (MGH-ExS)

Methodological detailsMGH-ExS, phase 3, substudy

MGH-ExS
Phase 3
Substudy

Primary result

As reported in the abstract

Hazard ratio

1.54

95% CI 1.35–1.76

P < 0.001

Per 15-second increase in VO2T12.5%

HR 1.54 (95% CI 1.35–1.76); P < 0.001

Per 15-second increase in VO2T12.5%, as printed

Further findings

Outcome	← Lower with aficamten ←→ Higher with aficamten →	OR (95% CI)
Improvement of VO2T12.5% by ≥15 seconds (SEQUOIA-HCM) · 24 weeksNNT=4.8	0.10.31310	3.7 (1.9–6.9)
	0.10.31310Odds ratio (log scale)

Outcome	Difference (seconds) (95% CI)	P value
Change in VO2T12.5% (SEQUOIA-HCM) · 24 weeksImproved; baseline VO2T12.5% 45±20 seconds	8 (−12 to −5)	P < 0.001

Change in VO2T12.5% (SEQUOIA-HCM): 263 participants with CPET at baseline and week 24

Exercise PCWP to cardiac output slope and peripheral oxygen extraction, VO2T12.5% ≥35 vs <35 seconds (MGH-ExS)

Elevated exercise pulmonary capillary wedge pressure to cardiac output slope with longer VO2T12.5%: P < 0.0001
No difference in peripheral oxygen extraction: P = 0.11

Correlation of VO2T12.5% shortening with NT-proBNP, hs-cTnI and LV outflow tract gradient

Shortening of VO2T12.5% correlated with reduced NT-proBNP, high-sensitivity cardiac troponin I and LV outflow tract gradient: all P<0.005

Original publication

Characterization and Application of Novel Exercise Recovery Patterns That Reflect Cardiac Performance: A Substudy of the SEQUOIA-HCM Trial. Circulation. Published 5 September 2025. doi:10.1161/circulationaha.124.073585

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