Beyond peak VO2: oxygen uptake at the first ventilatory threshold and clinical outcomes in transthyretin cardiac amyloidosis

Aims Oxygen uptake at the first ventilatory threshold (VT1) can be expressed as an absolute value (VO2VT1-abs), as a percentage of predicted peak VO2 (VO2VT1-%pred), or as a percentage of observed peak VO2 (VO2VT1-%obs). We compared their prognostic performance in transthyretin cardiac amyloidosis (ATTR-CM). Methods and Results Adults with ATTR-CM undergoing baseline cardiopulmonary exercise testing at two centres were studied. Endpoints were all-cause mortality and death or heart failure (HF) hospitalisation. Censoring-aware 2-year discrimination and age- and sex-adjusted Cox associations were assessed. Incremental model fit and discrimination beyond age, sex, peak VO2, and VE/VCO2 slope were evaluated, with bootstrap internal validation. Among 182 patients, VT1 was identifiable in 173 (95.1%). Mortality follow-up was available in 162 patients (44 deaths), and composite follow-up in 157 (66 events). Per 1-standard-deviation decrease, VO2VT1-abs and VO2VT1-%pred were associated with mortality (hazard ratio [HR] 2.86, 95% confidence interval [CI] 1.77–4.63; and HR 2.50, 95% CI 1.61–3.87; both P<0.001) and the composite endpoint (HR 2.25, 95% CI 1.53–3.31; and HR 2.38, 95% CI 1.65–3.43; both P<0.001). VO2VT1-%obs was not associated with either endpoint. Adding VO2VT1-abs or VO2VT1-%pred improved mortality model fit (likelihood-ratio P=0.019 and P=0.034), but bootstrap 95% CIs for both gains in C-index included zero. Severe-limitation analyses were exploratory, without significant interactions. Conclusion Absolute and predicted-normalised VT1 were associated with outcomes; non-proportional hazards warrant caution for absolute-VT1 mortality. Improved model fit does not establish improved predictive discrimination, clinical utility, or added value beyond comprehensive ATTR-CM risk stratification. External validation is required.