Multidimensional physiological reserve and long-term cardiovascular risk among breast cancer survivors: a prospective UK Biobank study

Background Cardio-oncology risk assessment has focused largely on treatment-related cardiac injury, whereas the prognostic significance of physiological reserve in breast cancer survivors remains uncertain. We investigated whether a multidimensional Physiological Reserve Index (PRI) identifies long-term cardiovascular vulnerability and improves risk stratification. Methods We analyzed 183,283 women in the UK Biobank, including 5,605 breast cancer survivors. PRI combined standardized forced expiratory volume in 1 second (FEV₁), grip strength, and waist circumference. Cox proportional hazards models assessed associations with heart failure, atrial fibrillation, and all-cause mortality. Population-attributable fractions and incremental predictive performance using Harrell’s concordance index (C-index) and 10-year time-dependent area under the receiver operating characteristic curve (AUC) were also evaluated. Results During a median follow-up of 16.7 years, breast cancer survivors had higher risks of heart failure (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.39–1.81), atrial fibrillation (HR 1.29, 95% CI 1.17–1.43), and all-cause mortality (HR 2.36, 95% CI 2.22–2.51) than women without breast cancer. Among survivors, each 1-standard-deviation higher PRI was associated with lower risks of heart failure (HR 0.55, 95% CI 0.47–0.63), atrial fibrillation (HR 0.75, 95% CI 0.67–0.84), and mortality (HR 0.76, 95% CI 0.71–0.81). Ten-year heart failure risk ranged from 0.80% to 3.61% across PRI strata. Under a hypothetical shift to the highest PRI category, the population-attributable fraction for heart failure was 49.8%. Adding PRI to conventional clinical factors increased the C-index for heart failure from 0.642 to 0.695 and the 10-year AUC from 0.668 to 0.712. Conclusions Physiological reserve captures substantial heterogeneity in long-term cardiovascular risk among breast cancer survivors and provides prognostic information beyond conventional clinical factors. Simple functional and anthropometric measures may complement cardio-oncology risk assessment and support future evaluation of reserve-oriented survivorship strategies.