Cross-physiological and fitness-adjusted assessment of rate–pressure product for residual mortality risk stratification in acute coronary syndrome

Background Despite marked reductions in in-hospital mortality after advances in reperfusion and guideline-directed therapy, the burden of acute coronary syndrome (ACS) has shifted towards long-term risk management, making precise residual mortality stratification a major challenge. The rate–pressure product (RPP), reflecting myocardial workload, is prognostic at rest in ACS, yet its significance under stress and its dynamic change from rest to peak exercise remain unclear. Moreover, peak RPP may be influenced by exercise capacity, warranting fitness-adjusted assessment. Purpose To evaluate the prognostic associations of cross-state and fitness-adjusted RPP indices with residual mortality risk in ACS and their utility for long-term risk stratification. Methods ACS patients undergoing CPET in three hospitals (January 2018–December 2024) were included. The primary outcome was all-cause mortality. Multivariable Cox models assessed associations of resting RPP, peak RPP, haemodynamic gain index (HGI), and fitness-adjusted RPP (RPPpeak/METpeak) with mortality. Kaplan–Meier and restricted cubic spline analyses were performed. Combined HGI and RPPpeak/METpeak phenotypes were also evaluated. Results Among 6,644 patients, 134 deaths occurred over a median 24 months (IQR 12–41). Resting and stress-derived RPP indices showed divergent associations with mortality. Each 1-SD increase in resting RPP was associated with 19% higher risk (aHR 1.19, 95% CI 1.00–1.41), whereas peak RPP and HGI were associated with 29% ((aHR=0.71, 95% CI: 0.59–0.86) and 46% (aHR=0.54, 95% CI: 0.43–0.67) lower risk. Fitness-adjusted RPP was associated with 33% higher mortality per 1-SD increment (aHR=1.33, 95% CI: 1.14–1.55). Associations were predominantly linear. Mortality risk increased stepwise across combined phenotypes, with the low HGI–high RPPpeak/METpeak group showing the highest risk (aHR=5.00, 95% CI: 2.75–9.08). These associations remained consistent across predefined clinical subgroups. Conclusions RPP exhibited state-dependent prognostic associations in ACS patients. Higher resting and fitness-adjusted RPP were associated with increased mortality risk, whereas higher peak RPP and greater HGI were associated with lower risk. Integrated cross-state and fitness-adjusted assessment was independently associated with residual mortality risk, with combined phenotypes demonstrating clear graded risk patterns. These findings provide robust evidence to support more refined residual risk stratification during long-term management of ACS.KM Survival Curves for HGI–RPPpeak/METpeak