AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Three-Dimensional Dose-Response Surfaces of Cumulative Anthracycline or HER2-Targeted Therapy Exposure, Cardioprotective Agent Dose, and Physical Activity Volume on Incidence of Cancer Therapy-Related Cardiac Dysfunction: A Tensor Spline Meta-Analysis
By Yathindra MR, Alupei E, Keswani K et al.
Background Cancer therapy-related cardiac dysfunction (CTRCD) remains a dose-limiting toxicity of anthracycline and HER2-targeted therapies. While cardioprotective agents and exercise interventions show promise, their synergistic effects across the full spectrum of chemotherapy exposure remain poorly characterized. We developed three-dimensional dose-response surfaces to identify optimal combinations of anthracycline dose, cardioprotection intensity, and physical activity volume that minimize CTRCD risk. Methods We conducted a systematic review and tensor-product meta-analysis of 27 studies (16 randomized controlled trials/meta-analyses, 11 observational cohorts; 17,530 patient-observations) published through 2026. Three continuous dimensions were modeled simultaneously: cumulative anthracycline dose (0-700 mg/m ² ), cardioprotective agent effect quantified as LVEF preservation (0-6.1%), and physical activity volume (0-16 MET-hours/week). Tensor-product thin-plate spline surfaces were fitted using radial basis function interpolation. Primary outcomes included CTRCD incidence (%), LVEF decline (%), and global longitudinal strain (GLS) worsening. Partial derivative analysis quantified synergistic interactions, and contour mapping identified "safe zones" for clinical practice. Results Without cardioprotection, mean CTRCD incidence was 23.1%. Exercise ≥8 MET-hours/week reduced incidence to 10.7%. Mean LVEF decline was 3.2% without cardioprotection, 1.8% with pharmacological agents and 1.4% with exercise. Specific cardioprotective effects included: dexrazoxane (RR 0.22 for clinical heart failure, N=1,269), beta-blockers (LVEF preservation +3.44%, N=1,291), ACE inhibitors/ARBs (+4.24%, N=1,095), statins (+6.08%, N=3,042), and sacubitril/valsartan (LVEF +1.47%, GLS –0.93%, N=412). Exercise trials demonstrated CTRCD rates of 0% versus control and 9.5% versus 18.2% control. Tensor surfaces revealed a "safe zone" at cumulative doses <300 mg/m ² combined with physical activity ≥10 MET-hours/week and high cardioprotection (CTRCD <10%, LVEF decline <1.5%). Partial derivative analysis demonstrated synergistic (additive-to-supra-additive) interactions between high physical activity and high cardioprotection at intermediate anthracycline doses (300-450 mg/m ² ), with combined interventions yielding greater risk reduction than predicted by additive models. Conclusions Three-dimensional dose-response modeling identifies practical "safe zones" combining anthracycline dose limitation, cardioprotective pharmacotherapy, and structured exercise that achieve CTRCD rates <10%. Synergistic effects at intermediate doses support multimodal cardioprotection strategies in cardio-oncology guidelines.