Physiology-Informed Digital Twin-AI Framework Predicts Pacing Therapy Response in HFpEF

Background and AimsHeart failure with preserved ejection fraction (HFpEF) exhibits profound phenotypic heterogeneity, which likely contributes to variable therapeutic response. We developed a physiology-informed digital twin-AI framework to predict individual hemodynamic and myocardial energetic responses to accelerated atrial pacing and tested whether simulated physiologic response corresponds to responders in the myPACE randomized clinical trial. MethodsPatient-specific digital twins were constructed for 146 HFpEF patients and used to train a variational autoencoder that generated a virtual HFpEF population (n = 25,000). The model simulated pacing-induced changes in left atrial pressure (LAP), systolic blood pressure (SBP), cardiac output (CO), and cardiac efficiency (CE; derived from myocardial oxygen-demand estimates). These simulations served as labels to train classifiers based on clinical variables available in myPACE, allowing us to examine associations with clinical end points and test a hypothesized relationship between CE and treatment response. ResultsSimulations revealed heterogeneous physiological responses, with 95.6% of virtual patients showing reduced LAP, 47.0% an SBP reduction greater than 8.5 mmHg, 93.8% increased CO, and 36.1% improved CE. Classifiers reproduced these patterns with high fidelity. In the myPACE trial, patients classified as having CE improvement or a larger SBP reduction experienced significantly greater 1-month improvements in quality-of-life scores and larger NT-proBNP reductions. ConclusionsA physiology-informed digital twin-AI framework can predict hemodynamic and energetic responses corresponding to clinical benefit in HFpEF patients receiving accelerated atrial pacing. CE improvement functioned as a mechanistic indicator, while SBP reduction served as an accessible clinical correlate, offering mechanistically grounded guidance for patient-specific pacing and motivating prospective validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/26347199v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@4a550eorg.highwire.dtl.DTLVardef@163b85org.highwire.dtl.DTLVardef@19db16dorg.highwire.dtl.DTLVardef@1eb6cf5_HPS_FORMAT_FIGEXP M_FIG C_FIG