Physiology-Driven Digital Twin for Pacing Response Prediction and Mechanistic Insights in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous condition, and current methods struggle to integrate extensive clinical data for personalized treatment. The myPACE clinical study [JAMA Cardiol. 2023, 8:213-221] demonstrated that moderate pacing can benefit HFpEF patients. However, the specific HFpEF subgroups that derive the most benefit and the underlying mechanisms remain unclear. We developed a physiology-driven digital twin, a computational framework that optimizes parameter sets and simulates cardiovascular function to phenotype HF patients. This framework, which has previously shown promise in guiding interpretable AI for HF diagnosis and prognosis, may also predict pacing response and provide mechanistic insights. To investigate its potential, we virtually paced 128 HFpEF patients from our previously published cohort. We analyzed short-term responses, including changes in cardiac output and pulmonary capillary wedge pressure (PCWP), and simulated long-term PCWP adaptation under stable hemodynamic conditions through physiological compensatory mechanisms. Our simulations demonstrated that a significant subset of patients exhibited a rapid response to pacing, characterized by increased cardiac output and reduced PCWP. Furthermore, simulations suggest that this approach has the potential to identify mechanisms underlying individual differences in PCWP responsiveness to pacing. Integrating with advanced AI algorithm, the physiology-driven digital twin approach provides a novel approach for identifying pacing responders versus non-responders in HFpEF. This framework could support virtual trials and aid in the design of real-world clinical studies. Additionally, it enables personalized heart rate (HR) optimization, suggesting broader applications in HF management. This work was supported by the National Institutes of Health under grants R01HL173346-01 and the Michigan Biology of Cardiovascular Aging Postdoctoral Fellowship. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.