Engineering the geriatric heart to model HFpEF

Heart failure with preserved ejection fraction (HFpEF) clinical trials suffer from high rates of attrition due to a biological mismatch between preclinical models and patients. While clinical HFpEF is fundamentally driven by advanced age, female sex, systemic inflammation, and progressive myocardial stiffness, preclinical screening still relies predominantly on young male rodents or foetal-like pluripotent stem cell derivatives. In this perspective, we propose a modular and testable geriatric engineering framework for reconstructing the myocardial features of this disease in vitro. The framework integrates four pathogenic drivers: inducible nuclear senescence to mimic ageing-like phenotypes, post-menopausal estrogen withdrawal, programmable biomaterial-driven stiffness, and macrophage-mediated immune activation. De-risking HFpEF drug development requires deliberately engineering this target pathophysiology, ensuring candidate compounds are evaluated against the biology of the ageing myocardium. Because such platforms isolate myocardial phenotypes from the broader multisystem clinical syndrome, we outline the strict model inputs, functional outputs, and clinical benchmarking criteria required to establish their translational validity.