BPS2026 - In silico analysis of atrial remodeling and arrhythmia susceptibility in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a growing public health burden and an independent risk factor for atrial fibrillation (AF), the most common sustained arrhythmia. Individuals with T2DM exhibit a significantly higher risk of AF onset and recurrence, as well as poorer outcomes following treatment. Although electrical remodeling in atrial myocytes is a well-established driver in arrhythmia risk, the specific electrophysiological mechanisms by which diabetes alters atrial function remain incompletely understood. To address this gap, we developed biophysically detailed computational models of human atrial myocytes that incorporate T2DM-specific remodeling of ionic currents, Ca 2+ handling, and myofilament cross-bridge dynamics by coupling the Ni et al. (2023) human atrial electrophysiology model with the Musgrave et al. (2025) myofilaments cross-bridge model. The diabetic model was parameterized to include experimentally informed modifications to key ion channels, Ca 2+ handling proteins, and myofilament function. The T2DM-specific atrial cardiomyocyte model was validated against key experimental biomarkers of diabetic atrial remodeling, including prolonged action potential duration, reduced resting membrane potential, and reduced Ca 2+ transient amplitude and decay time. Simulations revealed that T2DM-induced reductions in repolarizing K + currents drive action potential duration (APD) prolongation, while downregulation of Ca 2+ influx (I CaL ) and sarcoplasmic reticulum Ca 2+ reuptake impair Ca 2+ dynamics; together these changes increase susceptibility to APD alternans and afterdepolarizations at the single-cell level. At the tissue level, remodeling altered conduction velocity, refractory period, and wavelength, consistent with increased reentry propensity. This work establishes a validated human T2DM-specific electromechanical model. While our initial analysis centers on electrophysiological remodeling, the integrated framework provides a platform to probe how diabetes-induced mechanical remodeling interacts with electrical abnormalities to drive atrial dysfunction and arrhythmogenesis, thereby offering mechanistic insights and therapeutic opportunities.