Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation

Response to antiarrhythmic drugs varies markedly across patients with atrial fibrillation (AF), suggesting that treatment efficacy depends on the interaction between drug-specific mechanisms and patient-specific electrophysiological substrate. Here, we used population-based computational models to investigate how electrophysiological substrate and inter-individual ionic variability influence pharmacological efficacy and the underlying mechanisms. Two populations of human atrial models were generated from distinct substrates: a reference left atrial model and a second model incorporating inward-rectifier-enhancement (IRE) through a 2-fold increase in IK1 and IK,ACh. Both populations were independently calibrated against the same experimental datasets from patients with paroxysmal AF (pAF), yielding pAF and IRE-pAF populations. Sustained reentrant activity was induced in two-dimensional tissue simulations and subsequently used to assess cardioversion efficacy of flecainide, vernakalant and tertiapin-Q. Despite satisfying the same calibration criteria, IRE-pAF population exhibited a more arrhythmogenic phenotype: shorter refractoriness, higher dominant frequency (DF) and greater rotor stability. Antiarrhythmic efficacy markedly differed between substrates. Flecainide cardioversion decreased in IRE-pAF compared with pAF (34% vs 21%), whereas IK,ACh-targeting therapies preserved or improved efficacy in IRE-pAF (vernakalant: 41% vs 44%, tertiapin-Q: 11% vs 18%). Across drugs and substrates, rotor DF strongly influenced cardioversion outcome, with higher-frequency rotors showing lower termination rates. Drug-induced DF reduction emerged as a key mechanism associated with successful cardioversion, whereas effective refractory period (ERP) prolongation alone did not consistently explain treatment efficacy. In pAF, vernakalant achieved higher cardioversion efficacy than flecainide despite a smaller increase in ERP and greater DF reduction. Ionic analyses further showed that elevated IK,ACh favored responses to vernakalant and tertiapin-Q. These findings demonstrate that cardioversion efficacy emerges from the interaction between electrophysiological substrate, rotor dynamics and drug-specific mechanisms. In particular, substrates differing in inward rectifier activity exhibit distinct response patterns, while DF emerges as a robust marker of pharmacological susceptibility and a potential guide for drug-mediated AF termination.