Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation
Abstract
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.
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BibTeX
@misc{puchegarcia2026electrophysiological,
title = {{Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation}},
author = {V. Puche-Garcia and D. Filgueiras-Rama and L. Martinez-Mateu and L. Romero and J. Saiz},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752633},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752633v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation
AU - V. Puche-Garcia
AU - D. Filgueiras-Rama
AU - L. Martinez-Mateu
AU - L. Romero
AU - J. Saiz
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752633
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752633v1
AB - 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.
ER -