This computational study used population-based human atrial models to examine how electrophysiological substrate and inter-individual ionic variability modulate antiarrhythmic drug efficacy in paroxysmal atrial fibrillation (pAF). Two distinct model populations were generated and calibrated against the same experimental datasets from patients with pAF. The approach tested whether drug-specific mechanisms interact with patient-specific electrophysiology to determine cardioversion outcomes in tissue simulations of sustained reentry.
Two independent populations of left atrial models were created. The first was a reference pAF population. The second, designated IRE-pAF, incorporated inward-rectifier enhancement via a twofold increase in IK1 and IK,ACh. Both populations were calibrated independently against identical experimental data from pAF patients, meaning they satisfied the same calibration criteria despite differences introduced in inward-rectifier currents.
Sustained reentrant activity was induced in two-dimensional tissue simulations for each model instance. These sustained rotors served as the substrate on which the cardioversion efficacy of three pharmacological interventions was evaluated. Outcomes were determined by whether drug application terminated the reentrant activity in the simulated tissue.
Three pharmacological agents were tested: flecainide, vernakalant and tertiapin-Q. Flecainide is a clinically used antiarrhythmic with sodium channel–blocking properties. Vernakalant targets multiple atrial-specific currents including components linked to IK,ACh and other atrial currents. Tertiapin-Q is an IK,ACh-targeting agent. The simulations therefore probed both broad-spectrum and inward-rectifier–targeted therapies to assess how substrate differences modify responses.
Despite identical calibration against patient datasets, the IRE-pAF population exhibited a more arrhythmogenic profile than the reference pAF population. Key distinguishing features in IRE-pAF included:
These differences indicate that enhanced inward-rectifier activity can produce a substrate that is intrinsically more conducive to sustained, higher-frequency reentrant activity.
Cardioversion success varied by both drug and substrate. Reported cardioversion rates were:
These results show that flecainide’s efficacy decreased in the inward-rectifier–enhanced substrate, while therapies targeting IK,ACh (vernakalant and tertiapin-Q) preserved or improved efficacy in IRE-pAF compared with reference pAF.
Across drugs and substrates, dominant frequency (DF) of rotors was a strong determinant of cardioversion outcome: higher-frequency rotors were associated with lower termination rates. The analyses identified drug-induced reduction in DF as a key mechanism linked to successful cardioversion. In contrast, changes in effective refractory period (ERP) alone did not consistently predict termination.
The study found that ERP prolongation by itself did not reliably explain treatment efficacy. For example, in the pAF population vernakalant achieved higher cardioversion efficacy than flecainide despite producing a smaller ERP increase but inducing a greater reduction in DF. Ionic-level analyses indicated that elevated IK,ACh favored responsiveness to vernakalant and tertiapin-Q, highlighting that interactions between specific ionic currents and drug mechanisms shape outcomes.
The results support the concept that cardioversion efficacy emerges from the interplay among electrophysiological substrate, rotor dynamics and drug-specific mechanisms. Specifically:
The source reports findings from population-based computational models and tissue simulations; details beyond those described in the preprint (for example, translational experimental validation, clinical trial data, or patient-level predictors beyond ionic variations) were not reported in the source. The authors conclude that DF is a useful marker of drug susceptibility and that substrate differences—particularly inward-rectifier enhancement—shape antiarrhythmic drug response in pAF models.