AIM: Administration of antiarrhythmic drugs is the first-line treatment for Atrial Fibrillation (AF), but its efficacy is limited. This study aims to investigate the effect on the vulnerable window (VW) of drugs commonly used to treat AF (dofetilide,flecainide,vernakalant) at its different stages (paroxysmal-pAF, and persistent-peAF) as well as under a healthy scenario.
METHODS: Atrial electrophysiology was simulated using the Courtemanche human atrial model, including the parameters replicating the AF electrical remodelling. Cell simulations were performed to fit the in-silico drug response to experimental data from the literature for the drug action to be valid. Using a 2D tissue model, the VW was computed through S1-S2 protocol for each drug and AF stage. Four different drug concentrations were studied within a clinical range of therapeutic concentration.
RESULTS: Under control conditions, the healthy tissue showed VW=19ms (with lifespan<1s). In comparison, pAF (VW=34ms) and peAF (VW=38ms) remodelling led to a substrate more susceptible to re-entrant activity and generated sustained rotors (lifespan>1s) due mainly to the reduction of action potential duration. In healthy and pAF tissues, drugs managed to destabilize the rotor and increase the meandering helping to prevent and terminate rotor activity. Under healthy conditions, dofetilide (0.01µM) and flecainide (3µM) completely eliminated the VW while vernakalant (15µM) reduced it by 24ms. Under pAF-remodeling, all drugs reduced the VW in a use-dependent manner. Dofetilide (0. 01µM) reduced VW by 12ms, flecainide (3µM) by 9ms and vernakalant (15µM) by 24ms. Due to the severe remodelling in peAF tissue, drugs had a lower impact or even caused a slight increase in VW.
CONCLUSIONS: The results support that drug action reduces arrhythmic behaviour and its efficacy is dependent on the AF stage being greater in pAF tissue. This work is a preliminary step toward using computer modelling as a tool to investigate novel drugs in AF treatment.