Optimization of pharmacotherapy for familial atrial fibrillation in a numerical model of human atrial electrophysiology

Pharmacological therapy of atrial fibrillation (AF) is still a major clinical challenge. Particularly AF of early onset has a significant familiar component and was associated with various gene mutations. In this study, we designed and optimized antiarrhythmic agents for atrial substrates affected by human ether-à-go-go-related gene mutations L532P and N588K. A virtual multichannel blocker was designed aiming at a restoration of the wild-type (WT) action potential (AP) on the single cell and tissue level. Furthermore, the amiodarone and dronedarone concentrations yielding the smallest difference between WT and mutated APs were identified. The WT AP at a basic cycle length (BCL) of 1000 ms could be restored by significant block of I
Kr
and I
Kur
(≥39%) and less pronounced block of I
Ks
, I
Ca;L
, I
b;Na
, and I
b;Ca
(≤17%) for both mutations. Effective dronedarone concentrations of 88 nM for L532P and 40nM for N588K yielded matches almost as good while amiodarone could not sufficiently restore the WT AP. APD
90
restitution was effectively restored by the tuned N588K agent whereas differences of up to 34 ms were observed for low BCLs using the tuned L532P agent. Our results provide insight into the pharmacodynamic response of mutated myocytes and may aid in the optimization of patient group-specific therapeutic approaches.