Abstract:
Pharmacological therapy of atrial fibrillation (AF) is still a major clinical challenge. Particularly AF of early onset has a significant familiar component and was asso- ciated with various gene mutations. In this study, we de- signed and optimized antiarrhythmic agents for atrial sub- strates affected by human ether-a`-go-go-related gene mu- tations 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 concen- trations yielding the smallest difference between WT and mutated APs were identified. The WT AP at a basic cy- cle length (BCL) of 1000 ms could be restored by signifi- cant block of IK r and IK ur (\039%) and less pronounced block of IKs, ICa,L, Ib,Na, and Ib,Ca (17%) for both mutations. Effective dronedarone concentrations of 88 nM for L532P and 40 nM for N588K yielded matches almost as good while amiodarone could not sufficiently restore the WT AP. APD90 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 re- sponse of mutated myocytes and may aid in the optimiza- tion of patient group-specific therapeutic approaches.