© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model
aResearch Center, Montreal Heart Institute, 5000 Bélanger, Montréal, QC H1T 1C8, Canada
bDépartement de Physiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
cDepartment of Pharmacology, McGill University, Montreal, QC H3G 1Y6, Canada
dDépartement de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
msc{at}icm.umontreal.ca
* Corresponding author. Tel.: +1-514-376-3330 extn. 3490; fax: +1-514-376-1355
Recent advances in molecular electrophysiology have made possible the development of more selective ion channel blockers for therapeutic use. However, more information is needed about the effects of blocking specific channels on repolarization in normal human atrium and in atrial cells of patients with atrial fibrillation (AF). AF-induced electrical remodeling is associated with reductions in transient outward current (Ito), ultrarapid delayed rectifier current (IKur), and L-type calcium current (ICa,L). Direct evaluation of the results of ion channel depression is limited by the nonspecificity of the available pharmacological probes. Objectives: Using a mathematical model of the human atrial action potential (AP), we aimed to: (1) evaluate the role of ionic abnormalities in producing AP changes characteristic of AF in humans and (2) explore the effects of specific channel blockade on the normal and AF-modified AP (AFAP). Methods: We used our previously developed mathematical model of the normal human atrial AP (NAP) based on directly measured currents. We constructed a model of the AFAP by incorporating experimentally-measured reductions in Ito (50%), IKur (50%), and ICa,L (70%) current densities observed in AF. Results: The AFAP exhibits the reductions in AP duration (APD) and rate-adaption typical of AF. The reduction in ICa,L alone can account for most of the morphological features of the AFAP. Inhibition of Ito by 90% leads to a reduction in APD measured at –60 mV in both the NAP and AFAP. Inhibition of the rapid component of the delayed rectifier (IKr) by 90% slows terminal repolarization of the NAP and AFAP and increases APD by 38% and 34%, respectively. Inhibition of IKur by 90% slows early repolarization and increases plateau height, activating additional IK and causing no net change in APD at 1 Hz in the NAP. In the presence of AF-induced ionic modifications, IKur inhibition increases APD by 12%. Combining IKur and IKr inhibition under both normal and AF conditions synergistically increases APD. In the NAP, altering the model parameters to reproduce other typical measured AP morphologies can significantly alter the response to K+-channel inhibition. Conclusions: (1) The described abnormalities in Ito, IKur and ICa,L in AF patients can account for the effects of AF on human AP properties; (2) AP prolongation by IKur block is limited by increases in plateau height that activate more IK; (3) Blockers of IKur may be more effective in prolonging APD in patients with AF; 4) Inhibition of both IKur and IKr produces supra-additive effects on APD. These observations illustrate the importance of secondary current alterations in the response of the AP to single channel blockade, and have potentially important implications for the development of improved antiarrhythmic drug therapy for AF.
KEYWORDS Experimental; Heart; Cellular; Human; Electrophysiology; Arrhythmia mechanisms; Computer modeling; Membrane currents; Atrial fibrillation
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