Cardiovascular research
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Cardiovascular research · May 1999
Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model.
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. ⋯ (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.
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Cardiovascular research · May 1999
Pause induced early afterdepolarizations in the long QT syndrome: a simulation study.
The long QT syndrome (LQTS) is characterized by prolonged repolarization and propensity to syncope and sudden death due to polymorphic ventricular tachycardias such as torsade de pointes (TdP). The exact mechanism of TdP is unclear, but pause-induced early afterdepolarizations (EADs) have been implicated in its initiation. In this study we investigate the mechanism of pause-induced EADs following pacing at clinically relevant rates and characterize the sensitivity of different cell types (epicardial, midmyocardial, and endocardial) to EAD development. ⋯ APD is a very important determinant of arrhythmogenesis and its prolongation, either due to acquired or congenital LQTS, can result in the appearance of EADs. The formation of pause-induced EADs preferentially in M cells suggests a possible role for these cells in the generation of arrhythmias that are associated with abnormalities of repolarization (e.g., TdP). The ionic mechanism of pause-induced EADs involves reactivation of the L-type calcium current during the prolonged plateau of the post-pause AP.