title: Why are some antiarrhythmic drugs proarrhythmic? Cardiac arrhythmia study by bifurcation analysis.
abstract: This study employs a bifurcation analysis approach to elucidate the effect of the key ion channels on cardiac arrhythmias and thereby explain the efficacy of antiarrhythmic drugs in controlling arrhythmias. The model used for the analysis contains the key ion channels involved in the ventricular action potential--fast sodium, slow calcium, and background potassium channels. The cardiac tissue is modeled by a ring structure. The bifurcation diagram reveals that at a certain ring size, the amplitude of the action potential suddenly shrinks and the conduction velocity (CV) becomes unstable. Instability in CV leads to termination of reentrant arrhythmias. This ring size (ie, the critical ring size [CRS]) depends of the type of channel blocker. Blocking of the sodium channel leads to a decrease in the CRS, which in turn enhances stable reentry (proarrhythmia). Although calcium channel blockers do not alter the CV, they can exert the proarrhythmic effect by drastically shortening the CRS. The potassium channel blockers, on the other hand, are effective in controlling reentry in ventricular tissues by lengthening the CRS. Near blocking of the potassium channel, however, brings about another type of arrhythmia--the formation of ectopic foci. In the neighborhood of the CRS, the cycle length oscillates with an interesting pattern that depends on ring size and drug type. Although a critical reentrant loop length for stable reentrant excitation has been investigated for a long time, this study is the first demonstration of how the key ion channels in the plasma membrane affect the loop length. Furthermore, the analysis approach provides a theoretical basis for the increased mortality associated with class I drug use in the Cardiac Arrhythmia Suppression Trial Team.
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, PA 15260, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Chay
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002121:Calcium Channel Blockers / Q000009:adverse effects; D015220:Calcium Channels / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D008955:Models, Cardiovascular; D008956:Models, Chemical; D015233:Models, Statistical; D009431:Neural Conduction / Q000187:drug effects; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects; D016276:Ventricular Function / Q000187:drug effects; D018879:Ventricular Premature Complexes / Q000139:chemically induced
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007473:Ion Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels