Ionic mechanisms of electrophysiological heterogeneity and conduction block in the infarct border zone.
The increased incidence of arrhythmia in the healing phase after infarction has been linked to remodeling in the epicardial border zone (EBZ). Ionic models of normal zone (NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insights into how ion channel remodeling affects action potential (AP) duration (APD) and refractoriness, vulnerability to conduction block, and conduction safety postinfarction. We found that EBZ tissue exhibited abnormal APD restitution. The remodeled Na(+) current (I(Na)) and L-type Ca(2+) current (I(Ca,L)) promoted increased effective refractory period and prolonged APD at a short diastolic interval. While postrepolarization refractoriness due to remodeled EBZ I(Na) was the primary determinant of the vulnerable window for conduction block at the NZ-to-EBZ transition in response to premature S2 stimuli, altered EBZ restitution also promoted APD dispersion and increased the vulnerable window at fast S1 pacing rates. Abnormal EBZ APD restitution and refractoriness also led to abnormal periodic conduction block patterns for a range of fast S1 pacing rates. In addition, we found that I(Na) remodeling decreased conduction safety in the EBZ but that inward rectifier K(+) current remodeling partially offset this decrease. EBZ conduction was characterized by a weakened AP upstroke and short intercellular delays, which prevented I(Ca,L) and transient outward K(+) current remodeling from playing a role in EBZ conduction in uncoupled tissue. Simulations of a skeletal muscle Na(+) channel SkM1-I(Na) injection into the EBZ suggested that this recently proposed antiarrhythmic therapy has several desirable effects, including normalization of EBZ effective refractory period and APD restitution, elimination of vulnerability to conduction block, and normalization of conduction in tissue with reduced intercellular coupling.
Decker
Keith F
KF
Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University, St. Louis, Missouri 63130-4899, USA. kfd1@cec.wustl.edu
Rudy
Yoram
Y
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D004285:Dogs; D055724:Electrophysiological Phenomena / Q000502:physiology*; D006329:Heart Conduction System / Q000503:physiopathology*; D007473:Ion Channels / Q000502:physiology*; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D010496:Pericardium / Q000473:pathology / Q000503:physiopathology; D015221:Potassium Channels / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology
D015220:Calcium Channels; D007473:Ion Channels; D015221:Potassium Channels; D015222:Sodium Channels