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Computational Analyses in Ion Channelopathies

Heterogeneous gap junction remodeling stabilizes reentrant circuits in the epicardial border zone of the healing canine infarct: a computational study

¹Department of Pharmacology and ²Center for Molecular Therapeutics, College of Physicians and Surgeons, Columbia University; and ³Department of Computer Systems, New York City College of Technology and Graduate Center, City University of New York, New York

Submitted 31 March 2006 ; accepted in final form 16 August 2006

The ventricular tachycardias (VTs) that originate in the 5-day epicardial border zone (EBZ) of the healing canine infarcted heart are due to reentrant excitation. In cells surviving in the EBZ, both sarcolemmal ionic channels and gap junction conductance and distribution are remodeled. We previously showed that the heterogeneities in sodium current (I_Na) and L-type calcium channel current (I_CaL) of the center and outer pathway cells result in a homogenization of the refractory period that in turn stabilizes reentrant VTs for 10 beats. To understand how heterogeneities in transverse gap junctional conductance remodeling reported experimentally contribute to the stability of these tachycardias, we studied the dynamics of reentering waves in two-dimensional computer models of the EBZ. First we used a computer model with homogeneous ionic channel properties [infarcted border zone cell model (IZ)]. These simulations show that, in the absence of heterogeneities in ionic channel properties, reentrant waves tend to drift to localized regions of uncoupling and stabilize there. Second, we used a computer model with a more realistic representation of the heterogeneous EBZ, including cellular models for both the center (IZ_c) and outer (IZ_o) pathway cells. These simulations show that neither a region of uniform uncoupling nor a step transition between two regions with different side-to-side (transverse) cell coupling stabilizes reentry in this substrate. However, an area of localized uncoupling did stabilize reentry in such a model. We propose that in addition to the heterogeneities in I_Na and I_CaL properties, heterogeneities in gap junctional conductance in the EBZ causing regions of localized uncoupling stabilize VT in the EBZ. Previous experimental in situ activation maps of the 5-day EBZ show that the lines of block form in regions of slow transverse propagation. This is consistent with our findings that areas of localized uncoupling stabilize reentry.

computer simulations; infarct remodeling; ventricular tachycardia

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