Copyright © 2006, European Society of Cardiology
Heterogeneous gap junction remodeling in reentrant circuits in the epicardial border zone of the healing canine infarct
aDepartment of Pharmacology, College of Physicians and Surgeons, Columbia University, United States
bDepartment of Center for Molecular Therapeutics, College of Physicians and Surgeons, Columbia University, United States
cDepartment of Computer Systems, New York City College of Technology, City University of New York, United States
dSt Mary's Hospital and Imperial College School of Medicine, London, UK
* Corresponding author. Department of Pharmacology, Columbia University, 630 West 168th Street, P&S 7-446, New York, NY 10032, United States. Tel.: +1 212 305 4197; fax: +1 212 305 5740. Email address: cc296{at}columbia.edu
Background: The epicardial border zone (EBZ) of surviving myocytes in the healing, 4- to 5-day-old canine infarct is an arrhythmogenic substrate characterized by both structural and functional remodeling of Cx43. Unknown is whether the remodeling of gap junction conductance is heterogeneous in the EBZ like that of sarcolemmal ion channel remodeling and how remodeling of the gap junction influences conduction and anisotropy.
Methods and results: Ventricular tachycardia was initiated by programmed stimulation in healing canine infarcted hearts. Reentrant circuits were mapped and the central common pathway (CCP) and outer pathway (OP) regions localized. Epimyocardium removed from the CCP was disaggregated to generate myocyte pairs for conductance measurements. Cx43 distribution was determined by immunofluorescent confocal microscopy. While transverse coupling (gap junction conductance) was markedly decreased in OP cells, CCP cells with lateralized Cx43 gap junctions showed normal conductance. Longitudinal coupling in both OP and CCP was no different than normal. Consistent with conductance measurements, the anisotropic ratio in the CCP was similar to that of normal tissue. In the OP it was increased. Despite normal longitudinal and transverse conductance and anisotropic ratio, longitudinal and transverse conduction velocities were decreased in the CCP with respect to normal epicardium, possibly as a result of the remodeling of sarcolemmal ion channels in this region.
Conclusions: Gap junction conductance and distribution is heterogeneous in different regions of reentrant circuits. Lateralization of Cx43 gap junctions in CCP of reentrant circuits is associated with normal transverse conductance between cell pairs. In contrast, absence of lateralization in OP is associated with reduced transverse conductance. Despite normal anisotropic ratio, conduction velocity in CCP region remains slower than normal. This suggests that the effects of Cx43 remodeling in the infarcted heart should be interpreted in conjunction with other types of remodeling occurring in the EBZ (i.e. sarcolemmal ion channels).
KEYWORDS Infarction; Remodeling; Arrhythmia
1 Dr Cabo and Dr Yao contributed equally to this study.
Supported by Grants HL66140, HL30557 from the National Heart, Lung, and Blood Institute, National Institutes of Health, and a British Heart Foundation grant (RG/2000003, FS/98038) and American Heart Association Grant 0655807T (Heritage Affiliate) to CC.
Time for primary review 29 days
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