Remodeling of gap junctional channel function in epicardial border zone of healing canine infarcts
ABSTRACT The epicardial border zone (EBZ) of canine infarcts has increased anisotropy because of transverse conduction slowing. It remains unknown whether changes in gap junctional conductance (Gj) accompany the increased anisotropy. Ventricular cell pairs were isolated from EBZ and normal hearts (NZ). Dual patch clamp was used to quantify Gj. At a transjunctional voltage (Vj) of +10 mV, side-to-side Gj of EBZ pairs (9.2+/-3.4 nS, n=16) was reduced compared with NZ side-to-side Gj (109.4+/-23.6 nS, n=14, P<0.001). Gj of end-to-end coupled cells was not reduced in EBZ. Steady-state Gj of both NZ and EBZ showed voltage dependence, described by a two-way Boltzmann function. Half-maximal activation voltage in EBZ was shifted to higher Vj in positive and negative directions. Immunoconfocal planimetry and quantification showed no change in connexin43 per unit cell volume or surface area in EBZ. Decreased side-to-side coupling occurs in EBZ myocytes, independent of reduced connexin43 expression, and is hypothesized to contribute to increased anisotropy and reentrant arrhythmias.
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ABSTRACT: The role of the 3D infarct structure in arrhythmia generation and maintenance in hearts with myocardial infarction cannot be fully elucidated through experimental techniques alone. Our aim was to develop methodology to construct a high resolution computational model of the infarcted canine heart using magnetic resonance (MRI) and diffusion tensor images (DTI) and then to use the resulting model to study post-infarction ventricular tachycardia (VT). Segmentation of the MRI and DTI stacks using image processing techniques provided accurate representations of the myocardium, the infarct scar, and the border zone (BZ) surrounding the scar. Realistic electrophysiological properties were assigned to each region. Simulations using the novel model revealed that postinfarction VT is initiated and maintained by reentrant circuits located within the BZ.Computers in Cardiology, 2008; 10/2008
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ABSTRACT: 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. 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. 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).Cardiovascular Research 12/2006; 72(2):241-9. DOI:10.1016/j.cardiores.2006.07.005 · 5.81 Impact Factor
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ABSTRACT: Transmembrane potential responses of single cardiac cells stimulated at rest were studied with uniform rectangular field pulses having durations of 0.5-10 ms. Cells were enzymatically isolated from guinea pig ventricles, stained with voltage sensitive dye di-8-ANEPPS, and stimulated along their long axes. Fluorescence signals were recorded with spatial resolution of 17 microm for up to 11 sites along the cell. With 5 and 10 ms pulses, all cells (n = 10) fired an action potential over a broad range of field amplitudes (approximately 3-65 V/cm). With 0.5 and 1 ms pulses, all cells (n = 7) fired an action potential for field amplitudes ranging from the threshold value (approximately 4-8 V/cm) to 50-60 V/cm. However, when the field amplitude was further increased, five of seven cells failed to fire an action potential. We postulated that this paradoxical loss of excitation for higher amplitude field pulses is the result of nonuniform polarization of the cell membrane under conditions of electric field stimulation, and a counterbalancing interplay between sodium current and inwardly rectifying potassium current with increasing field strength. This hypothesis was verified using computer simulations of a field-stimulated guinea pig ventricular cell. In conclusion, we show that for stimulation with short-duration pulses, cells can be excited for fields ranging between a low amplitude excitation threshold and a high amplitude threshold above which the excitation is suppressed. These results can have implications for the mechanistic understanding of defibrillation outcome, especially in the setting of diseased myocardium.Biophysical Journal 05/2005; 88(4):3038-49. DOI:10.1529/biophysj.104.047142 · 3.83 Impact Factor