Effect of transverse gap-junction channels on transverse propagation in an enlarged PSpice model of cardiac muscle

BACKGROUND: In previous PSpice modeling studies of simulated action potentials (APs) in parallel chains of cardiac muscle, it was found that transverse propagation could occur between adjacent chains in the absence of gap-junction (gj) channels, presumably by the electric field (EF) generated in the narrow interstitial space between the chains. Transverse propagation was sometimes erratic, the more distal chains firing out of order. METHODS: In the present study, the propagation of complete APs was studied in a 2-dimensional network of 100 cardiac muscle cells (10 × 10 model). Various numbers of gj-channels (assumed to be 100 pS each) were inserted across the junctions between the longitudinal cells of each chain and between adjacent chains (only at the end cells of each chain). The shunt resistance produced by the gj-channels (R(gj)) was varied from 100,000 MΩ (0 gj-channels) to 1,000 MΩ (10 channels), 100 MΩ (100 channels) and 10 MΩ (1,000 channels). Total propagation time (TPT) was measured as the difference between the times when the AP rising phase of the first cell (cell # A1) and the last cell (in the J chain) crossed 0 mV. When there were no gj-channels, the excitation was transmitted between cells by the EF, i.e., the negative potential generated in the narrow junctional clefts (e.g., 100 Å) when the prejunctional membrane fired an AP. For the EF mechanism to work, the prejunctional membrane must fire a fraction of a millisecond before the adjacent surface membrane. When there were many gj-channels (e.g., 100 or 1,000), the excitation was transmitted by local-circuit current flow from one cell to the next through these channels. RESULTS: TPT was measured as a function of four different numbers of transverse gj-channels, namely 0, 10, 100 and 1,000, and four different numbers of longitudinal gj-channels, namely 0, 10, 100 and 1,000. Thus, 16 different measurements were made. It was found that increasing the number of transverse channels had no effect on TPT when the number of longitudinal channels was low (i.e., 0 or 10). In contrast, when the number of longitudinal gj-channels was high (e.g., 100 or 1,000), then increasing the number of transverse channels decreased TPT markedly. CONCLUSION: Thus, complete APs could propagate along a network of 100 cardiac muscle cells even when no gj-channels were present between the cells. Insertion of transverse gj-channels greatly speeded propagation through the 10 × 10 network when there were also many longitudinal gj-channels

Transverse propagation of action potentials between parallel chains of cardiac muscle and smooth muscle cells in PSpice simulations

BACKGROUND: We previously examined transverse propagation of action potentials between 2 and 3 parallel chain of cardiac muscle cells (CMC) simulated using the PSpice program. The present study was done to examine transverse propagation between 5 parallel chains in an expanded model of CMC and smooth muscle cells (SMC). METHODS: Excitation was transmitted from cell to cell along a strand of 5 cells not connected by low-resistance tunnels (gap-junction connexons). The entire surface membrane of each cell fired nearly simultaneously, and nearly all the propagation time was spent at the cell junctions, the junctional delay time being about 0.3 – 0.5 ms (CMC) or 0.8 – 1.6 ms (SMC). A negative cleft potential (V(jc)) develops in the narrow junctional clefts, whose magnitude depends on the radial cleft resistance (R(jc)), which depolarizes the postjunctional membrane (post-JM) to threshold. Propagation velocity (θ) increased with amplitude of V(jc). Therefore, one mechanism for the transfer of excitation from one cell to the next is by the electric field (EF) that is generated in the junctional cleft when the pre-JM fires. In the present study, 5 parallel stands of 5 cells each (5 × 5 model) were used. RESULTS: With electrical stimulation of the first cell of the first strand (cell A1), propagation rapidly spread down that chain and then jumped to the second strand (B chain), followed by jumping to the third, fourth, and fifth strands (C, D, E chains). The rapidity by which the parallel chains became activated depended on the longitudinal resistance of the narrow extracellular cleft between the parallel strands (R(ol2)); the higher the R(ol2 )resistance, the faster the θ. The transverse resistance of the cleft (R(or2)) had almost no effect. Increasing R(jc )decreases the total propagation time (TPT) over the 25-cell network. When the first cell of the third strand (cell C1) was stimulated, propagation spread down the C chain and jumped to the other two strands (B and D) nearly simultaneously. CONCLUSIONS: Transverse propagation of excitation occurred at multiple points along the chain as longitudinal propagation was occurring, causing the APs in the contiguous chains to become bunched up. Transverse propagation was more erratic and labile in SMC compared to CMC. Transverse transmission of excitation did not require low-resistance connections between the chains, but instead depended on the value of R(ol2). The tighter the packing of the chains facilitated transverse propagation

The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people

Gap-junction channels inhibit transverse propagation in cardiac muscle

<p>Abstract</p> <p>The effect of adding many gap-junctions (g-j) channels between contiguous cells in a linear chain on transverse propagation between parallel chains was examined in a 5 × 5 model (5 parallel chains of 5 cells each) for cardiac muscle. The action potential upstrokes were simulated using the PSpice program for circuit analysis. Either a single cell was stimulated (cell A1) or the entire chain was stimulated simultaneously (A-chain). Transverse velocity was calculated from the total propagation time (TPT) from when the first AP crossed a V_mof -20 mV and the last AP crossed -20 mV. The number of g-j channels per junction was varied from zero to 100, 1,000 and 10,000 (R_gjof ∞, 100 MΩ, 10 MΩ, 1.0 MΩ, respectively). The longitudinal resistance of the interstitial fluid (ISF) space between the parallel chains (R_ol2) was varied between 200 KΩ (standard value) and 1.0, 5.0, and 10 MΩ. The higher the R_ol2value, the tighter the packing of the chains. It was found that adding many g-j channels inhibited transverse propagation by blocking activation of all 5 chains, unless R_ol2was greatly increased above the standard value of 200 KΩ. This was true for either method of stimulation. This was explained by, when there is strong longitudinal coupling between all 5 cells of a chain awaiting excitation, there must be more transfer energy (i.e., more current) to simultaneously excite all 5 cells of a chain.</p