A Simulation Study of Cellular Hypertrophy and Connexin Lateralization in Cardiac Tissue

Abstract

Many cardiac diseases coincide with changes in cell size and shape. One example of such a disease is cardiac hypertrophy. It is established that cardiac impulse propagation depends on the cell size, as well as other factors, but interrelations between conduction velocity (CV), cell size, and gap junction (GJ) conductance (g(GJ)) are complex. Furthermore, cardiac diseases are often accompanied by connexin (Cx) lateralization. To analyze the effects of cell size and Cx lateralization in cardiac disease, a two-dimensional computer simulation of ventricular myocytes based on the Luo-Rudy model was used. Control cells (80 μm/20 μm (length/diameter)), long cells (160 μm/20 μm), and wide cells (80 μm/40 μm) were simulated as was a redistribution of lateral GJs (constant lateral g(GJ) and increased lateral g(GJ)). CV in long cells showed high stability, i.e., it declined very slowly when g(GJ) was gradually reduced. Wide cells, however, were more affected by reduced g(GJ), resulting in early transition to discontinuous propagation and low CV. Conduction block occurred earlier in enlarged cells than in control cells due to increased cell capacitance. Increased lateral g(GJ) stabilized longitudinal CV, which was a result of two-dimensional effects during planar wave propagation. Therefore, Cx lateralization may compensate for cardiac inhomogeneities. High lateral g(GJ) and enhanced cell diameter increased the susceptibility to conduction block at tissue expansion, providing a substrate for arrhythmia.

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

“…However, to increase extracellular volume they used mannitol, which also reduced cell width. A reduction in cell width, however, can strongly slow transverse velocity (Seidel et al, 2010;Toure and Cabo, 2010). Furthermore, with decreasing velocity the effect of gradual uncoupling (higher gap junction resistance) increases because of a switch from continuous to discontinuous propagation, preferably in transverse fiber direction (Seidel et al, 2010).…”

“…Both high sodium channel conductance and relatively low intercellular coupling increase conduction safety under these conditions. However, pathological changes like gap junction lateralization or cellular hypertrophy (increased sink), and reduced sodium channel availability (decreased source) can lead to unidirectional conduction block (Kléber and Rudy, 2004;Seidel et al, 2010). If unidirectional block occurs in a Purkinje fiber, this will slow ventricular activation and lead to an abnormal activation pattern.…”

“…However, mathematical models have shown that increased cell capacitance increases capacitive load and the discontinuity of action potential propagation. This steepens the relationship between gap-junction conductance and conduction velocity elevating the risk of conduction block both due to uncoupling and source-sink mismatch (Seidel et al, 2010). Furthermore, hypertrophy leads to increased length or diameter of cardiomyocytes, which has both been shown to influence conduction (McIntyre and Fry, 1997;Spach et al, 2000;Seidel et al, 2010).…”

“…In this regard, it is important to consider the ratio between the cell surface A m and the gap junction conductance g GJ (Seidel et al, 2010): increased diameter of the cell can enhance longitudinal propagation velocity θ L if g GJ is enhanced proportionally to A m . If g GJ remains constant, however, increased diameter reduces θ L .…”

“…Thus, it is important to analyze the ratio of g GJ /A m in order to understand whether a change in cell size will enhance or reduce θ L . Furthermore, transverse g GJ may contribute to longitudinal propagation, which cannot be described by a one-dimensional model (Seidel et al, 2010).…”