A Mathematical Model of Electrotonic Interactions between Ventricular Myocytes and Fibroblasts

Abstract

Functional intercellular coupling has been demonstrated among networks of cardiac fibroblasts, as well as between fibroblasts and atrial or ventricular myocytes. In this study, the consequences of these interactions were examined by implementing the ten Tusscher model of the human ventricular action potential, and coupling it to our electrophysiological models for mammalian ventricular fibroblasts. Our simulations reveal significant electrophysiological consequences of coupling between 1 and 4 fibroblasts to a single ventricular myocyte. These include alterations in plateau height and/or action potential duration (APD) and changes in underlying ionic currents. Two series of simulations were carried out. First, fibroblasts were modeled as a spherical cell with a capacitance of 6.3 pF and an ohmic membrane resistance of 10.7 G Omega. When these "passive" fibroblasts were coupled to a myocyte, they caused slight prolongation of APD with no changes in the plateau, threshold for firing, or rate of initial depolarization. In contrast, when the same myocyte-fibroblast complexes were modeled after addition of the time- and voltage-gated K(+) currents that are expressed in fibroblasts, much more pronounced effects were observed: the plateau height of the action potential was reduced and the APD shortened significantly. In addition, each fibroblast exhibited significant electrotonic depolarizations in response to each myocyte action potential and the resting potential of the fibroblasts closely approximated the resting potential of the coupled ventricular myocyte.

Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

“…The elastic modulus rises from (18±2) kPa in the normal heart muscle of non-infarcted animals to (55±15) kPa in significant fibroblast proliferous muscle of infarcted animals, an almost three-fold increase (Berry et al, 2006). Therefore, the functional roles of the fibroblasts in cardiac electrical and mechanical activities have attracted increasing interest, and have been explored in experimental studies (Miragoli et al, 2007;Zlochiver et al, 2008) and computational models (MacCannell et al, 2007;Tanaka et al, 2007;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008;Sachse et al, 2009). Both experimental and computational studies (Miragoli et al, 2006;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008) have illustrated that non-monotonic changes in conduction velocity (CV) are caused by increasing the fibroblast population.…”

“…ten Tusscher and Panfilov (2007) showed that CV decreased from 0.7 to 0.3 m/s as the percentage of fibroblast proliferous cells rose from 0 to 40% in two-dimensional (2D) tissue. In simulation studies, it was reported that myocyte-fibroblast coupling modulated AP morphology (MacCannell et al, 2007;Jacquemet and Henriquez, 2008;Sachse et al, 2009). Coupling two or four fibroblasts to a ventricular myocyte resulted in a decrease in action potential duration (APD) from a control value of 263 ms to 195 or 155 ms, respectively (MacCannell et al, 2007).…”

“…In simulation studies, it was reported that myocyte-fibroblast coupling modulated AP morphology (MacCannell et al, 2007;Jacquemet and Henriquez, 2008;Sachse et al, 2009). Coupling two or four fibroblasts to a ventricular myocyte resulted in a decrease in action potential duration (APD) from a control value of 263 ms to 195 or 155 ms, respectively (MacCannell et al, 2007). These studies suggest that the effects of fibroblasts on cardiac electrophysiology and mechanics should not be ignored.…”

“…These studies suggest that the effects of fibroblasts on cardiac electrophysiology and mechanics should not be ignored. So far, two electrophysiological models of ventricular fibroblasts, a passive model (Xie et al, 2009b) and an active model (MacCannell et al, 2007), have been developed. However, to the best of our knowledge, there is no mechanical model for cardiac fibroblasts, although some experimental studies on the mechanics of the fibroblasts have been reported Eastwood et al, 1998).…”

Spiral-wave Instability in a Medium with a Gradient in the Fibroblast Density: a Computational Study

“…The fibroblasts are modelled as passive cells; for these fibroblasts, we use the model given by MacCannell, et al [10].…”