The Multi-Domain Fibroblast/Myocyte Coupling in the Cardiac Tissue: A Theoretical Study.

Cardiac fibroblast proliferation and concomitant collagenous matrix accumulation (fibrosis) develop during multiple cardiac pathologies. Recent studies have demonstrated direct electrical coupling between myocytes and fibroblasts in vitro, and assessed the electrophysiological implications of such coupling. However, in the living tissues, such coupling has not been demonstrated, and only indirect coupling via the extracellular space is likely to exist. In this study we employed a multi-domain model to assess the modulation of the cardiac electrophysiological properties by neighboring fibroblasts assuming only indirect coupling. Numerical simulations in 1D and 2D human atrial models showed that extracellular coupling sustains a significant impact on conduction velocity (CV) and a less significant effect on the action potential duration. Both CV and the slope of the CV restitution increased with increasing fibroblast density. This effect was more substantial for lower extracellular conductance. In 2D, spiral waves exhibited reduced frequency with increasing fibroblast density, and the propensity of wavebreaks and complex dynamics at high pacing rates significantly increased.

Modulation of cardiac pacemaker inter beat intervals by sinoatrial fibroblasts -a numerical study.

The potential effect of sinoatrial fibroblasts on beat rate and variability of the cardiac pacemakers is not yet fully understood. Heterocellular coupling formation and fibroblast proliferation during diseased conditions may further signify the impact of those cells on sinoatrial node function. In this study we numerically modeled the impact of varying numbers of fibroblasts that are electrically coupled to a single pacemaker cell on several electrophysiological parameters. We employed cellular kinetics of the rabbit sinoatrial myocyte, and employed a range of potential gap junctional coupling between fibroblasts and myocytes. We show that increasing numbers of attached and coupled fibroblasts result in depolarization of the resting membrane potential of the pacemaker cell, as well as in attenuation in its action potential magnitude. We also demonstrate that the mean pacemaker inter-beat interval (IBI) was modulated in a non-linear, bi-phasic way by increasing numbers of attached fibroblasts, whereby an initial phase of decreasing IBIs was followed by a significant phase of exponentially increasing IBIs. These observations were more substantial for increased gap junctional coupling between the two cell types. We finally show that IBI variability exponentially increased with increasing numbers of attached and electrically coupled fibroblasts. Again, this effect was stronger with higher values of gap junctional coupling. We postulate that the last observation is related to the role of fibroblasts in amplifying membrane voltage fluctuations of attached myocytes.

Detection of abnormal cardiac activity using principal component analysis--a theoretical study.

Electrogram-guided ablation has been recently developed for allowing better detection and localization of abnormal atrial activity that may be the source of arrhythmogeneity. Nevertheless, no clear indication for the benefit of using electrograms guided ablation over empirical ablation was established thus far, and there is a clear need of improving the localization of cardiac arrhythmogenic targets for ablation. In this paper, we propose a new approach for detection and localization of irregular cardiac activity during ablation procedures that is based on dimension reduction algorithms and principal component analysis (PCA). Using an 8×8 electrode array, our method produces manifolds that allow easy visualization and detection of possible arrhythmogenic ablation targets characterized by irregular conduction. We employ mathematical modeling and computer simulations to demonstrate the feasibility of the new approach for two well established arrhythmogenic sources for irregular conduction--spiral waves and patchy fibrosis. Our results show that the PCA method can differentiate between focal ectopic activity and spiral wave activity, as these two types of activity produce substantially different manifold shapes. Moreover, the technique allows the detection of spiral wave cores and their general meandering and drifting pattern. Fibrotic patches larger than 2 mm(2) could also be visualized using the PCA method, both for quiescent atrial tissue and for tissue exhibiting spiral wave activity. We envision that this method, contingent to further numerical and experimental validation studies in more complex, realistic geometrical configurations and with clinical data, can improve existing atrial ablation mapping capabilities, thus increasing success rates and optimizing arrhythmia management.

Modulation of spiral-wave dynamics and spontaneous activity in a fibroblast/myocyte heterocellular tissue--a computational study.

Fibroblasts make for the most common nonmyocyte cells in the human heart and are known to play a role in structural remodeling caused by aging and various pathological states, which can eventually lead to cardiac arrhythmias and fibrillation. Gap junction formed between fibroblasts and myocytes have been recently described and were shown to alter the cardiac electrical parameters, such as action potential duration and conduction velocity, in various manners. In this study, we employed computational modeling to examine the effects of fibroblast-myocyte coupling and ratio on automaticity and electrical wave conduction during reentrant activity, with specific emphasis on dynamic phenomena and stability. Our results show that fibroblast density and coupling impact wave frequency in a biphasic way, first increasing wave frequency and then decreasing it. This can be explained by the dual role of the fibroblast cell as a current sink or a current source, depending on the coupled myocytes intracellular potential. We have also demonstrated that wave stability as manifested by the spiral-wave tip velocity and reentrant activity lifespan depends on fibroblast-myocyte coupling and ratio in a complex way. Finally, our study describes the required conditions in which spontaneous activity can occur, as a result of the fibroblasts depolarizing the myocytes' resting potential sufficiently to induce rhythmic pulses without any stimulation applied.