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bioRxiv · 10.1101/2025.09.26.678713

Computational modeling of optogenetic control in human atrial tissue: The role of fibrosis type and illumination strategy

Zhan, H.·Liu, K.·Wei, C.·Deng, D.·Yu, Y.
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Abstract

Atrial fibrosis promotes atrial fibrillation by stabilizing spiral waves, with focal fibrosis causing strong anchoring that resists termination. Optogenetics offers a low-energy alternative for rhythm control, but its efficacy in human atrial tissue remains under investigation. Here, we developed a two-dimensional computational model of human atrial tissue expressing the light-sensitive protein GtACR1, coupled with fibroblasts, to simulate spiral wave dynamics under varying degrees (0%-100%) and types (focal vs. diffuse) of fibrosis. We examined the effects of subthreshold illumination area (0%-100%) and spatial intensity profiles (uniform, parabolic, linear, exponential) on termination efficiency, and tested low-intensity periodic stimulation for wave drift induction. Results show that the minimum light area required for termination increases with fibrosis degree. At 25%-50% fibrosis, focal substrates require larger illumination areas than diffuse ones, confirming stronger anchoring. Crucially, the relationship between illumination area and termination time is non-monotonic. An "optimal light range" exists: smaller areas fail to eliminate the wave, while excessively large areas suppress wavefront collisions, prolonging termination. In diffuse fibrosis, low-intensity periodic illumination successfully induces drift and boundary collision, enabling self-termination. In contrast, in focal fibrosis, the spiral wave core remains anchored, and drift cannot be initiated by modulating stimulation frequency or intensity alone. Our findings demonstrate that fibrosis type and extent critically influence optogenetic control efficacy. The existence of an optimal illumination strategy highlights the need for spatially tailored interventions. These results provide a mechanistic basis for developing individualized, low-energy optogenetic defibrillation protocols. Author summaryAtrial fibrillation, a common heart rhythm disorder, is often sustained by rotating electrical waves in the heart muscle. Scarring (fibrosis) in the atria can anchor these waves, making them harder to eliminate. Optogenetics -- a technique that uses light to control genetically modified heart cells--offers a promising low-energy approach to stop these dangerous rhythms. However, how different patterns of scarring affect the success of optical interventions remains unclear. In this study, we developed a computational model of human atrial tissue expressing a light-sensitive protein (GtACR1) to investigate how two major types of fibrosis--localized "focal" scars versus widespread "diffuse" scarring -- influence the effectiveness of light-based rhythm control. We found that focal fibrosis strongly anchors spiral waves, requiring larger illuminated areas for termination, while diffuse fibrosis allows more efficient disruption with smaller light zones. Crucially, we discovered an "optimal light range": too little light fails to stop the wave, but too much can paradoxically prolong termination by suppressing wavefront collisions. Furthermore, we show that low-intensity periodic light can induce drift and self-termination in diffuse fibrotic tissue, but fails in focal substrates due to structural anchoring. Our findings highlight that one-size-fits-all optical strategies are suboptimal, and that personalized illumination protocols--tailored to individual fibrosis patterns--could enable safer, lower-energy defibrillation in the future.

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Zhan, H., Liu, K., Wei, C., Deng, D., Yu, Y.. 2025-09-29. Computational modeling of optogenetic control in human atrial tissue: The role of fibrosis type and illumination strategy. https://doi.org/10.1101/2025.09.26.678713

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