Gibbs Chelsea E, Boyle Patrick M
Department of Bioengineering, University of Washington, Seattle, WA, USA.
Department of Bioengineering, University of Washington, Seattle, WA, USA; Division of Cardiology, University of Washington School of Medicine, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA; eScience Institute, University of Washington, Seattle, WA, USA.
J Mol Cell Cardiol. 2025 Jul;204:5-16. doi: 10.1016/j.yjmcc.2025.04.010. Epub 2025 Apr 23.
Following a myocardial infarction (MI), a large portion of ventricular cells are replaced by scar, leading to adverse structural remodeling and heart failure. The use of stem cell-derived cardiomyocytes has shown promise in restoring cardiac function in animal models following an MI but leads to rapid focal ventricular tachycardia (VT). The VT in these animals can be variable, and its underlying mechanisms remain unknown. In this study, we used three distinct computational models derived from histological images of post-MI non-human primate ventricles to understand how human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) grafts can affect focal VT individually and synergistically. Specifically, we explored whether grafts could work cooperatively to create new arrhythmia and if geometric features such as graft tortuosity, area, host isolation, and amount of surrounding scar inhibited or enhanced the effect. We observed at least one instance of graft-host excitation (GHE) for eleven of the twenty-five individual grafts examined. Since we used a stochastic population-of-models-based approach to generate graft boundaries, we found that the number of configurations with GHE varied from graft to graft. We also examined grafts in aggregate and found that the high prevalence of GHE when all grafts were included arose from combinations of individually arrhythmogenic grafts (i.e., the overall increase in arrhythmogenicity resulted from graft complementarity rather than graft cooperativity). Further analysis of graft spatial features showed that arrhythmogenic grafts tend to be in areas with high host isolation (i.e., spatially confined regions of surviving myocardium interdigitated with engrafted cells) and when graft area and tortuosity were also high. These insights can aid in the design of novel injection schemes that could result in safer therapy for patients.
心肌梗死后，大部分心室细胞被瘢痕组织取代，导致不良的结构重塑和心力衰竭。在动物模型中，使用干细胞衍生的心肌细胞已显示出恢复心肌梗死后心脏功能的潜力，但会导致快速局灶性室性心动过速（VT）。这些动物的室性心动过速情况各异，其潜在机制尚不清楚。在本研究中，我们使用了三种不同的计算模型，这些模型源自心肌梗死后非人类灵长类动物心室的组织学图像，以了解人类多能干细胞衍生的心肌细胞（hPSC-CMs）移植物如何单独和协同影响局灶性室性心动过速。具体而言，我们探讨了移植物是否能协同作用产生新的心律失常，以及移植物曲折度、面积、宿主隔离和周围瘢痕量等几何特征是否会抑制或增强这种影响。在检查的25个单独移植物中，我们观察到11个至少有一例移植物-宿主兴奋（GHE）。由于我们使用基于随机模型群体的方法来生成移植物边界，我们发现出现GHE的构型数量因移植物而异。我们还对移植物进行了总体检查，发现当包括所有移植物时，GHE的高发生率源于单个致心律失常移植物的组合（即致心律失常性的总体增加是由于移植物互补性而非移植物协同作用）。对移植物空间特征的进一步分析表明，致心律失常移植物往往位于宿主隔离度高的区域（即存活心肌与植入细胞交错的空间受限区域），并且移植物面积和曲折度也较高。这些见解有助于设计新的注射方案，从而为患者带来更安全的治疗。
