The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.

机械力在塑造心脏结构和功能方面所起的作用对于了解心脏形成和疾病病因至关重要，但对患者进行研究具有挑战性。结合人类诱导多能干细胞 (hiPSC) 衍生的心肌细胞的工程心脏组织 (EHT) 有可能深入了解这些适应性和适应不良的变化。然而，大多数 EHT 系统无法同时模拟前负荷（腔室填充期间的拉伸）和后负荷（心脏必须对抗以排出血液的压力）。在这里，我们开发了一种新的动态 EHT (dyn-EHT) 模型，该模型使我们能够调整预紧力并获得 >10% 的无约束收缩缩短。去做这个，三维 (3D) EHT 与弹性聚二甲基硅氧烷条集成在一起，除了能够基于条弯曲测量收缩力外，还提供机械预载和后载。我们的研究结果表明，动态加载在施加力大小的基础上改善了野生型 EHT 的功能，从而改善了排列、传导速度和收缩性。对于疾病建模，我们使用来自因结粒斑蛋白基因突变而患有心律失常性心肌病患者的 hiPSC 衍生的心肌细胞。我们证明了这种桥粒相关疾病状态的表现需要 dyn-EHT 调节，并且不能使用 2D 或标准 3D EHT 方法诱导。因此，动态负荷策略对于激发舒张期延长的疾病表型是必要的，