Engineered cardiac microtissues were fabricated using pluripotent stem cells with a hypertrophic cardiomyopathy associated c. 2827 C>T; p.R943x truncation variant in myosin binding protein C (MYBPC3^+/−). Microtissues were mounted on iron-incorporated cantilevers, allowing manipulations of cantilever stiffness using magnets, enabling examination of how in vitro afterload affects contractility. MYPBC3^+/− microtissues developed augmented force, work, and power when cultured with increased in vitro afterload when compared with isogenic controls in which the MYBPC3 mutation had been corrected (MYPBC3^+/+(ed)), but weaker contractility when cultured with lower in vitro afterload. After initial tissue maturation, MYPBC3^+/− CMTs exhibited increased force, work, and power in response to both acute and sustained increases of in vitro afterload. Together, these studies demonstrate that extrinsic biomechanical challenges potentiate genetically-driven intrinsic increases in contractility that may contribute to clinical disease progression in patients with HCM due to hypercontractile MYBPC3 variants.

使用与c相关的肥厚性心肌病的多能干细胞制造工程心脏微组织。第2827章肌球蛋白结合蛋白 C (MYBPC3 ^+/- ) 中的 p.R943x 截短变体。将微组织安装在掺铁悬臂上，允许使用磁铁操纵悬臂刚度，从而能够检查体外后负荷如何影响收缩性。与 MYBPC3 突变已得到纠正的等基因对照相比，当体外后负荷增加时，MYPBC3 ^+/-微组织产生增强的力、做功和功率（MYPBC3 ^+/- (ed)），但在较低培养条件下培养时收缩性较弱。体外后负荷。初始组织成熟后，MYPBC3 ^+/- CMT 表现出增加的力、功和功率，以响应体外后负荷的急剧和持续增加。总之，这些研究表明，外在生物力学挑战会增强基因驱动的内在收缩性增加，这可能会导致由于 MYBPC3 过度收缩变异导致的 HCM 患者的临床疾病进展。