Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut.
Am J Physiol Heart Circ Physiol. 2021 Mar 1;320(3):H1112-H1123. doi: 10.1152/ajpheart.00325.2020. Epub 2021 Jan 15.
Comprehensive functional characterization of cardiac tissue includes investigation of length and load dependence. Such measurements have been slow to develop in engineered heart tissues (EHTs), whose mechanical characterizations have been limited primarily to isometric and near-isometric behaviors. A more realistic assessment of myocardial function would include force-velocity curves to characterize power output and force-length loops mimicking the cardiac cycle to characterize work output. We developed a system that produces force-velocity curves and work loops in human EHTs using an adaptive iterative control scheme. We used human EHTs in this system to perform a detailed characterization of the cardiac β-myosin specific inhibitor, mavacamten. Consistent with the clinically proposed application of this drug to treat hypertrophic cardiomyopathy, our data support the premise that mavacamten improves diastolic function through reduction of diastolic stiffness and isometric relaxation time. Meanwhile, the effects of mavacamten on length- and load-dependent muscle performance were mixed. The drug attenuated the length-dependent response at small stretch values but showed normal length dependency at longer lengths. Peak power output of mavacamten-treated EHTs showed reduced power output as expected but also shifted peak power output to a lower load. Here, we demonstrate a robust method for the generation of isotonic contraction series and work loops in engineered heart tissues using an adaptive-iterative method. This approach reveals new features of mavacamten pharmacology, including previously unappreciated effects on intrinsic myosin dynamics and preservation of Frank-Starling behavior at longer muscle lengths. We applied innovative methods to comprehensively characterize the length and load-dependent behaviors of engineered human cardiac muscle when treated with the cardiac β-myosin specific inhibitor mavacamten, a drug on the verge of clinical implementation for hypertrophic cardiomyopathy. We find mechanistic support for the role of mavacamten in improving diastolic function of cardiac tissue and note novel effects on work and power.
全面的心脏组织功能特征包括对长度和负荷依赖性的研究。在工程心脏组织 (EHT) 中，这些测量进展缓慢，其力学特性主要限于等长和近等长行为。对心肌功能的更现实评估将包括力-速度曲线以表征功率输出和力-长度环模拟心脏周期以表征功输出。我们开发了一种系统，该系统使用自适应迭代控制方案在人 EHT 中产生力-速度曲线和工作循环。我们在该系统中使用人 EHT 对心脏β肌球蛋白特异性抑制剂 mavacamten 进行了详细表征。与该药物在治疗肥厚型心肌病方面的临床应用一致，我们的数据支持 mavacamten 通过降低舒张僵硬和等长松弛时间来改善舒张功能的前提。同时，mavacamten 对长度和负荷依赖性肌肉性能的影响是混合的。该药物在较小的拉伸值下减弱了长度依赖性反应，但在较长的长度下表现出正常的长度依赖性。mavacamten 处理的 EHT 的峰值功率输出显示出预期的降低，但也将峰值功率输出转移到较低的负载。在这里，我们展示了一种使用自适应迭代方法在工程心脏组织中产生等张收缩系列和工作循环的强大方法。这种方法揭示了 mavacamten 药理学的新特征，包括对固有肌球蛋白动力学的以前未被认识到的影响以及在较长的肌肉长度下保持 Frank-Starling 行为。我们应用创新方法全面表征了经心脏β肌球蛋白特异性抑制剂 mavacamten 处理的工程人类心脏肌肉的长度和负荷依赖性行为，该药物即将用于肥厚型心肌病的临床实施。我们发现 mavacamten 在改善心脏组织舒张功能中的作用具有机械学支持，并注意到对工作和功率的新影响。
