Abstract:
Both diastolic filling and systolic pumping of the heart are dependent on the passive stiffness characteristics of various mechanical elements of myocardium. However, the specific contribution from each element, including the extracellular matrix, actin filaments, microtubules, desmin intermediate filaments, and sarcomeric titin springs, remains challenging to assess. Recently, a mouse model allowing for precise and acute cleavage of the titin springs was used to remove one mechanical element after the other from cardiac fibers and record the effect on passive stiffness. It became clear that the stiffness contribution from each element is context-dependent and varies depending on strain level and the force component considered (elastic or viscous); elements do not act in isolation but in a tensegral relationship. Titin is a substantial contributor under all conditions and dominates the elastic forces at both low and high strains. The contribution to viscous forces is more equally shared between microtubules, titin, and actin. However, the extracellular matrix substantially contributes to both force components at higher strain levels. Desmin filaments may bear low stiffness. These insights enhance our understanding of how different filament networks contribute to passive stiffness in the heart and offer new perspectives for targeting this stiffness in heart failure treatment.
摘要:
心脏的舒张充盈和收缩期泵送都取决于心肌各种机械元件的被动刚度特性。然而,每个元素的具体贡献,包括细胞外基质,肌动蛋白丝,微管,desmin中间长丝,和肌节肌动蛋白弹簧,评估仍然具有挑战性。最近,我们使用了一种小鼠模型,该模型允许对肌动蛋白弹簧进行精确和急性的分裂,以从心脏纤维中相继去除一个机械元素,并记录对被动刚度的影响。很明显,每个元素的刚度贡献取决于上下文,并且根据应变水平和所考虑的力分量(弹性或粘性)而变化;元素不是孤立地发挥作用,而是处于拉伸关系。Titin在所有条件下都是重要的贡献者,并且在低应变和高应变下都主导着弹性力。对粘性力的贡献在微管之间更平均地共享,替丁,和肌动蛋白。然而,在较高的应变水平下,细胞外基质基本上对两种力分量都有贡献。Desmin长丝可承受低刚度。这些见解增强了我们对不同灯丝网络如何导致心脏被动僵硬的理解,并为心力衰竭治疗中的这种僵硬提供了新的视角。