Copeland Katherine M, Chen Houjia, Chintapula Uday, Almasian Milad, Chung Duc Khang, Taylor Alan M, Ding Yichen, Sharma Gaurav, Jessen Michael E, Hong Yi, Nguyen Kytai T, Peltz Matthias, Bajona Pietro, Liao Jun
Department of Bioengineering, University of Texas at Arlington, Arlington, TX, United States.
Department of Bioengineering, University of Texas at Dallas, Richardson, TX, United States.
Front Bioeng Biotechnol. 2025 Jun 2;13:1620594. doi: 10.3389/fbioe.2025.1620594. eCollection 2025.
Hypertrophic cardiomyopathy (HCM) is often caused by genetic mutations, resulting in abnormal thickening of ventricular muscle, particularly the septum, and causing left ventricular outflow tract (LVOT) obstruction and inferior cardiac performance. The cell and microstructural abnormalities are believed to be the cause of the altered tissue mechanical properties and inferior performance. However, there is a lack of detailed biomechanical assessments of human hypertrophied septum and a lack of understanding of the structural-mechanical relationship between altered biomechanical properties and cellular hypertrophy, fibrotic overexpression, and microstructural disruptions. In this study, we performed thorough biomechanical and microstructural characterizations on the human hypertrophied septum and compared this with healthy septum. We found that the hypertrophied human septum was stiffer at the initial phase of tissue loading, but less nonlinear, less stiff in the linear region, and much weaker in mechanical strength when compared to the healthy human septum. The fibrosis-induced initial stiffening in the hypertrophied septum paradoxically coexists with compromised mechanical strength and integrity under physiological demands, correlating with the clinical observations of diastolic dysfunction and susceptibility to myocardial damage in HCM patients despite ventricular wall thickening. We also discovered that the human hypertrophied septum had significantly larger stress relaxation and slightly larger creep when compared to healthy septum. Moreover, the abnormal, disorganized cell-collagen microstructures in the hypertrophied septum make short-term stress release more difficult and require longer relaxation times to reach equilibrium. Biaxial testing performed at the initial phase of tissue loading showed that both the healthy septum and hypertrophied septum had nonlinear anisotropic stress-strain behavior and confirmed that, in the longitudinal direction, the hypertrophied septum was stiffer than the healthy septum. Our microstructural quantifications via histology and light-sheet microscopy revealed that (i) the heterogeneous cardiomyocyte enlargement and disarray, combined with disorganized collagen overexpression, create a mechanically inefficient tissue architecture in the hypertrophied septum, and (ii) the observed cell-collagen microstructural disruptions provide mechanistic explanations for the deteriorated biomechanical properties. Our viscoelastic mechanical data and microstructural characterizations build a strong foundation to understand the altered tissue behavior of the hypertrophied septum, the degree of deviation from the normal septum, and the underlying structural mechanisms.
肥厚型心肌病（HCM）通常由基因突变引起，导致心室肌异常增厚，尤其是室间隔增厚，并引起左心室流出道（LVOT）梗阻和心脏功能下降。细胞和微观结构异常被认为是组织力学性能改变和功能下降的原因。然而，目前缺乏对人类肥厚室间隔的详细生物力学评估，也缺乏对生物力学性能改变与细胞肥大、纤维化过度表达和微观结构破坏之间结构 - 力学关系的理解。在本研究中，我们对人类肥厚室间隔进行了全面的生物力学和微观结构表征，并与健康室间隔进行了比较。我们发现，与健康人类室间隔相比，肥厚的人类室间隔在组织加载的初始阶段更硬，但非线性程度较低，在线性区域更软，机械强度更弱。肥厚室间隔中由纤维化引起的初始硬化与生理需求下机械强度和完整性受损并存，这与HCM患者尽管心室壁增厚但仍出现舒张功能障碍和心肌损伤易感性的临床观察结果相关。我们还发现，与健康室间隔相比，人类肥厚室间隔的应力松弛明显更大，蠕变略大。此外，肥厚室间隔中异常、无序的细胞 - 胶原微观结构使短期应力释放更加困难，需要更长的松弛时间才能达到平衡。在组织加载初始阶段进行的双轴测试表明，健康室间隔和肥厚室间隔均具有非线性各向异性应力 -应变行为，并证实，在纵向方向上，肥厚室间隔比健康室间隔更硬。我们通过组织学和光片显微镜进行的微观结构定量分析表明：（i）心肌细胞的异质性增大和排列紊乱，加上无序的胶原过度表达，在肥厚室间隔中形成了机械效率低下的组织结构；（ii）观察到的细胞 - 胶原微观结构破坏为生物力学性能恶化提供了机制解释。我们的粘弹性力学数据和微观结构表征为理解肥厚室间隔的组织行为改变、与正常室间隔的偏离程度以及潜在的结构机制奠定了坚实基础。
