Effect of right-ventricular structural remodeling during pressure overload on the mechanical behavior of myofibers in excised human myocardium

摘要 右心室(RV)的慢性压力超负荷，如在肺动脉高压(PH)中所经历的， 当右室试图维持血流动力学功能时，会导致心肌的结构性重构。 重塑的特征是组成肌纤维层的慢性僵硬和重新排列。 心肌被认为在RV衰竭的晚期起着重要作用。潜在的 RV在疾病进展过程中的微观结构机制和重塑的确切作用尚不清楚 众所周知，很大程度上是由于目前的心脏成像方式和生物力学实验 在活体或台式实验中探索心肌微结构的技术。在这款F32中，一个新的 并提出了独特的台式实验配置，可以直接检测肌纤维伸展和 超声成像技术在人体右室切除组织二维被动拉伸过程中的旋转。这个 亚波长超声成像技术是基于对空间相干性的计算 背向散射超声场，具有临床应用的翻译潜力。实验配置 将被用来直接评估在离体人被动拉伸过程中右室肌纤维的力学行为 在慢性压力超负荷过程中发生结构重塑的右室组织。因此，建议的 实验将阐明RV结构重塑的微观力学本质。组织切片将 允许微观结构重塑和测量的机械性能差异之间的直接关联 重塑的心肌和健康对照组织之间的反应，从而揭示了微结构 慢性压力超负荷时右室结构重构的起源。特定目标#1使用被动 舒张期的伸展速度比舒张期慢得多，因此接近静态变形。具体目标2 研究舒张期以类似于活体经历的速度发生的伸展，因此动态 本课程将探讨右室肌纤维的被动力学行为。 拟议的研究是将进行的多方面培训和专业发展计划的一部分。 在颁奖期间。与执行特定目标相关的实验和分析将 为申请者提供生物医学超声成像方面的深入实践培训经验 实验生物力学研究技术。该提案的联合导师在以下方面有成功的记录 转化性生物医学研究，因此培训将包括弥合基础知识与基础知识之间差距的经验 研究和转化为临床应用--所谓的“死亡之谷”。协作环境 在匹兹堡大学医学中心的血管医学研究所内，包括一种 致力于培训NIH T32和F32学员，并提供丰富的机会分享和 与领先的研究人员讨论血管领域基础、翻译和临床研究的进展 通过研讨会、会议和其他机会促进医学专业发展。

ABSTRACT Chronic pressure overload in the right ventricle (RV), such as that experienced in pulmonary hypertension (PH), leads to structural remodeling of the myocardium as the RV attempts to maintain hemodynamic function. Remodeling is characterized by chronic stiffening and rearrangement of the myofiber layers that compose the myocardium, which is thought to play a significant role in the late stages of RV failure. The underlying microstructural mechanisms and the precise role of remodeling of the RV during disease progression are not well understood, largely due to the inability of current cardiac imaging modalities and biomechanical experimental techniques to probe the myocardium microstructure either in vivo or in bench-top experiments. In this F32, a new and unique bench-top experimental configuration is proposed that can directly detect myofiber stretches and rotations during two-dimensional passive stretch of excised human RV tissue using ultrasound imaging. The sub-wavelength ultrasound imaging technique is based on calculation of the spatial coherence of the backscattered ultrasound field, and has translational potential for clinical use. The experimental configuration will be used to directly assess the mechanical behavior of RV myofibers during passive stretch in excised human RV tissues that have undergone structural remodeling during chronic pressure overload. Thus the proposed experiments will elucidate the micromechanical nature of RV structural remodeling. Histological sectioning will allow for direct correlation between microstructural remodeling and the measured differences in mechanical response between remodeled myocardium and healthy control tissue, thus shedding light on the microstructural origins of structural remodeling of the RV during chronic pressure overload. Specific Aim #1 employs passive stretches that occur much slower than during diastole, thus approximating static deformations. Specific Aim #2 investigates stretches that occur at similar rates to those experienced in vivo during diastole, thus the dynamic passive mechanical behavior of RV myofibers will be explored. The proposed research is part of a multifaceted training and professional development plan that will take place during the award period. The experiments and analyses associated with the execution of the Specific Aims will involve in-depth and hands-on training experience for the applicant in both biomedical ultrasound imaging and experimental biomechanics research techniques. Co-mentors for the proposal have successful track records in translational biomedical research, thus training will include experience in bridging the gap between basic research and translation into clinical applications – the so-called “valley of death.” The collaborative environment within the Vascular Medicine Institute at the University of Pittsburgh Medical Center includes a culture that is dedicated to the training of NIH T32 and F32 trainees, and provides a wealth of opportunities to share and discuss advances with leading investigators in basic, translational, and clinical research in the field of vascular medicine through seminars, conferences, and other opportunities for professional development.