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

压力超负荷时右心室结构重塑对离体心肌肌纤维机械行为的影响

• 批准号: 10315080
• 负责人: John Cormack
• 金额: $ 7.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315080
• 关键词: Effect; right; ventricular; structural; remodeling

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.

摘要 右心室（RV）慢性压力超负荷，如肺动脉高压（PH）， 导致心肌的结构重构，因为RV试图维持血液动力学功能。 重塑的特征是慢性硬化和重组的肌纤维层，构成了 心肌，其被认为在RV衰竭的晚期阶段起重要作用。底层 在疾病进展过程中，RV的微观结构机制和重塑的确切作用并不清楚。 很好地理解，主要是由于目前的心脏成像模式和生物力学实验的能力， 在体内或在台式实验中探测心肌微观结构的技术。在这款F32中， 并提出了独特的台式实验配置，可以直接检测肌纤维拉伸， 使用超声成像在切除的人RV组织的二维被动拉伸期间的旋转。的 亚波长超声成像技术是基于对超声信号的空间相干性的计算。 反向散射超声场，并具有临床应用的转化潜力。实验配置 将用于直接评估在离体人体被动拉伸过程中RV肌纤维的力学行为 慢性压力超负荷期间发生结构重塑的RV组织。因此，建议 实验将阐明RV结构重塑的微观力学性质。组织切片将 允许微观结构重塑和机械性能的测量差异之间的直接相关性 重塑心肌和健康对照组织之间的反应，从而揭示了微结构 慢性压力超负荷期间RV结构重塑的起源。具体目标#1采用被动 拉伸发生的速度比在拉伸过程中慢得多，因此近似静态变形。具体目标#2 研究拉伸，发生在类似的速率，在体内经历的过程中，因此动态 将探索RV肌纤维的被动机械行为。 拟议的研究是一个多方面的培训和专业发展计划的一部分， 在颁奖期间。与执行具体目标相关的实验和分析将 为申请人提供生物医学超声成像和 实验生物力学研究技术。该提案的共同导师在以下方面有成功的记录： 转化生物医学研究，因此，培训将包括弥合基础之间的差距的经验 研究和转化为临床应用-所谓的“死亡之谷”。协同环境 在匹兹堡大学医学中心血管医学研究所内， 致力于NIH T32和F32学员的培训，并提供了丰富的机会分享和 与领先的研究者讨论血管领域基础、转化和临床研究的进展 通过研讨会，会议和其他专业发展的机会。