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: 10543042
• 负责人: John Cormack
• 金额: $ 1.08万
• 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/10543042
• 关键词: Acoustics; Anisotropy; Area; Award; Basic Science; Biomechanics; Biomedical Research; Biophysics; Blood Vessels; Cardiac; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Treatment; Development; Development Plans; Diagnosis; Diastole; Disease; Disease Progression; Evaluation; Heart failure; Histologic; Human; Human Rights; Image; Imaging Techniques; Imaging technology; Institute of Medicine (U.S.); Knowledge; Light; Link; Measurable; Measurement; Measures; Mechanics; Medical center; Medicine; Mentors; Mentorship; Monitor; Myocardium; Nature; Pathologic; Play; Process; Pulmonary Hypertension; Rattus; Records; Regulation; Research; Research Personnel; Research Technics; Research Training; Resources; Right ventricular structure; Role; Rotation; Science; Stretching; Techniques; Testing; Therapeutic; Thick; Time; Tissues; Training; Translational Research; Translations; Ultrasonography; United States National Institutes of Health; Universities; Ventricular; Ventricular Remodeling; Work; base; clinical application; clinical diagnosis; collaborative environment; course load; curative treatments; experience; experimental study; heart imaging; hemodynamics; imaging modality; in vivo; insight; mechanical behavior; mechanical load; mechanical properties; molecular imaging; pressure; pulmonary arterial hypertension; response; right ventricular failure; right ventricular remodeling; success; symposium; translational potential; translational scientist; two-dimensional; ultrasound

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.

抽象的 右通气（RV）中的慢性压力超负荷，例如肺动脉高压（pH）中经历的压力超负荷 随着RV试图维持血液动力学功能，导致心肌的结构重塑。 重塑的特征是组成的肌纤维层的慢性加强和重排 心肌，被认为在RV失败的后期阶段起重要作用。基础 微观结构机制和疾病进展过程中RV重塑的精确作用不是 良好的理解，很大程度上是由于当前的心脏成像方式和生物力学实验 在体内或台式实验中探测心肌微结构的技术。在此F32中，新的 并提出了独特的基准实验配置，可以直接检测肌纤维伸展 使用超声成像在二维无源人类RV组织中旋转。这 亚波长度超声成像技术基于计算的空间相干性 反向散射的超声场，并转化了临床使用的潜力。实验配置 将用于直接评估出色的人类被动拉伸过程中RV肌纤维的机械行为 在慢性压力超负荷期间经历结构重塑的RV组织。那就是提议 实验将阐明RV结构重塑的微机械性质。组织学分区将 允许微结构重塑与测量机械差异之间的直接相关性 重塑心肌和健康对照组织之间的响应，从而散发出微观结构的灯光 慢性压力超负荷过程中RV结构重塑的起源。特定目标＃1员工被动 伸展比舒张期慢得多，因此近似静态变形。特定目标＃2 研究的伸展运动与舒张期间经历的体内经历的延伸率相似，因此动态 将探索RV肌纤维的被动机械行为。 拟议的研究是将实施的多方面培训和专业发展计划的一部分 在奖励期间。与特定目的执行相关的实验和分析将 在生物医学超声成像和 实验生物力学研究技术。该提案的联合官员在 翻译生物医学研究，因此培训将包括弥合基本之间差距的经验 研究和翻译临床应用 - 所谓的“死亡谷”。协作环境 在匹兹堡大学医学中心的血管医学研究所内，包括一种文化 致力于培训NIH T32和F32学员，并提供了很多分享和 讨论在血管领域的基本，翻译和临床研究领域的领先研究人员的进展 通过半手，会议和其他专业发展机会的医学。