Adaptive remodeling of the right ventricle in response to pulmonary hypertension: towards physical understanding and prediction

右心室响应肺动脉高压的适应性重塑：物理理解和预测

• 批准号: 9316347
• 负责人: Reza Avazmohammadi
• 金额: $ 5.71万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316347
• 关键词: 3-Dimensional; Adopted; Anatomy; Animals; Architecture; Behavior; Cardiac Myocytes; Cells; Chronic; Clinical; Clinical Treatment; Collagen Fiber; Computer Simulation; Data; Development; Disease; Disease Progression; Elements; Evolution; Extracellular Matrix; Failure; Fiber; Future; Geometry; Goals; Growth; Heart; Heart Hypertrophy; Heart failure; Hospitalization; Hypertension; Hypertrophy; Individual; Intervention; Knowledge; Laws; Link; Magnetic Resonance Imaging; Measurement; Mechanics; Modeling; Morphology; Myocardium; Organ; Patients; Property; Pulmonary Hypertension; Rattus; Research; Right Ventricular Function; Right ventricular structure; Sarcomeres; Stem cells; Stress; Structural Models; Structure; Techniques; Therapeutic; Thick; Time; Tissues; Treatment Efficacy; United States; Woman; X-Ray Computed Tomography; base; clinical efficacy; computerized tools; design; experience; improved; in vivo; in vivo imaging; insight; light scattering; men; mortality; pressure; public health relevance; pulmonary arterial hypertension; response; simulation; soft tissue; tool

 DESCRIPTION (provided by applicant): The hypertrophy and remodeling of the heart right ventricle (RV) are key predictors of right heart failure in patients with pulmonary arterial hypertension (PAH) disease. These effects are induced by pressure overload in the RV and are associated with structural and mechanical changes of the RV free wall (RVFW) that eventually results in RV failure. New tools are needed to allow clinicians to use in vivo measurements of RV function into a model that can help predict the progression of this disease. Our long-term objective for this proposal is to improve our understanding on how the RV adapts to PAH, and to develop an experimentally- guided growth and remodeling (G&R) model that captures this adaptation. This model can be "personalized" using in vivo imaging data and thereby has the potential to provide the means for clinicians to predict the progression of RV hypertrophy and evaluate the efficacy of new clinical interventions. Recently, we developed a tissue-level constitutive (stress-strain) model that elucidates the relationship between structural and compositional arrangement in a healthy RVFW and its overall mechanical response; now there is a need to investigate how this arrangement at the cellular-level adapts to a chronic pressure overload, and what effects this adaptation has at tissue- and organ-level behaviors. Towards this goal, we propose to extend our model to a micromechanical model and to account for growth and remodeling response of the RVFW (Aim 1). We will then implement the model within a realistic computational setting and conduct comparisons with results from a rat model (Aim 2). Finally, we will use our model to quantify reversibility in a rat model of PAH subjected to an intervention (Aim 3). Three specific aims of this proposal are then summarized as: 1. Extend our current structural soft tissue constitutive model to a microstructurally accurate 3-D model and to include time-evolving hypertrophy and remodeling adaptation of the RVFW to a pressure overload 2. Develop an anatomically faithful FE model of biventricular rat heart and comparing the simulation results to in vivo data 3. Determine the point of 'no return' along the hypertrophy and remodeling progression by investigating changes in wall stress in a rat model undergoing stem-cell treatment

 描述(申请人提供)：心脏右室(RV)肥厚和重构是肺动脉高压(PAH)患者右心衰竭的关键预测指标。这些效应是由房车中的压力过载引起的，并与房车自由壁的结构和力学变化有关，最终导致房车失效。需要新的工具来允许临床医生将RV功能的活体测量应用到有助于预测这种疾病的进展的模型中。我们对这项建议的长期目标是提高我们对房车如何适应PAH的理解，并开发一个实验指导的生长和重塑(G&R)模型来捕捉这种适应。该模型可以利用活体成像数据进行个性化，从而有可能为临床医生提供预测右室肥大进展和评估新的临床干预措施的疗效的手段。最近，我们开发了一个组织水平的本构(应力-应变)模型，该模型阐明了健康的rvfw的结构和成分安排与其整体机械反应之间的关系；现在需要研究细胞水平的这种安排如何适应慢性压力超负荷，以及这种适应对组织和器官水平的行为有什么影响。为了实现这一目标，我们建议将我们的模型扩展到微观力学模型，并考虑rvfw的生长和重塑反应(目标1)。然后，我们将在现实的计算环境中实现该模型，并与RAT模型的结果进行比较(目标2)。最后，我们将使用我们的模型来量化接受干预的PAH大鼠模型的可逆性(目标3)。这一建议的三个具体目标概括如下：1.将我们现有的结构软组织本构模型扩展到微观结构上精确的3-D模型，并包括rvfw对压力超负荷的随时间演变的肥厚和重塑适应2.建立一个解剖上逼真的双室大鼠心脏有限元模型，并将模拟结果与活体数据进行比较3.通过研究接受干细胞治疗的大鼠模型壁应力的变化，确定沿肥厚和重塑进展的不返回点