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

 描述（由申请方提供）：心脏右心室（RV）肥大和重塑是肺动脉高压（PAH）疾病患者右心衰竭的关键预测因素。这些效应是由RV中的压力过载引起的，并且与最终导致RV失效的RV游离壁（RVFW）的结构和机械变化相关。需要新的工具来允许临床医生将RV功能的体内测量结果应用到可以帮助预测这种疾病进展的模型中。我们这项提案的长期目标是提高我们对RV如何适应PAH的理解，并开发一种实验指导的生长和重塑（G&R）模型，以捕获这种适应。该模型可以使用体内成像数据进行“个性化”，从而有可能为临床医生提供预测RV肥大进展和评估新临床干预措施疗效的方法。最近，我们开发了一个组织水平的本构（应力应变）模型，阐明了结构和组成的安排在一个健康的RVFW和其整体的机械响应之间的关系;现在有必要研究这种安排在细胞水平上如何适应慢性压力过载，以及这种适应在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（目的1）。然后，我们将在现实的计算环境中实现该模型，并与大鼠模型的结果进行比较（目标2）。最后，我们将使用我们的模型量化接受干预的PAH大鼠模型的可逆性（目的3）。该提案的三个具体目标总结如下：1.将我们目前的结构性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随时间推移的肥大和重塑适应压力超负荷2。建立了一个符合解剖学的大鼠双心室有限元模型，并将模拟结果与在体数据进行了比较。通过研究接受干细胞治疗的大鼠模型的室壁应力变化，确定肥大和重塑进展沿着的“不归点”

 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