The effect of systemic hypertension on prognosis of myocardial infarction: Understanding, prediction and therapy evaluation

项目摘要 心壁变薄和心脏左心室(LV)重构是心肌梗塞的主要后果。 心肌梗死(MI)。这些后果可能会受到LV压力过载的相当大的影响，因为 心肌梗死的危险因素和病理性心肌肥厚的原因。先天系统性疾病的影响 高血压(ASH)对心肌梗死后左室重构的影响，更重要的是对再生的成功 心肌梗死后的药物治疗仍然知之甚少。我们对这项建议的长期目标是 提高我们对左心室如何适应ASH下MI的理解，并开发一种经实验验证的 可以预测这种适应的计算模型。传统的测量方法，如左室扩张和梗塞面积 用于表征左室重构提供的心功能信息有限。新的 需要计算工具来揭示多尺度重塑的详细描述和预后 左心室梗死。根据LV壁应力调节LV重塑的开始和程度的假设， 我们将开发一个基于图像的计算模型，弥合局部微观结构和 左室心肌的机械适应与器官水平的功能变化。然后我们将扩展这一模式 模拟和预测ASH后梗死心肌收缩能力的可能改善 干细胞干预。该模型提供了一个平台来研究壁应力修复在修复中的作用 伴和不伴ASH的心肌梗死患者心肌收缩能力的改善。 为了达到我们的目标，我们建议从图像上确定局部肥大和重塑的机制。 基于正常血压和高血压大鼠心肌梗死模型的显微结构和力学数据 (目标1)。然后，我们将构建一个微观结构忠实的、特定于大鼠的有限元模型，该模型考虑了局部 生长和重塑，并使用来自心肌梗死大鼠模型的体内数据进行验证(目标2)。最后，我们将使用 我们的计算模型来研究墙体应力恢复和应力恢复之间的相关性 干细胞干预在我们的心肌梗死大鼠模型中的成功(目标3)。这项提议的三个具体目标是 总结为： 1.量化纤维、组织和组织的时间进程异质性肥大和重塑事件 ASH下心肌梗死后脏器水平。 2.建立了大鼠心脏随时间演化的计算模型，并利用该模型对模型进行了验证。 活体数据。 3.探讨壁应力恢复与干细胞治疗疗效的相关性 在MI之后。

Project Summary Thinning of the heart wall and remodeling of the heart left ventricle (LV) are key consequences of myocardial infarction (MI). These consequences can be considerably influenced by pressure overload in the LV as both a risk factor for MI and a cause of pathological myocardial hypertrophy. The effect of antecedent systemic hypertension (ASH) on the LV remodeling due to MI, and more importantly on the success of regenerative medicine therapies following MI remains poorly understood. Our long-term objective for this proposal is to improve our understanding on how the LV adapts to MI under ASH, and to develop an experimentally-validated computational model that can predict this adaptation. Traditional measures such as LV dilation and infarct size used to characterize the LV remodeling provide limited information on cardiac performance. New computational tools are needed to reveal detailed description and prognosis of multiscale remodeling of infarcted LV. Following the hypothesis that the LV wall stress regulates the onset and extent of LV remodeling, we will develop an image-based computational model bridging the gap between local microstructural and mechanical adaptations of LV myocardium and organ-level functional changes. We will then extend this model to simulate and predict possible improvements in the contractility of infarcted myocardium under ASH following stem-cell interventions. This model provides a platform to investigate the role of wall stress restoration in the improvement of myocardial contractility in infarcted hearts with and without ASH. Towards our goal, we propose to determine the regional hypertrophy and remodeling mechanisms from image- based microstructural and mechanical data obtained from normotensive and hypertensive rat models of MI (Aim 1). We will then build a microstructurally-faithful, rat-specific finite element model that accounts for local growth and remodeling and validate it using in vivo data from the rat models of MI (Aim 2). Finally, we will use our computational model to investigate the correlation between the restoration of the wall stress and the success of stem-cell interventions in our rat models of MI (Aim 3). Three specific aims of this proposal are then summarized as: 1. Quantify the time-course heterogeneous hypertrophy and remodeling events at fiber-, tissue-, and organ-levels following MI under ASH. 2. Develop a time-evolving rat-specific computational model of heart and validate the model using in vivo data. 3. Investigate the correlation between wall stress restoration and the efficacy of stem-cell therapy following MI.