MODEL-BASED DEVELOPMENT OF NEW DIAGNOSTIC MEASURES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 (A)目标 当前NBCR更新提案的主要推动力之一是增加连续性在临床诊断和治疗中的应用。弗吉尼亚大学的心脏生物力学小组（CBG）最近使用连续性开发了室壁运动的新测量方法，以提高心脏应力测试的准确性（Herz 2005，2006）。CBG与弗吉尼亚大学的心脏MRI和超声成像小组合作，目前正在扩展这种基于模型的开发方法，以解决其他诊断目标，包括在负荷测试期间改善先前未识别的心肌梗死（UMI）的诊断，收缩同步性的无创评估，（Ingrassia 2007），以及在心脏起搏治疗（CRT）期间引导起搏器电极导线植入的梗死组织解剖标测。这些努力得到NBCR建模能力的有力支持，但也提出了关于患者特定图像信息集成的新建模挑战。由于研究转基因小鼠的科学价值，UVa的心脏MRI组安装了一个专用的小动物扫描仪，其控制台和编程界面与我们的临床MRI单元相同。这使我们能够使用正在进行的小动物研究，同时开发和完善临床适用的诊断方法，如刺激回波位移编码（DENSE）（Kim 2004）。这一领域的工作将受益于改进的小鼠心脏模型。最后，整个范围的临床和小动物成像工作将受益于更好地结合多尺度信息的能力，例如缺血、激素刺激、钙循环中断等的细胞模型。 下面的三个具体目标总结了在这些领域中的每一个新提出的合作：现有的和新的细胞模型与现有的心脏有限元模型的整合，结合图像衍生的信息，以定制这些有限元模型，以特定的患者，并改进小鼠心脏的建模，用于开发和验证转基因模型中的新诊断方法。在每个例子中，将使用一个具体的原型例子来说明预期的方法，但开发的方法将适用于广泛的类似问题。 与NBCR拟议合作的具体目标是： 1)提高将新的和现有的细胞模型耦合到现有心脏有限元模型的多尺度能力（原型示例  局部缺血）。 2)开发用于结合源自图像的患者特异性功能信息的方法，以生成定制的心脏模型（原型示例  DENSE位移数据）。 3)完成并验证功能齐全的小鼠心脏有限元模型，以补充其他物种的现有模型（原型示例  小鼠中的梗塞后愈合）。 这些目标将依赖于Continuity中提出的新发展，特别是动态编写和编译细胞收缩和离子模型的能力[4A.2B目标1a]，以及将新模型与患者MRI和CT数据拟合以及求解和优化患者特定模型的能力[4A.2B目标3]。该合作项目将有助于推动核心2B研究和技术开发的基础科学和转化应用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (A) OBJECTIVES One of the major thrusts of the current NBCR renewal proposal is increased application of Continuity to clinical diagnosis and treatment. The Cardiac Biomechanics Group (CBG) at the University of Virginia has recently used Continuity to develop novel measures of wall motion to improve the accuracy of cardiac stress testing (Herz 2005, 2006). In collaboration with the cardiac MRI and ultrasound imaging groups at the University of Virginia, the CBG is now expanding this model-based development approach to address other diagnostic goals, including improved diagnosis of prior unrecognized myocardial infarction (UMI) during stress testing, noninvasive assessment of synchrony of contraction (Ingrassia 2007), and anatomic mapping of infarct tissue to guide pacemaker lead implantation during cardiac resynchronization therapy (CRT). These efforts are strongly supported by the modeling capabilities of the NBCR but have also raised new modeling challenges regarding the integration of patient-specific image information. Due to the scientific value of studying transgenic mice, the cardiac MRI group at UVa has installed a dedicated small-animal scanner with a console and programming interface identical to our clinical MRI units. This allows us to use ongoing small-animal studies to simultaneously develop and refine clinically applicable diagnostic methods such as Displacement-Encoding with Stimulated Echoes (DENSE) (Kim 2004). Work in this area would benefit from improved models of the mouse heart. Finally, a whole range of clinical and small-animal imaging work would benefit from the ability to better incorporate multi-scale information such as cellular models of ischemia, hormonal stimulation, disrupted calcium cycling, etc. The three Specific Aims below summarize new proposed collaborations in each of these areas: integration of existing and new cellular models with existing cardiac finite-element models, incorporation of image-derived information to tailor those finite-element models to specific patients, and improved modeling of the mouse heart for use in developing and validating new diagnostic methods in transgenic models. In each example, a specific prototypic example will be used to illustrate the intended approach, but the methods developed will be applicable to a wide range of similar problems. The Specific Aims of the proposed collaborative work with the NBCR are: 1) Improve multi-scale capabilities for coupling new and existing cellular models to existing cardiac finite-element models (prototypic example  regional ischemia). 2) Develop methods for incorporating image-derived patient-specific functional information to generate customized cardiac models (prototypic example  DENSE displacement data). 3) Complete and validate a fully functional mouse cardiac finite-element model to complement existing models of other species (prototypic example  post-infarction healing in the mouse). These aims will rely on proposed new developments in Continuity, especially the ability to dynamically author and compile cellular contractile and ionic models [4A.2B Aim 1a], and the ability to fit new models to patient MRI and CT data and to solve and optimize patient-specific models [4A.2B Aim 3]. This Collaborative Project will help drive the basic science and translational applications of Core 2B research and technology development.