MODEL-BASED DEVELOPMENT OF NEW DIAGNOSTIC MEASURES

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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.