MRI of Myocardial Function in Post-Infarct Knockout Mice

描述（由申请人提供）：在过去的10年里，利用转基因和基因敲除小鼠的实验显著推进了心血管疾病研究的广泛领域。绝大多数此类研究采用离体方法来评估基因操作（表型）的结果，如免疫染色组织样本，以及心功能，在离体langendorff灌注心脏中进行基于导管的左心室（LV）压力测量。特别是对于心功能的研究，无创成像提供了直接反映复杂体内生理的测量的可能性。基本的超声心动图和核磁共振成像技术已经发展并应用于小鼠，特别是核磁共振成像，由于其通用性和准确性，显示出很大的希望。我们建议开发先进的MRI方法来成像小鼠心肌梗死（MI）和局部心肌内功能，并将这些方法应用于心肌梗死后左室功能障碍的研究。具体来说，我们将使用新的位移编码MRI技术来研究急性和慢性心肌梗死的心肌功能障碍，重点关注一氧化氮合酶（iNOS）诱导形式产生的过量一氧化氮（NO）的作用。虽然这些研究侧重于基本机制，但它们具有临床相关性，因为心肌梗死后左室功能障碍和重构是美国死亡的主要原因。了解左室功能障碍和重塑的基本机制可能会导致药物开发和改善治疗。因此，我们的具体目标是：开发用于心肌梗死后小鼠心脏成像的新型MRI方法，在相位重建图像中测量二维（2D）和三维心内组织位移和应变，同时在对比增强幅度重建图像中将心肌梗死区域描述为超增强区域。2. 开发图像分析技术，自动分割心肌，检测延迟超增强区域，计算心肌功能定位于梗死区域，邻近区域和偏远区域。3. 利用MRI，包括Aims 1和Aims 2中开发的方法，通过敲除小鼠和直接基因转移方法阐明一氧化氮（NO）和诱导型一氧化氮合酶（iNOS）在ml后LV功能障碍中的作用。

DESCRIPTION (provided by applicant): Over the past 10 years experiments utilizing transgenic and knockout mice have significantly advanced broad areas of cardiovascular disease research. The vast majority of such research has employed ex vivo methods for assessing the results of gene manipulation (phenotyping) such as immunostaining tissue samples, and, for heart function, performing catheter-based measurements of left-ventricular (LV) pressure in isolated Langendorff-perfused hearts. For studies of cardiac function in particular, noninvasive imaging offers the possibility of making measurements that directly reflect complex in vivo physiology. Basic echocardiographic and MRI techniques have already been developed and applied to mice, and MRI in particular, due to its versatility and accuracy, shows great promise. We propose to develop advanced MRI methods for imaging myocardial infarction (MI) and regional intramyocardial function in mice and to apply these methods to the study of LV dysfunction after MI. Specifically, we will use novel displacement-encoded MRI techniques to study myocardial dysfunction in the settings of acute and chronic MI, focusing on the role of excess nitric oxide (NO) derived from the inducible form of nitric oxide synthase (iNOS). While these studies focus on basic mechanisms, they are clinically relevant because post-MI LV dysfunction and remodeling are a major cause of mortality in the United States. Understanding the basic mechanisms underlying LV dysfunction and remodeling may lead to drug development and improved treatment. Accordingly, our specific aims are 1. To develop novel MRI methods for post-MI mouse heart imaging that measure two-dimensional (2D) and 3D intramyocardial tissue displacement and strain in phase-reconstructed images and simultaneously depict the area of myocardial infarction as a region of hyper enhancement in contrast-enhanced magnitude-reconstructed images. 2. To develop image analysis techniques to automatically segment the myocardium, detect the area of delayed hyper enhancement, and compute measures of myocardial function localized to the infarcted, adjacent, and remote regions. 3. To use MRI, including the methods developed in Aims 1 and 2, to elucidate the roles of nitric oxide (NO) and the inducible form of nitric oxide synthase (iNOS) on post-Ml LV dysfunction using knockout mice and direct gene transfer methods.