MRI of Myocardial Function in Post-Infarct Knockout Mice

描述(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极大地推进了心血管疾病研究的广泛领域。绝大多数此类研究使用了体外方法来评估基因操作(表型)的结果，例如免疫染色组织样本，以及对于心功能，使用基于导管的方法在离体朗宁多夫灌流心脏中测量左心室(LV)压力。特别是对于心脏功能的研究，无创成像提供了直接反映复杂的活体生理的测量的可能性。基本的超声心动图和磁共振成像技术已经被开发出来并应用于小鼠，特别是磁共振成像，由于其多功能性和准确性，显示出巨大的前景。我们建议开发先进的MRI方法来成像小鼠的心肌梗死(MI)和局部心肌内功能，并将这些方法应用于MI后左心功能障碍的研究。具体地说，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时的心肌功能障碍，重点是来自诱导型一氧化氮合酶(INOS)的过量一氧化氮(NO)的作用。虽然这些研究集中在基本机制上，但它们具有临床意义，因为心肌梗死后左室功能障碍和重塑是美国死亡的主要原因。了解左心室功能障碍和重构的基本机制可能有助于药物开发和改进治疗。因此，我们的具体目标是1.发展新的心肌梗死后磁共振成像方法，在相位重建图像中测量二维(2D)和三维心肌内组织的位移和应变，同时在增强幅度重建图像中将心肌梗死区域描绘为高强化区域。2.开发图像分析技术，自动分割心肌，检测延迟高增强区域，并计算定位于梗死区、邻近区和远区的心肌功能指标。3.应用MRI，包括AIMS 1和AIMS 2中发展的方法，通过基因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mLLV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.