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.
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