Non-Invasive NMR Imaging of Cardiac Remodeling in Aging

该项目旨在研究衰老对心血管系统的影响以及与年龄相关的细胞外基质变化。正常衰老导致肌细胞损失、纤维化和心肌僵硬增加以及收缩性降低。衰老还与心脏肥大发生率的显著增加相关，通常伴随细胞外基质的变化，如胶原沉积和纤维化增加。因此，心肌重塑在随着年龄增长而出现的心功能不全的发展中起着重要作用。然而，正常衰老和潜在疾病过程的影响之间的区别很难评估。目前，评估重塑程度的唯一定量方法是组织学或生物化学方法，需要固定或提取组织样本。显然，这种方法对于研究人类衰老、左心室（LV）重塑和收缩功能之间的关系不是最佳的。磁共振成像（MRI）在无创检测和监测心脏疾病及其对治疗的反应方面具有巨大的临床潜力。除了高质量的解剖信息，它还可以用来获得整体和局部LV功能的定量信息。最近，我们证明MRI可以检测心肌缺血时水扩散的变化。在令人兴奋的新研究中，我们证明了弥散MRI可用于以高精度确定心肌纤维角度方向，并且使用高弥散梯度揭示了与组织中不同隔室（细胞外，细胞内等）相关的多种弥散成分。该建议的主要假设是：1）水扩散的减少将与胶原蛋白积聚和纤维化的增加相关，以及2）心肌纤维角取向的测量与扩散测量相结合将用于区分正常衰老的影响和心脏肥大的发展。为了检验这些假设，将对分离自6和18月龄自发性高血压大鼠（SHR）和年龄匹配的非高血压Wister-Kyoto大鼠的灌注心脏进行扩散张量MRI实验。心肌的羟脯氨酸含量将用作总组织胶原蛋白含量的量度。这一建议将提供扩散MRI在定量评价正常和病理生理重构的心肌中的应用的基础。非侵入性地确定心肌细胞外基质变化的能力，加上纤维取向的测量，将构成理解衰老对心脏结构和功能的影响的一个重大进展。

This project is directed toward the effects of aging on the cardiovascular system and age-related changes in extracellular matrix. Normal aging results in myocyte loss, increased fibrosis and myocardial stiffness, and depressed contractility. Aging is also associated with a significant increase in the incidence of cardiac hypertrophy, often accompanied by changes in the extracellular matrix such as increased collagen deposition and fibrosis. Thus, myocardial remodeling plays an important role in the development of cardiac dysfunction seen with increased age. However, the distinct between normal aging and the effects of underlying disease processes is difficult to assess. Currently the only quantitative methods available to assess the extent of remodeling are histological or biochemical, and require fixation or extraction of tissue samples. Clearly such methods are not optimal for the investigation of relationships between aging, left ventricular (LV) remodeling, and contractile function in humans. Magnetic resonance imaging (MRI) has great clinical potential for the non-invasive detection and monitoring of cardiac disease and its response to therapy. In addition to high quality anatomic information, it can also be used to obtain quantitative information of both global and regional LV function. Recently, we demonstrated that MRI could detect changes in the diffusion of water during myocardial ischemia. In exciting new studies, we demonstrated that diffusion MRI could be used to determine myocardial fiber angle orientation with a high degree of precision, and the use of high diffusion gradients uncovers multiple diffusion components that correlate to different compartments in the tissue (extracellular, intracellular, etc.) The main hypotheses of this proposal are: 1) that decreased diffusion of water will be correlated with a increase in collagen accumulation and fibrosis, and 2) that measurements of myocardial fiber angle orientation combined with diffusion measurements will be used to distinguish between the effects of normal aging and the development of cardiac hypertrophy. In order to test these hypotheses diffusion tensor MRI experiments will be carried out on perfused hearts isolated from 6 and 18 month old spontaneously hypertensive rats (SHR) and age-matched non- hypertensively Wister-Kyoto rats. Hydroxyproline content of the myocardium will be used as a measure of the total tissue collagen content. This proposal will provide the foundation for the application of diffusion MRI in the quantitative evaluation of both normal and pathophysiological remodeling that occurs in the myocardium. The ability to non-invasively determine changes in the extracellular matrix of the myocardium coupled with measurements of fiber orientation will constitute a major advance in understanding the effects of aging on cardiac structure and function.