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衰老相关的细胞外基质的变化。正常衰老会导致心肌细胞丢失，增加纤维化和心肌僵硬，并抑制收缩能力。衰老还与心肌肥厚的发生率显著增加有关，通常伴随着细胞外基质的变化，如胶原沉积增加和纤维化。因此，随着年龄的增长，心肌重构在心脏功能障碍的发展中起着重要的作用。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。目前唯一可用于评估重建程度的定量方法是组织学或生化方法，需要固定或提取组织样本。显然，这些方法并不是研究人类衰老、左室(LV)重构和收缩功能之间关系的最佳方法。磁共振成像(MRI)在非侵入性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外，它还可以用于获取整体和局部左心功能的定量信息。最近，我们证明了MRI可以检测到心肌缺血时水的扩散的变化。在令人兴奋的新研究中，我们证明了扩散磁共振可以高精度地用于确定心肌纤维的角度方向，并且使用高扩散梯度揭示了与组织中不同间隔(细胞外、细胞内等)相关的多个扩散成分。这一建议的主要假设是：1)水的扩散减少将与胶原堆积和纤维化的增加相关，以及2)心肌纤维角度取向的测量结合扩散测量将用于区分正常衰老和心肌肥厚的影响。为了验证这些假说，我们将在6月龄和18月龄自发性高血压大鼠(SHR)和年龄匹配的非高血压Wister-京都大鼠的灌流心脏上进行弥散张量MRI实验。心肌中的羟脯氨酸含量将作为衡量组织总胶原含量的指标。这将为磁共振扩散成像在定量评价心肌正常和病理生理学重构方面的应用奠定基础。非侵入性测定心肌细胞外基质变化的能力，再加上纤维取向的测量，将是理解衰老对心脏结构和功能影响的重大进步。

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.