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.
