The goal of this proposal is to quantify the effects of aging on the three dimensional architecture of the ventricular extracellular matrix and myocytes at the cellular level in experimental animals with disatolic dysfunction. The applicants proposed to elucidate the dynamic consequences of abnormal cardiac architecture and composition that accompany the aging process by measuring intrinsic microscopic material properties such as mass density, elasticity and viscosity, which will be correlated with regional myocardial function. In addition, the applicant would define the role of associated pathological comorbid condision such as diabetes and hypertension on specific strucutrla alterations of interstitial matrix components that may play a role in the exacerbation of diastolic dysfunction. New gas chromatography mass spec methods would be used to measure advance glycation end products indicative of protein crosslinking for direct correlation with measure material properties. The applicant proposed to demonstrate the utility of novel ultrasound and magnetic resonance imaging methods for characterizing cardiac fiber architecture, material properties and motion, and deliniate paradigms for clinical applications of these methods. They would further quantify potential regression or improvemten of extracellular matrix remodeling under these pathologic conditions a pharmacologic therapy with angiotensisn converting enxyme inhibitors and inhibitors of protein crosslinking e.g. amino guanidine which may affect tissue matrix orgaization composition and or material properites. The significance of the proposed research resides in elucidation of the effects of aging on estracellular matrix remodeling, based on characterization of tissue material properties and organization at the cellular level, which will definitively answer the question of whether fundamental visco elastic stiffness coefficients of the cardiac microarchitecture differ between aging and young hearts, and if so which cellular mechanisms.
