The interstitial fibrous matrix plays a key role in the process of cardiac remodeling and is intimately related to both systolic and diastolic dysfunction. However, few tools are available for studying the effects of the remodeling process on material properties at the cellular level and the potentially salutary effects of pharmacologic agents such as angiotensin-converting enzyme (ACE) inhibitors on microscopic cardiac material properties. The overall goal of this proposal is to apply quantitative methods for ultrasonic tissue characterization to define the functional consequences of abnormal matrix architecture at the cellular level. The experimental protocol comprises four parts. FIRST, determinants of ultrasonic scattering and attenuation will be defined in remodeling ventricles under experimental conditions of infarction (rats), cardiomyopathy (Syrian hamsters), and hypertensive hypertrophy (spontaneously hypertensive rats) by measuring the specific organization, composition, and material properties of cardiac interstitial fibrous matrix at the cellular level. Specifically, measurements of collagen cross-linking, maturity and type will be related to ultrasonic indexes of material properties acquired with 50 MHz acoustic microscopy. The extent of collagen cross-linking will be manipulated by feeding copper deficient diets to further define its role in matrix remodeling. SECOND, microscopic effects of therapy with afterload reducing agents (ACE inhibitors) on tissue matrix composition, collagen cross-linking, and material properties will be determined by high frequency ultrasound in experimental infarction, cardiomyopathy, and hypertrophy. THIRD, mathematical modeling of the physical determinants of ultrasonic scattering from myocardium will be performed with an elastic wave theory formalism developed in the last grant interval that incorporates realistic material properties of elasticity, density, size, shape, and orientation of scatterers to """"""""predict"""""""" pathologic scattering behavior from remodeled tissue. These predictions will be cross-correlated with estimates of cardiac material properties developed with a proven finite element model of cardiac systolic and diastolic function. FOURTH, high frequency ultrasonic tissue characterization will be implemented in a commercially available imaging platform to provide a method for performing nondestructive intracardiac """"""""ultrasonic biopsy"""""""" to elucidate ventricular remodeling in patients with stunned myocardium and cardiac transplant rejection. These data should enhance our understanding of the evolution of interstitial matrix remodeling and its effects on microscopic properties, which will facilitate identification of cellular mechanisms of regional and global systolic and diastolic dysfunction.
Showing the most recent 10 out of 69 publications
