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The progressive increase in stiffening of the myocardium associated with the aging process and abetted by comorbid conditions such as diabetes may be linked to an excessive number of collagen cross links within the myocardial extra-cellular matrix. To determine whether ultrasound can delineate changes in the physical properties of heart tissue undergoing cross linking, the authors employed a model in which increased cross linking was induced by treating rat myocardial tissue with specific chemical fixatives. Rat hearts (n=5 each group) were arrested at end-diastole, insonified (30 to 50 MHz) fresh within a few minutes of excision in a phosphate buffered solution, placed in a fixative (10% formalin or 2.5% glutaraldehyde) and insonified at 30-minute intervals thereafter for 24 hours. Ultrasonic attenuation increased in tissues cross linked with formalin (maximal change: 27.2/spl plusmn/3.4 dB/cm) and glutaraldehyde (maximal change: 40.2/spl plusmn/5.6 dB/cm) over a 24-hour period. The frequency dependence of the attenuation coefficient increased as a function of the extent of collagen cross links in formalin (maximal change: 0.8/spl plusmn/0.3 dB/cm-MHz) and glutaraldehyde (maximal change: 0.9/spl plusmn/0.6 dB/cm-MHz). This study represents the first time that the precise time course of myocardial protein cross linking in situ has been characterized by using real time monitoring, and the physiologic effect has been delineated on microscopic material properties.

Targeted acoustic contrast agents are designed to enhance the sensitivity and specificity of ultrasonic diagnoses. The authors have previously developed a ligand targeted ultrasonic contrast system which is a liquid, lipid encapsulated perfluorocarbon emulsion. The emulsion particles are small (250 nm) and have inherently low echogenicity unless bound to a surface by a pretargeted ligand through avidin-biotin interactions. The authors have recently proposed a simple acoustic transmission line model that treats the emulsion particles as a thin layer over the targeted surface. The acoustic reflectivity of the contrast layer is related to the longitudinal velocity and density of the perfluorocarbon. Improvement of the contrast effect may be achieved by using perfluorocarbons with slower longitudinal velocities and/or lower densities. The authors report the longitudinal velocities as a function of frequency of 20 perfluorocarbons using a broadband phase spectroscopic approach for estimating phase velocities. Experimentally determined velocities ranged from 520/spl plusmn/2 m/sec (perfluorohexane) to 705/spl plusmn/5 m/sec (perfluorodecalin). No measurable dispersion was observed over the useful bandwidth of 2 to 22 MHz. Increasing carbon backbone chain length and fluorine substitution with halogens of greater atomic weight increased the measured speed of sound. The authors' experimental data were consistent (R=0.87) with a published empirical model that predicts velocity as a function of molecular structure. These data provide a rational basis for optimizing targeted perfluorocarbon-based contrast agents and offer further insight into the physical mechanisms responsible for the observed enhancement of the acoustic scattering.

Specific ultrasonic tissue characterization parameters were correlated with the three-dimensional architecture and material properties (density, compressibility, size, and orientation) of aortic elastic elements at the microscopic level. The medial layer of 10 samples of normal canine aorta were insonified in vitro utilizing acoustic microscopy from 30 to 44 MHz. The following quantitative indexes exhibited substantial anisotropic elastic behavior in radial (R), circumferential (C), and longitudinal (L) directions: backscatter coefficient (R:0.9/spl plusmn/0.2; C:0.008/spl plusmn/0.0008; L:0.0077/spl plusmn/0.0008 sr/sup -1/ cm/sup -1/); frequency dependence of backscatter (R:3.3; C:1.4; L:1.5); attenuation coefficients (R:105/spl plusmn/22; L:135/spl plusmn/13; C:131/spl plusmn/14 dB/cm). Thus, the ultrasonic indexes are anisotropic: equivalent in the C and L directions, but markedly different in the R direction. These data are indicative of an aortic microstructure that interacts with ultrasonic waves as thin sheet-like elastic layers instead of independent elastin fibers. This specific sheet-like organization of elastin microfibers may function to limit shear injury to concentric aortic lamellae and prevent aortic dissection. The marked anisotropic behavior of normal aortas suggests that ultrasound may be useful for nondestructive characterization of vascular integrity.

Targeted acoustic contrast agents offer the potential for sensitive ultrasonic detection of pathologic tissues. We have previously reported the development of a ligand-targeted, lipid-encapsulated, liquid perfluorodichlorooctane ultrasonic contrast system with a small nominal particle size (approximately 250-nm diameter)Perfluorocarbon nanoparticles substantially increase reflectivity when bound to targeted surfaces, and we propose that this system can be approximated physically as a simple, thin layer, acoustic transmission line. In this study, we evaluate this model and compare the ultrasonic reflectivity of different perfluorocarbon formulations with widely varying acoustic impedances targeted to either nitrocellulose membranes or plasma thrombi in vitro. Five perfluorocarbons were investigated: perfluorohexane (PFH), perfluorooctane (PFO), perfluorooctyl bromide (PFOB), perfluorodichlorooctane (PFDCO), and perfluorodecalin (PFD). Ultrasonic reflection was measured by acoustic microscopy (17 to 35 MHz). Acoustic reflectivity was increased (P < 0.05) by all targeted perfluorocarbon formulations, and the magnitude of the contrast effect was inversely correlated with the perfluorocarbon acoustic impedance. PFH nanoparticles exhibited the greatest enhancement, and PFD nanoparticles showed the least. The acoustic transmission line model predicted well the relative differences in acoustic reflectivity and frequency dependence among the perfluorocarbon formulations. For future clinical applications, PFO nanoparticles may provide the best combination of acoustic enhancement, in vivo physical stability, and safety.