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Increased myocardial stiffness in aging and diabetes that may result in pathologies such as diastolic dysfunction has been attributed, in part, to an increase in cross linking of extracellular matrix proteins such as collagen. With the development of new approaches to cardiovascular therapy, it becomes increasingly important to develop noninvasive approaches for monitoring changes in myocardial cross linking. The objective of this study was to use ultrasound at frequencies used in clinical echocardiography to measure changes in myocardial attenuation resulting from increased cross linking as a function of angle of insonification over a complete rotation. Through- transmission radiofrequency-based measurements were performed on 36 specimens from 12 freshly excised ovine hearts at room temperature, which were then fixed in formalin to induce protein cross linking prior to repeated measurements. For angles near perpendicular to the myofiber direction, the measured slope of attenuation increased from 0.52 plusmn 0.07 dB/(cmldrMHz) (mean plusmn one standard deviation) for freshly excised to 0.85 plusmn 0.08 dB/(cmldrMHz) for formalin-fixed myocardium. In contrast, results for parallel insonification exhibit considerable overlap (1.88 plusmn 0.17 for freshly excised and 1.75 plusmn 0.19 dB/(cmldrMHz) for formalin- fixed myocardium). Results of this study suggest that the response of the extracellular collagenous matrix to changes in cross linking is directionally dependent. The anisotropy of ultrasonic attenuation thus may provide an approach for noninvasive monitoring of the extent and progression of myocardial disease associated with changes in protein cross linking. Accounting for effects due to anisotropy may be essential for the future detection of such changes using ultrasonic attenuation in vivo.