Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics.

Rapid myocardial relaxation is essential in maintaining cardiac output, and impaired relaxation is an early indicator of diastolic dysfunction. While the biochemical modifiers of relaxation are well known to include calcium handling, thin filament activation, and myosin kinetics, biophysical and biomechanical modifiers can also alter relaxation. We have previously shown that the relaxation rate is increased by an increasing strain rate, not a reduction in afterload. The slope of the relaxation rate to strain rate relationship defines Mechanical Control of Relaxation (MCR). To investigate MCR further, we performed in vitro experiments and computational modeling of preload-adjustment using intact rat cardiac trabeculae. Trabeculae studies are often performed using isometric (fixed-end) muscles at optimal length (Lo, length producing maximal developed force). We determined that reducing muscle length from Lo increased MCR by 20%, meaning that reducing preload could substantially increase the sensitivity of the relaxation rate to the strain rate. We subsequently used computational modeling to predict mechanisms that might underlie this preload-dependence. Computational modeling was not able to fully replicate experimental data, but suggested that thin-filament properties are not sufficient to explain preload-dependence of MCR because the model required the thin-filament to become more activated at reduced preloads. The models suggested that myosin kinetics may underlie the increase in MCR at reduced preload, an effect that can be enhanced by force-dependence. Relaxation can be modified and enhanced by reduced preload. Computational modeling implicates myosin-based targets for treatment of diastolic dysfunction, but further model refinements are needed to fully replicate experimental data.

Myocardial Fiber Mapping of Rat Hearts, Using Apparent Backscatter, with Histologic Validation.

Myocardial fiber architecture is a physiologically important regulator of ejection fraction, strain and pressure development. Apparent ultrasonic backscatter has been shown to be a useful method for recreating the myocardial fiber architecture in human-sized sheep hearts because of the dependence of its amplitude on the relative orientation of a myofiber to the angle of ultrasonic insonification. Thus, the anisotropy of the backscatter signal is linked to and provides information about the fiber orientation. In this study, we sought to determine whether apparent backscatter could be used to measure myofiber orientation in rodent hearts. Fixed adult-rat hearts were imaged intact, and both a transmural cylindrical core and transmural wedge of the left ventricular free wall were imaged. Cylindrical core samples confirmed that backscatter anisotropy could be measured in rat hearts. Ultrasound and histologic analysis of transmural myocardial wedge samples confirmed that the apparent backscatter could be reproducibly mapped to fiber orientation (angle of the fiber relative to the direction of insonification). These data provided a quantitative relationship between the apparent backscatter and fiber angle that was applied to whole-heart images. Myocardial fiber architecture was successfully measured in rat hearts. Quantifying myocardial fiber architecture, using apparent backscatter, provides a number of advantages, including its scalable use from rodents to man, its rapid low-cost acquisition and minimal contraindications. The method outlined in this study provides a method for investigators to begin detailed assessments of how the myocardial fiber architecture changes in preclinical disease models, which can be immediately translated into the clinic.