Effect of right-ventricular structural remodeling during pressure overload on the mechanical behavior of myofibers in excised human myocardium

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ABSTRACT Chronic pressure overload in the right ventricle (RV), such as that experienced in pulmonary hypertension (PH), leads to structural remodeling of the myocardium as the RV attempts to maintain hemodynamic function. Remodeling is characterized by chronic stiffening and rearrangement of the myofiber layers that compose the myocardium, which is thought to play a significant role in the late stages of RV failure. The underlying microstructural mechanisms and the precise role of remodeling of the RV during disease progression are not well understood, largely due to the inability of current cardiac imaging modalities and biomechanical experimental techniques to probe the myocardium microstructure either in vivo or in bench-top experiments. In this F32, a new and unique bench-top experimental configuration is proposed that can directly detect myofiber stretches and rotations during two-dimensional passive stretch of excised human RV tissue using ultrasound imaging. The sub-wavelength ultrasound imaging technique is based on calculation of the spatial coherence of the backscattered ultrasound field, and has translational potential for clinical use. The experimental configuration will be used to directly assess the mechanical behavior of RV myofibers during passive stretch in excised human RV tissues that have undergone structural remodeling during chronic pressure overload. Thus the proposed experiments will elucidate the micromechanical nature of RV structural remodeling. Histological sectioning will allow for direct correlation between microstructural remodeling and the measured differences in mechanical response between remodeled myocardium and healthy control tissue, thus shedding light on the microstructural origins of structural remodeling of the RV during chronic pressure overload. Specific Aim #1 employs passive stretches that occur much slower than during diastole, thus approximating static deformations. Specific Aim #2 investigates stretches that occur at similar rates to those experienced in vivo during diastole, thus the dynamic passive mechanical behavior of RV myofibers will be explored. The proposed research is part of a multifaceted training and professional development plan that will take place during the award period. The experiments and analyses associated with the execution of the Specific Aims will involve in-depth and hands-on training experience for the applicant in both biomedical ultrasound imaging and experimental biomechanics research techniques. Co-mentors for the proposal have successful track records in translational biomedical research, thus training will include experience in bridging the gap between basic research and translation into clinical applications – the so-called “valley of death.” The collaborative environment within the Vascular Medicine Institute at the University of Pittsburgh Medical Center includes a culture that is dedicated to the training of NIH T32 and F32 trainees, and provides a wealth of opportunities to share and discuss advances with leading investigators in basic, translational, and clinical research in the field of vascular medicine through seminars, conferences, and other opportunities for professional development.