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DIAMOND (Displacement Analysis of Myocardial Mechanical Deformation) to Uncover Segmental Susceptibility to Doxorubicin-Induced Cardiac Injury and Regeneration

  • Author(s): Chen, Junjie
  • Advisor(s): Hsiai, Tzung
  • et al.
Abstract

Current methods of cardiac functional assessment such as ejection fraction (EF), strain imaging, and ventricular inflow diastology have known limitations. We developed and applied a semi-automated, open-source software tool (DIAMOND) for quantitative assessment of segmental cardiac function with applicability to physiological and chemotherapy-induced cardiomyopathy conditions. Zebrafish embryos were imaged in vivo using a light-sheet fluorescence microscopy system, and the 4-D heart synchronized to address cardiac motion. Following re-orientation and isotropic resampling along the true ventricular short axis, resampled data were saved in different matrices. The ventricle was then divided based on a virtual centerline into 8 segments. To conform to the complexity of cardiac structures and deformation, we artificially created a group of rectangular parallelepipeds for 3-D rigid registration and derivation of a transformation matrix (Tm). Tm was utilized to align the diastolic myocardium to the systolic coordinate system, thereby maintaining their relative position. Therefore, DIAMOND allowed measurement of the 3-D displacement of segmental myocardial mass centroids in the same coordinate system. Following treatment of transgenic zebrafish lines with doxorubicin and by chemically and genetically manipulating the Notch signaling pathway, we demonstrate that global EF and focal DIAMOND displacement provide complementary information, with basal segments adjacent to the atrioventricular canal displaying the highest 3-D displacement, contributing the most to EF, and being the most susceptible to chemotherapy-induced cardiac injury. By utilizing a Tp1 Notch reporter line, FUCCI transgenic line, and DIAMOND, we established a temporal sequence of Dox-induced injury, Notch activation, cardiomyocyte proliferation, trabeculation restoration, and cardiac function normalization within two days post doxorubicin treatment. In conclusion, DIAMOND provides a novel approach for focal cardiac mechanics assessment to localize, track, and quantify segmental myocardial function in response to doxorubicin-induced cardiac injury and Notch signaling-medicated myocardial regeneration.

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