Abstract 482: Assessing myocardial stiffness changes in a non-human primate anthracycline-induced cardiotoxicity model utilizing a biomechanical elasticity imaging methodology
Authors: Miller Caroline , Jordan Jennifer H. , Thomas Alexandra , Meléndez Giselle , Weis Jared A. 
Published: June 2022

Scope: Anthracyclines are a routine regimen for adjuvant therapy of breast cancer, but pose dose-dependent cardiotoxicity risks. With breast cancer diagnoses trending younger, there is a critical need for accurate non-invasive methods for assessing early cardiac degradation for mitigating cardiotoxicity due to cancer therapies.

Methods: We developed a biomechanical model-based elasticity imaging method (BEIM) for assessing direct, functional mechanical stiffness of the left ventricle (LV) to indicate early cardiac degradation1. In this study, we examined the use of BEIM in a cohort of 5 African Green monkeys (AGM) receiving human equivalent doses of doxorubicin (cumulative dose: 240mg/m2) over 10 weeks. Cardiac magnetic resonance (CMR) imaging was acquired before and 15 weeks after final doxorubicin dose. Mechanical elasticity was estimated throughout the mid-plane of the LV utilizing BEIM. After necropsy, histopathology with picrosirius red of the matching LV mid-plane was conducted at 15 weeks after the final doxorubicin dose to calculate collagen volume fraction (CVF) indicative of anthracycline-associated cardiac fibrosis. Archival, age-and gender-matched LVs from healthy, chemotherapy naïve AGM were used as histopathological controls.

Results: Two-dimensional circumferential, radial, and shear elasticity maps of the mid-plane of the LV indicate substantial changes in mechanical elasticity between baseline and 15 weeks post-doxorubicin CMR acquisitions. Average global change between baseline and post-doxorubicin image acquisitions in circumferential, radial, and shear modulus were 4.8, 5.7, and 5.2-fold increases respectively, with an average 1.9-fold change of CVF. Global circumferential, radial, and shear modulus values at baseline and 15 weeks post-doxorubicin were compared to CVF values for each subject and indicate a very strong correlation between circumferential, radial, and shear modulus with CVF, represented by Pearson’s correlation coefficients of 0.91, 0.92, and 0.89, respectively.

Conclusions: We developed BEIM to assess changes in LV mechanical elasticity utilizing routine CMR imaging data with a goal of non-invasively identifying cardiac stiffening associated with cardiotoxicity. To validate our methodology, we utilized CMR data from an AGM model of anthracycline-induced cardiotoxicity to estimate changes in LV elasticity and compare to CVF values from histopathology. Our results show an increase in both CVFs and mechanical elasticity between baseline and 15 weeks following the last doxorubicin dose. Elasticity measures exhibit a very strong correlation with histopathological assessment of cardiac fibrosis. Results demonstrate the ability of our BEIM to identify changes in elasticity related to increased collagen deposition from anthracycline-induced cardiotoxicity.

Citation Format: Caroline Miller, Jennifer H. Jordan, Alexandra Thomas, Giselle Meléndez, Jared A. Weis. Assessing myocardial stiffness changes in a non-human primate anthracycline-induced cardiotoxicity model utilizing a biomechanical elasticity imaging methodology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 482.