Abstract 756: Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model With Dynamically Tunable Afterload

Abstract

Introduction: Anti-angiogenic tyrosine kinase inhibitors (TKIs) have efficacy against many solid neoplasms. Unfortunately, their on- and off-target effects frequently cause hypertension (HTN) and heart failure. Nearly all cases of cardiac dysfunction are associated with HTN, but the mechanism for this association is unclear. Aims: We have developed a novel in vitro 3D tissue engineering platform that uses a magnetically tunable elastomer to create dynamic alterations in afterload felt by cardiac microtissues. We are using this platform to examine the impact of increased in vitro afterload (a proxy for HTN) on cardiotoxicity of the TKI sunitinib. Hypotheses: 1) Increased afterload augments sunitinib-induced cardiotoxicity 2) Repeat exposures to sunitinib and increased afterload will further augment this toxicity. Methods: Human induced pluripotent stem cell cardiomyocytes (96%) and human cardiac fibroblasts (4%) from a commercial vendor (NCardia, Inc.) were allowed to self-assemble and form cardiac microtissues. Microtissues were exposed to sunitinib (0μM-10μM) at differing levels of afterload for a minimum of 8 hours. After a washout period, tissues were either harvested for analysis or exposures to sunitinib and afterload were repeated. Outcomes measured after each drug exposure included caspase activation, contractile ability, and force generation. Results: The applied magnetic field produced increases in afterload from 0.509±0.032 to 0.698±0.031 μN/μm. At 36 hours after exposure to supratherapeutic concentrations of sunitinib, recovery of contractile function as measured by force generation of microtissues was greater under soft afterload conditions compared with stiff afterload conditions (2.52μN soft vs 1.16μN stiff). Conclusion: Our platform creates dynamic alterations in afterload in engineered cardiac microtissues. Use of this versatile platform to examine the cardiotoxic effects of sunitinib has given promising initial results. Future studies examining removal/application of afterload, repeat exposures to sunitinib, and exposure to cardioprotective drugs will allow for insight into the mechanisms, treatment, and prevention of sunitinib-induced cardiotoxicity.