INTRA-MYOCARDIAL ALGINATE HYDROGEL INJECTION ACTS AS A LEFT VENTRICULAR MID-WALL CONSTRAINT IN SWINE.

ABSTRACT Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge about the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To identify the mechanism of action, we examined previously unobtainable measurements of cardiac function from in vivo, ex vivo, and in silico states of clinically relevant heart failure (HF) in large animals. High-resolution ex vivo magnetic resonance imaging and histological data were used along with state-of-the-art subject-specific computational model simulations. Ex vivo data were incorporated in detailed geometric computational models for swine hearts in health (n=5), ischemic HF (n=5), and ischemic HF treated with alginate hydrogel injection therapy (n=5). Hydrogel injection therapy mitigated elongation of sarcomere lengths (1.66 ± 0.15μm [treated] vs. 1.79 ± 0.16μm [untreated], p 99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as an LV mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated HF controls without causing negative secondary outcomes to cardiac function. [229 words]