Injectable Shear-Thinning Hydrogels Prevent Ischemic Mitral Regurgitation and Normalize Ventricular Flow Dynamics

Abstract

Injectable hydrogels are known to attenuate left-ventricular (LV) remodeling following myocardial infarction (MI), dependent on material mechanical properties. The effect of hydrogel injection on ischemic mitral regurgitation (IMR) resultant from LV remodeling remains relatively unexplored. This study uses multiple imaging methods to evaluate the efficacy of injectable hydrogels with tunable modulus to prevent post-MI development of IMR. Posterolateral MI was induced in 20 sheep with subsequent epicardial injection of saline (control (MI); n = 7), soft hydrogel (guest-host crosslinking, modulus <1 kPa, n = 7), or stiff hydrogel (dual-crosslinking, modulus = 41.4 ± 4.3 kPa, n = 6) within the infarct region and 8-week follow-up. IMR and valve geometry were assessed by echocardiography. LV geometry (long-axis dimension, posterior chordae length) and ventricular flow dynamics were assessed by magnetic resonance imaging. IMR developed in MI controls at 8 weeks and was attenuated with hydrogel treatment (IMR grade for MI: 1.86 ± 0.69; guest-host crosslinking: 1.29 ± 1.11; dual-crosslinking: 0.50 ± 0.55, P = 0.02 vs MI). Tethering of the posterior leaflet increased in MI controls, but not with stiff hydrogel treatment. Across cohorts, IMR was correlated with changes in the long-axis dimension (Spearman R = 0.77) and posterior chordae length (Spearman R = 0.64). Intraventricular flow dynamics were highly disturbed in MI controls, but stiff hydrogel treatment normalized flow patterns and reduced the prevalence of large (≥2+ MR, >5 mL) regurgitant volumes. Injectable hydrogels attenuated subvalvular remodeling and leaflet tethering, preventing IMR development and normalizing LV flow dynamics. Hydrogels with a supraphysiological modulus yielded best outcomes.