Abstract 4144104: Intramyocardial Hydrogel Injections in Porcine Model of Infarction Remodeling Demonstrates Improved Left Ventricular Performance on Pressure-Volume Analysis Associated with Decreased Matrix Metalloproteinase Activation

Introduction: Following myocardial infarction (MI), extracellular matrix (ECM) degradation significantly contributes to adverse left ventricular (LV) remodeling mediated by the activation of matrix metalloproteinases (MMPs). Intramyocardial injection of hydrogels that locally release MMP inhibitors are designed to modulate MMP activation, increase wall thickness, reducing wall stress, resulting in improved regional mechanics and function. Pressure-volume (PV) analysis is an established approach for evaluation of cardiac performance. Methods: Chronic reperfused MI was created by a 90-min LAD occlusion in swine (n=16). PV loop analysis was performed using simultaneous 3D echocardiography and invasive LV pressures at baseline and 5 weeks post-MI. Therapeutic hydrogels were delivered by direct intramyocardial injection (9x100 μl) at 7 days post-MI using hyaluronic acid hydrogels alone (HA-Only) (n=4) or hyaluronic acid that releases an MMP inhibitor doxycycline (HA-DOX) (n=5) into the MI region. Outcomes were compared to control MI pigs (n=7) at 5 weeks post-MI to assess therapeutic benefits. MMP inhibition was measured by uptake of the SPECT MMP targeted radiotracer, 99m Tc-RP805 in the infarct region. Results: Quantitative indices of remodeling from representative PV loops are shown in Figure 1 A-C. LV end-diastolic volume (LVEDV) corrected for body weight (BW) was significantly greater in the MI-controls at 5 weeks post-MI compared to the HA-DOX group (Fig 1D, p=0.035, t-test). There was a statistically significant difference in LV end-diastolic pressure (LVEDP) (Fig 1E) between MI-controls and HA-DOX (p=0.025, ANOVA). There was a trend for decreased LV compliance (Fig 1F) in MI-controls based on the EDPVR V30. These changes correlated with a significant decrease in 99m Tc-RP805 in the MI region of HA-DOX animals compared to controls (Fig 1G). Conclusion: LV PV analysis demonstrated significant adverse remodeling in control pigs that was reduced by early intramyocardial delivery of a DOX releasing hydrogel post-MI. Delivery of both hydrogels prevented some measures of adverse LV remodeling, with prevention of LV dilatation and reduction in LVEDP and correlated with a decrease in MMP activation by SPECT 99m Tc-RP805.