Intramyocardial hydrogel delivery post myocardial infarction results in increased integrin activation and reduction in left ventricular modeling.

Introduction: Left ventricular (LV) remodeling and heart failure are known complications of myocardial infarction (MI). Intramyocardial delivery of hydrogel post-MI is currently being evaluated as a therapeutic option for prevention of LV remodeling. The optimal delivery and effects from these hydrogels remain uncertain, although improved hemodynamics, angiogenesis and myocardial blood flow after delivery are presumed. We evaluated the feasibility of using multimodality imaging approach to guide delivery and evaluate the effects of an imageable hydrogel. Specifically, we used ^99mTc-maraciclatide a known radiopharmaceutical that targets the α_vβ₃ integrin for evaluation of angiogenesis post-MI.

Methods: Six Yorkshire pigs subjected to 90 min balloon occlusion and reperfusion were randomized 5 days post MI to intramyocardial delivery of hydrogel (n=3) or controls (n=3). ^99mTc-Tetrofosmin was injected during the occlusion to assess area at risk. Contrast cineCT angiography was performed at baseline, 5 days post MI and 1 week post hydrogel delivery. Hybrid ²⁰¹Tl SPECT/CT imaging was performed prior to hydrogel delivery to define MI region. The imageable hydrogel (Hyaluronic Acid/Gelatin modified with Aldehydes and Hydrazides, with 100 mg/mL iohexol) was delivered intramyocardial in a 3x3 grid 5 days post-MI. Ex vivo dual isotope hybrid SPECT/CT imaging with ²⁰¹Tl and ^99mTc-maraciclatide 1 week post-hydrogel delivery was performed for evaluation of myocardial perfusion and angiogenesis, respectively. The LV was divided into slices and radial segments for gamma well counting. Raw counts were spill up, spill down and decay corrected and converted to percentage of injected dose per gram of tissue.

Results: The average area at risk was 14.3±5.9% of LV with no difference between the hydrogel and the control group (16±7.4 vs 12.7±4.0 % of LV, p=0.282). The hydrogel was successfully delivered to the MI region with guidance of in vivo SPECT/CT. The hydrogel was visualized with cineCT post-delivery within perfusion defect. Both groups had a similar increase in end diastolic volume (EDV) 5 days post MI (p=0.971). EDV was significantly reduced 7 days post hydrogel delivery in the hydrogel group (6.0 ± 2.0 ml reduction) compared to the control group (6.3 ± 4.4 ml increase, p=0.042). Relative ²⁰¹Tl activity was matched between hydrogel and control groups in MI region (0.49±0.03 vs 0.50± 0.04, p=0.764), border region (0.73±0.01 vs 0.74±0.01, p=0.586) and normal myocardium (0.87± 0.01 vs 0.87±0.003, p=0.423). There was significant increase in ^99mTc-maraciclatide activity in MI region in the hydrogel group (1.87±0.17) compared to control group (1.40±0.01, p=0.048; figure 1A). The increased activity of ^99mTc-maraciclatide in the infarct region was confirmed visually with ex vivo hybrid SPECT/CT imaging (figure 1B and 1C).

Conclusions: Intramyocardial delivery of hydrogel post-MI resulted increased integrin activation in MI region and decreased LV remodeling. Multimodality imaging is a feasible approach for guiding delivery and monitoring the effects of a therapeutic hydrogel in a chronic porcine MI model.

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