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Matrix Metalloproteinase-Targeted SPECT/CT Imaging for Evaluation of Therapeutic Hydrogels for the Early Modulation of Post-Infarct Myocardial Remodeling

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Abstract

Following myocardial infarction (MI), maladaptive upregulation of matrix metalloproteinase (MMP) alters extracellular matrix leading to cardiac remodeling. Intramyocardial hydrogel delivery provides a vehicle for local delivery of MMP tissue inhibitors (rTIMP-3) for MMP activity modulation. We evaluated swine 10–14 days following MI randomized to intramyocardial delivery of saline, degradable hyaluronic acid (HA) hydrogel, or rTIMP-3 releasing hydrogel with an MMP-targeted radiotracer (99mTc-RP805), 201Tl, and CT. Significant left ventricle (LV) wall thinning, increased wall stress, reduced circumferential wall strain occurred in the MI region of MI-Saline group along with left atrial (LA) dilation, while these changes were modulated in both hydrogel groups. 99mTc-RP805 activity increased twofold in MI-Saline group and attenuated in hydrogel animals. Infarct size significantly reduced only in rTIMP-3 hydrogel group. Hybrid SPECT/CT imaging demonstrated a therapeutic benefit of intramyocardial delivery of hydrogels post-MI and reduced remodeling of LA and LV in association with a reduction in MMP activation.

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Acknowledgements

We would like to acknowledge the assistance of the University of South Carolina and Yale University veterinarian staff for their assistance with ensuring the health and well-being of the animals in this study. We also acknowledge the technical assistance of Christi Hawley.

Funding

This work was supported by the National Institute of Health grants: R01HL113352 (AJS), R01HL137365 (AJS), T32HL098069 (AJS), S10RR025555 (AJS), and R42HL131280 (FGS).

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Authors and Affiliations

  1. Section of Cardiovascular Medicine, Department of Medicine, School of Medicine, Yale University, DANA-3, PO Box 208017, New Haven, CT, 06520, USA

    Stephanie L. Thorn & Albert J. Sinusas

  2. Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, SC, USA

    James A. Shuman, Heather Doviak & Francis G. Spinale

  3. Department of Surgery, Ohio State University College of Medicine, Columbus, OH, USA

    Mitchel R. Stacy

  4. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Brendan P. Purcell & Jason A. Burdick

  5. Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, DANA-3, PO Box 208017, New Haven, CT, 06520, USA

    Albert J. Sinusas

  6. Department of Biomedical Engineering, Yale University, DANA-3, PO Box 208017, New Haven, CT, 06520, USA

    Albert J. Sinusas

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  1. Stephanie L. Thorn
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Correspondence to Albert J. Sinusas.

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No human studies were carried out by the authors for this article. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees at the University of South Carolina and Yale University.

Conflict of Interest

F.G. Spinale is the founder of MicroVide, LLC, and A.J. Sinusas is a limited partner and consultant of MicroVide, LLC, which holds the license for the use of 99mTc-RP805 in myocardial applications.

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Associate Editor Craig M. Stolen oversaw the review of this article

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Thorn, S.L., Shuman, J.A., Stacy, M.R. et al. Matrix Metalloproteinase-Targeted SPECT/CT Imaging for Evaluation of Therapeutic Hydrogels for the Early Modulation of Post-Infarct Myocardial Remodeling. J. of Cardiovasc. Trans. Res. 16, 155–165 (2023). https://doi.org/10.1007/s12265-022-10280-7

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