Section of Cardiovascular Medicine, Department of Medicine, School of Medicine, Yale University, DANA-3, PO Box 208017, New Haven, CT, 06520, USA.
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, SC, USA.
J Cardiovasc Transl Res. 2023 Feb;16(1):155-165. doi: 10.1007/s12265-022-10280-7. Epub 2022 Jun 13.
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 (Tc-RP805), Tl, 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. Tc-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.
心肌梗死后（MI），细胞外基质中基质金属蛋白酶（MMP）的失调表达会导致心脏重构。心肌内水凝胶递药为 MMP 组织抑制剂（rTIMP-3）的局部递药提供了载体，从而调节 MMP 活性。我们在 MI 后 10-14 天对猪进行随机分组，分别接受心肌内生理盐水、可降解透明质酸（HA）水凝胶或 MMP 靶向放射性示踪剂（Tc-RP805）、Tl 和 CT 标记的 rTIMP-3 释放水凝胶的治疗。在 MI-生理盐水组中，MI 区域出现左心室（LV）壁变薄、壁应力增加、周向壁应变减少以及左心房（LA）扩张，而在两种水凝胶组中，这些变化都得到了调节。MI-生理盐水组中 Tc-RP805 的活性增加了两倍，而在水凝胶动物中则减弱了。只有在 rTIMP-3 水凝胶组中，梗死面积才显著减少。杂交 SPECT/CT 成像显示，MI 后心肌内水凝胶递药具有治疗益处，并与 MMP 激活减少相关联，从而减少 LA 和 LV 的重构。
