Targeted Regional Injection of Biocomposite Microspheres Alters Post–Myocardial Infarction Remodeling and Matrix Proteolytic Pathways

Abstract

Although localized delivery of biocomposite materials, such as calcium hydroxyapatite (CHAM), have been demonstrated to potentially attenuate adverse left ventricular (LV) remodeling after myocardial infarction (MI), the underlying biological mechanisms for this effect remain unclear. This study tested the hypothesis that targeted CHAM injections would alter proteolytic pathways (matrix metalloproteinases [MMPs] and tissue inhibitors of MMPs [TIMPs]) and would be associated with parameters of post-MI LV remodeling. MI was induced in adult sheep followed by 20 targeted injections of a total volume of 1.3 mL (n=6) or 2.6 mL of CHAM (n=5) or saline (n=13) and LV end-diastolic volume (EDV) and MMP/TIMP profiles in the MI region were measured at 8 weeks after MI. LV EDV decreased with 2.6 mL CHAM versus MI only (105.4 ± 7.5 versus 80.6 ± 4.2 respectively, P<0.05) but not with 1.3 mL CHAM (94.5 ± 5.0, P=0.32). However, MI thickness increased by 2-fold in both CHAM groups compared with MI only (P<0.05). MMP-13 increased 40-fold in the MI only group (P<0.05) but fell by >6-fold in both CHAM groups (P<0.05). MMP-7 increased approximately 1.5-fold in the MI only group (P<0.05) but decreased to referent control values in both CHAM groups in the MI region (P<0.05). Collagen content was reduced by approximately 30% in the CHAM groups compared with MI only (P<0.05). Differential effects on LV remodeling and MMP/TIMP profiles occurred with CHAM. Thus, targeted injection of a biocomposite material can favorably affect the post-MI remodeling process and therefore holds promise as a treatment strategy in and of itself, or as a matrix with potentially synergistic effects with localized pharmacological or cellular therapies.