title: Targeted injection of a biocomposite material alters macrophage and fibroblast phenotype and function following myocardial infarction: relation to left ventricular remodeling.
abstract: A treatment target for progressive left ventricular (LV) remodeling prevention following myocardial infarction (MI) is to affect structural changes directly within the MI region. One approach is through targeted injection of biocomposite materials, such as calcium hydroxyapatite microspheres (CHAM), into the MI region. In this study, the effects of CHAM injections upon key cell types responsible for the MI remodeling process, the macrophage and fibroblast, were examined. MI was induced in adult pigs before randomization to CHAM injections (20 targeted 0.1-ml injections within MI region) or saline. At 7 or 21 days post-MI (n = 6/time point per group), cardiac magnetic resonance imaging was performed, followed by macrophage and fibroblast isolation. Isolated macrophage profiles for monocyte chemotactic macrophage inflammatory protein-1 as measured by real-time polymerase chain reaction increased at 7 days post-MI in the CHAM group compared with MI only (16.3 ± 6.6 versus 1.7 ± 0.6 cycle times values, P < 0.05), and were similar by 21 days post-MI. Temporal changes in fibroblast function and smooth muscle actin (SMA) expression relative to referent control (n = 5) occurred with MI. CHAM induced increases in fibroblast proliferation, migration, and SMA expression-indicative of fibroblast transformation. By 21 days, CHAM reduced LV dilation (diastolic volume: 75 ± 2 versus 97 ± 4 ml) and increased function (ejection fraction: 48 ± 2% versus 38 ± 2%) compared with MI only (both P < 0.05). This study identified that effects on macrophage and fibroblast differentiation occurred with injection of biocomposite material within the MI, which translated into reduced adverse LV remodeling. These unique findings demonstrate that biomaterial injections impart biologic effects upon the MI remodeling process over any biophysical effects.
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: McGarvey
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sara
authors.initials: S
authors.lastname: Pettaway
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: James A
authors.initials: JA
authors.lastname: Shuman
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Novack
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kia N
authors.initials: KN
authors.lastname: Zellars
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Parker D
authors.initials: PD
authors.lastname: Freels
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Echols
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Gorman
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.affiliation: Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (S.P., J.A.S., C.P.N., K.N.Z., P.D.F., R.L.E., F.G.S.); and Department of Bioengineering (J.A.B.) and Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.H.G., R.C.G.), University of Pennsylvania, Philadelphia, Pennsylvania cvctrc@uscmed.sc.edu.
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D017886:Durapatite / Q000008:administration & dosage; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007267:Injections; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008863:Microspheres; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D010641:Phenotype; D011897:Random Allocation; D013552:Swine; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D001672:Biocompatible Materials; D017886:Durapatite