title: VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function.
abstract: Angiogenesis induced by growth factor-releasing microspheres can be an off-the-shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene-glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 × 10(6) 15-μm microspheres at 0.5 × 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition.
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: André
authors.initials: A
authors.lastname: Uitterdijk
authors.affiliation: Department of Cardiology and Radiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Tirza
authors.initials: T
authors.lastname: Springeling
authors.affiliation: Department of Cardiology and Radiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Matthijs
authors.initials: M
authors.lastname: van Kranenburg
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Richard W B
authors.initials: RW
authors.lastname: van Duin
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Ilona
authors.initials: I
authors.lastname: Krabbendam-Peters
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gorsse-Bakker
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Stefan
authors.initials: S
authors.lastname: Sneep
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Rorry
authors.initials: R
authors.lastname: van Haeren
authors.affiliation: OctoPlus, Leiden, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Verrijk
authors.affiliation: Department of Cardiology and Radiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Robert-Jan M
authors.initials: RJ
authors.lastname: van Geuns
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van der Giessen
authors.affiliation: OctoPlus, Leiden, The Netherlands.
authors.forename: Tommi
authors.initials: T
authors.lastname: Markkula
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.affiliation: Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands; h.vanbeusekom@erasmusmc.nl.
authors.forename: Heleen M M
authors.initials: HM
authors.lastname: van Beusekom
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008863:Microspheres; D055806:Microvessels / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy*; D018919:Neovascularization, Physiologic; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016276:Ventricular Function
chemical_list: D016207:Cytokines; D011091:Polyesters; D042461:Vascular Endothelial Growth Factor A; C041733:poly(1,4-butylene terephthalate); D011092:Polyethylene Glycols
keywords: angiogenesis; biocompatibility; drug delivery and release; growth factors; microspheres