VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function

• Published in: American journal of physiology. Heart and circulatory physiology 2015-08, Vol.309 (3), p.H396-H406
• Main Authors: Uitterdijk, André, Springeling, Tirza, van Kranenburg, Matthijs, van Duin, Richard W B, Krabbendam-Peters, Ilona, Gorsse-Bakker, Charlotte, Sneep, Stefan, van Haeren, Rorry, Verrijk, Ruud, van Geuns, Robert-Jan M, van der Giessen, Willem J, Markkula, Tommi, Duncker, Dirk J, van Beusekom, Heleen M M
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Cytokines - blood; Female; Humans; Male; Microspheres; Microvessels - physiology; Myocardial Infarction - drug therapy; Neovascularization, Physiologic; Polyesters - chemistry; Polyethylene Glycols - chemistry; Swine; Vascular Endothelial Growth Factor A - administration & dosage; Vascular Endothelial Growth Factor A - adverse effects; Vascular Endothelial Growth Factor A - pharmacokinetics; Vascular Endothelial Growth Factor A - therapeutic use; Ventricular Function
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00698.2014

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.