VEGF_165Amicrosphere 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.

Time course of VCAM-1 expression in reperfused myocardial infarction in swine and its relation to retention of intracoronary administered bone marrow-derived mononuclear cells

“…Myocardial infarction was produced in 33 swine (30.5±0.3kg) as previously described [14, 24, 25]. For this purpose, swine were sedated with an intramuscular injection of midazolam (1mg/kg), ketamine (20 mg/kg) and atropine (1mg).…”

Tissue Engineering of the Microvasculature

“…Regardless of the exact method used to load degradable polymers with angiogenic factors, numerous studies have shown the therapeutic efficacy of these materials. For instance, intracoronary infusion of poly(ethylene glycol-co-butylene terephthalate) microspheres that were loaded with VEGF-A 165 increased capillary density in ischemic pig heart, although they did not improve cardiac function (598). In the ischemic mouse hindlimb, PLGA scaffolds that were loaded with VEGF-A 165 released the growth factor over several weeks (551).…”

Validation of 4D flow CMR against simultaneous invasive hemodynamic measurements: a swine study

“…Cardiovascular magnetic resonance (CMR) imaging has been used for flow visualization and quantification in daily clinical practice for several decades [ 1 , 2 ]. CMR is the gold standard for non-invasive quantification of left and especially right heart function and shunt fraction [ 3 , 4 ].…”