Abstract 14176: Preclinical Evaluation of the Engineered Stem Cell Chemokine Stromal Cell-Derived Factor 1-alpha in a Translational Ovine Myocardial Infarction Model
Background: Following MI, there is inadequate blood supply to the myocardium and the surrounding borderzone becomes hypocontractile, leading to adverse ventricular remodeling. The modified endothelial progenitor stem cell (EPC) chemokine engineered stromal cell-derived factor 1-alpha analogue (ESA) targets EPCs to the ischemic borderzone, inducing angiogenesis. To develop a clinically translatable therapy, we hypothesized that in an ovine model of MI, intramyocardial delivery of ESA would successfully induce EPC chemotaxis to microrevascularize the heart, limit adverse ventricular remodeling, and preserve borderzone contractility.
Methods and Results: Adult sheep underwent ligation of the LAD inducing an anteroapical infarct and were randomized to borderzone injection of ESA (n=10) or saline (n=10). Ventricular function, geometry, and regional strain were assessed using cardiac MRI, pressure-volume catheter transduction and aortic flow probe measurements. Bone marrow was harvested at terminal surgery for in-vitro analysis. ESA induced greater chemotaxis of EPCs compared to saline, and was equivalent to recombinant stromal cell-derived factor 1-alpha (p<0.01). When compared to saline injection, animals in the ESA group had significant reductions in infarct size (p<0.01), increased maximal principle strain in the borderzone (p<0.01), and steeper slope of the end systolic pressure volume relationship (p<0.05). Ejection fraction (p<0.05) and cardiac output (p<0.05) were also substantially improved in the ESA group. ESA treated animals had reduced levels of MMP-2 in the borderzone, with elevated levels of TIMP-1 and elastin in the infarct (p<0.05).
Conclusions: The biomolecularly-designed peptide ESA induces chemotaxis of EPCs, preserves borderzone contractility, and limits infarct expansion in an ovine model of MI. These findings support the efficacy of ESA as a therapeutic option for the translational treatment of heart failure.
- Stem/progenitor cells
- Myocardial contraction
- Magnetic resonance imaging
- Endothelial progenitor cell
- Ventricular remodeling
- © 2013 by American Heart Association, Inc.