Objectives and Specific Aims Myocardial ischemia and infarction with resultant adverse ventricular remodeling and heart failure form an increasingly prevalent global health problem for which medical and surgical treatments are limited. Innovative therapies are greatly needed. This proposal seeks to investigate and develop a novel acute endogenous revascularization therapy which upregulates endothelial progenitor cells (EPCs) and specifically targets them to ischemic myocardium. This post- infarction angiogenic therapy to augment myocardial microcirculation will study three specific aims: 1) Mobilization and targeted chemokinesis of EPCs to revascularize ischemic myocardium. 2) Angiogenic reengineering of regional myocardial biomechanical properties to attenuate adverse ventricular remodeling and improve cardiac function. 3) Translational preclinical large animal model testing of endogenous revascularization therapy utilizing progressively less invasive, clinically-available technologies. Research Design and Methods: In a rat model of myocardial infarction and ventricular remodeling, bone marrow production of EPCs will be stimulated with granulocyte macrophage colony stimulating factor (GMCSF). The upregulated EPCs will be targeted to the ischemic heart with direct intramyocardial administration of the potent EPC chemokine stromal cell derived factor-11 (SDF). Specific mechanisms will be elucidated by ex vivo tagged EPCs as well as an extracardiac SDF decoy. EPCs will be tracked with flow cytometry and immunohistochemistry. Angiogenesis will be quantified with lectin microangiography. The impact of microrevascularization on ischemic myocardial contractility will be determined with dobutamine stress echocardiography and myocardial tissue properties will be studied utilizing atomic force microscopy and tensile strength measurements. Ventricular remodeling and myocardial function will be assessed at multiple time points with echocardiography and an intracavitary pressure-volume conductance microcatheter. A well-established ovine model of ischemic heart failure will be utilized to study the efficacy of SDF/GMCSF therapy in a clinically translatable animal model. A stepwise evaluation of progressively less invasive, clinically available delivery technologies, from minimally invasive thoracotomy to Stiletto endocardial injection catheter to percutaneous intracoronary administration, will be undertaken to optimize cytokine delivery.

Public Health Relevance

Heart attack and its complications comprise a global health problem for which there are few highly effective treatments. As an innovative therapy, this proposal seeks to amplify the body's native repair machinery by stimulating vascular progenitor cells in the bone marrow and then specifically directing them to the heart to grow new perfusing blood vessels to the damaged heart muscle and providing a clinically viable treatment for human disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089315-05
Application #
8230794
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Adhikari, Bishow B
Project Start
2008-03-15
Project End
2013-11-28
Budget Start
2012-03-01
Budget End
2013-11-28
Support Year
5
Fiscal Year
2012
Total Cost
$389,813
Indirect Cost
$142,313
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Trubelja, Alen; MacArthur, John W; Sarver, Joseph J et al. (2014) Bioengineered stromal cell-derived factor-1? analogue delivered as an angiogenic therapy significantly restores viscoelastic material properties of infarcted cardiac muscle. J Biomech Eng 136:
Atluri, Pavan; Miller, Jordan S; Emery, Robert J et al. (2014) Tissue-engineered, hydrogel-based endothelial progenitor cell therapy robustly revascularizes ischemic myocardium and preserves ventricular function. J Thorac Cardiovasc Surg 148:1090-7; discussion 1097-8
Cohen, Jeffrey E; Purcell, Brendan P; MacArthur Jr, John W et al. (2014) A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circ Heart Fail 7:619-26
Macarthur Jr, John W; Cohen, Jeffrey E; McGarvey, Jeremy R et al. (2014) Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1* analog in a translational ovine myocardial infarction model. Circ Res 114:650-9
MacArthur Jr, John W; Purcell, Brendan P; Shudo, Yasuhiro et al. (2013) Sustained release of engineered stromal cell-derived factor 1-* from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation 128:S79-86
Shudo, Yasuhiro; Cohen, Jeffrey E; Macarthur, John W et al. (2013) Spatially oriented, temporally sequential smooth muscle cell-endothelial progenitor cell bi-level cell sheet neovascularizes ischemic myocardium. Circulation 128:S59-68
MacArthur Jr, John W; Trubelja, Alen; Shudo, Yasuhiro et al. (2013) Mathematically engineered stromal cell-derived factor-1* stem cell cytokine analog enhances mechanical properties of infarcted myocardium. J Thorac Cardiovasc Surg 145:278-84
Atluri, Pavan; Trubelja, Alen; Fairman, Alexander S et al. (2013) Normalization of postinfarct biomechanics using a novel tissue-engineered angiogenic construct. Circulation 128:S95-104
Hiesinger, William; Brukman, Matthew J; McCormick, Ryan C et al. (2012) Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1* angiogenic therapy for acute myocardial infarction in a murine model. J Thorac Cardiovasc Surg 143:962-6
Hiesinger, William; Vinogradov, Sergei A; Atluri, Pavan et al. (2011) Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy. J Appl Physiol 110:1460-5

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