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J Thorac Cardiovasc Surg 2005;130:321-329
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy

^a Division of Cardiothoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa
^b Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pa

Received for publication August 26, 2004; revisions received October 12, 2004; accepted for publication November 11, 2004.

^_* Address for reprints: Y. Joseph Woo, MD, Division of Cardiothoracic Surgery, Department of Surgery, University of Pennsylvania, Silverstein 4, 3400 Spruce St, Philadelphia PA 19104 (Email: wooy{at}uphs.upenn.edu).

OBJECTIVE: Ischemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor.

METHODS: Ischemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter.

RESULTS: The saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 ± 3.2 vs 9.6 ± 3.1 CD34⁺/vascular endothelial growth factor receptor 2–positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 ± 5.5 versus 23.8 ± 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 ± 0.1 mm vs 10.1 ± 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 ± 0.19 vs 1.41 ± 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 ± 3.2 vs 71.7 ± 3.1 mm Hg, P < .001; maximum dP/dt: 3513 ± 303 vs 2602 ± 201 mm Hg/s, P < .05; cardiac output: 21.3 ± 2.7 vs 13.3 ± 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 ± 0.4 vs 0.5 ± 0.2 mm Hg/µL, P < .01.)

CONCLUSION: This novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy.

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