title: Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy.
abstract: 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/microL, P < .01.)
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. wooy@uphs.upenn.edu
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Grand
authors.forename: Mark F
authors.initials: MF
authors.lastname: Berry
authors.forename: Pavan
authors.initials: P
authors.lastname: Atluri
authors.forename: Mireille A
authors.initials: MA
authors.lastname: Moise
authors.forename: Vivian M
authors.initials: VM
authors.lastname: Hsu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohen
authors.forename: Omar
authors.initials: O
authors.lastname: Fisher
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burdick
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Suzanne
authors.initials: S
authors.lastname: Zentko
authors.forename: George
authors.initials: G
authors.lastname: Liao
authors.forename: Max
authors.initials: M
authors.lastname: Smith
authors.forename: Steve
authors.initials: S
authors.lastname: Kolakowski
authors.forename: Vasant
authors.initials: V
authors.lastname: Jayasankar
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Gardner
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D017202:Myocardial Ischemia / Q000150:complications; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D016276:Ventricular Function / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016178:Granulocyte-Macrophage Colony-Stimulating Factor