Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy.
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.
Woo
Y Joseph
YJ
Division of Cardiothoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. wooy@uphs.upenn.edu
Grand
Todd J
TJ
Berry
Mark F
MF
Atluri
Pavan
P
Moise
Mireille A
MA
Hsu
Vivian M
VM
Cohen
Jeffrey
J
Fisher
Omar
O
Burdick
Jeffrey
J
Taylor
Matthew
M
Zentko
Suzanne
S
Liao
George
G
Smith
Max
M
Kolakowski
Steve
S
Jayasankar
Vasant
V
Gardner
Timothy J
TJ
Sweeney
H Lee
HL
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
D043925:Angiogenesis Inducing Agents; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016178:Granulocyte-Macrophage Colony-Stimulating Factor