Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia.
OBJECTIVE
We tested the hypothesis that intramyocardial injection of autologous bone marrow (ABM) promotes collateral development in ischemic porcine myocardium. We also defined, in vitro, whether bone marrow (BM) cells secrete vascular endothelial growth factor (VEGF) and macrophage chemoattractant protein-1 (MCP-1).


BACKGROUND
The natural processes leading to collateral development are extremely complex, requiring multiple growth factors interacting in concert and in sequence. Because optimal angiogenesis may, therefore, require multiple angiogenic factors, we thought that injection of BM, which contains cells that secrete numerous angiogenic factors, might provide optimal therapeutic angiogenesis.


METHODS
Bone marrow was cultured four weeks in vitro. Conditioned medium was assayed for VEGF and MCP-1 and was added to cultured pig aortic endothelial cells (PAEC) to assess proliferation. Four weeks after left circumflex ameroid implantation, freshly aspirated ABM (n = 7) or heparinized saline (n = 7) was injected transendocardially into the ischemic zone (0.2 ml/injection at 12 sites). Echocardiography to assess myocardial thickening and microspheres to assess perfusion were performed at rest and during stress.


RESULTS
Vascular endothelial growth factor and MCP-1 concentrations increased in a time-related manner. The conditioned medium enhanced, in a dose-related manner, PAEC proliferation. Collateral flow (ischemic/normal zone X 100) improved in ABM-treated pigs (ABM: 98 +/- 14 vs. 83 +/- 12 at rest, p = 0.001; 89 +/- 18 vs. 78 +/- 12 during adenosine, p = 0.025; controls: 92 +/- 10 vs. 89 +/- 9 at rest, p = 0.49; 78 +/- 11 vs. 77 +/- 5 during adenosine, p = 0.75). Similarly, contractility increased in ABM-treated pigs (ABM: 83 +/- 21 vs. 60 +/- 32 at rest, p = 0.04; 91 +/- 44 vs. 36 +/- 43 during pacing, p = 0.056; controls: 69 +/- 48 vs. 64 +/- 46 at rest, p = 0.74; 65 +/- 56 vs. 37 +/- 56 during pacing, p = 0.23).


CONCLUSIONS
Bone marrow cells secrete angiogenic factors that induce endothelial cell proliferation and, when injected transendocardially, augment collateral perfusion and myocardial function in ischemic myocardium.
Fuchs
S
S
Cardiovascular Research Institute, Washington Hospital Center, Washington, DC 20010, USA. sxf6@mhg.edu
Baffour
R
R
Zhou
Y F
YF
Shou
M
M
Pierre
A
A
Tio
F O
FO
Weissman
N J
NJ
Leon
M B
MB
Epstein
S E
SE
Kornowski
R
R
D000818:Animals; D016026:Bone Marrow Transplantation / Q000295:instrumentation / Q000379:methods*; D002478:Cells, Cultured; D018932:Chemokine CCL2; D002908:Chronic Disease; D003097:Collateral Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004452:Echocardiography; D004699:Endocardium; D016228:Endothelial Growth Factors; D005080:Exercise Test; D005240:Feasibility Studies; D007267:Injections / Q000295:instrumentation / Q000379:methods; D008222:Lymphokines; D009200:Myocardial Contraction / Q000502:physiology*; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010446:Peptide Fragments; D011897:Random Allocation; D013552:Swine; D014182:Transplantation, Autologous / Q000379:methods; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018932:Chemokine CCL2; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C106929:monocyte chemoattractant protein 1 (9-76)