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J Am Coll Cardiol, 2001; 37:1726-1732
© 2001 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDY

Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia

Shmuel Fuchs, MD*, Richard Baffour, PhD*, Yi Fu Zhou, MD*, Matie Shou, MD*, Anthony Pierre, BSc*, Fermin O. Tio, MD{dagger}, Neil J. Weissman, MD*, Martin B. Leon, MD{ddagger}, Stephen E. Epstein, MD* and Ran Kornowski, MD*

* the Cardiovascular Research Institute, Washington, DC, USA
{dagger} Biomedical Research Foundation of South Texas Inc., San-Antonio, Texas, USA
{ddagger} Cardiovascular Research Foundation, Lenox Hill Hospital, New York, New York, USA

Manuscript received December 12, 2000; revised manuscript received January 9, 2001, accepted January 24, 2001.

Reprint requests and correspondence: Dr. Shmuel Fuchs, Cardiovascular Research Institute, Washington Hospital Center, 110 Irving St. Northwest, 4B-1, Washington, DC 20010
sxf6{at}mhg.edu

OBJECTIVES

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.

Abbreviations and Acronyms
  ABM = autologous bone marrow
  BM = bone marrow
  H&E = hematoxylin and eosim
  LTCM = long-term culture medium
  MCP-1 = macrophage chemoattractant protein-1
  PAEC = pig aortic endothelial cells
  VEGF = vascular endothelial growth factor




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T.-S. Li, K. Hamano, M. Nishida, M. Hayashi, H. Ito, A. Mikamo, and M. Matsuzaki
CD117+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation
Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H931 - H937.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
C. A. Thompson, B. A. Nasseri, J. Makower, S. Houser, M. McGarry, T. Lamson, I. Pomerantseva, J. Y. Chang, H. K. Gold, J. P. Vacanti, et al.
Percutaneous transvenous cellular cardiomyoplasty: A novel nonsurgical approach for myocardial cell transplantation
J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1964 - 1971.
[Abstract] [Full Text] [PDF]


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Eur. J. Cardiothorac. Surg.Home page
G. H.L. Tang, P. W.M. Fedak, T. M. Yau, R. D. Weisel, A. Kulik, D. A.G. Mickle, and R.-K. Li
Cell transplantation to improve ventricular function in the failing heart
Eur. J. Cardiothorac. Surg., June 1, 2003; 23(6): 907 - 916.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
S. Fuchs, L. F. Satler, R. Kornowski, P. Okubagzi, G. Weisz, R. Baffour, R. Waksman, N. J. Weissman, M. Cerqueira, M. B. Leon, et al.
Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: A feasibility study
J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1721 - 1724.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
J.e. Garot, T. Unterseeh, E. Teiger, S. Champagne, B.e. Chazaud, R. Gherardi, L. Hittinger, P. Gueret, and A. Rahmouni
Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium
J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1841 - 1846.
[Abstract] [Full Text] [PDF]


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CirculationHome page
E. C. Perin, H. F.R. Dohmann, R. Borojevic, S. A. Silva, A. L.S. Sousa, C. T. Mesquita, M. I.D. Rossi, A. C. Carvalho, H. S. Dutra, H. J.F. Dohmann, et al.
Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure
Circulation, May 13, 2003; 107(18): 2294 - 2302.
[Abstract] [Full Text] [PDF]


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J. Appl. Physiol.Home page
G. C. Hughes, M. J. Post, M. Simons, and B. H. Annex
Translational Physiology: Porcine models of human coronary artery disease: implications for preclinical trials of therapeutic angiogenesis
J Appl Physiol, May 1, 2003; 94(5): 1689 - 1701.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
A. Luttun and P. Carmeliet
De novo vasculogenesis in the heart
Cardiovasc Res, May 1, 2003; 58(2): 378 - 389.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
H. Masuda and T. Asahara
Post-natal endothelial progenitor cells for neovascularization in tissue regeneration
Cardiovasc Res, May 1, 2003; 58(2): 390 - 398.
[Abstract] [Full Text] [PDF]


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Eur Heart JHome page
Y Schwartz and R Kornowski
Progenitor and embryonic stem cell transplantation for myocardial angiogenesis and functional restoration
Eur. Heart J., March 1, 2003; 24(5): 404 - 411.
[Full Text] [PDF]


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CirculationHome page
B. E. Strauer and R. Kornowski
Stem Cell Therapy in Perspective
Circulation, February 25, 2003; 107(7): 929 - 934.
[Full Text] [PDF]


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CirculationHome page
E. C. Perin, Y.-J. Geng, and J. T. Willerson
Adult Stem Cell Therapy in Perspective
Circulation, February 25, 2003; 107(7): 935 - 938.
[Full Text] [PDF]


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CirculationHome page
A. Kawamoto, T. Tkebuchava, J.-I. Yamaguchi, H. Nishimura, Y.-S. Yoon, C. Milliken, S. Uchida, O. Masuo, H. Iwaguro, H. Ma, et al.
Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells for Therapeutic Neovascularization of Myocardial Ischemia
Circulation, January 28, 2003; 107(3): 461 - 468.
[Abstract] [Full Text] [PDF]


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Card Surg AdultHome page
M. Ruel, R. A. Kelly, and F. W. Sellke
Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy
Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750.
[Full Text]


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CirculationHome page
B. Assmus, V. Schachinger, C. Teupe, M. Britten, R. Lehmann, N. Dobert, F. Grunwald, A. Aicher, C. Urbich, H. Martin, et al.
Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI)
Circulation, December 10, 2002; 106(24): 3009 - 3017.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
H. Kamihata, H. Matsubara, T. Nishiue, S. Fujiyama, K. Amano, O. Iba, T. Imada, and T. Iwasaka
Improvement of Collateral Perfusion and Regional Function by Implantation of Peripheral Blood Mononuclear Cells Into Ischemic Hibernating Myocardium
Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1804 - 1810.
[Abstract] [Full Text] [PDF]


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CirculationHome page
E. C. Perin, G. V. Silva, R. Sarmento-Leite, A. L.S. Sousa, M. Howell, R. Muthupillai, B. Lambert, W. K. Vaughn, and S. D. Flamm
Assessing Myocardial Viability and Infarct Transmurality With Left Ventricular Electromechanical Mapping in Patients With Stable Coronary Artery Disease: Validation by Delayed-Enhancement Magnetic Resonance Imaging
Circulation, August 20, 2002; 106(8): 957 - 961.
[Abstract] [Full Text] [PDF]



 
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