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Therapeutic Angiogenesis for Coronary Artery Disease

Saul Benedict Freedman, MB, BS, PhD; and Jeffrey M. Isner, MD
[+] Article and Author Information

From St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, and Concord Repatriation General Hospital, University of Sydney, Sydney, Australia.


†Deceased.

Note: Jeffrey Isner, MD, died suddenly during the preparation of proofs of the manuscript.

Acknowledgments: The authors thank Rene Tio, MD, James F. Symes, MD, Peter R. Vale, MD, Douglas W. Losordo, MD, and Charles Milliken, BS, MS, who contributed to several of the studies summarized in this paper, and Mrs. Mickey Neely for preparation of the manuscript.

Requests for Single Reprints: Mickey Neely, St. Elizabeth's Medical Center, 736 Cambridge Street, Boston, MA 02135; e-mail, mneely222@aol.com.

Current Author Addresses: Dr. Freedman: Department of Cardiology, Concord Repatriation General Hospital, University of Sydney, Hospital Road, Concord, New South Wales 2139, Australia.


Ann Intern Med. 2002;136(1):54-71. doi:10.7326/0003-4819-136-1-200201010-00011
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A large body of evidence in animal models of ischemia shows that administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization. Many cytokines have angiogenic activity; those that have been best studied in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with end-stage coronary artery disease have shown increases in exercise time and reductions in anginal symptoms and have provided objective evidence of improved perfusion and left ventricular function. Larger-scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein and have not yet shown significant improvement in exercise time or angina compared with placebo. Larger-scale placebo-controlled studies of gene transfer are in progress.Clinical studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors and the utility of adjunctive endothelial progenitor-cell or stem-cell supplementation, to provide safe and effective therapeutic myocardial angiogenesis. Determination of which growth factors or cells are required to optimize therapeutic neovascularization in an individual patient should be a goal of future research.

Figures

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Figure 1.
Mechanisms of neovascularization: angiogenesis, vasculogenesis, and arteriogenesis.EPC

Angiogenesis involves capillary sprouting by proliferation and migration of fully differentiated endothelial cells. Vasculogenesis involves bone marrow-derived endothelial progenitor cells ( ), which naturally circulate in peripheral blood, home to areas of ischemia (bottom part of figure), and incorporate into neovascular foci. Arteriogenesis involves enlargement of preexisting collateral vessels.

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Figure 2.
Catheter gene transfer of vascular endothelial growth factor (VEGF)-2.A.leftrightB.arrowC.left

The catheter ( ) and the 27-gauge needle advanced ( ). Position of the catheter tip ( ) in the left ventricle. A combination of electromechanical mapping and fluoroscopy is used to guide catheter positioning in the ventricle. Electromechanical maps before and after VEGF-2 gene transfer. Under “Before Gene Transfer,” the left panel (“viability”) is the maximum unipolar voltage electrical endocardial map; the changes from green through blue to purple indicate viable hypocontractile areas. The points chosen for gene transfer are marked in brown. The right panel (“wall motion”) is the linear local shortening map; an area of hypocontractility is indicated by the red, yellow, green, and blue areas in the anterolateral wall. Surrounding areas have normal contractility (purple). Hypocontractile areas were inferred to be either ischemic or hibernating. The maps labeled “After Gene Transfer,” obtained in the same patient 12 weeks after gene transfer, show that viability is preserved (no change in the unipolar voltage map [ ]), whereas the right-hand map of linear local shortening shows complete normalization of contraction in the previously hypocontractile area, as indicated by the uniform purple color.

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Figure 3.
Intramyocardial administration of vascular endothelial growth factor (VEGF) DNA.Top.topleftBottom.asteriskarrows

This transepicardial two-dimensional echocardiogram shows the distribution of VEGF DNA solution injected directly into ischemic porcine myocardium. The anterolateral free wall ( ) and the mitral valve plane ( ), before injection. A bright needle artifact ( ) is seen in the anterolateral wall near two echolucent zones ( ) after injection; the echolucency is the result of injected fluid containing the plasmid VEGF DNA.

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Figure 4.
Rest and dipyridamole stress single-photon emission computed tomographic sestamibi myocardial perfusion images before (top) and 60 days after (bottom) vascular endothelial growth factor-1 gene transfer via mini-thoracotomy.arrows

White and yellow areas indicate maximal radionuclide uptake; red areas indicate impaired uptake. Before therapy, an essentially fixed inferoseptal defect ( ) and a reversible inferolateral defect were observed. After gene transfer, resting perfusion and stress defects in the inferoseptal and inferolateral walls resolved.

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