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THERAPEUTIC ANGIOGENESIS :A STRATEGY FOR MYOCARDIAL ISCHAEMIA
Robert J Whitbourn
Director of Coronary Care, St Vincent’s Hospital Melbourne, 41, Victoria Parade, Fitzroy, Victoria - 3065, Australia.
Myocardial ischaemia as a result of coronary artery disease carries significant morbidity and mortality. Traditional coronary revascularization therapies such as coronary angioplasty or bypass graft surgery, act by restoring blood flow through the preexisting coronary vessels. One limitation of these approaches, however, may be the failure to normalize myocardial perfusion, due to the concomitant presence or small of resistance vessel disease.
In contrast, therapeutic angiogenesis is based on the concept that coronary collateral development may be stimulated by pharmacological or molecular means and can limit myocardial ischaemia.MECHANISMS OF NEW BLOOD VESSEL FORMATION
The rate and magnitude of development of a collateral circulation determines its ability to limit ischaemic damage. Vascular growth does not occur spontaneously in normal myocardium. Endothelial cells in adult blood vessels remain in a non-proliferative state, unless stimulated by inflammation, ischaemia, mechanical effects or other stimuli that promote angiogenesis. Localized cellular injury with damage to myocytes initiates an inflammatory response, which in turn leads to vessel growth in a process similar to that of wound repair. Physical or mechanical determinants may include alterations in intravascular wall shear stresses or intravascular pressure gradients.
New capillary formation requires several steps including migration, adhesion, proliferation and formation of a tube of endothelial cells. For larger vessels, vascular smooth muscle cells must also migrate and adhere to the forming tube. A pathway for direct stimulation of endothelial cell growth and migration appears to be induction by various cytokines and growth factors. Such growth factors include acid and basic fibroblast growth factors (a-FGF, b-FGF) Transforming growth factors alpha and beta (TGF-a, TGF-b) and vascular endothelial growth factor (VEGF). VEGF is a peptide, direct acting growth factor, subgroups of which may be expressed in high concentrations in different tissues. The various growth factor types and subtypes may be present in different tissues or under different circumstances. VEGF-B for example, is particularly expressed in cardiac tissues and during acute ischaemia, whereas b-FGF is increased during chronic ischaemia. [1, 11]
The process of neovascularization may also be quite different in the setting of chronic ischaemia compared to that which occurs following myocardial infarction. Necrosis may induce a quite distinct macrophage-dependent angiogenic response. [5]MOLECULAR MANIPULATION OF ANGIOGENESIS
Therapeutic angiogenesis is dependent upon the ability of these cytokines and growth factors to stimulate new vessel growth regionally. Two distinct strategies for the molecular manipulation of angiogenesis exist.Animal studies have demonstrated the local angiogenic potential of many growth factors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).2 Human basic fibroblast growth factor (b-FGF), has also been shown to be able to stimulate production of new vessels in ischaemic hearts of rats and rabbits. [4]
- Protein therapy, which involves delivery of the growth factor directly into the ischaemic target tissue, or
- Gene therapy, where delivery of DNA stimulates synthesis of growth factors by cells locally.
The transfer of genes that code for these growth factors and their site specific expression, has also been demonstrated in animal models. [3]
The most effective means for delivery of growth factors is still to be determined. In swine, direct intracoronary application of b-FGF to infarcted myocardium has been shown to enhance myocardial neovascularization within 2 weeks. [6] Other methods of administration include direct injection of factors into the ischaemic myocardium, raising the challenge for development of the ideal delivery device.
There are some questions as to whether the total number of newly developed collateral vessels is enhanced by these strategies, or whether simply their rate of development is increased.
In a canine model of chronic single-vessel coronary occlusion, basic fibroblast growth factor (b-FGF) was shown to enhance coronary collateral perfusion in the short term (5 weeks), whilst collateral flow in control dogs reached parity with that of b-FGF treated dogs after 6 months. In addition, b-FGF did not induce further collateralization in dogs after they had developed mature collateral vessels, underscoring the priming role of ischaemia for b-FGF induced collateral development. [9]HUMAN STUDIES IN ANGIOGENESIS
Human growth factor FGF, obtained from genetically manipulated E. coli bacteria and highly purified, has also been investigated as an additional therapeutic agent at the time of coronary bypass graft surgery. In a double blind study of 40 patients with CHD half were the growth factor treated group where FGF was injected into the myocardium around the internal mammary artery (IMA) graft and the other half were a control group. Twelve weeks later, the IMA grafts were selectively demonstrated by intra-arterial digital subtraction angiography.
In all patients of the growth factor group, the formation of new vessels could be demonstrated in the region where FGF had been administered with a capillary net sprouting from the coronary artery. Computer-supported evaluation of the angiographs also showed a significant increase in the blood supply in the region of the injected myocardium. Authors concluded that local injection of FGF may be a useful adjunctive therapy to bypass surgery, particularly for patients with a stenosis that cannot be operatively revascularized. [7, 8] This key study affirms that fibroblast growth factor can induce angiogenesis in patients with ischaemic heart disease. Whether this will translate into a clinically significant improvement in myocardial perfusion is not yet known.
Similarly, induction of angiogenesis by VEGF gene transfer in patients with critical limb ischaemia has also been demonstrated. Naked plasma DNA encoding phVEGF165 was administered into 10 ischaemic limb muscles of 9 patients with non-healing ischaemic ulcers and/or rest pain due to peripheral vascular disease. At eight weeks post treatment, newly developed collateral vessels could be seen angiographically in 7 limbs and there was an improvement in mean ankle/toe-brachial blood pressure index from 0.33 at baseline to 0.45 at eight weeks (p=0.16, 10 limbs). Lower limb oedema was observed in 6 patients, consistent with the effects of VEGF augmenting vascular permeability. [10]
This landmark study demonstrates that geneover-expression may be used to clinical advantage, in this case, to improve chronic limb ischaemia.DISCUSSION
Therapeutic angiogenesis is an exciting new concept with significant clinical potential. Multiple animal studies and a small number of preliminary human studies have confirmed the concept of stimulation of collateral development by pharmacological or molecular means. This includes direct delivery of growth factors into the ischaemic target tissue, or of genes that encode for synthesis of growth factors by target tissues.
Issues that must be overcome to enable clinical application of therapeutic angiogenesis include adequate means of delivery, limitation of effect to a specific targeted region and adequacy of treatment to reduce symptoms of ischaemia.
Endothelial dysfunction of newly developed collateral vessels may limit their potential for beneficial effects on tissue blood flow. Although administration of VEGF or basic FGF may augment collateral development by enhancing neovascularity, the true measure of success of these strategies will be the demonstration of improved perfusion or reduction in clinical endpoints such as death, angina or exercise tolerance.
Decisive for the future human use of growth factors for the treatment of coronary heart disease will be the results of experiments designed to exclude the possibility that growth factors may initiate or stimulate neoplasia.CONCLUSION
The ability to pharmacologically influence vascular growth and development, marks a "new generation" of therapeutic strategies.REFERENCES
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