Background— Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2). Methods and Results— FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 μg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall P=0.035) and the physical component summary scale of the Short-Form 36 ...

http://www.angiogenesis-center.org/documents/phase%20II%20FGF%20study.pdf

Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2 Double-Blind, Randomized, Controlled Clinical Trial

Deprivation of oxygen and nutrients provides a serious threat for tissue viability. Nature’s response to the development of profound tissue ischemia includes the upregulation of angiogenic growth factors and mobilization of circulating cellular elements that together enable development of an accessory vasculature.1 The involved paradigm, not surprisingly, recapitulates many aspects of embryonic circulatory development. Multiple angiogenic factors and inhibitors have been implicated in the formation and correct patterning of functional blood vessels. Although hampered by several ambiguous clinical trials, transfer of genes encoding for proangiogenic factors is still an important therapeutic option to induce vascular growth after critical ischemia. Recent studies provide further evidence that neovascularization is regulated by infiltrating circulation cells, including bone marrow–derived endothelial progenitor cells or inflammatory cells. The use of “cell therapy” for therapeutic vasculogenesis will be discussed in the second part of this review article.

### Candidate Genes: Experimental Evidence

Potential therapeutic genes for improvement of angiogenesis or arteriogenesis include growth factors, which predominantly act on endothelial cells to promote endothelial cell proliferation, migration, and tube-forming activity (Table 1). Concomitantly, most of the growth factors render endothelial cells less sensitive for apoptosis induction. Among the first growth factors identified to improve angiogenesis were members of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) families. Meanwhile, various isoforms of VEGF have been identified. VEGF-A and its splice variants and VEGF-B preferentially activate the VEGF receptors 1 and 2, whereas VEGF-C and VEGF-D stimulate the VEGF receptors 2 and 3, thereby contributing to lymphangiogenesis. The VEGF receptors 1 and 2 are both expressed on endothelial cells and hematopoietic stem cells. The expression of VEGF receptors on hematopoietic stem cells in particular appears to be of major importance for VEGF-dependent regulation of endothelial progenitor cells (see Part II). More recently, another member of the VEGF family, the placenta-derived growth …

Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines.

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.

Therapeutic Angiogenesis for Coronary Artery Disease

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

Methods, devices, kits and compositions to treat a myocardial infarction. In one embodiment, the method includes the prevention of remodeling of the infarct zone of the ventricle using a combination of therapies. The method may include the introduction of structurally reinforcing agents. In other embodiments, agents may be introduced into a ventricle to increase compliance of the ventricle. The prevention of remodeling may include the prevention of thinning of the ventricular infarct zone. Another embodiment includes the reversing or prevention of ventricular remodeling with electro-stimulatory therapy. The unloading of the stressed myocardium over time effects reversal of undesirable ventricular remodeling. These therapies may be combined with structurally reinforcing therapies. In other embodiments, the structurally reinforcing component may be accompanied by other therapeutic agents. These agents may include but are not limited to pro-fibroblastic and angiogenic agents.

Methods and compositions to treat myocardial conditions

Therapeutic angiogenesis is a novel approach to the treatment of myocardial ischemia based on the use of proangiogenic growth factors to induce the growth of new blood vessels to supply the myocardium at risk. This study was designed to assess the safety and efficacy of a single intrapericardial injection of basic fibroblast growth factor (FGF-2) in a porcine model of chronic myocardial ischemia. Yorkshire pigs underwent ameroid placement around the left circumflex coronary artery. At 3 weeks, animals were randomized to receive a single intrapericardial injection of either saline (n = 10), 3 mg of heparin (n = 9), 3 mg of heparin + 30 microgram of FGF-2 (n = 10), 200 microgram of FGF-2 (n = 10), or 2 mg of FGF-2 (n = 10). Coronary angiography, microsphere flow, magnetic resonance functional, and perfusion imaging were performed before and 4 weeks after treatment, at which time histologic analysis was also performed on 3 animals in each group. In ischemic pigs, FGF-2 treatment resulted in significant increases in left-to-left angiographic collaterals and left circumflex coronary artery blood flow. These benefits were accompanied by improvements in myocardial perfusion and function in the ischemic territory, as well as histologic evidence of increased myocardial vascularity without any adverse effects. Not one of these benefits was seen in saline- or heparin-treated ischemic animals. A single intrapericardial injection of FGF-2 in a porcine model of chronic myocardial ischemia results in functionally significant myocardial angiogenesis, without any adverse outcomes. This mode of FGF-2 administration may prove to be a useful therapeutic strategy for the treatment of patients with ischemic heart disease.

http://www.angiogenesis-center.org/documents/Laham%20et%20al.%20JPET.pdf?presentation_id=1404

Debborah Novicki

Papers

Intrapericardial delivery of fibroblast growth factor-2 induces neovascularization in a porcine model of chronic myocardial ischemia.