B

improved in the VEGF group in the regional ischemic area, but not compared to DMR and controls. The later two groups had no changes in myocardial perfusion measured by PET. The randomized double-blind placebo-controlled EUROINJECT -1 trial was the first larger gene therapy study using the percutaneous delivery technique [35, 36]. Forty patients received ten injections of plasmid

VEGF-A165 (total dose 0.5 mg) and 40 patients received ten placebo plasmid injections in an ischemic region of the left ventricle. The plasmids were delivered via the percutaneous route, using the percutaneous NOGA catheter system (Biosense Webster, Cordis, Warren, US). Myocardial perfusion improved (P < 0.02) following VEGF gene transfer in 44%, was unchanged in 41% and impaired in 15% of

P < 0.05

Placebo phVEGF

Figure 2. Results from the Euroinject One gene therapy trial with VEGF-A165 plasmid injection or placebo into ischemic myocardium in patients with chronic refractory myocardial ischemia. (a) Changes in myocardial perfusion measured with SPECT in placebo and VEGF-A165 plasmid treated patients. (b) Changes in local contractility in ischemic myocardium measured with NOGA in placebo and VEGF-A165 plasmid treated patients

Placebo phVEGF

Figure 2. Results from the Euroinject One gene therapy trial with VEGF-A165 plasmid injection or placebo into ischemic myocardium in patients with chronic refractory myocardial ischemia. (a) Changes in myocardial perfusion measured with SPECT in placebo and VEGF-A165 plasmid treated patients. (b) Changes in local contractility in ischemic myocardium measured with NOGA in placebo and VEGF-A165 plasmid treated patients the patients (Figure 2a). Although, there was no statistical change in myocardial perfusion in the placebo group, the improvement in the phVEGF-A165 group was not statistically different compared to placebo. Measured with the NOGA method the local linear shortening of the treated region increased significantly in the follow-up period in both groups (from 7.0 ± 1.1 to 12.6 ± 0.9%, P < 0.001 with VEGF and from 7.2 ± 1.0 to 9.9 ± 0.9%, P = 0.05 with placebo) (Figure 2b). The follow-up local linear shortening was significantly higher in patients with VEGF gene transfer in comparison to those on placebo (P = 0.05) A significant reduction in angina pectoris attacks and nitroglycerine consumption was seen in the phVEGF-A165 treated group but not in the placebo group. However, only the nitroglycerine consumption was reduced significantly in the VEGF gene transfer group compared to the placebo group. An improvement in CCS and a tendency to improved exercise capacity was seen in both treatment groups.

Haematopoietic stem cells from the bone marrow have the potential to induce vasculogenesis in animals with an acute myocardial infarction. [37, 38] Recent human studies indicate that mononuclear cell solutions aspirated from the bone marrow can induce vasculogenesis both in acute and chronic myocardial ischemia. [39-45] However, it remains unknown, whether the vasculogenesis is induced by the few (2-3%) stem cells within the mononuclear cells suspension [43] or by cytokines released from the leucocytes. It has been demonstrated, that treatment with Granulocyte Colony Stimulating Factor (G-CSF) in order to mobilize stem cells from the bone marrow does not induce vasculogenesis in patients with chronic myocardial ischemia [46, 47] or following acute myocardial infarction. [48] Animal studies suggest, that a combination of treatment with VEGF-A gene transfer followed by G-CSF mobilization of stem cells might be superior to either of the therapies. [49].

In a recent published trial Ripa et al [50] has combined the VEGF-A gene transfer and G-CSF stem cell mobilization treatment in patients with stable chronic myocardial ischemia. The authors treated prospectively treated 16 patients with severe chronic coronary artery disease and no option for further revascularization with open-label VEGF-A165 gene transfer followed by G-CSF treatment. Patients were treated with direct intramyocardial injections of the VEGF-A165 plasmid followed one week later by in-hospital daily subcutaneous injection of 10 ^gram/kg body weight G-CSF (Neupogen®) for six days. The treatment was compared with two control groups; I) 16 patients treated with VEGF gene transfer alone and II) 16 patients treated with placebo gene injections. The combined VEGF-A165 and G-CSF treated group could not demonstrate any changes in myocardial perfusion at rest and stress between baseline and follow-up, and they had identical summed difference perfusion scores. Left ventricular end-diastolic and end-systolic volumes, and ejection fraction showed not significant difference in any of the three groups from baseline to follow-up, and there were no differences between changes in these parameters between groups. In addition, regional wall thickening and motion were unchanged from baseline to follow-up in the group treated with VEGF-A165 and G-CSF.

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