Therapeutic angiogenesis and arteriogenesis is a potential treatment option for patients with severe symptomatic coronary artery disease who are otherwise no or no more candidates for conventional therapy such as balloon angioplasty and bypass surgery. Angiogenic growth factors such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been shown to induce therapeutic angiogenesis in myocardial ischemia . Growth factors can be applied by injection into the myocardium  or by infusion into the coronary artery [44, 45]. However, in these studies intracoronary application has typically been successful
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Figure 3. (a) Implantation of a reduction stent in the LAD (pig model) led to chronic occlusion of this coronary artery between day 7 (d7, perfusion checked fluoroscopically) and d28. (c) At d28, hibernating myocardium was obtained using 18FDG and 13NH4 positron emission tomography. (d) In these experiments, an increased blood flow was obtained in the ischemic (LAD) region after FGF-2 retroinfusion 3 weeks earlier
Figure 3. (a) Implantation of a reduction stent in the LAD (pig model) led to chronic occlusion of this coronary artery between day 7 (d7, perfusion checked fluoroscopically) and d28. (c) At d28, hibernating myocardium was obtained using 18FDG and 13NH4 positron emission tomography. (d) In these experiments, an increased blood flow was obtained in the ischemic (LAD) region after FGF-2 retroinfusion 3 weeks earlier only if delivery was prolonged, by either surgical implantation of a minipump  or microembolization with beads containing growth factors . Because these techniques are not suitable for patients, clinical studies with growth factors have been performed in general either using a single intracoronary injection or multiple intramyocardial injections .
Placebo-controlled clinical trials, however, using intracoronary injection of recombinant angiogenic proteins showed only weak evidence for efficacy . The short passage time with limited tissue binding of the growth factor might have been responsible for the lack of efficiency. Sustained cellular production of angiogenic growth factors by gene transfer has been proposed to overcome these limitations [39, 40, 42,48-51]. Whether adenoviral vectors or naked cDNA have been used for inducing VEGF or FGF expression, or whether these were applied intracoronary or intramyocardially, none of these approaches have shown consistent evidence for a sustained clinical benefit of the patients after treatment so far .
Among the reasons for limited clinical success of angiogenic and arteriogenic strategies, low efficiency of intracoronary delivery and spotty nonhomogenous distribution after intramyocardial injection may be addressed by using a delivery system which leads to a more efficient and at the same time homogenous distribution of angiogenic and arteriogenic substrates in the targeted myocardium.
Selective pressure-regulated retroinfusion of the coronary veins provides a unique intravascular access to ischemic myocardium which cannot be reached through severely diseased or occluded coronary arteries. Moreover, as capillary sprouting originates mainly from venules and capillaries, retrograde administration into the vein may target angiogenic growth factors to these vessel segments most receptive and responsive to them [53, 54]. Thus, pressure-regulated retroinfusion may target regional delivery of recombinant growth factors, DNA carrying liposomes or viral gene vectors encoding for angiogenic or arteriogenic proteins.
Proof of the concept studies with retrograde delivery of the angiogenic and arteri-ogenic protein FGF-2 have been performed in pig models of chronic myocardial ischemia [55, 56]. Tissue binding of radiolabeled FGF-2 was clearly enhanced 2-3 fold following retrograde delivery compared to antegrade delivery. Moreover, arteri-ogenesis and angiogenesis induced by selective pressure-regulated retroinfusion of bFGF-2 in the targeted LAD region was associated with an increased regional myocardial blood flow of collaterals circumventing the chronic total LAD occlusion and a functional improvement in the treated pigs (Figure 3) . More recent data also indicate that overexpression of eNOS using retrograde delivery of liposomal eNOScDNA may result in substantial improvement of collateral development and regional myocardial blood flow in our pig model of hibernating myocardium .
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