4. Discussion
DFS, amputation, ischemia, lower limb ischemia, necrotic, pain, disability, diabetes
PROLIFERATION, INFLAMMATION, ISCHEMIA, LOWER LIMB ISCHEMIA, ADVERSE EVENTS, NECROTIC, NEOVASCULARIZATION, INTERMITTENT CLAUDICATION, COMPLICATIONS, DIABETES
DFS is one of the main practical problems encountered in angiology and vascular surgery. Owing to the huge prevalence of diabetes, its real epidemic, and the scale of its possible complications, it is one of the main causes of amputation and disability. The surgical approach, an attempt at revascularization, should always be considered. However, this is not always possible. The model of a multidisciplinary approach seems to be applicable and the most effective, with the care of a diabetologist, podiatrist, physiotherapist, and orthopedist, as well as an angiologist and vascular surgeon. Open surgery or endovascular revascularization is necessary in many cases. Their spectrum is very wide and depends on the specific situation. However, it should always aim to improve the supplementation of a limb or a specific angiosome, or even better perfused, with the hope that it will improve the neighboring angiosomes through collateral circulation. In addition to surgical revascularization, resection of necrotic tissues, drainage, load reduction, exercise, oxygen therapy, antibiotics, and metabolic therapy, it is necessary to search for new methods. This is particularly important for the group of patients in whom, due to the extent and advancement of the lesions, the possibilities of surgical treatment have been exhausted (NCR patients). Progress in vascular surgery, especially in endovascular interventions, does not allow the treatment of all patients with lower limb ischemia in the course of diabetes, especially since the pathologies usually concern small vessels, often more strongly expressed in some angiosomes, leaving others in a better condition. If surgical revascularization is not possible, conservative therapy remains, such as pharmacotherapy, load reduction, and improvement of their general condition, which is often insufficient, although necessary.Gene therapy that stimulates the formation of new, even small, vessels seems to be an interesting concept. Stimulation of the formation of small vessels and collaterals allows the development of collateral circulation in the long axis of the limb as well as between angiosomes within the lower leg and foot. Effectively improving the influx to the impaired angiosomes. Gene therapy is associated with a few mild side effects. There is a limited pool of complications, and the condition of the limb does not deteriorate. This is confirmed by our previous experiences [In addition to VEGF and HGF, other growth factors have been tried in gene therapy. Creager et al. used hypoxia-inducible factor 1-alpha (HIF-1α)-encoding for treatment, but this did not prove to be an effective treatment for patients with intermittent claudication [The process of neovascularization requires the cooperation of many cells and proteins. Based on the literature as well as our own experience, we chose HGF and VEGF for gene therapy, which we believe is the most optimal combination [The whole process, its stability, and its lasting effect require other factors, such as HGF. HGF has been shown to be a potent activator of cell proliferation, and in addition, compared to other growth factors, it does not induce inflammation, which is its unique value and may affect the efficiency of the angiogenesis process [Considering these successes, we decided to use the synergistic action of the two proangiogenic factors. In order to optimize gene therapy as much as possible, vascular mapping and ultrasound were performed prior to VEGF/HGF administration. The choice of the intramuscular route of administration was based on its greatest efficacy in promoting angiogenesis from the available literature data and our own experience [In this study, in the VEGF/HGF gene treatment group, lesion healing by week 12 occurred in four patients (50% of the group), the ABI increased from values in the range of 0.20–0.55 to values in the range of 0.5–0.9, by an average of 0.25, and TcPO2 increased from values in the range of 25–46 mmHg to values in the range of 58–91 mmHg, by an average of 30.4 mmHg. In patients in the control group, lesion healing by week 12 occurred in six patients (66.67% of the group), the ABI increased from values in the range of 0.20–0.55 to values in the range of 0.45–0.85, by an average of 0.14, 0.11 less than in the gene therapy group. TcPO2 increased from values in the range of 25–49 mmHg to values in the range of 52–85 mmHg, an average of 27.1 mmHg, 3.3 mmHg less than in the gene therapy group. In our other study, bicistronic VEGF/HGF gene therapy achieved satisfactory results in the treatment of DFS. After 90 days of therapy, significant reductions in pain and increases in the ABI were observed [In addition to gene therapy, other mechanisms to enhance neovascularization should be considered. It has become apparent in recent years that there are extensive similarities between the development of nerves and blood vessels. Both are branched structures that require guidance to reach their proper targets. A variety of molecules that were previously thought to be restricted to axonal guidance processes have now been shown to modulate blood vessel guidance as well. These insights are of significance as they could have potential therapeutic applications [In our study, treatment outcomes after complementary gene therapy were comparable to the control group. The small size of the study group does not allow us to claim that the changes are statistically significant. This is related to the assumption of obtaining as homogeneous a group as possible of patients with diabetes, burdened by DFS, critical ischemia, and after revascularization procedures. The results are certainly not worse in the study group (after gene therapy) than in the control group and no adverse events were observed. A precise determination of the synergistic effect of the therapy will be possible on a larger statistically significant group. With the safety of this method proven, the study can be continued.