Treatment of arterial ischemic diseases of the lower extremities

  With the improvement of living standards and the growth of the elderly population, the incidence of peripheral arterial diseases is increasing year by year, among which atherosclerotic occlusions and diabetic atherosclerosis are common. These chronic arterial ischemic diseases have seriously affected human health, and even amputation is required in severe cases. The literature shows that the incidence of chronic lower extremity arterial ischemia is 3% in people <60 years old, 17% in people aged 60-75 years old, and up to 29% in people >75 years old. Among patients with severe cardiovascular disease, 75% have peripheral arterial occlusion.  Once lower limb artery ischemia occurs, the amputation rate is as high as 5%. With the increase in the number of people over 60 years of age in China, chronic lower extremity arterial ischemia has become another disease that seriously affects the health of the elderly in addition to cardiovascular diseases. The treatment of these diseases requires long-term medication and, in some cases, percutaneous transluminal angioplasty (PTA) or vascular bypass grafting. Neither pharmacological nor interventional or surgical treatment can ultimately stop the progression of the disease completely. In some cases of chronic arterial ischemic disease, the amputation rate is as high as 8%-30% if the drug therapy is not effective and the surgical or interventional treatment is not available. Seeking a more effective and long-lasting treatment is the direction of development in dealing with this type of disease.  In recent years, autologous stem cell transplantation has been gradually developed to bring light to such patients. Moreover, this type of treatment has entered the clinical application stage both in China and abroad.  Bone marrow stem cells are a type of cells with self-renewal and multi-directional differentiation ability, which can survive and add value in suitable in vitro culture and preserve multi-directional differentiation potential, and can produce offspring cells with the exact same phenotype and genotype as themselves, and also differentiate into various functional cells. Bone marrow-derived stem cells include hematopoietic stem cells (HSC) and mesenchymal stem cells (MSCs), and recent studies have shown that MSCs also have multipotent differentiation.  The most valuable product in current research is the Endothelium Pregenital Cells (EPCs). It was previously thought that EPCs appeared only at the stage of embryonic vascular development and did not exist after birth, but recent studies have shown that CD34+ cells or flk 1+ cells or AC133+ cells from cord blood, adult peripheral blood, and bone marrow can differentiate into endothelial cells after two weeks of ex vivo culture, thus confirming the presence of EPCs in adult individuals. EPCs in peripheral blood were found to be of bone marrow origin. Granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF) and VEGF165 gene transfection mobilize the bone marrow to release EPC. Bone marrow stromal cells, which have pluripotent differentiation potential, can differentiate into osteoblasts, neuronal cells, endothelial progenitor cells, etc. These cells are characterized by small, single-nucleated cells that grow against the wall when cultured in vitro. Studies have shown that endothelial progenitor cells can form a neovascular system locally in ischemia. However, endothelial progenitor cells are rare in peripheral blood, only 0.2% of bone marrow, which makes it difficult to accomplish the therapeutic purpose, but many patients are unwilling to accept the treatment method of bone marrow blood extraction for various reasons.  With reference to the experience of others, our treatment method is to first mobilize endothelial progenitor cells from bone marrow to proliferate and release into peripheral blood, and then take endothelial progenitor cells from peripheral blood and make local transplantation so that endothelial progenitor cells can form a new blood vessel network in the ischemic site or area to resupply the blood needed by the limb to achieve the treatment purpose.  Clinical trials of angiogenic therapy for ischemic diseases have been conducted for many years, and the understanding of the concept of angiogenesis has changed significantly from therapeutic angiogenesis with endothelial growth factor gene introduction to therapeutic vasculogenesis with EPC transplantation. EPC and bone marrow cell transplantation have the potential to become one of the new therapeutic measures for severe ischemic heart disease and occlusive atherosclerosis.  Our department has performed autologous peripheral blood stem cell transplantation for several patients suffering from severe lower extremity arterial supply disorders since March 2004. The patients were aged 36-87 years old, and their diseases included arteriosclerosis obliterans (ASO), diabetic foot, and thromboangiitis obliterans (TAO). Patients mostly had foot/toe ulcers, resting pain, ankle-brachial index less than 0.5 in all affected limbs, and dorsalis pedis artery pressure 20-50 mmHg (2.67-6.67kPa, Doppler flowmetry).  All of the above patients were treated with regular antiplatelet, anticoagulation, vasodilator and prostaglandin E drugs for the primary disease and treatment for ulcers, but there was no improvement of ischemic symptoms and ulcers in the lower limbs, and magnetic resonance angiography (MRA), CT angiography (CTA) or digital subtraction angiography (DSA) suggested that surgical treatment was not appropriate.  All patients had varying degrees of relief of resting pain 1 week after treatment. In patients followed up for 1 to 3 months, the resting pain was completely relieved; the application of pain medication was reduced and discontinued in 80% of patients after discharge, while cold sensation in the extremities was reduced.