Coronary artery bypass is the favored treatment for heart disease and ischemic stroke. It's not the only bypass operation in medical practice. At the far end of the body, remote from the heart, lie the lower limbs – thigh, calf, feet and toes. They also require arterial bypass surgery for atherosclerosis of the extremities. "Such surgical treatment is not very effective in patients with ischemia of the lower limbs," observed cardiologist Hiroaki Matsubara, at Kansai Medical University (Osaka, Japan). He attributes the etiology of leg ischemia "mainly to diabetes mellitus, with hypercholesterolemia, hyperlipidemia and atherosclerosis." He pointed out that "leg ischemia affects 1% of the population in Japan, 3% in the U.S. – and that's too many."
Matsubara is co-lead author of a paper in the Aug. 10, 2002, issue of The Lancet titled "Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bone-marrow cells: a pilot study and a randomized controlled trial."
"Implantation of bone marrow-mononuclear cells could be a safe and effective strategy for achievement of therapeutic angiogenesis because of the natural ability of marrow cells to supply endothelial progenitor cells and then secrete various angiogenic factors," Matsubara said. "Current surgical or medical treatments have no effect on the ischemic conditions. Right now, vascular endothelial growth factor [VEGF] therapy is reported to be effective in patients, but our treatment is more efficacious for removal of pain, in terms of the angiogenic functions."
He added: "In preclinical studies, implantation of bone marrow-mononuclear cells, including endothelial progenitor cells, into ischemic limbs increased collateral blood vessel formation by angiogenesis." Advancing from animal to clinical trials, he and his co-authors began with a pilot study in which 25 patients suffering from unilateral leg ischemia received bone marrow-mononuclear cells injected into the calf muscle of the constricted limb.
"We then recruited 22 patients with bilateral leg ischemia," Matsubara said. "These we randomly injected with our bone-marrow fraction and administered peripheral blood-mononuclear cells to the other limb as a control." Patients who received the peripheral cells experienced inhibition of ischemic leg pain, he noted, "but this treatment did not elevate the transcutaneous oxygen pressure. However, the bone marrow cells not only inhibited leg pain, but also raised that blood pressure in the lower limb." Of 45 patients enrolled, 38 were men, seven women. Ten had unhealing ulcers, 18 gangrene. Most were diagnosed with hypertension, hyperlipidemia and diabetes.
"Four weeks after the procedure," Matsubara said, "37 of 45 patients saw their pain reduced or relieved completely. Fifteen of 20 were able to avoid scheduled amputation of a toe, and leg ulcers improved in six of 10 patients." He said that results of angiography show "a striking increase in number of visible collateral vessels; positive benefits of the bone marrow cell transplantation were still evident six months after the intervention."
He added that the mononuclear portion of the bone marrow cells included progenitor stem cells but not mature neutrophils. "Neutrophils produce inflammation, which is not good for angiogenesis." The mononuclear cells contained both cytokines and endothelial [blood vessel] progenitors. The immature mononuclears harbor progenitors – stem cells. But the mature ones contain the cells that release angiogenic factors – various VEGFs and cytokines.
Matsubara said that peripheral blood "did not elevate blood pressure and inhibited less pain." He added that the statistical difference between marrow cells and peripherals "was significant – three times higher in bone marrow, which is a good therapeutic result." But the research paper sounds a caveat: "A great deal more clinical experience is needed to resolve safety concerns such as potentiation of pathological angiogenesis (e.g., malignancy) and so-called bystander effects of delivered factors (e.g., effects on kidney or atheroma.)." It added, "Treatment with various angiogenic growth factors might be preferable in future treatments."
Ongoing in Matsubara's immediate clinical agenda is moving from leg ischemia to coronary artery disease. "I have already treated one cardiac patient with this bone marrow therapy six months ago. He had attacks of chest pain – angina pectoris – 15 times a day. Right now this patient's chest pain is gone, and he is very well. No more angina."
That transition required open-heart surgery to inject the bone marrow-mononuclear cell therapeutic. "Our target was so-called ischemic areas of hibernation – sleeping muscle patches of ischemia," Matsubara said. "Using complicated procedures, we found these areas. First we opened the patient's chest under general anesthesia in the OR. Then we located the target areas by means of scintigraphy, echocardiography and other sophisticated scanning machinery. Then we injected the cells directly into the open heart." He added, "Right now I am watching this first patient for any signs of side effects. If after completion of one year he shows none, next year we are going to go into many patients with angina."