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Bone marrow cell transplant treats clogged leg arteries
November 18, 2002

CHICAGO, IL (AHA) – Bone marrow cells implanted into blood-starved (ischemic) legs formed new blood vessels, increased blood flow and prevented amputation in people with peripheral artery disease, researchers reported at the American Heart Association’s Scientific Sessions 2002.

"This is the first multicenter and double-blind clinical study to prove the clinical efficacy of growing new blood vessels (angiogenesis) using bone marrow cell transplantation," says the study's lead author Hiroya Masaki M.D., Ph.D. He hopes that transplanting bone marrow cells will establish a new therapy for peripheral artery disease (PAD).

PAD is a condition similar to coronary artery disease in which fatty deposits build up along artery walls and reduce blood circulation, mainly in arteries leading to the legs and feet. In its early stages, a common symptom is cramping or fatigue in the legs and buttocks during activity. PAD causes severe pain, ulcers and sores. In its later stages, it can lead to gangrene or a dangerous lack of blood flow, called critical limb ischemia, which can be treated by revascularization (such as angioplasty) or amputation.

Bone marrow cells are promising for this type of therapy because they have the natural ability to supply endothelial progenitor cells, says Masaki, an associate professor in the department of laboratory medicine and clinical sciences at Kansai Medical University in Osaka, Japan. Endothelial progenitor cells can develop into endothelial cells, which, in turn, can form new blood vessels.

The researchers randomly implanted either a person's own bone marrow mononuclear cells or saline (a placebo) into the calf muscles of 45 PAD patients. Twenty patients had bilateral ischemia (both legs) and 25 had unilateral ischemia (one leg). There was a "striking" increase in new capillary formation in the legs of patients who received bone marrow mononuclear cell transplants. Patients injected with saline showed much smaller increases in collateral perfusion.

Researchers found that CD34-cells, which can develop into endothelial progenitor cells, expressed basic fibroblast growth factor, vascular endothelial growth factor and angiopoietin-1. These vascular growth factors play key roles in angiogenesis.

"Endothelial progenitor cells have vascular growth factors inside the cells," Masaki says. "This is very advantageous for angiogenesis. By implanting the bone marrow mononuclear cells, we deliver endothelial progenitor cells and vascular growth factors at the same time."

In limbs that received the bone marrow cells, researchers noted an increase in ankle-brachial pressure index (ABI) in 31 of 45 patients. Baseline ABI was 0.35. Four weeks after implantation it was 0.42, and at 24 weeks it was 0.46. The ankle-brachial index test measures blood pressure at the ankle and in the arm and divides the two to help predict the severity of PAD. A normal resting ABI is 0.30 – 0.91. Patients with leg pain typically have ABI indexes ranging from 0.41 – 0.90, and those with critical leg ischemia have indexes of 0.4 or less.

Researchers also noted newly visible collateral vessels in 27 limbs. Pain occurring at rest in the ischemic limbs diminished significantly in 39 of 45 patients, and the amount of time they could walk on a treadmill without pain was significantly improved (from 1.3 minutes at baseline to 3.6 at week four and 3.7 at week 24). Participants' ischemic ulcers or gangrenes were healed in 21 of 28 limbs.

Masaki says, the study's findings can be applied to today's patients. However, he warns that more research is needed to prove the treatment's long-term efficacy and safety. "This new angiogenesis therapy using bone marrow cell transplantation may help many patients suffering with ischemic limbs," he says.

Co-authors are Eriko Tateishi-Yuyama, M.D.; Hiroaki Matsubara, M.D., Ph.D.; Toyoaki Murohra, M.D., Ph.D.; Satoshi Shintani, M.D., Ph.D.; Katsuya Amano, M.D.; Uichi Ikeda, M.D., Ph.D.; Kazuyuki Shimada, M.D., Ph.D.; Hakuo Takahashi, M.D., Ph.D.; Toshiji Iwasaka, M.D.; and Tsutomu Imaizumi, M.D., Ph.D.

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