November 18, 2002
Skeletal Muscle Cells Transplanted Into Human Hearts

Two new results reported on transplanting cells into damaged hearts. The first with humans increased the pumping capacity of hearts:

Researchers conducted the multi-center trial, overseen by the U.S. Food and Drug Administration, in patients who had suffered heart attacks or heart failure and whose hearts had reduced pumping ability evidenced by left-ventricular ejection fraction (EF) less than 30 percent. EF measures the quantity of blood pumped from the heart with each beat. A healthy heart pumps out a little more than half the heart's volume of blood with each beat for an EF of 55 percent or higher.

Eleven patients were undergoing coronary artery bypass surgery (CABG) and five were having a left ventricular assist device (LVAD) implanted. An LVAD helps a failing heart until a donor heart becomes available for transplant.

The patients' myoblasts cells (immature cells that become muscle cells) were extracted from thigh muscle. Large quantities of the cells were grown in the laboratory for three to four weeks using a controlled cell expansion manufacturing process. During the surgery, one to 30 direct injections – containing 10 million cells each – were made into the damaged area of the hearts. The dosages ranged from 10 million to 300 million cells.

"We found that the transplanted myoblasts survived and thrived in patients. Areas damaged by heart attack and cardiovascular disease showed evidence of repair and viability," Dib says.

No significant adverse reactions were found related to the cell transplant procedure in either group of patients in follow-up testing nine months later.

There was one death due to infection of the device in the LVAD group three months after cell transplantation, and one patient in the CABG group had non-sustained ventricular tachycardia – a fast heart rate that starts in the lower chambers (ventricles).

While the trial was not designed to evaluate the effect of cell transplant on cardiac function, Dib calls the results extremely encouraging. Examining the heart by echocardiogram, magnetic resonance imaging (MRI), and positron emission tomography (PET scan) showed evidence of scar tissue regeneration in the area of the graft, which indicates repair.

EF rates improved, on average, from 22.7 percent to 35.8 percent – a 58 percent increase – after 12 weeks.

The second result with rats showed transplanted cells can repair the heart beat transmission signals that currently require artificial pacemakers to treat:

CHICAGO, Nov. 17 – Preliminary findings of a study in rats suggests that a person's own cells might one day replace artificial pacemakers, researchers reported today at the American Heart Association's Scientific Sessions 2002.

Studies conducted at Children's Hospital Boston tested the ability of immature skeletal muscle cells to interconnect with heart cells and spread the electrical impulses that keep the heart beating properly.

"The cells have survived in rats for more than a year and they appear to have made connections with cardiac cells," says Douglas B. Cowan, Ph.D., a cell biologist who led the study. "The electrical pathway developed within 10 weeks of implantation.

"Ultimately – maybe a decade down the road – we may be able to use such cell-based technologies in humans to free them from cardiac pacemaker devices," says Cowan, also an assistant professor of anesthesia at Harvard University Medical School in Boston.

Heart contraction starts with an electrical signal that begins in the atrium, a tiny area of the heart's upper-right chamber. The signal then moves to the other chambers. Damage to the electrical pathway between the atrium and ventricles (the lower chambers) can result in complete heart block, a potentially fatal condition that can only be treated by implanting a cardiac pacemaker.

"We have gathered preliminary evidence that immature skeletal muscle cells can establish a pathway to transmit electrical signals from the heart's upper right chamber to its lower right chamber," he says.

In one sense these treatments were fairly low tech (though heart surgey isn't exactly low tech). It wasn't necessary to apply complex chemical treatments to embryonic stem cells in order to get them to differentiate into heart cells. They used myoblasts which are essentially muscle stem cells. Also, their method of growing them up may be fairly sophisticated. It seems logical to expect that in the longer run younger sources of myoblast cells will eventually be used because they will be more efficient and last longer.

Update: A third result has blood vessels being grown from human skin cells:

CHICAGO, Nov. 17 – Researchers have built mechanically sound blood vessels out of tissue from human skin cells, according to a study reported today at the American Heart Association's Scientific Sessions 2002. The technique involves tissue engineering, an emerging science that takes cells from the body, manipulates them in the laboratory to create functional tissue, and puts the new tissue back into the patient.

The goal is to produce healthy, functioning blood vessels built exclusively from a person's own cells, so the body's immune system won't reject the new tissue. Such vessels would be important in heart and leg bypass operations and for vessels called arteriovenous shunts used for dialysis patients.

The scientists reported that tissue-engineered blood vessels didn't burst or develop blood clots in laboratory tests and short-term animal experiments.

"The study's most important findings were: First, the technology works from a commercial perspective, meaning we can build mechanically sound vessels for a wide array of patients using the exact same protocol," says Todd McAllister, Ph.D., president and chief executive officer of Cytograft Tissue Engineering in Novato, Calif., which developed the vessel-building technique.

"Second, we demonstrated that thrombogenesis (the formation of blood clots) does not appear to be a problem in the short term – up to 14 days. Short-term blood clots are the biggest challenge facing most synthetic materials, whether they are used for blood vessels, new heart valves, or other vascular prostheses. We expect to begin this research in humans within 18 months."

Update II: A fourth result show bone marrow transplantation improving arteries in the legs and feet:

“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.

Update III: A fifth result shows bone marrow transplantation improves the function of damaged hearts:

The study by British researchers adds to mounting evidence that muscle-generating cells in bone marrow can rejuvenate hearts deadened by infarctions, or loss of blood to the tissue. Previously, scientists had considered that damage irreversible.

"It has been the belief in general that you are born with a fixed number of [heart muscle cells], and that when they die they die forever," says Dr. Manuel Galinañes, a heart surgeon at the University of Leicester and leader of the research effort. "This has been challenged."

Share |      Randall Parker, 2002 November 18 12:18 PM  Biotech Therapies

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