It's a tantalizing thought: injecting stem cells isolated from a person's own blood into an ailing heart in hopes of repairing years of accumulated decay. But so far, human trials testing cell therapies for heart attacks have yielded mixed results, creating controversy over various aspects of the treatment: the types of cells that are used, the way they are delivered, and when in the course of the disease they are given. With the next round of trials, scientists hope to nail down the precise set of conditions needed to effectively heal a sickly heart.

"If it works, it could revolutionize cardiology," says Amish Raval, a cardiologist at the University of Wisconsin, Madison, who is running a stem-cell trial for heart failure.

Nearly five million people in the United States have heart failure caused by damage to the heart that interferes with its ability to pump blood, and nearly a million people suffer heart attacks each year. And despite a series of advances in cardiovascular care over the past decades, heart disease accounts for one in every 2.8 deaths in the United States. "In the past, we've relied on medication or mechanical therapies to open blood vessels and improve heart function," says Raval. "But there are still people who fail those therapies. Stem cells may have the potential to improve on that."

In terms of the clinical testing of stem-cell therapies, heart disease is arguably the furthest along of the common diseases. But cell-based therapies are proving trickier to test than traditional drugs and medical devices are. They seem to require the perfect combination of ingredients and execution. Scientists must determine the best cells to transplant, the best way to prepare cells, and when and how they should be delivered.

The largest stem-cell trials for heart disease to date--three were published last year and one in 2005--used cells derived from the patients' own bone marrow to treat myocardial infarction, or heart attack. The results were mixed: some studies found moderate improvements in a few measures of heart function, but none were able to show a clear health benefit. "Are you living longer or having less heart failure? Those are questions that are still out there," says Stefan Janssens, head of the cardiac clinic at the University Hospital Gasthuisberg, in Belgium.

Janssens and others suspect that variability comes from different methods used to purify the stem cells. So he and others in Europe are planning a larger trial, testing 1,000 to 2,000 patients, in which the researchers will specifically assess the numbers and function of cells transplanted into each patient. The goal? To determine if stem-cell therapy can actually save lives.

One unknown concerning cell therapies for heart disease is related to the fact that bone marrow contains two types of stem cells: blood-forming stem cells, which give rise to blood cells, and mesenchymal stem cells, which can form muscle and bone. While previous trials have used a mixture of these two types of cells, some scientists think that isolating one or the other of the cell types from the mix will boost healing power. "Benefits noted in previous trials weren't sustained, so selecting cells with therapeutic potential is a better idea," says Raval.

To sort out the question, a new trial is now under way at a number of research sites around the country. The trial, funded by Baxter Healthcare, will use a specific type of blood-forming stem cell to treat heart-failure patients for whom all other treatments have been unsuccessful. These patients have chest pain, shortness of breath, and, often, an inability to exercise due to chronic insufficient blood flow to the heart.

A specific type of blood-forming stem cell will be injected directly into the heart muscle, a method that Raval suspects will work better than infusing the cells, a method used in previous studies. "Sending stem cells directly into the muscle might offer better cell retention and a better chance for cells to exert therapeutic effect," he says.

Researchers think that this type of cell will boost growth of new blood vessels, thereby increasing blood flow to the heart. "With heart failure, we think there is loss of microvasculature [the smallest blood vessels]," says Douglas Losordo, director of the Cardiovascular Research Institute at Northwestern University's Feinberg School of Medicine, in Chicago, and head of the multicenter trial. "That's what we're trying to treat with the cells."

Mesenchymal stem cells--the other type of stem cell in bone marrow--are also under scrutiny. This weekend Joshua Hare, chief of cardiology at University of Miami Miller School of Medicine, will report initial results of a trial testing these cells in heart-attack patients. Preclinical research suggests that these cells induce growth of new cells in heart muscle. While Hare won't comment on the specific findings before his announcement, he says that results are exciting. He now aims to start a larger trial for heart-attack patients, as well as an additional small-scale trial to test the therapy in patients with heart failure.

Hare's trial is unique in that he uses cells isolated from another person and then grown in the lab. The cells come from Osiris Therapeutics, a stem-cell company based in Baltimore that is sponsoring the trial. These cells appear not to trigger an immune reaction in the recipient--a fear when it comes to cell-transplant therapies. Patients did not receive immunosuppressants during the tests.

While all the human trials to date have used adult stem cells, scientists are not giving up on the potential of embryonic stem cells. These cells are easier to grow and manipulate, potentially providing a more abundant and controlled source of cells for transplant. Scientists have already been able to push embryonic stem cells to develop into clusters of heart cells that can actually beat, and they are now testing different cell types for their healing power. In some ways, ongoing tests with adult cells will prepare scientists for the day when embryonically derived cells are ready for human testing. "When someone tells me that they have a cell type that can regenerate new muscle or improve function in some way," says Raval, "we'll be ready to deliver them."