Heart Therapy Aims to Harness Body’s Power
About 14 million Americans suffer from coronary artery disease, which can transform routine daily activities into gasp-for-breath tasks. But many of them are poor candidates for the most commonly performed repairs.
For those patients, doctors have been studying chemicals that encourage the creation of tiny, new channels to get around clogged arteries, essentially inducing patients to grow their own bypasses.
Promoting the creation of those new blood vessels--through a process called angiogenesis--to fight heart disease is a nifty concept that patients would welcome as an alternative to bypass and angioplasty. But it can be thorny in practice, as researchers are learning.
Angiogenesis studies have become the hot new frontier in medicine.
At medical schools and biotechnology companies, angiogenesis researchers are racing to unlock the mysteries of what makes blood vessels flourish--or wither away. Finding those answers, they hope, could lead to potentially lucrative treatments for heart disease, cancer, blindness, arthritis and psoriasis.
The search began nearly 30 years ago, when Dr. Judah Folkman, a researcher at Boston Children’s Hospital, suggested angiogenesis was an essential process in cancer. By cutting off a tumor’s blood supply, and thus its supply of nutrients and oxygen, he proposed doctors could literally starve a tumor to death--a notion ridiculed by many colleagues. Soon afterward, he helped discover a molecule that would stop blood vessel formation--a first step toward demonstrating the merit of his theory. Since that time, scientists have identified more than 300 other angiogenesis inhibitors.
Although the field has blossomed in the last few years, many people may have first heard about angiogenesis in May 1998, when a controversial front-page article in the New York Times quoted Nobel Prize winner Dr. James Watson as saying that Folkman’s anti-angiogenesis work in mice could lead to a cancer cure in two years. Scientists said the mouse research was far too preliminary for any claims about cures.
As Folkman and colleagues around the world try to stop angiogenesis in tumors, many cardiac researchers want to encourage it within the heart. They’re trying to harness the power of new blood vessels to move nourishing blood through weakened hearts. In 1997, researchers announced with great fanfare that they were able to grow new arteries in the legs of heart patients with poor circulation using a gene for vascular endothelial growth factor.
Looking at the Results of a Promising Study
Last week, thousands of heart doctors jammed a room at the American College of Cardiology meeting in Anaheim to learn about the results of a much-anticipated angiogenesis study. It was designed to determine whether a genetically engineered protein called basic fibroblast growth factor could stimulate the growth of new vessels in diseased hearts. The therapy had looked promising in earlier studies involving animals, and researchers were hopeful it would work in humans.
But the results, many meeting participants said, were kind of a bust.
The study, sponsored by a Northern California-based biotechnology company, Chiron Corp., involved 337 patients with severe coronary artery disease, some of whom received a single infusion of the protein directly into the heart, and others who received a placebo, a dummy treatment. To evaluate the effectiveness of the protein treatment, the researchers looked for improvement in the patients’ endurance during physical exercise.
After three months, the group that got the protein reported being able to exercise on a treadmill for an additional 65 seconds; those on the placebo improved their endurance by 45 seconds--a statistically insignificant difference.
Researchers were encouraged, however, by two other findings. The oldest and sickest patients reported less chest pain, or angina. Using nuclear imaging, doctors saw that their hearts indeed had sprouted new blood vessels.
One of the study’s lead investigators, Dr. Michael Simons, head of angiogenesis research at Beth Israel Deaconess Medical Center in Boston, said these secondary findings gave researchers an idea of which patients might benefit the most from angiogenesis and were promising enough to warrant further study.
At the same meeting, Dr. Jeffrey Isner, a cardiologist with St. Elizabeth’s Medical Center in Boston, reported positive results of a small preliminary study of 30 heart disease patients treated with another vascular growth factor. Twenty-one patients reported significantly fewer episodes of chest pain; nine of them were pain-free.
Premature Assumptions Could Give False Hope
Such results, some doctors warn, tend to raise the hopes of heart patients who may be too sick to endure open-heart surgery or who are poor candidates for the artery-clearing procedure known as angioplasty. That is why it is important, for the medical community--and the media--to be careful about not hyping the results of early studies.
“Very important questions still need to be answered,” said Dr. Timothy Henry, a cardiologist and angiogenesis researcher at Hennepin County Medical Center in Minneapolis.
Some doctors are cautious about manipulating growth factors in the body because they fear unwanted effects, like promoting tumors. And some cardiologists worry that angiogenesis may contribute to the very problem they’re trying to fight, by fueling the growth of plaque inside the arteries.
“We’re playing with the very things that regulate wound healing, cell growth and cell death,” warned Dr. Americo Simonini, an assistant professor of medicine at UCLA Medical Center who has investigated angiogenesis in the formation of cardiac plaque. “In a way, we’re playing with fire.”
The Anaheim meeting gave angiogenesis researchers an opportunity to take stock of their findings and to discuss fundamental questions as how best to measure their progress. Simons, who led the Chiron trial, questioned whether patients’ endurance on a treadmill is the proper benchmark for judging success of angiogenesis trials: “It may not matter if Mrs. Jones can exercise 60 seconds more, but is Mrs. Jones having angina?” he said.
Dr. David Cohen, a cardiologist at Beth Israel Deaconess, suggested doctors should give greater weight to quality-of-life measures, like chest pain and shortness of breath, when assessing the benefits of angiogenesis therapies in cardiac patients. The FDA has used quality-of-life measures to approve several drugs for sale, such as Vioxx for arthritis, Imitrex for migraines and Viagra for male impotence.
Cohen noted that the placebo effect--the reduction of symptoms among patients who feel better even if they don’t get an active drug--is powerful in pain patients. In arguing for control subjects in angiogenesis experiments, he said, “the only way to get rid of the placebo effect is to have a placebo.”
Dr. William W. Li, president of the Angiogenesis Foundation, a Cambridge, Mass., group that promotes angiogenesis drug research, said investigators trying to encourage angiogenesis may overlook commonly prescribed medications that can thwart it. He’s concerned about “what happens when angiogenesis stimulators meet angiogenesis inhibitors” such as the COX-2 inhibitors given for arthritis or Lovastatin, one of the cholesterol-lowering compounds. He said some patients’ failure to respond to angiogenesis drugs may be due to medications they’re taking.
Given the big-picture task of addressing whether angiogenesis therapy is “ready for prime time,” Dr. David Dichek, a researcher with the Gladstone Institute of Cardiovascular Disease in San Francisco, concluded it’s not.
Such a field, “where you combine charismatic investigators, desperate patients and high technology, is a crucible for the placebo effect,” he proposed. Because the angiogenesis arena lends itself to hype, he advised more controlled trials and “conservative reporting of data.”
In closing the meeting, Li drew laughter when he called the angiogenesis approach to cardiac illness “an attempt to treat a disease we don’t understand with agents we don’t know how to use, using end points we cannot assess.”
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Helping Clogged Hearts
In heart bypass surgery, a vein graft (1) is used to get around a blocked portion of an artery. In angioplasty, a meshlike sent (2) is inserted to hold open a clogged artery. Angiogenesis drugs are being tested to promote the sprouting of new blood vessels (3) to improve blood flow in patients who are poor candidates for bypass or angioplasty.
Sources: Angiogenesis Foundation, Cambridge, Mass., and Steven Moskowitz, Advanced Medical Graphics.
