Synthetic 'Good' Cholesterol Helps Clear Arteries Small Study Indicates the Possibility That Drug Therapy Could Reverse Heart Disease

By Rob Stein
Washington Post Staff Writer
Wednesday, November 5, 2003.

A synthetic form of "good" cholesterol has been shown to quickly shrink blockages clogging coronary arteries, offering for the first time the possibility of a drug that could actually rapidly reverse heart disease, researchers reported yesterday.

In a small, preliminary study, the laboratory-made substance, which mimics a type of cholesterol discovered in a group of surprisingly healthy villagers in rural Italy, significantly reduced in just six weeks the amount of plaque narrowing the arteries of patients who had suffered heart attacks or had chest pain.

Because the approach attacks the underlying source of many heart attacks, the results could mark a milestone in the search for new ways to treat the nation's No. 1 killer, researchers said.

"For the first time, we've shown that you can reverse coronary disease with drug therapy in a matter of weeks," said Steven E. Nissen, a cardiologist at the Cleveland Clinic who coordinated the nationwide study. "We really have, for the first time, the opportunity to attack this disease at its fundamental basis. It's a paradigm shift. It's opening a new door."

While drugs that lower cholesterol and blood pressure can cut the risk of developing heart disease, and aspirin protects against heart attacks, one of the Holy Grails of modern medicine has been to find a way to reverse the deadly process once it has begun. The results of the new study suggest that synthetic HDL may finally offer such a medicine.

Nissen and other researchers cautioned that the study involved only 47 patients, and further studies are needed to confirm the findings, fully evaluate the drug's safety and determine whether the treatment actually cuts the risk of heart attacks and strokes.

"It's extremely preliminary," said Susan K. Bennett, clinical director of the George Washington University Hospital Women's Heart Program, speaking on behalf of the American Heart Association. "But it is very intriguing."

Regardless of whether this particular drug eventually offers a practical, effective treatment, other experts said the study has opened up an entirely new way to approach treating atherosclerosis, known commonly as hardening of the arteries.

"This is the first true test of the concept that specifically targeting HDL, the good cholesterol, can impact plaque and atherosclerosis in humans," said Daniel J. Rader, director of preventive cardiology at the University of Pennsylvania, who wrote an editorial accompanying the study in today's Journal of the American Medical Association.

Scientists have long known that there are two forms of cholesterol: One is low-density lipoprotein (LDL), which is the "bad" cholesterol because it accumulates inside artery walls, causing the vessels to narrow and setting the stage for heart attacks and strokes. The other is high-density lipoprotein (HDL), called the good cholesterol because it protects against heart disease, primarily by lowering LDL levels.

About 30 years ago, researchers discovered a group of about 40 people living in the rural northern Italian town of Limone sul Garda who had a surprisingly low rate of heart disease despite their extremely low HDL levels. Scientists determined that their HDL was slightly unusual, raising the possibility that it provided powerful protection against heart disease.

Esperion Therapeutics Inc. of Ann Arbor, Mich., developed a genetically engineered form of this version of HDL, dubbed ApoA-I Milano, and showed that it reduced plaque inside the arteries of laboratory animals. The company then asked Nissen to test it in people.

In the study, Nissen and colleagues at 10 centers around the country gave weekly infusions of either the synthetic HDL or an inert placebo to heart disease patients for five weeks. The plaques clogging the walls of their arteries were carefully measured before and after the treatment using an extremely precise ultrasound technique.

Compared with those who received the placebo, the patients who received the synthetic HDL experienced about a 4 percent reduction in the plaques lining their arteries, a reduction 10 times as great as anything scientists had tried previously, the researchers found.

"When the statisticians delivered the data to me, I fell off my chair," Nissen said in a telephone interview. "We've run across something that can literally clear out the plaque in just a few weeks. That's unprecedented."

Rader agreed. "I don't think anyone thought you could induce regression in six weeks -- that's the single most surprising thing about this study," he said.

The only other thing that may reduce plaque inside arteries is long-term use of anti-cholesterol drugs such as statins. Some research has also suggested people who strictly adhere to the high-fiber, low-fat, vegetarian Dean Ornish diet can also somewhat reverse their heart disease. But the amount of plaque reduction in those cases was just a fraction of what patients taking the synthetic HDL experienced, and it took many years.

It remains unclear how this form of HDL works, but it may be especially adept at transporting LDL out of the blood and back into the liver, where it is harmlessly processed.

Rader noted that there could be nothing particularly special about the synthetic HDL. It could be that it is the only one that has been tested this way because it is a form of HDL that can be patented. Other companies are trying to develop different ways of using HDL to fight heart disease, such as drugs that boost the body's own production of HDL.

In the meantime, Esperion plans to conduct a follow-up study that will involve thousands of patients who would be followed for a year to determine whether the treatment reduces the risk for heart attacks and the need for angioplasties and bypass surgery to restore blood flow to the heart muscle.

"This is a landmark study in our mind that validated the whole HDL hypothesis -- that it is something that could change the way medicine is practiced," said Roger Newton, Esperion's president and chief executive.

B) 2003 The Washington Post Company