Drug removes arterial plaque in surprising clinical trial

New treatments possible using `good cholesterol'

November 05, 2003|By Thomas H. Maugh II | Thomas H. Maugh II,LOS ANGELES TIMES

A small clinical trial has shown for the first time that it is possible to use drugs to remove plaque from clogged arteries, a finding that could lead to radically new ways to treat heart disease, the No. 1 killer in the United States.

Infusions of a genetically engineered mutant form of high-density lipoprotein, the so-called good cholesterol, over a five-week period were shown to reduce plaque volume in patients suffering from chest pain.

"This is an extraordinary and unprecedented finding," said Dr. Steven E. Nissen of the Cleveland Clinic Foundation, who led the study reported in today's issue of The Journal of the American Medical Association.

Current therapies targeting cholesterol use a family of drugs called statins to reduce levels of low-density lipoproteins, the "bad cholesterol."

Increasing good cholesterol, or HDL, is not only substantially more effective at reducing plaque, but also appears to change its composition, stabilizing it so that chunks are less likely to break off and cause heart attacks or strokes.

Surgical alternatives for eliminating blockages include angioplasty (in which a balloon is used to smash the plaque flat) and coronary artery bypass surgery. Both treat only small blockages, however, while the new approach works throughout the body.

"The results of this study are surprising to even the most optimistic supporters of the concept of targeting HDL as a therapy for atherosclerosis," wrote Dr. Daniel J. Rader of the University of Pennsylvania School of Medicine in an editorial in the same issue. He suggested that HDL-targeted therapies could be one of the most important clinical developments of the next two decades.

And researchers owe it all to a young man named Giovanni Pomarelli, who was born in the small northern Italian village of Limone sur Garda in 1780. Although he didn't know it, he was born with a genetic mutation that proved highly beneficial.

Two centuries later, a team led by Dr. Cesare Sirtori of the University of Milan discovered that about 40 residents of Limone had unusually low levels of HDL but were nonetheless exceptionally healthy. Even though they ate poor diets and most of them smoked, their arteries were largely free of cholesterol deposits. Their one common ancestor was Pomarelli.

Sirtori found that they carried a mutant gene that served as the blueprint for a protein called apolipoprotein A-1, or ApoA-1, a key component of HDL. Those with this mutant form, called ApoA-1 Milano, have HDL that is apparently unusually aggressive at removing LDL from the circulation. In essence, the mutant HDL seemed to protect its bearer from heart disease.

This speculation was confirmed during the 1990s in an elegant set of animal experiments by Dr. P.K. Shah of the Cedars-Sinai Medical Center in Los Angeles. Shah found that infusions of a synthetically produced ApoA-1 Milano in a complex with phospholipids could block the buildup of plaque in the arteries of mice and rabbits with high cholesterol and could even repair damage that had already been done, actually causing plaque to shrink.

The mutant HDL also changed the composition of the remaining plaque, removing triglycerides and inflammatory cytokines, thereby making the plaque more stable and less likely to fragment.

Nissen and his colleagues decided to test this approach in humans, even though they were skeptical that it would work.

"It seemed improbable, but it appeared the drug had the potential to cull plaque out of arteries in weeks, not years," he said. "We thought it was a long shot, not even a 1-in-10,000 chance, but it did work. We were rather pleased, but very surprised."

They enrolled 57 patients with acute coronary syndrome, all of whom suffered chest pains, had high levels of cholesterol and suffered partial artery blockages that were not yet severe enough to require angioplasty or bypasses; 47 completed the study.

Thirty-six of the patients received weekly infusions of the synthetic mutant HDL - produced by Esperion Therapeutics Inc. of Ann Arbor, Mich. - for five weeks and 11 received a placebo. The size of their atherosclerotic plaques was measured before and after the treatment using an ultrasound probe that fit inside the artery.

They reported that the volume of plaque was reduced by an average of 4.2 percent in those receiving the treatment, while the volume increased slightly in those receiving the placebo. Although that seems a small decrease, it is actually much larger than that achieved with any other technique, Nissen said.

With the statin drugs, "reversal of plaque is rare and, even when it occurs, it takes many months to years to see regression," Shah said. The new results "provide proof of the concept that HDL-based therapy has the potential to rapidly and favorably change human atherosclerotic plaques."

Nissen said the speed with which results were observed "tells us something very important about the biology of heart disease: that it is a dynamic process that can be reversed rapidly."

Researchers already knew that lowering LDL was an important way of fighting heart disease.

"Now we know that raising HDL is a really important therapeutic target," Nissen said. "If we can find a way to both lower LDL and raise HDL, we have a real chance to make a huge impact on millions of patients with coronary heart disease."

The next step is a much larger trial to determine whether the therapy reduces the incidence of heart attacks and strokes. Nissen and others have begun planning such a trial, but it is not clear who will pay for it, he said.

Now that his group has proved that HDL manipulation can be clinically useful, Nissen said, "There is going to be a frenzy of activity to understand what happened, why it worked, and how we can do this for the most patients at the least cost."

The Los Angeles Times is a Tribune Publishing newspaper.

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