Potential Heart Disease Breakthrough

An amazing new treatment promises to unclog arteries — even in people with advanced heart disease.

An amazing new treatment promises to unclog arteries — even in people with advanced heart disease. It’s called ApoA-I Milano. The original molecule was found in the blood of an Italian family with unusually healthy arteries — despite high levels of fats in their blood and low levels of protective “good” HDL cholesterol. Now a genetically engineered version of this “good” HDL cholesterol protein has been tested in a small human trial. The results — published in the Nov. 5 issue of the Journal of the American Medical Association –astounded even the doctors who performed the trial. Steven E. Nissen, MD, medical director of The Cleveland Clinic’s cardiovascular coordinating center, gave five weekly injections of ApoA-1 Milano to patients with acute heart disease caused by plaque-clogged arteries. “We really didn’t think it was going to work,” Nissen tells WebMD. “Nobody was more shocked than I was when the statisticians handed me the data. … It is unprecedented. Nobody has ever seen this kind of plaque regression. It really is an epiphany.” Surprise — and Vindication The findings exceed even the most optimistic expectations, says Daniel J. Rader, MD, director of preventive cardiology at the University of Pennsylvania School of Medicine in Philadelphia. Rader’s editorial comment on the Nissen study appears in the same issue of JAMA. “This is, frankly, very surprising. I haven’t talked to a single person in the field who isn’t surprised,” Rader tells WebMD. “And the speed with which the change occurred is remarkable. Nobody ever expected you could impact plaque in that short a time. This opens door to treating atherosclerosis in a more acute way to try to stabilize and regress plaque in patients with acute heart disease. This paper suggests it’s no longer theory but reality.” But one person isn’t surprised. That’s Prediman K. (PK) Shah, MD, director the atherosclerosis research center at Cedars-Sinai Medical Center, Los Angeles, and professor of medicine at UCLA. Shah has been studying ApoA-I Milano for nine years. He’s the first major researcher to argue in favor of the once-laughed-at theory behind the new treatment. His animal studies led directly to the new treatment, dubbed ETC-216 by Esperion Therapeutics Inc., Ann Arbor, Mich. Shah serves as a consultant to the company. “We’ve seen this in animal studies over the last eight years: Plaque regression in five weeks, with positive changes in 48 hours,” Shah says. “For us, it was not a surprise. The unprecedented nature of the human study is the rapid plaque regression in just five weeks. It’s never been seen before.” How It Works Everybody has heard that there are two kinds of cholesterol. There’s the “bad” LDL cholesterol, which clogs the walls of your arteries when there’s too much of it. And there’s the “good” HDL cholesterol, which removes excess cholesterol from the body and takes it to the liver for elimination. Both LDL and HDL are packages in which cholesterol is linked to a molecule called apolipoprotein or Apo. HDL particles carry a form of Apo called ApoAI. It’s the key to cholesterol removal. In 1979, an Italian man from the picturesque little town of Limone sul Garda, near Milan, got a medical check-up. His blood was full of fats, but had very low levels of HDL. His arteries should have been choked with plaque — but instead, they were perfectly healthy. Further investigation showed that he, and some 40 relatives, had a mutant form of ApoAI — ApoAI Milano. These people had little heart disease and tended to live long lives. Further study showed that the Milano version of ApoAI has a special chemical property that seems to help it bind cholesterol in plaque very quickly. Esperion’s ETC-216 is a genetically engineered version of ApoAI Milano. “Would normal ApoAI do the same things as Milano? There has never been a comparison,” Shah says. “However, several years ago we studied a form of the normal ApoAI and compared it with Milano. Milano was twice as effective in a rabbit model of atherosclerosis. Unfortunately, we couldn’t guarantee the purity of the normal ApoAI, so this question remains unproven.” Rader says that the normal form of ApoAI reduces plaque in animals. “This is intriguing, because plaque reduction may not be a unique property of the Milano version of ApoAI,” he says. “It may be that the garden-variety Apo would have been just as effective in the Nissen study.” One Study Deserves Another The Nissen study shows that ApoAI Milano shrinks plaque deposits in humans. But it’s a small study. Only 55 patients got the drug, and only 36 completed the study. Moreover, Nissen’s study didn’t look at whether the patients’ health got better. It only used a sophisticated imaging device — intravascular ultrasound or IVUS — to measure plaque reduction. “We have absolutely no idea whether changes in IVUS make a difference in heart attack risk,” Rader warns. “If we see plaque change in people, we like to think they have less heart attack risk. But until we see clinical changes, we really don’t know what it means.” Another issue is the degree of change seen in patients’ plaque. In five weeks, patients treated with ApoAI Milano had about a 4% decrease in plaque volume. That’s 10 times greater reduction than ever seen before — but in the grand scheme of things, 4% isn’t a huge number. However, this 4% reduction came in only five weeks. “On an absolute basis, 4% reduction in plaque volume is small. If it happened over four years, you’d wonder what this means,” Rader says. “But I saw a patient this morning who happens to be a cardiologist. I told him about the study and the first thing he said is, ‘Wow, 4% in five weeks! That’s nearly 1% per week!’ I never thought about it that way, but he is right. It is the 4% over five weeks that is the striking part. It impresses because of the rapidity of change.” Obviously, larger clinical trials are needed. Those trials are still in the planning stage, Nissen says. A Change in Thinking The fact that plaque can so quickly be removed from arteries means a sea change in treatment. Now, doctors treating patients with serious heart disease think only about trying to keep arteries from getting more clogged. Now they can think about unclogging them — without a risky operation. The idea is called reverse-cholesterol transport. And ApoAI Milano may be only the tip of the iceberg. Shah is working on a gene therapy that would give patients a version of the ApoAI Milano gene carried by the Italian family. He’s tested it in mice bred to have clogged arteries — and says the animals have 60% to 70% less plaque. Clinical studies may begin in two or three years. “Not very far down the road we are going to use a combination of statins and HDL-raising agents as a means to really dramatically change the outcome for patients with coronary artery disease,” Nissen says. “This study is opening a door to the future that needed to be opened. We will look back at this and say, ‘This is the time we saw what could happen if we really turned on reverse cholesterol transport in patients with acute coronary disease.” ——————————————————————————–SOURCES: Nissen, S.E. Journal of the American Medical Association, Nov. 5, 2003; vol 290: pp 2292-2300. Steven E. Nissen, MD, medical director, cardiovascular coordinating center, The Cleveland Clinic, Ohio. Daniel J. Rader, MD, director, preventive cardiology, University of Pennsylvania School of Medicine, Philadelphia. Prediman K. (PK) Shah, MD, director, division of cardiology and the Atherosclerosis Research Center, Cedars-Sinai Medical Center; professor, University of California School of Medicine, Los Angeles: WebMD Health News: November 2003)