Drano for the Heart
	An experimental drug no one expected to work is surprisingly effective at rooting out cholesterol By Michael D. Lemonick

Nov. 17, 2003
When they signed up for this week's annual conference of the American Heart Association in Orlando, Fla., thousands of doctors, scientists and pharmaceutical-company reps knew that they would be hearing about the very latest research into the causes of heart disease and the potential treatments. What they probably didn't suspect was that the meeting rooms and hallways would be abuzz with news that broke before the gathering even began — news that may signal an entirely new approach to fighting the nation's leading cause of death.

By infusing patients with an experimental drug, reported Dr. Steven Nissen of the Cleveland Clinic in last week's Journal of the American Medical Association, he and his colleagues reduced the fatty arterial plaque that triggers most heart attacks by an average of 4.2% — about 10 times better than statins, the most effective drugs now on the market, and in the almost unbelievably short period of just five weeks. With only 47 patients, the study was too small to be definitive, but, says Dr. Daniel Rader, the University of Pennsylvania cardiologist who wrote an accompanying editorial in J.A.M.A., "it's very exciting for the field. It's something that I think no one expected. It really has everyone scratching their heads."

The story begins in 1974, when doctors discovered that a man named Valerio Dagnoli, from the northern Italian town of Limone sul Garda, had vanishingly low levels of HDL, the so-called good cholesterol, which keeps arteries from accumulating brittle plaque that can break off and choke blood flow. Surprisingly, though, Dagnoli had no heart disease. Neither did the 40 or so other townspeople researchers turned up who had minimal HDL.

Further study revealed that their HDL was of a rare type, later named ApoA-1 Milano, that is evidently much more protective than ordinary HDL. In the 1990s Dr. P.K. Shah of Cedars-Sinai Medical Center in Los Angeles injected a synthetic version of this variant HDL into rabbits and mice. He showed that ApoA-1 Milano could not only reverse plaque buildup but also stabilize and reduce inflammation of what was left.

ApoA-1 Milano eventually became the property of Esperion Therapeutics, in Ann Arbor, Mich., which persuaded Nissen to conduct the studies that led to last week's report. If the results hold up in larger trials, they could be revolutionary. Statin drugs, which lower the bad LDL cholesterol that causes plaque in the first place, reduce the risk of dying from heart disease only 30% or so. By targeting HDL as well, the risk might be halved. Says Nissen: "We're starting to talk about really limiting what this disease can do."

The study also suggests that coronary-artery disease is much more dynamic than anyone had thought. "For a long time we saw coronary atherosclerosis as a chronic, progressive disease that just kind of marches along," says Nissen. "Maybe you slow it down, but you don't really change it very much." However, if you can reduce plaque buildup significantly in just a few weeks, he says, "that's a big shift in thinking."

Nevertheless, there's plenty of work ahead before ApoA-1 Milano is certified as an effective treatment for heart disease. For one thing, says Rader, it may be logical to assume that reducing plaque always lowers the risk of heart disease, but "we have no proof of that. That's a big assumption." Besides, he says, "we really have no idea how ApoA-1 Milano did what it did." The prevailing theory is that it works by what he calls the "dump truck" mechanism, binding to cholesterol molecules in plaque and carting them off to the liver, but that's also unproved. "In medicine, whenever you really don't understand a mechanism, you always have to be a little uncertain about what it's really going to mean."

Even if ApoA-1 Milano turns out to be too good to be true, it's just the opening salvo in an entirely new strategy for fighting heart disease. After two decades of focusing on lowering LDL, doctors are now looking hard at raising HDL. Predicts Nissen: "Every pharmaceutical company and a lot of academic researchers and the NIH are going to work on ways to do this."

Reported by Sora Song/New York

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