Cholesterol: Size Does Matter (2)

Summarized by Robert W. Griffith, MD
December 4, 2003

Introduction

By now, most health-conscious people know about the two main types of cholesterol: low-density lipoprotein (LDL) cholesterol, often called the "bad" cholesterol, and high-density lipoprotein (HDL) cholesterol, termed the "good" cholesterol. While LDL particles tend to stick to the cells lining the blood vessel walls, HDL particles move more freely through the blood vessels, and carry cholesterol away from the arteries back to the liver.

There's a small village in northern Italy, Limone sul Garda, where there are 40 people who have a variation of a naturally occurring lipoprotein, Apo-I Milano. These individuals have very low blood levels of HDL, but (paradoxically) they also have increased longevity, and a lower amount of atherosclerosis than would be expected based on their HDL levels.

Because atherosclerosis was reduced in these people with Apo-I Milano lipoprotein, investigators decided to see if administration of this protein, or something very like it, might delay or reverse atherosclerosis in animals. They prepared a complex of Apo-I Milano with a naturally occurring phospholipid, to mimic the properties of HDL. Studies in mice and rabbits showed a rapid reduction in experimental atherosclerosis as soon as 48 hours after an intravenous infusion of the complex. Clearly, studies in humans were indicated. The first such study is summarized here.

What was done

A double-blind randomized study¹ was done in 57 patients with 'acute coronary syndromes' (e.g. unstable angina, or a heart attack with specific ECG changes). Intravenous ultrasound was used to measure the degree of atherosclerosis, using catheterization of the appropriate coronary artery. This was done before and after the experimental treatment.

Patients were given 5 weekly intravenous infusions of either a placebo, a low dose, or a high dose of the Apo-I Milano complex. The most important measurement made was the change in the percentage volume of atheroma (the deposits of waxy material in the walls of the coronary arteries that occurs in atherosclerosis) after 5 weeks' therapy. Other measures made were changes in the average thickness of the atheroma at its widest part, and the total volume of atheroma in a given length of artery.

What was found

Of the 57 patients in the study, 12 received placebo infusions, 23 received the low- dose, and 22 the high-dose infusions. At the baseline ultrasound exam, the average percentage volume of atheroma ranged from 35% to 40%, and the average maximum thickness from 0.65 mm to 0.82 mm.

After the 5-week experimental treatment, the percentage volume of atheroma had increased a little (0.14%) in the placebo group, and was considerable decreased (-1.06%) in the low- and high-dose treatment groups, when their results were combined. There was no indication that the higher dose was more effective than the low dose infusion in this respect.

The average thickness of atheroma was reduced by 0.042 mm with the treatment, and the average volume of atheroma by 14 cubic mm, compared with virtually no changes in the placebo patients.

Slight nausea was reported by patients from all three treatment groups. One patient in the high-dose group had a reaction that was considered to be possibly due to the therapy - chills, nausea, vomiting, and a mild rash.

What do these findings mean?

This was a very preliminary study of an entirely new approach to the problem of coronary atherosclerosis. That's why it was relatively small, and rather short, without any long-tem follow-up. And it may seem, to the uninitiated, that the changes demonstrated were very small. In fact, however, the findings are quite startling. They were statistically significant, i.e. they could not, with any degree of likelihood, have occurred by chance alone. Although atherosclerosis takes years to develop, significant reversal was demonstrated here with only 5 weekly treatments.

How does this complex produce its effect? The investigators point out that Apo-I Milano differs from other apo-lipoproteins in a way that allows the formation of large HDL particles. And a recent publication, summarized in a companion article on these pages - "Cholesterol: Size Does Matter (1)" - reports how larger HDL particles are linked with less atherosclerosis and increased longevity.

In one of the news interviews given by the investigators, someone spoke of the Apo-I Milano complex as being "like Drano for the arteries". Certainly, anything that can clean out atheroma, and send the cholesterol back to the liver for disposal, is a potentially valuable addition to the medicine chest.

Source

• Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes. SE. Nissen, T. Tsunoda, EM. Tuzcu,  et al., JAMA, 2003, vol. 290, pp. 2292--2300

Footnotes
1. Double-blind means that neither the patient nor the investigating physician knows which experimental treatment the patient receives; randomized means that patients are allocated to receive different experimental treatments (or placebo - dummy treatment) at random i.e. by chance.

Related Links
Cholesterol: Size Does Matter (1)
Disease Digest: Cholesterol, Other Lipids, and Lipoproteins
Artery Wall Thickness and the Risk of MI or Stroke

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