NOVEMBER / DECEMBER 2006

AROUND HARVARD

This article originally appeared in the October 2006 Harvard Heart Letter and is provided courtesy of Harvard Health Publications.

Crystallizing moment
Needle-like crystals of cholesterol could promote, trigger heart attacks.

What sets off a heart attack?

The steps leading up to one have been fairly well worked out: Cholesterol accumulating in patches along artery walls is attacked by white blood cells, eventually creating a gooey fluid covered by a skinlike cap. It often takes decades for these cholesterol-filled plaques to develop, and they can sit snugly in an artery wall for years. But what makes a plaque break open and leak its contents into the bloodstream, causing a clot that can block an artery supplying the heart (starting a heart attack) or brain (starting a stroke)?

No one really knows. It could be a spike of high blood pressure or the surge of chemical messages that accompany anger or stress. It could be the result of white blood cells that have been chewing through the plaque and are finally taking their last bites. Two Michigan State University researchers think that it could also be due to the action of crystallizing cholesterol.

Using experiments reminiscent of those grow-your-own crystal kits that children sometimes play with, Drs. George Abela and Kusai Aziz demonstrated that liquid cholesterol can quickly crystallize and break through tissue similar to the cap that keeps plaque in place. They also found cholesterol crystals in ruptured plaque.

Crystals in plaque
Our arteries contain two basic types of plaque. Fibrotic plaque contains little cholesterol and few white blood cells. Like an old scar, it’s covered with a thick cap of tough tissue. This isn’t the type that usually ruptures. Vulnerable plaque is softer, packed with viscous cholesterol and swarming with white blood cells. It is capped with a thin layer of collagen, the stringy protein found in skin and tendons. Vulnerable plaque doesn’t usually bulge into arteries, meaning it doesn’t necessarily restrict blood flow or register on an angiogram. But vulnerable plaques do burst, usually unpredictably.

Could cholesterol crystals somehow break apart plaque? To explore this possibility, Abela and Aziz melted pure, powdered cholesterol in test tubes and let it cool. As the cholesterol solidified, it expanded, eventually taking up significantly more space than the liquid did. (Water does the same thing when it changes to ice.) The solidifying cholesterol also grew crystals. The electron microscope revealed that the cholesterol crystals took two main forms: sharp, needle-like crystals and flat hexagonal crystals.

Abela and Aziz repeated this experiment, but this time they tied animal membranes that were physically similar to the cap that covers plaque over the tops of the test tubes. As the crystals grew, they “pushed, distorted, and tore the membrane while protruding through it,” the investigators wrote in the January/February 2006 issue of the journal Scanning.

To see if what happens in test tubes could also happen in humans, Abela and Aziz obtained a segment of a left anterior descending coronary artery with a ruptured plaque from an autopsy of a man who had suddenly died of a heart attack. Because alcohol dissolves cholesterol crystals, they used alcohol-free techniques for preparing the tissue for viewing under a microscope. What they saw were cholesterol crystals perforating the torn plaque cap (see figure) and poking into the endothelium, the inner wall of the artery.

Photo from an electron microscope showing cholesterol crystals poking through human plaque.

New directions?
This isn’t the first time that crystals have been implicated in human disease. Cholesterol crystals have been seen in the eye, where they can cause the cornea to cloud up. A more common condition, gout, is caused by painful deposits of sharp crystals of uric acid in joints. Like plaque rupture, gout comes and goes, brought on by stressful events, alcohol or drugs, or another illness. And both gout and plaque rupture are driven by inflammation.

The findings are interesting for several reasons. The ability of supersaturated cholesterol to crystallize quickly in response to changes in pressure, temperature, stress, or chemical signals could explain how a plaque suddenly ruptures. In addition, “cholesterol crystals that poke into the endothelium could account for some of the inflammation that drives atherosclerosis,” says Dr. Abela, the chief of cardiovascular medicine at Michigan State. The fact that alcohol dissolves cholesterol crystals could also account for the link between moderate alcohol drinking and lower risk of heart attack.

This certainly isn’t a stop-the-presses finding with immediate take-home lessons. But it could be one of those quirky results that points the way to strategies for stabilizing plaque or preventing it from breaking open.

Copyright 2006 Harvard Medical International