"Almost everybody in the industrialized world has a legion of atherosclerotic plaques in their arteries,” says Dr. Ira Tabas, Vice-President of Research at Columbia University’s Department of Medicine. This isn’t as bad as it sounds. In fact, for mystery lovers, it’s the start of a puzzle as exciting as Sherlock Holmes’ deductions from the fact that a dog did not bark. If everybody has these plaques in such quantities, why don’t we all suffer heart disease as a result? “Only a few of the plaques are dangerous,” Dr. Tabas explains. “Most are asymptomatic. It’s those that progress to become what we call vulnerable plaques that cause problems.” While the majority of plaques remain safely attached to the arterial walls, vulnerable plaques may rupture or erode, letting materials loose in the bloodstream that can clog up vessels. Heart attack, stroke, and angina can be the result. From this perspective, the challenge is not so much to try to prevent atherosclerotic plaques, but rather to stop them from progressing to the dangerous vulnerable stage. This is Dr. Tabas’s goal, and recent discoveries in his lab make it seem closer than ever before. Dr. Tabas’s research focuses on two of the most important factors in the formation of vulnerable plaques: necrosis, or cell death, and inflammation. “The cells that die are white blood cells that normally fight infections, but here they’re getting involved in the plaques,” he says.

A Different Kind of ER
Further investigation implicated signaling pathways within the endoplasmic reticulum, or ER, of the white blood cells. However, knowing this wasn’t enough to start the search for a treatment. “One wouldn’t want to block ER signaling altogether, because it usually has beneficial effects,” Dr. Tabas says. “Normally, these pathways help build new proteins, or help repair cells in which there is a problem with protein construction.”
The key insight was that unusual amounts of cholesterol were present in the white blood cells that were involved in vulnerable plaque formation. Following up on this clue led to a vital discovery.