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Editor’s Note: This piece was originally published in our May 2002 issue. We are posting it because of news from the JUPITER trial.
AS RECENTLY AS FIVE YEARS AGO, most physicians would have confidently described atherosclerosis as a straight plumbing problem: Fat-laden gunk gradually builds up on the surface of passive artery walls. If a deposit (plaque) grows large enough, it eventually closes off an affected “pipe,” preventing blood from reaching its intended tissue. After a while the blood-starved tissue dies. When a part of the cardiac muscle or the brain succumbs, a heart attack or stroke occurs.
Few believe that tidy explanation anymore. Investigations begun more than 20 years ago have now demonstrated that arteries bear little resemblance to inanimate pipes. They contain living cells that communicate constantly with one another and their environment. These cells participate in the development and growth of atherosclerotic deposits, which arise in, not on, vessel walls. Further, relatively few of the deposits expand so much that they shrink the bloodstream to a pinpoint. Most heart attacks and many strokes stem instead from less obtrusive plaques that rupture suddenly, triggering the emergence of a blood clot, or thrombus, that blocks blood flow.
The research has, moreover, established a key role for inflammation in atherosclerosis. This process—the same one that causes infected cuts to become red, swollen, hot and painful—underlies all phases of the disorder, from the creation of plaques to their growth and rupture. When microbial invaders threaten to hurt us, inflammation (literally meaning “on fire”) helps to ward off infection. In the case of atherosclerosis, though, the inflammation proves harmful. In other words, our own defenses bombard us with friendly fire, just as happens in more famously inflammatory conditions, such as rheumatoid arthritis.
This revised conception suggests new ideas for detecting and treating atherosclerosis. It also resolves some disturbing mysteries—notably, why many heart attacks strike without warning and why certain therapies meant to avert heart attacks frequently fail. Society sorely needs advances in prevention, detection and therapy of atherosclerosis. Contrary to public perception, the heart attacks and strokes that result from this condition exceed cancer as a cause of death in industrial nations and are growing more prevalent in developing countries as well.
LACKING TOOLS to describe interactions among cells and molecules, the ancients who first defined inflammation had to focus on what they could see and feel. Today we know that the outward signs reflect a pitched struggle playing out on a microscopic battlefield. After sensing (rightly or wrongly) that a microbial attack has begun, certain white blood cells— the immune system’s frontline warriors— convene in the apparently threatened tissue. There they secrete an array of chemicals intended to limit any infection. These chemicals include oxidants (able to damage invaders) and signaling molecules, such as small proteins called cytokines, that orchestrate the activities of defensive cells. Researchers therefore document an inflammatory response by identifying inflammatory cells or mediators of their activities in a tissue.
The clearest picture of inflammation’s role in the onset of atherosclerosis comes from investigations into low-density lipoprotein, a.k.a. bad cholesterol. LDL particles, composed of fatty molecules (lipids) and protein, transport cholesterol (another lipid) from their source in the liver and intestines to other organs. Scientists have long known that although the body needs LDL and cholesterol, excessive amounts promote atherosclerosis. Until recently, however, no one could explain how a surplus leads to plaque formation.