By David N. Leff

Arthritis, heart disease and cerebral stroke are all known to afflict the elderly - people past their prime of life. But think again.

Over the past half-century, deaths from heart disease have gone down in the U.S. But among young people they've gone up. From 1989 to 1996, sudden cardiac deaths among 15- to 34-year-olds rose by 10 percent. Adding to this trend are cigarette smoking and juvenile obesity, fueled by high-cholesterol foods and couch-potato cum dot-com levels of exercise.

So these risk factors for atherosclerosis - hardening of the arteries - turn out to be no respecters of age. However, pediatricians and family physicians tend to ignore this threat to their young and young-adult patients. But increasingly, doctors are counseling their middle-aged and older patients to swallow one "baby aspirin" - 81 milligrams - daily, to ward off heart and brain ischemia caused by atherosclerosis-blocked arteries.

"If you had previously had a heart attack or stroke," observed cardiovascular disease specialist Garret FitzGerald, who chairs the department of pharmacology at the University of Pennsylvania in Philadelphia, "and if you take aspirin to prevent an acute event - in other words, a second heart attack or stroke - many substantial controlled clinical trials have shown that the risk is reduced by about a quarter.

"What is still unestablished," FitzGerald continued, "is the risk/benefit ratio of people taking aspirin who have never had an event. So if you're looking at the benefit of aspirin preventing the first event, the answer from the four controlled trials that have been done so far is that there is a smaller but very significant benefit.

"On the other hand," he added, "the number of such events prevented in that population are almost effectively balanced by the number of upper gastrointestinal bleeds caused by aspirin. So as far as the acute events are concerned, it remains very controversial as to whether physicians should recommend to people, say on the basis of family history or other risk factors, to take aspirin to prevent heart attacks.

"What we're looking at here is a different scenario," FitzGerald said. "We're looking at the underlying progress of the disease, and that has never been evaluated in a controlled fashion for aspirin or any nonsteroidal drug."

High-Cholesterol Knockout Mice Take Over

FitzGerald has just broken this negative record in a research paper of which he is senior author. Published in the current Proceedings of the National Academy of Sciences (PNAS) dated March 13, 2001, it bears the title: "Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice."

"This study," FitzGerald told BioWorld Today, "suggests that a product of the cyclooxegenase enzyme known as COX-1 - the form targeted by aspirin in prevention of heart attacks - may also have a part to play in the gradual hardening of the arteries that precedes heart attack or stroke. It also demonstrates," he went on, "that a separate class of drugs that specifically target the COX-2 enzyme - the so-called anti-arthritis 'super aspirins' such as Pfizer's Celebrex and Merck's Vioxx - do not speed up the development of atherosclerosis.

"A couple of years ago," FitzGerald recalled, "we had shown that selective COX-2 inhibitors depressed the formation of a prostaglandin called prostacyclin [PC] that had properties suggestive of atherosclerosis protection. And we know that COX-2 is inducted by regular shearing of cells in blood vessels, but is not induced by the types of turbulent shear forces that occur in the vasculature at sites where atherosclerosis develops. And where flow is disturbed," he pointed out, "is where atherosclerosis begins, so the question is whether a relative lack of COX-2-dependent prostacyclin formation is relevant to the lack of atherosclerosis protection at those sites.

"The thing that sharpened our interest," he recounted, "is that we had made knockout mice that lacked the receptor for prostacyclin. When we crossed them into atherosclerotic mice we found that the absence of both copies of the PC receptor accelerated the progress of the underlying disease. So it became imperative for us to determine if the incomplete but substantial suppression of the PC formation that occurs with selective COX-2 inhibitors might accelerate the disease. And that would have particular relevance to juvenile patients with arthritis who might take these drugs for an extended period, while consuming a typical Western American diet.

"Platelets," FitzGerald explained, "are circulating cells in the body that when activated become very sticky. And sticking together they form a substrate for the assembly of proteins that constitute a blood clot. So the first step in forming a clot that blocks your artery is the activation of platelets. Suppression of the platelet COX-1 product, thromboxane, is how aspirin protects against heart attack and stroke.

"COX-1 is thought to be the enzyme that makes prostaglandins for housekeeping functions," FitzGerald explained. "It plays an important role in terms of hemostasis - the ability to stop bleeding when you cut yourself; also in protecting the lining of your gut from GI insults, and other things."

Clinical Messages Bespeak Reassurance

FitzGerald suggests, "The bottom line in terms of the clinical extrapolation from this work is that on the one hand it's reassuring in terms of the prospects of long-term consumption of COX-2 inhibitors by individuals - particularly juvenile arthritis consumers - that there's no evidence for an enhanced acceleration of underlying vascular disease.

"And the second clinical message," he went on, "is that when you assemble the results in this PNAS paper with other studies of thromboxane antagonists, it points the finger to it really being timely to evaluate in a controlled fashion, the effects of aspirin or aspirin-like drugs that are deep TX antagonists on the progress of atherosclerosis in humans. These drugs are all in humans, and could be evaluated by modern imaging methods, such as electron-beam computer tomography, which can give some quantitative impression of the disease progress. Such scanning images the presence of calcium in the plaque, which is extraordinarily widespread in Western populations.

"We're working with other animal models," FitzGerald concluded, "looking at structurally distinct inhibitors, such as those for COX-2, to see if we can get more bang for our buck." n