Arthritis, heart disease and cerebral stroke all are 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%. Adding to this trend are cigarette smoking and juvenile obesity, fueled by high-cholesterol foods and couch-potato/computer-addict levels of exercise.
So these risk factors for atherosclerosis turn out to be no respecters of age. While pediatricians and family physicians tend to ignore this threat to their young and young adult patients, doctors increasingly 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," said cardiovascular disease specialist Garret FitzGerald, who chairs the department of pharmacology at the University of Pennsylvania (Philadelphia, Pennsylvania), "and if you take aspirin to prevent 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 said, "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."
FitzGerald noted, "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." Now it has. In a research paper of which he was senior author, published in the March 13 issue of the Proceedings of the National Academy of Sciences (PNAS), Fitzgerald reported on a study "that 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 said, "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."
He said that his research group had shown a couple of years ago 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." Where flow is disturbed, FitzGerald said, "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."
He noted, "When we crossed knockout mice that lacked the receptor for prostacyclin 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." That, he said, 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.
The first step in forming a clot that blocks your artery, FitzGerald said, 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 – it plays an important role in terms of hemostasis," he noted.
"The bottom line in terms of the clinical extrapolation from this work," FitzGerald said, "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 added, "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 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."