Chemoprevention of Coronary Atherosclerosis: The Role of Lipid Interventions. A Position Paper of the American Council on Science and Health

John C. LaRosa, MD

In This Article

Abstract and Introduction

Atherosclerosis is not an inexorable part of aging. Addressing unhealthy lifestyle behaviors will go a long way toward reducing the current burden of atherosclerosis without widespread drug therapy. The question is whether this is possible, given the demand of our modern culture. It is not yet clearly established precisely where pharmaceutical lipid lowering or chemoprevention fits in the broader spectrum of prevention and treatment of atherosclerosis and its complications. Anatomic interventions, such as angioplasty or bypass surgery, targeted to obstructing but stable lesions, are likely to be only of limited effectiveness. On the other hand, cholesterol interventions, not only as a long-term means of dealing with atherosclerotic sequelae but as a short-term means of reducing plaque activity and events, are demonstrably effective. Aggressive cholesterol lowering will, moreover, substantially reduce the requirement for angioplasty and bypass procedures. Although more difficult to prove, earlier intervention can almost surely lower the risk of later, potentially lethal, coronary events.

Atherosclerosis is, to a large degree, a preventable disease. There are still populations in the world that, even in old age, show little evidence, either clinically or pathologically, of the disease.[1] The ultimate origins of the epidemic of atherosclerosis in the western world during the 20th century (and in the developing world in the last 20 years) have to do less with changing population genetics than with the increasing prevalence of unhealthy lifestyle behaviors such as smoking and excess dietary intake of animal fat.

Humans are omnivores: we are able to exist on diets composed of calories from both animal and vegetable sources. Our teeth are flat, for grinding, and our are intestines long, suited to digesting high-fiber foods. Our cholesterol is carried predominantly in low-density lipoprotein (LDL). True carnivores, on the other hand, have long, sharp teeth and short intestines. They carry their cholesterol mostly in the high-density lipoprotein (HDL). Atherosclerosis appeared in epidemic proportions in humans when a decline in fatal infectious diseases in childhood, improved sanitation and nutrition, and the development of antibiotics and other pharmaceuticals, plus an increasing availability of low-cost animal fat, allowed humans to survive long enough to develop and exhibit clinical evidence of atherosclerosis.[2]

Atherogenesis, or the production of atherosclerotic plaques, has traditionally been viewed as a process in which circulating lipoproteins deposit cholesterol gradually over a period of years until the deposit (and the resultant cellular reaction) is large enough to create a lesion that blocks blood flow in the lumen of affected arteries. A variation on that theme has been the concept that the lesion need not be large enough to completely block blood flow, but simply large enough to slow flow. Blood clotting then occurs, and a thrombus that obliterates the lumen develops. When this process occurs in a coronary artery, the result is necrosis of myocardial tissue distal to the artery. This, of course, is a myocardial infarction, or "heart attack." If the same process occurs in the cerebral circulation, the result is necrosis of some portion of the brain and a "stroke" (the term "brain attack" has been proposed for this condition). The same process occurring in peripheral arteries, such as those supplying the leg, can result in gangrene of distal anatomic structures such as the toes.

This rather straightforward concept of atherogenesis has been challenged in recent years by evidence that the atheromatous plaque is not simply a passive obstruction, but an active inflammatory lesion whose pathophysiology may result in sudden blockage of luminal space even from lesions (called vulnerable plaques) that are not large enough to compromise blood flow to any significant degree.[3,4]

There are many characteristics that have been epidemiologically associated with the development of atherosclerosis. These are traditionally called "risk factors" and include such conditions as hypertension, hyperlipidemia, smoking, diabetes mellitus, male sex, and age. Other conditions, like obesity, lack of exercise, and family history, may act through those primary risk factors. The new Adult Treatment Panel (ATP) III guidelines incorporate some of these risk factors as quantitative predictors (see below).[5]

Epidemiologic observational data, however, cannot prove a cause-and-effect relationship. That is, such data cannot prove that there is benefit to changing such risk factors. However, the benefits of intervention on some risk factors have been clearly demonstrated in clinical trials. For other risk factors, no such trial data is available. Overall, what has emerged is strong evidence that the level of circulating cholesterol, particularly that carried in LDLs, is of central importance in the development of atherosclerosis.[6] As will be discussed, moreover, lowering LDL cholesterol is of prime importance in preventing or retarding its development.

As a result of those observations, various guidelines have been developed for the management of circulating lipids felt to be central to the process of atherosclerosis. That issue, the prevention of atherosclerosis by pharmaceutical manipulation of circulating lipids -- the chemoprevention of coronary heart disease -- will be the primary subject of this article.


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