THE BATTLE AGAINST ATHEROSCLEROSIS

STEVEN VON ELTEN

Heart disease is still mostly a behavioral modification problem

Ischemic heart disease (IHD), caused by an obstructed flow of arterial blood to the heart muscle, is the leading reason for premature death and death rates overall, both of men and women in the United States and in most industrialized countries. After six decades of intensive research and millions of dollars in research funds, we know that IHD is caused by atherosclerosis, or the depositing of fatty material and an increase of fibrous tissue in the inner layers of the arteries.

The history of ischemic heart disease research has yielded many treatments with effective, but spotty, results. All have failed to lower significantly the risks associated with the disease in a larger, more universal group. Only now do we seem poised to unravel the true causes of atherosclerosis and the complexity of relationships involved in the development of heart disease. Current medical technology, coupled with substantial patient behavior modification, can allow primary care physicians to begin tackling atherosclerosis and making significant inroads into arresting the progression of IHD.

UNRAVELING THE MYSTERY

Five decades ago, heart disease was rampant in the US population and was closely linked to high rates of premature death. Death rates from IHD rose until 1960, peaking in 1963. Large-scale, longterm population-based studies were initiated in Framingham, Massachusetts, and Tecumseh, Michigan. These studies began to yield significant data on the causes of IHD. Once these early works implicated high serum cholesterol as a contributing factor in the origins and development of atherosclerosis, the chase was on to define and classify lipid disorders with more precision, unravel the causes of these disorders, and isolate and identify other risk factors. Ultimately, these studies led to therapeutic options to thwart the numberone cause of mortality in our society.

In the 1960s, researchers were able to classify lipid disorders. A 1960 study of seven industrialized nations further identified cholesterol levels and saturated fat intake as risk factors for IHD. Initially, scientific studies in the 1980s focused on manipulating cholesterol intake through diet and/or medicinal therapies to achieve a significant decrease in blood cholesterol levels. The American public was encouraged to “eat leaner” and shift to a more carbohydrate-based caloric intake, in the hope of lowering saturated fat intake. Unfortunately, the US population and food service providers were simultaneously “supersizing” the portions marketed and consumed by the public. The increased calories, coupled with decreasing exercise, or energy expenditure, led to higher body mass and fat reserves in the overall population, and particularly for the average adult. We became a health-conscious nation of obesity.

Other studies throughout the 1980s focused on additional risks associated with an unhealthy diet. A 1986 trial looked at the overall health of 356,222 Americans and found a strong relationship between elevated blood cholesterol levels, death, and coronary heart disease. The risk rose for serum cholesterol at levels greater than 180 milligrams/deciliter (mgm/dl), accelerated at levels above 200 mgm/dl, doubled at 220 mgm/dl, and tripled for levels of 245 mgm/dl. A National Institutes of Health investigation concentrating on lowering dietary fat showed that a corrected diet reduced cholesterol by 11-12 percent. These studies revealed a relationship between the percentage decrease in total cholesterol and the corresponding percentage decrease in coronary heart disease rates. Thus, a 1 percent decrease in total cholesterol led to a 2 percent decrease in the appearances of heart attacks.

Therapeutic trials followed with the drug therapies of the day. Cholestyramine (a bile acid resin binder) trials showed that the drug was able to decrease total cholesterol and low density lipoprotein, or what we refer to more familiarly as LDL cholesterol, by 10-20 percent. These treatments decreased coronary heart disease among trial participants by 20 percent. The Coronary Drug Project revealed additional success with both clofibrate, which lowers triglycerides and raises high density lipoprotein (HDL), and nicotinic acid,which inhibits the production of very low density lipoprotein (VLDL) and, subsequently, LDL, and also raises HDL. These two drugs decreased coronary heart disease by 9.5 percent and 19.8 percent, respectively. In the 1987 Helsinki Heart Study, gemofibrozil increased HDL an average of 11 percent and reduced the appearance of new coronary disease occurrences by approximately 34 percent.

THE NEW CHOLESTEROL-BUSTERS

While these studies were being conducted, drug manufacturers were racing to create new pharmaceuticals to fight cholesterol and atherosclerosis. Eventually, newer drugs came to the market in the late 1980s with the introduction of a class of drugs called STATINS. This next generation of pharmacological weapons against atherosclerosis has been very successful in lowering LDL and overall cholesterol levels.

To date, US doctors have accumulated 150,000 patient-years of experience with STATIN studies. These studies have broadly demonstrated consistent decreases in mortality, heart attacks, and strokes, as well as a significant decrease in the need for angioplasties and heart bypass surgeries. Like earlier studies, the STATIN studies corroborate the 2 percent decline in heart attacks for every 1 percent decline in total cholesterol.

The early success of STATINS led to a number of studies in the 1990s, starting with secondary prevention trials. In these studies, patients with pre-existing coronary heart disease were given a STATIN drug to lower total and LDL cholesterol. These studies revealed a decrease in coronary heart disease occurrences and a 30-40 percent drop in mortality rate. More recently, preliminary data from The Heart Protection Study revealed that individuals who took the drug simvistatin, regardless of their level of serum cholesterol, received a benefit in risk reduction. Presently, there are five STATIN drugs on the market. All are effective, although they vary in their ability to lower total cholesterol and LDL. To what extent cholesterol should be lowered, and exactly who should be treated, are questions still to be solved by the further studies presently under way.

In an alternative approach to lipid management, a Veterans Affairs study focused on lowering triglycerides and increasing HDL (“good” cholesterol) with the use of gemfibrozil. This approach lowered coronary heart disease by approximately 22 percent. The studies involving HDL manipulations have demonstrated that for every 1 percent increase in HDL, there is a 3 percent decrease in coronary disease rates and mortality.

In another trial, 3,090 patients with previous coronary artery disease were randomly selected to use bezafibrate (a fibrate drug not available in the United States) versus a placebo. Although bezafibrate increased HDL by 18 percent, lowered triglycerides by 21 percent, and decreased LDL by 6 percent, the number of fatal and nonfatal myocardial infarctions, as well as sudden death, were not statistically significantly different. However there was a 40 percent reduction in heart attacks in a subset of patients with high triglycerides (>200 mg/dl), if the HDL increased by more than 5 mg/ml or the triglycerides were reduced by more than 28 percent.

UNDERSTANDING VASCULAR BIOLOGY

Our understanding of vascular biology also has evolved. Previous thinking tended to oversimplify events, such as a heart attack, thereby preventing fully effective treatment. During the 1950s and 1960s, the term “coronary thrombosis” implicated clotting as the principal disease-causing mechanism. By the 1970s, the notion of vascular spasm as the precipitating event had its proponents, and was implicated as the fundamental cause of myocardial infarctions.

Today we view the artery walls as dynamic conduits, capable not only of contracting, but also of dilating in reaction to various stimuli. We recognize that the innermost single cell layer, the endothelium, controls vascular integrity and regulates the vascular tone through a number of chemicals, the most notable being nitric oxide. Healthy arteries produce nitric oxide, enabling them to dilate in the presence of a noxious or adverse stimulus, such as ischemia, or the localized obstruction of oxygenated blood flow. This mechanism allows the arteries to compensate for the loss of oxygenated blood.

We now look at endothelial function-dysfunction not only in terms of constricting and dilating, but also in terms of allowing LDL (or “bad”) cholesterol to be deposited in the wall, and further allowing the migration of cellular components (monocytes) to enter and infiltrate the innermost lining and ingest or absorb the lipid. The process is probably an attempt by the artery to heal itself. Unfortunately, these monocytes transform into macrophages (which normally function to help protect the body from infection or harmful substances), ingest the deposited lipid, become overstuffed with oxidized LDL, and initiate the process of plaque formation.

Another consequence of a dysfunctional endothelium is the secretion of “adhesion” molecules, a series of molecules that allow cells from the bloodstream to bind to the endothelial lining of the arteries. These chemicals not only allow the monocytes to bind to the endothelium, but also attract them. Other chemicals stimulate the normally smooth muscle cells of the middle arterial wall to migrate up to the surface of the developing plaque to form a fibrous cap.

We now recognize that plaque formation can progress through vastly different mechanisms. Plaque deposits can increase and choke off an artery slowly over decades, or the plaque can become “unstable,” splitting or caving in to expose membranes and chemicals in the endothelium just below the surface. This process can initiate clotting that may suddenly obstruct arterial blood flow, causing a heart attack if the artery is totally blocked. Painful angina results if the blood flow is only partially blocked.

Among middle-aged men who have heart attacks, 75 percent have attacks caused by this mechanism of “plaque instability.” More importantly, the plaques that are most prone to rupture typically range from 30-50 percent of the size of the open conduit of an artery. Plaques of this dimension are difficult to detect by EKGs, stress tests, or other routine diagnostic procedures since the blockages do not significantly compromise arterial flow. Thus a patient could have a negative stress test one day, and succumb to a myocardial infarction the next.

Until recently, it was always conceptualized that as plaques grow in the wall they would always indent the lumen, the blood’s pathway through the artery. To complicate the diagnostic dilemma even more, smaller plaques frequently grow outside of the arterial lumen. These unstable plaques are often difficult to visualize diagnostically by cardiac catheterization and other tools. As the plaque grows, the artery compensates by “remodeling” and the plaque ends up forming on the outside of the artery until the plaque reaches a lumen diameter of some 40-50 percent. Plaques larger than this will encroach into the lumen. Plaques protruding into the lumen will be more likely to cause symptoms of angina by obstructing flow. These larger plaques then can be visualized during cardiac caths (coronary angiography).

THE NEXT PIECE OF THE PUZZLE

Recent studies suggest that there may be another force at work in the development of atherosclerosis. We now believe that inflammation often accompanies atherosclerosis. For years, it has been recognized that a serum marker for inflammation (C reactive protein) can be elevated in patients with myocardial infarctions. Over the last decade, a number of molecular compounds have been associated as markers of inflammation and indicators of atherosclerosis. Researchers have identified hsCRP (highly sensitive C reactive protein) as the most sensitive marker for detecting low-grade, silent, or asymptomatic inflammation. HsCRP and other markers are independent of cholesterol and lipids in predicting risk, and are sensitive and valid in also determining who is at risk for heart disease. Unfortunately, neither markers of inflammation nor lipid abnormalities are specific and solely reliable in defining an individual’s actual risk. Merely having an elevated level of either (or both) does not necessarily confer a high degree of probability in developing abnormal arterial walls.

Certainly, possessing an increasing number of risk factors does increase an individual’s risk. But like cholesterol tests, hsCRP evaluations have limitations. Because of its variability from individual to individual, this protein is more useful in large, population-based studies, where small differences in averages become apparent. Recognizing that atherosclerosis is an inflammatory process has been a great advancement in our knowledge of this process, although we have yet to capitalize on this recognition and develop therapies to alter directly the inflammatory process. It does appear that aspirin, in its current therapeutic dosing recommendation, also provides an anti-inflammatory mechanism. Many doctors already suggest a daily dose of aspirin to help inhibit blood clots. STATIN drugs, interestingly, also reduce inflammation and hsCRP, reducing coronary events through another mechanism separate from cholesterol and LDL reduction.

While a more precise understanding of the arterial system creates more opportunities for better treatment, the effectiveness of these tools increases considerably when complemented by more accurate measurements of cholesterol and the associated lipoproteins. During the past three decades, medical researchers have made critical discoveries about the structures and metabolic functions of cholesterol and lipids. We can now routinely quantify an individual’s “good” and “bad” cholesterol, and use these findings to make specific diagnoses and recommend specific treatments. We have identified lipoprotein (a) or [Lp (a)] as a particularly nasty subset of LDL, the “bad” cholesterol. Not only does this compound produce degenerative changes in arterial walls, it also tends to cause the blood to clot more quickly.

Recent research has led to the identification and subsequent measurements of various subfractions of LDL and HDL through the use of new technologies, including gradient gel electrophoresis, ultracentrifugation, and nuclear magnetic resonance. Although we have demonstrated certain subtypes of LDL or HDL are better or worse to have, the next task will be to conduct studies involving the therapeutic manipulation of these subfractions, and then measure the outcomes in terms of coronary heart disease occurrence rates. Such studies will be necessary to develop more effective treatments based on these superior research refinements.

TYING IT ALL TOGETHER

As our knowledge of the relationship between lipids and atherosclerosis has progressed, so has our understanding of other risk factors, such as hypertension, cigarette smoking, diabetes, increasing age, family history of coronary heart diseases, lack of exercise, and elevated serum levels of an amino acid called homocysteine. Hypertension has received increasing attention, and blood pressure levels previously considered borderline are now recognized to confer additional risk. Similarly, our research on blood sugar levels now makes it clear that it is not only the diabetic with fasting blood sugars over 126 who is at greater risk of developing coronary heart disease. We now know that those in the borderline group (those with fasting blood-sugar levels of 110-126) are considered to be at two times the risk of developing heart disease. And “high-normal” individuals (those with fasting blood-sugar levels of 100-110) are now thought to be at one and one-half the average risk.

So, what have we done with this vast wealth of knowledge? In all likelihood, approximately 75 percent of the readers of COSMOS 2002-2003 have cholesterol levels over 180, and have an increased risk of coronary heart disease. Fifty percent of us eventually will succumb to this disease process. But 25 percent of all myocardial infarctions occur in individuals with serum cholesterol levels in the desirable range of less than 180.

There are some partial victories in the war against heart disease, however. The incidence of ischemic heart disease decreased 57 percent from 1963-1990 and continues to fall slowly. The reasons are numerous and varied: a decrease in cigarette smoking in middle age; a decrease in consumption of animal fat and cholesterol; improved control of hypertension; and improved treatment of IHD, both medically and surgically (through angioplasty and cardiac bypass surgery).

The biggest challenge for all of us, however, is making the necessary changes in our diets and lifestyles. In 1995, primary care physicians and cardiologists achieved success only 18-19 percent of the time in terms of lowering LDL-cholesterol levels of their patients with coronary heart disease consistent with the recommended US guidelines issued in 1993. Recently, this statistic has increased, somewhat encouragingly, but by most standards the rate remains well below 50 percent.

For all the immense effort by legions of researchers, the mountains of resulting published data, countless journal articles, and incredible financial investiture, our greatest challenge is to encourage patients to “buy in” to proven dietary, medicinal, and exercise therapies. Sadly, relatively few funds have been earmarked for studies on increased patient acceptance and compliance with medicines, let alone towards encouraging proper diet and exercise. We must invest not only in finding ways to encourage patient compliance, but also look at ways to motivate, educate, and instruct physicians to accomplish this task.

Although the theoretical gross concepts of atherosclerosis, as debated during the past five decades, have evolved into the vast field of “lipidology” and vascular biology, the real challenges ahead may lie in changing human behavior in terms of good health habits with a view to the rapidly increasing longevity, not only of Americans, but of populations in much of the world. The bumper sticker that self-admonishes “IF I KNEW I WOULD LIVE THIS LONG, I WOULD HAVE TAKEN BETTER CARE OF MYSELF!” should strike a more serious chord in each of us.

Steven von Elten (CC ’01) has been a family physician in Warrenton, Virginia, for 20 years. Board certified in both family practice and emergency medicine, Dr. von Elten is also certified in geriatric medicine.

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