P&S Medical Review: Apr 1995, Vol.2, No.2
Atherosclerotic Cardiovascular Disease: A Major Health Problem Around The World and The Focus of a Major Research and Therapeutic Effort at Columbia

HENRY N. GINSBERG, M.D.
Tilden Weger Beiler Professor of Preventive Medicine
Columbia University College of Physicians and Surgeons, New York, N.Y.

INTRODUCTION

Atherosclerosis and its associated clinical entities, coronary artery (CHD), cerebrovascular, and peripheral vascular disease, is the major cause of death in the United States. Each year approximately one million Americans suffer a myocardial infarction, and almost 500,000 individuals die from CHD. Several hundred thousand coronary artery bypass operations and percutaneous trans-coronary angioplasty procedures are done annually as well. The total cost to the economy of the United States is more than 100 billion dollars each year.

Atherosclerosis is a complex pathologic process that is significantly modulated by both genetic and environmental factors. At one extreme of the spectrum of genetic and environmental modulators are mutations in the gene for the low density lipoprotein (LDL) receptor that characterize the disease familial hypercholesterolemia, which in the homozygous form can lead to myocardial infarction in the first decade of life. At the other end of the spectrum is the increased consumption of dietary saturated fats that characterizes entire populations with high rates of CHD. In between these extremes are numerous genes regulating the apoproteins, lipid-enzymes, and lipoprotein receptors. Also involved are numerous environmental factors which impact those genes: caloric intake, dietary composition, physical activity, and smoking. It is the complex interaction between genetic and environmental factors that produces the heterogeneity in the phenotypic expression of atherosclerosis and makes it difficult to develop simple algorithms for risk evaluation and intervention strategies.

EPIDEMIOLOGY

The twentieth century has seen the near disappearance of several infectious diseases in Western societies and the explosion of chronic diseases, particularly atherosclerosis. The rising incidence of CHD has paralleled increased caloric intake, particularly intake of saturated fats. Natural, sociologic experiments attest to the importance of these factors: during World War II the incidence of CHD fell dramatically in occupied countries.1 In contrast, Japanese men who migrated to Hawaii and then to California and consumed increased quantities of saturated fats were shown to have rising plasma cholesterol levels and suffered more from CHD in comparison to matched controls in Japan.2 In the United States, the switch from a farming to an industrial society, together with a switch from a high carbohydrate to a high fat diet, paralleled our epidemic of CHD in the 1950s, 1960s, and 1970s.3,4

Environmental factors can be amplified by genetic predispositions in both individuals and populations. Individual differences in the effects of obesity, diet and physical activity on the risk profile of individuals is a well known fact. Winston Churchill is an example of an individual who ate a high fat diet, smoked heavily, never exercised, but lived to be more than 90 years of age. However, he is the exception. More important to present-day public health policy are population differences in sensitivity to the Western life-style. Recent and dramatic evidence of population-sensitivity has come from Asia, where the incidence of hypercholesterolemia and diabetes mellitus (the adult or non-insulin dependent type) has risen dramatically during the past decade. These increases have been coincident with the switch from farming to factory-based economies, and an increase in calorie and saturated fat intake. Indeed, CHD has become the major cause of death in several countries where it was rare two decades ago. Mexico, Central America and South America are also experiencing rapid increases in diabetes and hypercholesterolemia, particularly amongst their Indian populations.5 Thus, atherosclerosis has attacked these "virgin" populations with a vengeance, almost certainly because of genetic predispositions that are more prevalent than in European groups. It will be a major challenge in the twenty-first century to reverse the present trends; this can only be done with rationally developed programs designed to maintain traditional diets that are low in fat, and to increase physical activity in the face of increasing industrialization.

PATHOPHYSIOLOGY

Atherosclerosis, particularly coronary artery disease, is a chronic and progressive multi-staged process that culminates in an acute event. There is no doubt that abnormalities in plasma lipids and lipoproteins are major, if not crucial, factors in the development of the atherosclerotic lesion. LDL, as well as very low density lipoproteins (VLDL), and lipoprotein (a), a variant of LDL, have all been found in the atherosclerotic plaque. Recent studies from a number of laboratories have provided a detailed scheme that begins with increased numbers of lipoprotein particles entering the subendothelial space in the vessel wall. This initial step, which appears to depend primarily on elevations in LDL and/or VLDL, is linked to modification of the lipid and protein components of these particles (oxidative modification) which, in turn, stimulates the release of chemotactic and growth factors from endothelial cells. Blood-borne monocytes are attracted to the sites where these modified lipoproteins have accumulated. The monocytes differentiate into macrophages, which then become "foam cells" by engulfing the modified lipoproteins. The foam cells are the hallmark components of the early atherosclerotic lesion. Further stages of lesion development include the proliferation of smooth muscle cells and the laying down of extracellular connective tissue elements. It is this stepwise process, which begins when excessive lipoproteins enter the vessel wall, that is the target of primary and secondary prevention strategies focusing on plasma lipid and lipoprotein concentrations.

All of these processes occur over many years, with the slow accumulation of cells and matrix material and the constant gradual narrowing of the artery lumen. When critical narrowing occurs in the coronary artery, the sign of insufficient blood flow, angina pectoris, is observed during exertion. However, very recent studies suggest that the acute catastrophic event, the myocardial infarction, occurs with subcritical or moderately critical stenosis. In particular, rupture of the atherosclerotic plaque, with release of thrombogenic materials, results in the formation of an intravascular clot. Total occlusion of the vessel follows, and the result is a myocardial infarction. Significant research efforts have been focused on the thrombotic process, leading to therapeutic approaches such as thrombolysis during the acute event, and the use of aspirin in primary and secondary prevention. It cannot be over-stressed that prevention of even subcritical plaque formation would make thrombolytic and antiplatelet regimens unnecessary.

PREVENTION OF CHD

Any discussion of prevention of atherosclerotic cardiovascular disease must include a review of the controversy associated with this strategy. The major controversy focuses on primary prevention, the treatment of healthy individuals who are at higher risk for developing atherosclerotic cardiovascular disease. Primary prevention programs aimed at high risk individuals with hypercholesterolemia have consistently resulted in reduced cardiovascular events, including fatal and non-fatal myocardial infarctions. Clinical trials which have used diet, or diet plus drugs, have produced similar benefits.6,7,8 As cholesterol-lowering agents have become more efficacious, the results of the trials have become more convincing. So why is there controversy?

The controversy arises from the two ways to look at epidemiologic and clinical trial data. If one uses relative risk and relative reductions in events as guidelines, it is easy to see that someone with a high cholesterol level has a "much higher" risk for CHD (several times higher) than someone else with a low cholesterol level. In the same way, one can determine that lowering plasma cholesterol with diet and drugs can reduce that risk of CHD significantly (20-30%). However, if one uses the absolute rates of disease in the population, or the absolute reductions in events during trials, the data are much less impressive. This is because the absolute number of events that occur in a middle aged population over two to seven years (the typical time for most studies or trials) is low. For example, in the Lipid Research Clinic (LRC) Trial, which included hypercholesterolemic men between the ages of 35-55 years, a 10% reduction in serum cholesterol was associated with a 20% reduction in myocardial infarctions. Another view of this study was that 1,800 men were treated with diet and cholestyramine for seven years to prevent about 20 myocardial infarctions. This latter view suggests that it would be "too expensive" to carry out such prevention at a national level; one would have to treat about one hundred men to prevent one myocardial infarction. How does one reconcile this with the fact that myocardial infarctions kill about 500,000 people each year? More importantly, how does one develop safe and cost-effective programs to reduce that number?

One way is to approach prevention by focusing both on large societal groups and on individuals. The population approach includes attempts to reduce the intake of dietary saturated fat and cholesterol, reduce the rising incidence of obesity, increase physical activity, and reduce the use of cigarettes. There can be no argument that strategies to achieve these goals will be safe and cost effective; even if 500 people have to change their diet to prevent one myocardial infarction, there is no "down-side" to dietary therapy. Additionally, these non-pharmacological interventions can be used for a lifetime, making it more likely that group benefit will be achieved, even though each individual's absolute risk is low at the start of the program. These strategies are the foundation of primary prevention. It is unfortunate that many of these prevention strategies have not been central to insurance reimbursement plans, which until recently did not pay for a visit to a nutritionist but did reimburse for the first, second and third angioplasties. It remains to be seen if managed care will put more emphasis on primary prevention of atherosclerosis. Since the long-term basis of economically viable managed care programs is required for the long-term health of participants, preventive medicine should be a high priority. It should be cost-effective for these plans to include risk factor reduction strategies in their programs; this would reduce the subsequent need for stress-thallium tests, angiograms, angioplasties, and coronary artery bypass graft operations. Since these negative and costly procedures will be required much later if only younger participants are recruited into a managed care program, it would also be cost-effective in the short-term for managers not to provide risk factor reduction strategies, but to simply sell the program after several years. At this early stage in the health care revolution one can only hope that common sense and ethics prevail over short-term greed.

Primary prevention can be carried out at a more aggressive level if one selects the right patients. Since more aggressive primary intervention necessitates the use of medications, this must be reserved for individuals with significantly increased risk for CHD. The guidelines developed by the National Cholesterol Education Program provide physicians with an algorithm for evaluating and treating high risk individuals. The late Dr. DeWitt Goodman was chairman of the first Adult Treatment Panel, which organized for the first time a step-wise guide for the treatment of hypercholesterolemia. Recently, a second Adult Treatment Panel Report8 refined the algorithm and focused much more on secondary prevention; that is, the treatment of individuals with clinical CHD. The key is to use the serum cholesterol level as part of the overall risk profile of an individual. People who have multiple risk factors (hypertension, smoking, diabetes, family history of CHD, low HDL cholesterol) together with hypercholesterolemia are very likely to develop clinical atherosclerotic cardiovascular disease during their lives. Treating these individuals should be cost effective.

Secondary prevention, treatment to reduce risk in individuals who already have clinical atherosclerotic cardiovascular disease, is a very different strategy. The risk of additional CHD events and death in people who have clinical atherosclerosis is extremely high. Furthermore, numerous secondary prevention trials have demonstrated marked reductions in CHD events. The recently reported and very impressive Scandinavian Simvastatin Survival Study showed not only reduced cardiovascular events and mortality, but also a 30% reduction in all cause mortality in the treated group.9 In the study, more than 4,000 Scandinavian men and women with plasma cholesterol levels greater than 200 mg/dl and atherosclerotic cardiovascular disease received either placebo or the HMG-CoA reductase inhibitor, simvastatin. Plasma LDL cholesterol levels fell 35% in the group receiving active drug and were unchanged in the placebo group. After about six years of follow-up, mortality from all causes, including major cardiac events, was reduced by one-third in the treated group. Major cardiac events were also reduced by one-third in the active treatment group. There were no increases in accidental, traumatic or suicidal deaths in the treatment group compared to the placebo group. Similarly, cancer deaths were the same in the drug and the placebo group. This conclusive study should end any debate about the efficacy of secondary prevention strategies to lower serum and LDL cholesterol levels.

In summary, primary prevention must be conducted with the understanding that middle age men and women who have hypercholesterolemia in the absence of other risk factors show low absolute rates of death from CHD. Non-pharmacological modalities should be the foundation of prevention in this group. In hypercholesterolemic individuals who do not have clinical atherosclerotic cardiovascular disease but who do have several other risk factors for CHD, treatment with drugs will often be necessary. Although medicine is practiced on an individual basis, the guidelines provided by the National Cholesterol Education Program can be very helpful. Physicians must initiate aggressive treatment programs for patients with established atherosclerotic cardiovascular disease. There really is no good rationale to be conservative in such patients and the new National Cholesterol Education Program goal of an LDL cholesterol equal to or below 100 mg/dl is appropriate.8

Atherosclerosis Research at Columbia

The College of Physicians and Surgeons has a long tradition of conducting outstanding research related to atherosclerosis and lipoprotein metabolism. Dr. DeWitt Goodman was, for many years, Principal Investigator of a NIH sponsored Special Center of Research (SCOR) in Arteriosclerosis and a NIH supported Training Grant in Atherosclerosis Research. A few years before his death, Dr. Goodman became the Director of the Institute of Human Nutrition which has a major focus on preventive medicine.

At present, the SCOR is directed by Dr. Alan Tall, the head of the Division of Molecular Medicine. Dr. Richard Deckelbaum is the Director of the Institute of Human Nutrition, and he also heads the Division of Pediatric Gastroenterology and Nutrition and the Children's Cardiovascular Health Center, where families with children who have hypercholesterolemia are evaluated. I am the Principal Investigator of the Training Grant in Atherosclerosis, and head of the Division of Preventive Medicine and Nutrition.

The Division of Preventive Medicine and Nutrition has three other faculty members whose research focuses on atherosclerosis: Dr. Ira Goldberg studies the regulation of a key enzyme in chylomicron and VLDL metabolism-lipoprotein lipase; Dr. Lars Berglund is studying the mechanisms regulating the plasma levels of another atherogenic lipoprotein, Lp(a); Dr. Neil Shachter is creating transgenic mice which are models of hypertriglyceridemia and possibly diabetes mellitus. In addition, the Division of Preventive Medicine and Nutrition includes Drs. William Blaner and David Talmage whose research interests focus on the metabolism and mechanism of action of retinoids.

The Division of Preventive Medicine and Nutrition also has an Arteriosclerosis Research Center where patients with lipid metabolism disorders and atherosclerosis are seen and evaluated.

Research activities at Columbia in atherosclerosis and lipid/lipoprotein metabolism are among the strongest and most productive in the world. My own research ranges from clinical studies of nutrition and lipoprotein metabolism to investigations focused upon the assembly and secretion of VLDL from cultured liver cells. One of the major efforts has focused on diet effects on plasma lipids and lipoproteins. In collaboration with the Irving Center for Clinical Research (particularly their nutrition research team headed by Wahida Karmally), we have conducted carefully controlled feeding studies in which participants (including many P&S students) receive precisely prepared diets for several weeks, during which time blood samples were collected. These studies have contributed to our knowledge of the effects of dietary fats and cholesterol on plasma lipid and lipoprotein levels. We showed that monounsaturated fats (for example, olive oil) do not lower LDL cholesterol themselves; rather, they act as a neutral replacement for the cholesterol-raising saturated fats.10 We also demonstrated that dietary cholesterol, in the form of eggs, raises plasma cholesterol only modestly in young, healthy men and women.11,12 More recently, employees of the medical center and students have been recruited to participate in the first multi-center controlled diet study ever carried out in the United States. This year we are investigating the relative benefits of a low saturated fat/high carbohydrate diet and a low saturated fat/high monounsaturated fat diet.

At the other end of the spectrum, my laboratory is very excited about the assembly and secretion of lipoproteins like LDL from liver cells. Using cultured liver cells, we have found that apoprotein B, the major protein component of both VLDL (the triglyceride-carrying lipoprotein) and LDL, is degraded rapidly after synthesis. It is only when excess triglyceride is available that significant proportions of newly made apoprotein B are assembled into lipoprotein particles and secreted. Thus, there is regulation of this lipid transport protein by lipid-availability. We are now examining the mechanisms underlying this regulation in the hope of finding new therapeutic approaches to reduce the secretion of triglyceride and cholesterol from the liver, thereby reducing blood levels of these lipids.

The research programs described above have been successful and productive, receiving over three million dollars in NIH support. Atherosclerosis research efforts at Columbia range from molecular to clinical, and are combined with patient care and student, housestaff and fellow training. Continuing the traditions established by Dr. DeWitt Goodman during his three decades at Columbia, the investigators involved are proud of their contributions to the field and the institution. As preventive medicine becomes more critical in the practice of medicine in the next century, we believe that the College of Physicians and Surgeons will continue to be at the forefront of efforts to eliminate atherosclerosis and other chronic diseases.

From the Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, N.Y. Address correspondence to author.

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