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Circulation. 2000;102:IV-94-IV-102

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(Circulation. 2000;102:IV-94.)
© 2000 American Heart Association, Inc.

Special Anniversary Issue

Risk Reduction

Valentin Fuster, MD, PhD; Antonio M. Gotto, Jr, MD, DPhil

From Mt Sinai Medical Center (V.F.) and Weill Medical College of Cornell University (A.M.G.), New York, NY.

Correspondence to Antonio M. Gotto, Jr, c/o Mr Jesse Jou, Weill Medical College of Cornell University, 445 E 69th St, Olin Hall 205, New York, NY 10021. E-mail amg_editorial{at}med.cornell.edu


Key Words: prevention • atherosclerosis • lipids • pathology

In the 1950s, atherosclerosis, the disease process underlying coronary heart disease (CHD), was considered an inevitable, irreversible, and degenerative consequence of aging. Today we understand that coronary disease is treatable, that atherosclerotic plaque progression may be stabilized, and that prevention through risk factor modification can yield significant clinical benefits.

Because atherosclerosis develops silently over several decades and begins as early as young adulthood,1 most investigators foresee a blurring of the distinction between primary and secondary prevention in the new millennium. However, asymptomatic patients may be unaware of their atherosclerotic burden and may undervalue the impact of an unfavorable risk profile.2 3 At the same time, physicians, concerned by a healthcare environment in flux, receive the consistent message that secondary prevention is the most cost-effective means of management.4 However, waiting until the patient has experienced a coronary event before intervening raises troublesome ethical concerns that must be addressed before excluding primary prevention altogether. Treatment of coronary risk factors is not as vigorous as it must be. For example, many physicians do not treat lipid disorders to the goals established by national guidelines.5

Although invasive revascularization procedures are sophisticated and may alleviate the physical symptoms of obstructive plaque and may improve survival in some patients with more severe disease,6 the majority of clinical coronary events arise from lesions that may be angiographically invisible and only moderately stenotic.7 Therefore, traditional interventional cardiology can only be part of the solution to the toll of cardiovascular disease. As we enter the 21st century, there is a clear mandate for aggressive promotion of primary prevention and risk factor control, a mandate long championed by the American Heart Association (AHA) and other groups. The last 50 years have seen rapid growth in the area of risk reduction and several important contributions from a large number of investigators and their laboratories. Table 1Down describes a few of these major milestones that have influenced profoundly the course of clinical practice in the prevention of coronary disease.


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  		Table 1. Timeline of Important Events in Risk Reduction Related to Lipid Modification

Establishment of the Major Coronary Risk Factors

In the area of risk reduction, the Framingham Heart Study, now in its fifth decade, is perhaps the most significant longitudinal study in cardiovascular research. Long-term follow-up of this large cohort of men and women clearly demonstrated that the risk for CHD is a function of lipids, blood pressure, and smoking, the 3 cornerstones of coronary risk modification.8 Although each of these risk factors warrants special attention, the identification and validation of the role of lipid modification in risk reduction were especially contentious and important and have been reviewed extensively elsewhere.9

Validation of the Lipid Hypothesis
In the landmark Seven Countries Study, Keys and colleagues10 correlated the levels of fat intake in various countries with plasma cholesterol levels and, in turn, with the incidence of CHD. However, early dietary interventional trials were inconclusive and raised concerns about the safety of lipid intervention.

In the 1980s and 1990s, the Lifestyle Heart Study investigated the premise that aggressive, comprehensive lifestyle changes could alter the clinical and angiographic progression of coronary disease.11 The original trial analyzed both lipid and quantitative angiographic parameters after a 12-month intervention period that included intensive lifestyle changes involving diet (strict vegetarian, with 10% of calories obtained from fat), aerobic exercise, stress management, smoking cessation, and group psychosocial support. Comprehensive risk factor reduction resulted in a 37.2% reduction in LDL cholesterol (LDL-C) levels, which was associated with a decrease of 91% in the frequency of anginal episodes. The Lifestyle Heart Trial also demonstrated improvement in the angiographic manifestations of CHD in the group randomized to intensive risk factor management. Striking angiographic changes and fewer clinical events in the intensive-treatment group were seen at the 5-year follow-up.12 Although the study sample was small and the interventional strategy extremely rigorous, the Lifestyle Heart Trial clearly suggested that modifications of lifestyle alone, including diet, smoking, exercise, and stress exposure, in a highly motivated population may yield measurable benefits. Recently, the US government has committed to undertaking a trial to compare the effects of this type of program with popular low-carbohydrate, high-protein diets.

Another important diet study was the Lyon Diet Heart Study, which compared the effect of a Mediterranean diet with that of a prudent Western-type diet on the risk for recurrent coronary events in a total of 605 subjects who had suffered an acute myocardial infarction.13 The Mediterranean diet has fewer calories and a significantly lower content of both saturated fats and polyunsaturated fats relative to the Western diet. As reported last year in Circulation, at the 46-month follow-up period, the event rate for cardiac death and nonfatal myocardial infarction in the intervention group was 1.24 per 100 patients per year compared with 4.07 events per 100 patients per year in the control group (72% risk reduction, P=0.0001). The all-cause mortality rate was also significantly reduced (56% risk reduction, P=0.03). Therefore, the composition of the Mediterranean diet appears to be cardioprotective and associated with improved outcomes in secondary prevention.

The Landmark Statin Trials
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT)14 of cholestyramine and the Helsinki Heart Study15 of gemfibrozil demonstrated in the 1980s that primary preventive lipid modification could reduce the risk for nonfatal heart attack and coronary death. However, the agents used had only modest effects on total cholesterol and LDL-C values, and the Helsinki Heart Study raised mild controversy about the safety of fibrate therapy. In 1987, the release of lovastatin, the first 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, represented an important milestone in the treatment of lipid disorders and was followed by the release of pravastatin, simvastatin, fluvastatin, atorvastatin, and cerivastatin. Through inhibition of HMG-CoA reductase, the rate-limiting enzyme of endogenous cholesterol synthesis, statins reduce plasma LDL-C by 20% to 60%.

Since 1987, 5 major trials of statins have been published that address the spectrum of cardiovascular risk in a broad range of patient populations, as well as resolve the issue of the safety of lipid modification as a preventive strategy. The Scandinavian Simvastatin Survival Study (4S) demonstrated conclusively that LDL-C reduction in 4444 men and women with CHD and very high cholesterol levels produced a 30% reduction (P=0.0003) in deaths from all causes of mortality.16 All cardiovascular events were favorably affected in the 5.4-year trial. In both the Cholesterol and Recurrent Events (CARE)17 study and the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID)18 study, treatment with a fixed dose of pravastatin (40 mg/d) was associated with impressive reductions in CHD events in men and women with heart disease and average LDL-C elevations. The results of LIPID reinforced those of the 4S by reporting a 22% reduction in total mortality. Reductions in stroke and other cerebrovascular events were also seen in all 3 studies. Because stroke has a relatively weak association with cholesterol, these results question whether there may be other protective effects of the statins beyond LDL-C lowering. Animal models of induced stroke suggest that simvastatin and lovastatin appear to reduce vascular injury, independent of lipid changes.19 Clearly, the precise mechanism of stroke protection warrants further study.

Benefit with statin therapy has been extended to primary prevention in 2 large studies. In the West of Scotland Coronary Prevention Study (WOSCOPS), treatment with pravastatin in high-risk men reduced the rate of nonfatal myocardial infarction and CHD death by 31% (P<0.001) and the all-cause mortality rate by 22% (P=0.051).20 The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) included men and women with average total cholesterol and LDL-C values and a below-average HDL cholesterol (HDL-C) level. Lovastatin treatment reduced the risk for the first acute major coronary event by 37% (P<0.001).21

The similarities in the results of these trials are much greater than the differences. In each trial, clinical events, including stable and unstable angina, were decreased. The need for clinical interventions such as bypass surgery or angioplasty was also reduced. None of the trials reported a significant excess of adverse experiences with treatment. Therefore, LDL-C reduction with these drugs is associated with important clinical effects.

Now being explored is the precise quantitative relation between cholesterol reduction and achievable clinical benefit: whether the benefit is mediated by reaching a target goal or by treating for a percent reduction in cholesterol, and whether there is a threshold cholesterol concentration beyond which further lipid reduction is unnecessary.22 Also of interest is the question of whether the more robust risk reductions with the statins reflect the greater degree of cholesterol lowering than previously studied agents or whether the so-called pleiotropic effects of the statins, such as the effect on endothelial function, platelet function, oxidative modification of lipoproteins, or macrophage activity and inflammation, are clinically important.

Insights Into Atherosclerosis

The "Response-to-Injury" Hypothesis of Russell Ross and the Initiation of Atherosclerosis
In the 19th century, there were 2 major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,23 proposed in 1852 and modified by Duguid,24 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow25 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. Over the last 3 decades, the 2 hypotheses became integrated into a more complex "response-to-injury" hypothesis developed by Ross,26 which represents the prevalent view of the initiation of atherosclerosis.27

As originally formulated, the endothelial injury hypothesis postulated the loss of endothelial cell integrity; however, a number of experimental studies failed to show any frank loss of endothelium over developing fatty lesions. Specifically, chronic minimal injury to the arterial endothelium is physiological and is often the result of a disturbance in the pattern of blood flow at bending points and near bifurcations of the arterial tree. In addition to local shear forces that are probably enhanced in hypertension, chronic minimal endothelial injury or dysfunction, which leads to accumulation of lipids and monocytes (macrophages), is produced by hypercholesterolemia, advanced glycation end-products in diabetes, chemical irritants in tobacco smoke, circulating vasoactive amines, immune complexes, and perhaps infections.27 28 The "response-to-injury" hypothesis of Russell Ross, with this most recent modification, has been a landmark in the understanding of the initiation of the atherosclerotic process.

The AHA Classification of Atherosclerosis and the "Vulnerable Plaque" in the Acute Coronary Syndromes
According to the criteria of the AHA Committee on Vascular Lesions, plaque progression can be subdivided into the 5 phases and different lesion types shown in Figure 1Down.29 30 The so-called "vulnerable" type IV and type Va lesions (phase 2) and the so-called "complicated" type VI lesions (phase 4) are the most relevant to the acute coronary syndromes. Type IV lesions consist of confluent cellular lesions with a great deal of extracellular lipid intermixed with fibrous tissue covered by a fibrous cap, whereas type Va lesions possess a predominant extracellular lipid core also covered by a thin fibrous cap. Disruption of a type IV or type Va lesion leads to the formation of a thrombus, or "complicated" type VI, lesion.



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  		Figure 1. Figure 1Up. Description of lesion morphology and phases of progression of coronary atherosclerosis: relation to clinical findings. Colors indicate lipid accumulation (yellow), thrombosis and hemorrhage (red), and calcification and fibrous tissue (green). Roman numerals indicate lesion types: type I–III lesions (early lesions) with isolated macrophage/foam cells (I), multiple foam cell layers (II), or isolated extracellular lipids (III); type IV–Va lesions (advanced lesions, atheromatous or fibrolipid plaques) with confluent extracellular lipid pools (atheroma, IV) or fibromuscular tissue layers and atheroma (Va); type VI lesions (advanced lesions, complicated plaques) with surface defects and/or hemorrhage and/or thrombi deposition; type Vb–Vc lesions (advanced lesions) with calcifications (Vb) or fibrous tissue (Vc). Reproduced with permission from Fuster and colleagues.29 33

Vulnerable plaques tend to be relatively small or nonstenotic at angiography but are nevertheless soft or vulnerable to "passive" disruption because of their high lipid content.7 31 In addition, a macrophage-dependent "active" phenomenon of plaque disruption (related to matrix metalloproteinases) and thrombosis (related to tissue factor) is evolving.32 33 Specifically, the continuing entry, survival, and replication of monocytes, macrophages, and lymphocytes within plaques are in part dependent on factors such as endothelial adhesion molecules (ie, P-selectin, vascular cell adhesion molecule-1), monocyte chemotactic protein-1, monocyte colony stimulating factor, and for lymphocytes, interleukin-2. Macrophages, after what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with the subsequent release of matrix metalloproteinases and tissue factor.

After the successful results of the lipid-lowering trials and based on pathological observations, it can be postulated that when high LDL-C levels predominate over the influx of LDL-C, there is a decrease in the softness of the plaque and so presumably, in the "passive" phenomenon of plaque disruption33 ;in vivo magnetic resonance imaging (MRI) observations in the rabbit model34 as well as in human aortic arch disease,35 and recently in coronary artery disease,36 support this concept. These stabilized lesions appear to represent the type Vb lesions of the AHA classification. Furthermore, when low HDL-C is increased experimentally, there is partial decrease in the number and activity of the macrophages and so presumably, stabilization of the "active" phenomenon of plaque disruption and thrombus formation.37

Contributions of the AHA to Prevention

Attention to Nutrition and Dietary Fat
A major accomplishment in 1957—with broad implications for both the medical profession and the general public—was the issuance of a special statement entitled "Atherosclerosis and the Fat Content of the Diet." It was prepared by the Nutrition Committee of the AHA in conjunction with the American Society for the Study of Arteriosclerosis and was published in Circulation.38 The statement was based on the observations of 5 scientists; the senior author of the report was Irvine H. Page, MD, of the Cleveland Clinic. Dr Page and his colleagues stated that diet may play an important role in the development of atherosclerosis. They also stated that fat content and total calories may be the dominant contributing factors, and the balance between saturated and certain unsaturated fats may be important. In 1961, an ad hoc committee of the AHA updated Dr Page’s report by adding the following additional conclusions39 : overweight Americans should reduce their intake of calories in an attempt to achieve ideal weight; weight reduction could be helped along by regular, moderate exercise; the composition of the diet should be changed to reduce intake of total fats, saturated fats, and cholesterol and by increasing polyunsaturated fats; particular attention should be given to diet changes in men at increased risk for heart disease or stroke; and for those people at high risk, diet changes should be carried out under medical supervision.

During the decades of the 1960s to the 1980s, the AHA position on diet was updated several times because the committee perceived that a change in scientific knowledge required a new advisory for physicians and the general public. Thus, the Step I diet, typically recommended for people at risk of cardiovascular disease and stroke, and the Step II diet, typically recommended for patients who have had a cardiovascular event, have been widely implemented, particularly in the 1990s. In addition to dietary guidelines, over the years the AHA has pioneered the concept of consistent physical activity programs for all Americans.40

Again, the AHA dietary guidelines have been revised and updated periodically to reflect new scientific advances and recommendations on the role of diet in the prevention of cardiovascular disease and stroke. Accordingly, the upcoming 2000 version reflects a shift in the emphasis from specific nutrients to recommendations based on healthful food patterns (Table 2Down). The new guidelines have been expanded to include recommendations for individuals with specific conditions such as hypercholesterolemia, high blood pressure, diabetes and insulin resistance, congestive heart failure, and renal disease, as well as recommendations for healthy people (Table 2Down). The new version also identifies emerging areas of interest on the role of specific nutrients such as antioxidants and soy protein, which may provide additional health benefits, but for which further research is needed before population-wide dietary recommendations can be made.


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  		Table 2. AHA Dietary Guidelines: 2000

Launching of the NCEP
In early 1985, the National Heart, Lung, and Blood Institute (NHLBI) held a series of planning meetings for the proposed cholesterol education program with potential partner organizations such as the AHA, and in November 1985, the institute officially launched the National Cholesterol Education Program (NCEP).41 Since 1985, the NCEP has carried out a wide array of educational activities directed to professionals, patients, and the public. Foremost among these has been the development of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel [ATP]), which published the first set of clinical guidelines for cholesterol management (ATP I) in 198842 and the second report (ATP II), which contains the updated current guidelines and was published in Circulation in 1994.43

The second report of the NCEP was issued without the benefit of multiple, recently published, large clinical trials. To analyze the panel’s guidelines for treatment of high cholesterol levels in the context of currently available clinical trial results, an ATP III report is underway. Thus far, it appears that lipid-lowering therapy generally should be more aggressively applied to patients with diabetes and/or at the time of CHD diagnosis. The evidence for statin use in secondary CHD prevention in postmenopausal women outweighs current evidence for use of estrogen replacement in this setting. Further studies are needed to address the effects of lipid modification in primary prevention of CHD in populations other than middle-aged men and to study markers of lipid metabolism other than LDL-C.44

In over more than a decade under the auspices of the NHLBI and in collaboration with the AHA and other organizations, the NCEP has made significant progress toward its goal of reducing the prevalence of high blood cholesterol. The impact of cholesterol education is clearly visible in 3 major trends: (1) increasing professional and public cholesterol awareness; (2) declining dietary intakes of saturated fat, total fat, and cholesterol; and (3) decreases in serum cholesterol levels.41 Nevertheless, cholesterol levels are still being undertreated, especially in patients with CHD, and substantial scientific and educational challenges remain.

Decline in Coronary Mortality
Since the AHA began to evolve in 1948, its mission has been fighting death and disability from these diseases through research and education. In research, the AHA focuses on identifying and providing initial support to talented, young investigators and disseminating scientific discoveries to scientists, physicians, and other healthcare professionals through the AHA journals and scientific programs. The medical community, as well as the public, is the target audience of the AHA’s educational efforts to promote prevention and early treatment of cardiovascular disease and stroke.

In part, as a direct result of research sponsored by the AHA and the NHLBI, and certainly as a consequence of professional and public education, fewer people are dying of cardiovascular disease and stroke in the United States. A comparison of mortality data from 1973 and 1993 reveals that the decrease in death is most apparent in CHD among young and middle-aged people, regardless of their race or sex (Figure 2Down).45 46 According to recent data from the Atherosclerosis Risk in Communities (ARIC) Study, such favorable trends are in large part a result of improvements in acute treatment and subsequent secondary prevention,47 and in minor part, presumably result from primary prevention. In reality, the severe impact of cardiovascular disease and stroke on mortality has been postponed. That is, people are living longer after having suffered a heart attack or stroke or being diagnosed with hypertension or another form of cardiovascular disease. Thus, they are dying of these diseases but at later ages.46



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  		Figure 2. Figure 2Up. CHD deaths in United States. Comparison between 1973 and 1993 reveals that mortality is being postponed for several years. Reproduced with permission from Lenfant.45

A challenge facing cardiovascular disease and stroke initiatives is whether it is realistic to expect that the still very high incidence in the United States and the present spread to less-developed countries can be modified through research as well as professional and public education, or whether there is perhaps a need for more aggressive implementation strategies.46 The 1996 Bethesda Conference identified at least 6 barriers to implementing effective preventive measures.48 Two involved professional factors: a lack of incentive or reimbursement for physicians and a lack of time to adequately carry out prevention activities. Two barriers involved patient education: a lack of knowledge or motivation and inadequate access to preventive care. Two other problems involved health-system support: lack of reimbursement for prevention services and facilities and a lack of sound policies and standard guidelines.

On June 27, 1998, the AHA’s delegate assembly approved the ambitious impact goal of reducing CHD, stroke, and risk by 25% by the year 2008. Two strategies will be critical in meeting that goal: prevention targeted at high-risk individuals and populations and earlier acute treatment of heart and stroke events.49

Leadership in New Approaches of Risk Assessment: Global Risk
The past decade has witnessed major strides in the prevention of CHD through modification of its causes. The most dramatic advance has been the demonstration that aggressive medical therapy will substantially reduce the likelihood of recurrent major coronary syndromes in patients with established CHD (secondary prevention). The AHA and the American College of Cardiology have published joint recommendations for medical intervention in patients with CHD and other forms of atherosclerotic disease.50

A similar potential exists for risk reduction in patients without established CHD (primary prevention). However, the risk status of persons without CHD varies greatly, and this variability mandates a range in the intensity of interventions. Effective primary prevention thus requires an assessment of risk to categorize patients for selection of appropriate interventions.

Based on the Framingham Heart Study,51 endowed and supported by the AHA,52 the major and independent risk factors for CHD are cigarette smoking of any amount, elevated blood pressure, elevated serum total cholesterol and LDL-C, low serum HDL-C, diabetes mellitus, and advancing age (Table 3Down). The quantitative relationship between these risk factors and CHD risk has been elucidated by the Framingham Heart Study51 and other studies. These studies show that the major risk factors are additive in predictive power. Accordingly, the total risk of a person can be estimated by summing the individual risk imparted by each of the major risk factors. Other factors are associated with increased risk for CHD (Table 3Down). These are of 2 types: conditional risk factors and predisposing risk factors. The conditional risk factors are associated with an increased risk for CHD, although their causative, independent, and quantitative contributions have not been well documented. The predisposing risk factors are those that worsen the independent risk factors. Two of them–physical inactivity and obesity—are now designated major risk factors by the AHA.39 52


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  		Table 3. Risk Factors

Traditionally, preventive efforts should target each major risk factor. Any major risk factor, if left untreated for many years, has the potential to produce cardiovascular disease. Nonetheless, an assessment of total or "global" risk based on the summation of all major risk factors can be clinically useful for 3 purposes: (1) identification of high-risk patients who deserve immediate attention and intervention, (2) motivation of patients to adhere to risk-reduction therapies, and (3) modification of intensity of risk-reduction efforts based on the total risk estimate. For the latter purpose, patients at high risk because of multiple risk factors may require intensive modification of >=1 risk factor to maximize risk reduction. Guidelines for the management of individual risk factors are provided by the second Adult Treatment Panel report (ATP II) of the NCEP, the sixth report of the Joint National Committee of the National High Blood Pressure Education Program, and the American Diabetes Association. All of these guidelines are currently endorsed or supported by the AHA and the American College of Cardiology. These reports advocate adjusting the intensity of risk factor management to the "global" risk of the patient. In ATP II and the Joint National Committee report, overall risk is estimated by adding the categorical risk factors. They do not use a total risk estimate based on summation of risk factors that have been graded according to severity; this latter approach has been advocated recently by Framingham investigators.51 The use of categorical risk factors has the advantage of simplicity but may be lacking in some of the accuracy provided by graded risk factors.

The AHA’s task force on risk reduction recently issued a scientific statement53 that reviewed and assessed the utility of Framingham scoring as a guide to primary prevention (Table 4Down). A recent report expands on this assessment and considers factors that must be taken into account when the Framingham algorithm is used, such as the predisposing and conditional risk factors.


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  		Table 4. CHD Risk in Women According Framingham Scoring

Identifying the High-Risk Patient for Primary Prevention: Evolving Noninvasive and Imaging Technology

The AHA recently set forth guidelines for aggressive medical therapy in patients with established CHD and other forms of atherosclerotic disease50 (secondary prevention) as well as the above-mentioned "global" risk approach for the general population (primary prevention).53 A more recent issue under consideration was the development of strategies to identify high-risk patients without established CHD who are candidates for aggressive medical therapies for primary prevention, the so-called Prevention Conference V document.54 One of the task forces examined techniques used to estimate atherosclerotic burden for the purpose of risk prognostication. The ankle/brachial blood pressure index emerged as a powerful, independent predictor of future coronary events. Several reports further indicate that measures of carotid intimal-medial thickness by B-mode ultrasonography provide an independent assessment of coronary risk.

Importantly, measures of coronary calcium by computed tomography show a high correlation with the extent of coronary atherosclerosis. Furthermore, preliminary studies suggest that coronary calcium scores provide an independent estimate of future coronary events. However, an upcoming joint statement of the American College of Cardiology and the AHA suggests that, thus far, available studies are insufficient to define the magnitude of independent prediction.

Finally, MRI has been shown to characterize tissue noninvasively in many different study systems. Therefore, research has begun to focus on the use of in vivo MRI to evaluate the vessel wall in several animal models and humans. Thus, after a study of carotid arteries in humans,55 a more recent study of patients with plaques in the thoracic aorta showed that in comparison with transesophageal echocardiography, plaque composition and size are accurately characterized and measured by MRI.35 Thus, carotid and aortic atherosclerotic assessment with MRI may lead to its use as a screening tool for predicting future cardiovascular events and evaluating therapeutic interventions. Preliminary studies in normal human subjects and patients with coronary artery disease suggest that the MRI technique may eventually be applicable to the study of human coronary arteries in vivo (Figure 3Down).56



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  		Figure 3. Figure 3Up. X-ray angiogram from 76 year-old male patient shows high-grade stenosis in proximal left anterior descending coronary artery (LAD; arrows in A). In vivo cross-sectional black-blood MR images of LAD lumen (B) show obstructed lumen (elliptical lumen shape); wall image (C) shows large eccentric plaque with heterogeneous signal intensity. LV represents left ventricle; RV, right ventricle; and RVOT, right ventricular outflow tract. Reproduced with permission from Fayad et al.36

In conclusion, in the past 50 years, the AHA has made great strides—a source of great pride to all of us. But at the turn of the century, the AHA and indeed the world of cardiology face several serious challenges: (1) How will we support and energize research, which is so crucial to preventing the still-evolving epidemic of cardiovascular disease and stroke? (2) Is it realistic to expect that this epidemic can be lessened or avoided solely by professional and public education, or is there a need for more aggressive implementation strategies? (3) Would a more integrated and cooperative approach, involving many of the national and international organizations, maximize the effectiveness of individual organizations and their volunteers?

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