Skip main navigation

Increasing Burden of Cardiovascular Disease

Current Knowledge and Future Directions for Research on Risk Factors
Originally published 1998;97:1095–1102

    Lewis A. Conner was the first president of the American Heart Association and founding editor of the American Heart Journal. In the inaugural issue of that journal, in October 1925, Dr Conner wrote that the “newly awakened interest in disorders of the cardiovascular system” has rapidly led to the recognition of heart disease as a significant public health problem that “can no longer be disregarded.”1 In the ensuing years, the United States first experienced a 40-year increasing epidemic of cardiovascular disease, followed by remarkable gains in prevention and treatment that led to a dramatic 30-year decline in mortality from coronary heart disease (CHD) and stroke. At present, however, heart disease remains far and away the leading cause of mortality in the United States, responsible for about one of every three deaths. Stroke accounts for 6% to 7% of all deaths, so overall cardiovascular disease remains responsible for about 40% of all US deaths.2

    Further gains in the prevention and treatment of cardiovascular disease will require concerted efforts—and the necessary allocation of resources—on at least two major fronts. First, public policy and health efforts must vigorously promote those measures in prevention and treatment for which abundant evidence of clear benefits already exists. Second, funding must be provided for current research to evaluate new possible preventive and therapeutic interventions and to expand frontiers in genetic, thrombotic, atherogenic, and inflammatory markers of cardiovascular disease risk.

    Advances in knowledge proceed on several fronts, optimally simultaneously. Basic researchers provide biological mechanisms and answer the crucial question of why an agent or intervention reduces premature death. Clinicians are providing enormous benefits to affected patients through advances in diagnosis and treatment and formulate hypotheses from their clinical experiences in case reports and case series. Clinical investigators address the relevance of basic research findings to affected patients and healthy individuals. Epidemiologists and statisticians, optimally collaborating with researchers in other disciplines, formulate hypotheses from descriptive studies and test these in analytical studies, both observational case-control and cohort as well as, where necessary, randomized trials. This strategy answers the equally crucial and complementary question of whether an agent or intervention reduces premature death. Thus, each discipline and indeed every strategy within a discipline provide importantly relevant and complementary information to a totality of evidence on which rational clinical decisions for individuals and policy decisions for the health of the general public can be safely based.3

    This article reviews the increasing burden of cardiovascular disease, contributions of different types of evidence, and direction of current and future research on risk factors.

    Increasing Burden of Cardiovascular Disease

    In the United States today, heart disease becomes the leading killer of men by 45 years of age and women by 65 years of age. Heart disease is responsible for one in three deaths in women and men and accounts for approximately 750 000 fatalities each year in the United States. Moreover, there are alarming indications that the decline in cardiovascular disease mortality in the United States that began in the 1960s has leveled off and that rates may even be beginning to rise. For the first time in decades, the age-adjusted death rate from cardiovascular disease in the United States increased slightly from 1992 to 1993, the last years for which complete data are available.4

    With regard to racial differences in CHD, mortality rates remain substantially higher in blacks than in whites, with 1992 age-adjusted rates of 190.3 per 100 000 among white men and 264.1 per 100 000 among black men.5 For women, the rates were 98.1 in whites and 162.4 in blacks. In addition, although there were decreases in CHD mortality among all groups throughout the 1980s, the percentage decline in the rates from 1980 to 1992 was much greater in whites than in blacks.5

    There have been alarming trends in the health status of US teenagers, among whom there are currently troubling increases in the prevalence of cigarette smoking6 and obesity7 and decreases in participation in physical activity programs.8 Specifically, each year from 1991 to 1996, cigarette smoking rates have increased in the United States among 8th, 10th, and 12th grade students,6 while more than one in five US adolescents are overweight, an increase of >50% in the prevalence of adolescent obesity since the late 1970s.7 In terms of physical activity levels, there was no change in the proportion of US high school students engaged in regular vigorous physical activity from 1991 through 1995, and there has been a decrease in the participation of high school students in daily physical education classes.8 This backslide in the health status of US teenagers has far-reaching consequences for future overall morbidity and mortality in general and for cardiovascular disease in particular.

    Worldwide, cardiovascular disease is also assuming an increasing role as a major cause of morbidity and mortality. Between 1990 and 2020, the proportion of worldwide deaths from cardiovascular disease is projected to increase from 28.9% to 36.3%.9 Moreover, in terms of number of years of life lost, it is projected that cardiovascular disease will jump in ranking from fourth to first, while as a cause of premature death and disability, it will rise from fifth to first. The projected increases in the importance of cardiovascular disease worldwide are related principally to two trends in developing countries: (1) the eradication of malnutrition and infectious diseases as primary causes of death, which is allowing for an aging of the population, and (2) marked increases in cigarette smoking.10

    Thus, the enormous and increasing burden of cardiovascular disease among those in middle and older age in developed countries, the alarming trends in cardiovascular risk profiles of young people, and the emerging pandemic of cardiovascular disease all underscore the crucial need to redouble both policy and research efforts in treatment and prevention.

    Contributions of Different Types of Evidence

    It is crucial to consider the totality of evidence for any question because each research discipline has its unique strengths and limitations (Table 1). Basic research has the unique strength of precision, meaning the ability to achieve virtually complete control of all exposures, including both environment and genetics. Further, basic research provides the scientific underpinnings for all applied research in humans. Thus, basic research provides unique and crucial information concerning disease mechanisms. However, basic research also has the disadvantage of potential lack of relevance to free-living humans because of such differences as species specificity, dose, and routes of administration of exposures. Thus, the results from basic research may differ so greatly from those that apply to free-living humans as to render them of questionable direct relevance. The inability to predict the applicability of findings from a particular species of animals to humans was underscored by John Cairns, who wrote, “Who could have guessed that Homo sapiens would share with the humble guinea pig the unenviable distinction of being incapable of synthesizing ascorbic acid, or share with armadillos a susceptibility to the bacterium that causes leprosy, or that intestinal cancer usually occurs in the large intestine of humans and the small intestine of sheep?”11

    While the findings from basic research may be limited in their ability to provide a reliable quantitative estimate of human disease risk, the precision possible in such research provides unique and crucial information that is of great value in setting priorities for studies in free-living humans to test their relevance.

    Epidemiology, on the other hand, because it is based directly on observations of free-living humans, has the unique advantage of relevance. However, for this very reason, epidemiological studies have the potential disadvantage of imprecision. Indeed, in contrast to basic research, epidemiology is crude and inexact because observations in free-living humans can never take place under the controlled conditions possible in the laboratory. Nonetheless, epidemiology contributes essential information to a totality of evidence, which then can support a judgment of a cause-effect relationship.

    Making such a judgment involves several steps, the first being to establish whether there is in fact a valid statistical association. To conclude that an association is valid, alternative explanations for the finding must be ruled out, including the potential roles of chance, bias, and confounding. If a valid statistical association is present, the question then becomes, Is it one of cause and effect? To render this judgment, the totality of evidence from all sources must be considered, with particular attention given to the strength of the association, the consistency of the evidence from different studies, and the existence of a plausible biological mechanism to explain the findings.

    Epidemiological studies can be either descriptive (case reports and case series, correlational studies, and cross-sectional surveys) or analytical (observational case-control or cohort studies and randomized trials). Descriptive studies are useful primarily for the formulation of hypotheses; analytical studies, for hypothesis testing. Whereas observational analytical studies are often criticized because of their potential for bias—case-control studies in the selection of individuals into the study and in their recall of prior events and cohort studies in losses to follow-up—many exposure-disease relationships have been well established from observational evidence.12

    There are two chief strengths of observational evidence. The first relates to the evaluation of exposures that require long duration; the second is the ability to detect moderate to large effects, which can be roughly translated to mean those effects with relative risks >1.5. With respect to the evaluation of exposures that require long duration, one example of the strength of observational studies is the evaluation of the relationship between blood pressure and risk of myocardial infarction (MI). Basic research had suggested mechanisms for a benefit of blood pressure lowering on risks of stroke and MI, and observational studies had consistently demonstrated a statistically significant 40% to 45% increased risk of stroke and a 25% to 30% increase in risk of MI associated with a prolonged 6 mm Hg difference in diastolic blood pressure.13 In contrast, although individual randomized trials of pharmacological therapy of mild to moderate hypertension indicated that blood pressure lowering by 6 mm Hg resulted in a comparable 40% decrease in risk of stroke, there was a far smaller and less certain benefit on MI than that suggested by the observational evidence. The apparent inconsistency remained even after the availability of results from 14 individual randomized trials of drug therapy in 37 000 subjects. This led some to conclude that treatment of hypertension did not benefit the risk of subsequent MI. However, a comprehensive overview, or meta-analysis, of the trials demonstrated that a decrease of 6 mm Hg in diastolic blood pressure significantly reduced stroke by 42% and MI by a smaller but statistically significant 14%.14 A subsequent meta-analysis, which included several additional trials, demonstrated the reduction in risk of MI to be 16%.15 The 14% to 16% reduction in risk of MI seen in the randomized trials over 3 to 5 years of treatment was about half the 28% reduction one would predict from the results of observational studies of blood pressure lowering over decades. This discrepancy may well have been due to chance but also could have been due to the fact that stroke risk immediately decreases after blood pressure levels are lowered, whereas MI risk may be affected by prolonged effects of hypertension on the more chronic processes of atherogenesis and thus would require far longer than the usual 3 to 5 years of treatment in trials to observe the full impact. Thus, basic research and observational studies with long durations of exposure have been crucial components of the totality of evidence concerning the relationship of blood pressure lowering with risk of MI.

    The second strength of observational studies lies in evaluating associations in which the relative risk is moderate to large in size—relative risks >1.5. In this regard, observational evidence has provided both the necessary and sufficient information on which to judge a cause and effect relationship for a large number of important questions of clinical importance and public health significance. Chief among these has been the health effects of cigarette smoking. Starting in 1950 with case-control studies by Doll and Hill in the United Kingdom16 and Wynder and Graham in the United States,17 observational epidemiological studies established a clear association between smoking and lung cancer, with risks among long-term smokers about 20 times greater than those of nonsmokers. Based on their observational evidence, Doll and Hill judged smoking to be a cause of lung cancer years before there was any clear understanding of the actual mechanism of alterations in DNA by initiators or promoters of cancer. In 1964 the US Surgeon General also judged smoking a definite cause of this disease, still years before the biological mechanism was clearly understood.18 Thus, although basic research is crucial in identifying mechanisms that explain causal or preventive factors, direct answers to the questions of whether particular exposures are associated with risks of disease may derive from straightforward observation of what actually happens in free-living human populations.

    With regard to smoking and CHD, the finding that current cigarette smokers have about an 80% increased risk has been consistently demonstrated over the last 30 years by different investigators in a large number of case-control and cohort studies involving millions of person-years of observation.19 It is interesting that smoking was not judged to be a cause of CHD until far later than the judgment that it caused lung cancer. Part of this related to the lack of a clear biological mechanism. However, another reason related directly to a limitation in interpreting the findings from any observational study; namely, that as the relative risk gets smaller, there is increasing concern that some factor other than the exposure being studied may explain all or at least part of the findings. For example, cigarette smokers may share other characteristics or lifestyle practices that independently affect their risk of CHD. Information can be collected on any potential confounding variables known to the investigator and then used in the data analysis to adjust for any impact of these factors. However, there can be no adjustment for the effects of unmeasured or unmeasurable confounding variables.

    When a large effect is seen, such as with smoking and lung cancer, the amount of uncontrolled confounding may affect the magnitude of the relative risk estimate, making it, for example, as high as 22 or as low as 18. It is unlikely, however, that complete control of confounding would materially change the conclusion that there is a strong positive association between smoking and lung cancer. Even in the case of current smoking and CHD, although uncontrolled confounding may mean that the true relative risk is as small as 1.6 or as large as 2.0 instead of the 1.8 most consistently seen in observational studies, that range of uncertainty does not materially affect the conclusion that current cigarette smoking increases the risk of CHD. On the other hand, when the most plausible effect size is only 20% to 40%, as is the case with most promising interventions today, a small amount of uncontrolled confounding could mean the difference between a relative risk of 0.8, indicating a 20% decreased risk; 1.0, indicating no effect; or 1.2, indicating a 20% increased risk.

    A recent example that illustrates some of these issues is the possible role of antioxidant vitamins in prevention of cardiovascular disease and cancer. Basic research has provided evidence of plausible mechanisms for antioxidant vitamins in the prevention of these diseases. As regards cardiovascular disease, antioxidant vitamins can inhibit the oxidation and/or uptake of LDL cholesterol, the particularly atherogenic form of cholesterol. In addition to descriptive studies, a large number of analytical observational studies have examined the antioxidant hypothesis. Several large-scale prospective cohort studies have found decreased cardiovascular disease risks among subjects with higher intake of antioxidant vitamins, either through diet or supplements.20

    The problem with all these studies, however, is that the decreased risk seen in those with the highest intake or blood levels tended to be modest in size, on the order of 20% to 40%. Such small to moderate benefits may have a tremendous public health impact for a common and serious disease, but they are statistically very difficult to demonstrate reliably. In the case of antioxidant vitamins, it may be, for example, that those with greater intake of antioxidant vitamins share other dietary or nondietary lifestyle practices that account for all or some of the observed association with antioxidant vitamins. Adjustments can be made for known confounding variables for which data are collected. However, observational studies are unable to control for the potential effects of confounding variables not collected or known to the investigators. In searches for modest-sized effects, the amount of uncontrolled confounding may be as large as the most likely effect.

    For all these reasons, only randomized trials of sufficient sample size and duration of treatment and follow-up are able to detect reliably small to moderate treatment effects. If the trials are large enough, the randomization process will, on average, evenly distribute among treatment groups known and unknown confounding variables. In addition, very large trials will be necessary to avoid the possible uninformative null result of no benefit when in fact a modest-sized benefit truly exists. For many, if not most, hypotheses, randomized trials are neither necessary nor desirable. For detecting small to moderate effects, however, they represent the most reliable research design strategy.

    With respect to antioxident vitamins, four large-scale randomized trials of beta-carotene supplementation have been completed.21222324 Overall, their results for CHD have not supported the promising evidence that accumulated from basic research, descriptive studies, and analytical observational investigations. The results certainly do not preclude the possibility that some benefit may yet emerge for antioxidants. Indeed, several trials ongoing trials are evaluating antioxidants in both primary and secondary prevention of cardiovascular disease, and the evidence remains particularly promising for vitamin E. However, with respect to beta-carotene supplementation, the data currently available from completed trials indicate no overall benefits on cardiovascular disease among well-nourished populations. These data suggest that the findings from observational studies of possible benefits may indeed have reflected some influence of confounding variables associated with beta-carotene intake that explain all or some of the decreased risks of cardiovascular disease among those with high intake levels. The findings also raise the possibility that the antiatherogenic mechanisms for beta-carotene described in basic research may not have direct relevance to the effects of supplementation with this antioxidant on human disease risk.

    Risk Factors: Current Knowledge and Future Directions for Research

    Genetics certainly plays a role in cardiovascular disease risk, but there is also clear evidence from international differences in disease rates and migrant studies that cardiovascular disease must have important environmental determinants. Studies of Japanese migrants have been particularly informative in this regard. The Ni-Hon-San study25 tracked the health experience of Japanese men living in the Japanese cities of Hiroshima and Nagasaki, men of Japanese ancestry living in the Honolulu area of Hawaii, and Japanese men in the San Francisco Bay area in California. The study revealed substantial differences in CHD mortality rates between the three groups, with men in Japan having the lowest rates, those in Hawaii having somewhat higher rates, and men in the San Francisco area having the highest rates.25 Thus, in these findings among genetically similar populations, migration and the adoption of lifestyle practices of the local population were accompanied by a substantial increase in CHD death rates.

    With respect to the identification of modifiable risk factors, during the 20th century, the contributions of basic research, clinical investigation, observational epidemiology, and randomized trials have yielded a totality of evidence on which it has been possible to judge proof beyond a reasonable doubt that modification of several factors decreases risks of cardiovascular disease (Table 2). These include cigarette smoking, elevated cholesterol levels, and hypertension. Other factors, such as obesity, physical inactivity, and diabetes, are clearly associated with increased risks of cardiovascular disease, but the evidence currently is less clear that modification of these factors yields decreased risks of CHD.26 For all of these risk factors, however, public policy recommendations have been issued by such major health organizations and institutions as the AHA, the NHLBI, and the National Institute for Neurological Diseases and Stroke, and efforts must be redoubled to achieve wider implementation of these existing recommendations.

    Although substantial gains can be achieved through control or elimination of established risk factors for cardiovascular disease, it is also important to consider that in data from the United Kingdom Heart Disease Prevention Project and other cohorts, approximately half of all patients suffering a CHD event have no established risk factors.27 This situation has prompted the investigation of promising interventions that could have widespread utility in treatment and primary prevention of cardiovascular disease. These include antioxidant vitamins, low-dose aspirin, and hormone replacement therapy in women.

    With respect to low-dose aspirin, in 1971, Sir John Vane, who later received the Nobel prize for his work, demonstrated that in platelets, small amounts of aspirin irreversibly acetylate the active site of cyclooxygenase, which is required for the production of thromboxane A2, a powerful promoter of platelet aggregation.28 Higher doses provided no additional benefit, and it has been postulated that far higher doses might reverse this tendency because of activation of vessel wall enzymes. A totality of evidence is now available, which includes randomized trials in secondary prevention or treatment among patients with a wide range of occlusive vascular diseases, in the acute phase of evolving MI, and in primary prevention among apparently healthy individuals.29 For secondary prevention3031 and acute evolving MI,32 there is conclusive evidence in both men and women of net benefits of aspirin on subsequent MI, stroke, and overall vascular death. Thus, extensions of the existing labeling indications for aspirin are clearly needed to include virtually all patients who have suffered an occlusive vascular disease event. Wider use of aspirin in these conditions would avoid 10 000 premature deaths each year in the United States. For primary prevention, there is conclusive evidence in men of benefit on risk of a first MI,33 but the data are currently inconclusive on stroke and vascular death. Further, there is a possible increase in hemorrhagic stroke. Thus, while we await the results of primary prevention trials, such as the ongoing Women’s Health Study among 40 000 female health professionals,34 the decision to prescribe aspirin in primary prevention must be an individual clinical judgment between the healthcare provider and each of his or her patients. Such a judgment must take into account the patient’s risk profile, the side effects of aspirin, and its clear benefit in reducing the risk of a first MI. In addition, the use of aspirin should always be as an adjunct, not alternative, to control or elimination of the established risk factors for cardiovascular disease.

    With respect to hormone replacement therapy, basic research has provided plausible mechanisms for benefits, including improvements in lipid profile, and observational epidemiological studies have indicated that women who self-select for hormone treatment have decreased risks of CHD.35 Women using hormones also experience reductions in menopausal symptoms and osteoporosis but increased risks of uterine cancer with unopposed estrogen and increases in gallbladder disease and breast cancer.36

    However, it is important to note that all these findings have been made in case-control and observational cohort studies, so the self-selection by women and their healthcare providers of hormone replacement therapy may be responsible, in part or perhaps even wholly, for the observed associations. Thus, despite the fact that MI kills about eight times as many women as breast cancer, whether the benefits of hormone replacement therapy outweigh the risks for all women is not yet clear. Several ongoing randomized trials, the largest of which is the Women’s Health Initiative, will provide the necessary direct evidence for this question.

    In addition to these promising hypotheses, we are also markedly increasing our understanding of the multifactorial causes of CHD. These genetic and environmental determinants include both atherogenic and thrombotic factors. For acute MI, the primary underlying cause is atherosclerosis, whereas the proximate cause of virtually all cases is thrombosis.37 In this context, many potential new markers of CHD are under investigation (Table 3).38 These include the primarily atherogenic marker homocysteine, the primarily thrombotic marker fibrinogen, and other primarily inflammatory markers, such as C-reactive protein.

    With respect to possible atherogenic markers, there is increasing interest in the possible role of homocysteine in cardiovascular disease.39 Basic research has shown methionine to be an essential amino acid that depends on several enzymes related to B12 and folate metabolism for conversion from homocysteine. In clinical studies, individuals with homocystinuria develop very premature onset of severe CHD. Regardless of the source of the defect, all patients with elevated levels of homocysteine have increased risks of CHD.

    Several observational epidemiological studies, both case-control and cohort, have shown that those with higher levels of homocysteine tend to have increased risks of CHD. This emerging totality of evidence has raised the question of whether reducing levels of homocysteine would, in turn, decrease risks of cardiovascular disease.

    In the Physicians’ Health Study, the significant predictors of higher homocysteine are age, the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotype, and current smoking; whereas predictors of lower homocysteine levels are current multivitamin use and higher intakes of folate.40 These and other data have raised the hypothesis that folate may lower homocysteine and decrease risks of MI. Only randomized trials can address this issue definitively. Currently, one secondary prevention trial of folate is ongoing among patients with prior stroke, and several other trials have been proposed.

    With respect to thrombotic markers, >40 years ago, plasma fibrinogen levels were demonstrated to be higher among patients with acute thrombosis. The first prospective study to show an association between fibrinogen levels and subsequent cardiovascular disease risk was the Swedish Gothenborg Heart Study in 1984.41 In the Northwick Park Heart Study in the United Kingdom, fibrinogen and factor VII appeared to be as effective as total cholesterol in predicting future risk of CHD.42 It remains unclear, however, whether elevated fibrinogen level is a cause or consequence of atherosclerosis.38

    Whether modification of fibrinogen levels will lower risks is now being evaluated in several secondary prevention trials.43 With regard to the fibrinogen hypothesis, however, because the agents being tested all have potential benefits on other markers of risk, including lipids, the results, even if positive, may be difficult to interpret. Nonetheless, randomized trials to determine the ability of an agent to modify a thrombotic factor and to assess whether such modification in fact decreases risks of subsequent occlusive events will be a crucial component in translational research on any of the new markers from being a focus of research investigation to clinical and public health relevance.

    C-reactive protein, a marker of systemic inflammation, has recently been evaluated as a potential risk factor for cardiovascular disease in the Physicians’ Health Study, a randomized trial of aspirin and beta-carotene in the prevention of cardiovascular disease and cancer. In a prospective nested case-control analysis using baseline blood specimens, increased levels of C-reactive protein were associated with increased risks of subsequent MI and ischemic stroke.44 The use of aspirin was associated with significant reductions in the risk of MI (55.7%, P=.02) among men in the highest quartile but with only a small, nonsignificant reduction among those in the lowest quartile (13.9%, P=.77). These findings on MI raise the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.

    With respect to inflammation and cardiovascular disease, proinflammatory cytokines raise markers such as C-reactive protein. Proinflammatory cytokines also increase coagulation45 and cause an unfavorable lipid profile of a peculiar form, with decreased cholesterol, decreased HDL cholesterol, and increased triglycerides.46 It also appears that infection,4748 smoking,49 diabetes,50 and periodontal disease51 all increase proinflammatory cytokines, whereas aspirin,44 nonsteroidal antiinflammatory drugs,52 antioxidants,53 and glucocorticoids54 may decrease proinflammatory cytokines. These complex interrelationships and their possible clinical relevance require further evaluation in basic, clinical, and epidemiological research.

    Thus, we are now entering new frontiers of research that have the potential for greatly expanding our understanding of risk factors for cardiovascular disease. In addition to homocysteine and fibrinogen, the promising atherosclerotic and/or thrombotic markers include factor VII, endogenous tissue plasminogen activator, plasminogen activator inhibitor, d-dimer, and lipoprotein(a). From a pathophysiological perspective, further research is needed on the balance between procoagulant factors—such as factor VII, impaired fibrinolysis, tissue plasminogen activator levels, and plasminogen activator inhibitor—and evidence of ongoing clot formation—such as fibrinogen or d-dimer. Potential genetic markers requiring further research include possible predictors of arterial disease, such as the MTHFR genotype, the ACE gene, and angiotensinogen, as well as possible predictors of venous disease, such as the factor V mutation. There is also increasing interest in the relationship of psychosocial factors, socioeconomic status, environmental stresses, and social disparity with cardiovascular disease risk.

    The current totality of evidence supports a complex multifactorial model as more plausible than any single genetic marker to predict risk of CHD. Because we are at the early stages of research on all these new fronts, many important questions remain, including whether measurement of these potential new risk factors will complement or overlap with established risk factors. Specifically, the research on these new markers raises three important questions. First, does the assessment of any new marker add to the ability to predict who is at elevated risk over and above the predictive value of established risk factors? Second, are there means of favorably modifying levels of atherosclerotic and/or thrombotic markers? And third, would knowledge of genetic factors affect clinical practice?

    With continued research, it seems likely that some environmental factors, including atherosclerotic, thrombotic, and inflammatory markers, as well as genetic factors, may well becomeas routinely measured as part of the assessment of the cardiovascular risk profile of an individual. It seems less likely, however, that such measurements would ever replace our focus on established risk factors.

    In that regard, we should not let the perfect be the enemy of the possible. Substantial benefits can still be gained from control or elimination of established cardiovascular risk factors. Specifically, in terms of blood cholesterol, a 10% decrease corresponds to roughly a 30% decrease in risk of CHD.26 With the publication of the Scandinavian Simvastatin Survival Study,55 the West of Scotland Coronary Primary Prevention Study,56 and most recently the Cholesterol and Recurrent Events trial57 in the United States, the totality of evidence now indicates clear benefits of cholesterol lowering by HmG-CoA reductase inhibitors, or statins, on MI, stroke, cardiovascular death, and total mortality.58 For blood pressure, a 6 mm Hg decrease in diastolic pressures >90 mm Hg through pharmacological therapy among those with mild to moderate hypertension results in a 16% decrease in CHD and a 42% decrease in stroke.1415 Cessation of cigarette smoking yields about a 50% decrease in risk of CHD,19 even among the elderly,59 beginning within months of cessation. The benefits of smoking cessation assume particular importance in light of the epidemic of tobacco use now occurring in developing countries, which will cause a substantial increase in their cardiovascular disease rates during the next several decades.10 Finally, the continuing epidemic of obesity in the United States is perhaps second only to smoking as the leading avoidable cause of all premature deaths.606162

    The clear need for more public education concerning the continuing epidemic of cardiovascular disease is reflected in the results of a recent Gallup poll, in which 46% of women perceived breast cancer to be their major health risk, while only 4% believed this to be the case for heart disease.63 The reality, however, is that although 1 in 25 women will die from breast cancer, 1 in 3 will die from heart disease.

    Thus, for established risk factors, we clearly must redouble our clinical and public policy efforts. The dividends this will yield are clear and immediate. For the promising newer potential risk factors, we need an increase in the commitment of research funding. From 1985 to 1995, the total NIH budget increased by 31.3%. At the same time, however, NHLBI funding rose by just 4.5%—and the portion allocated for heart disease research actually decreased by 5%.64 We have, in some senses, been victims of our own success, as the remarkable progress made over the past several decades in decreasing mortality from cardiovascular disease has contributed to a widespread misperception that the cardiovascular disease “problem” has been solved.

    More than 50 years ago, in the landmark federal report “Science: The Endless Frontier,” presidential adviser Vannevar Bush wrote, “Progress in the war against disease depends on a flow of new scientific knowledge. New products, new industries and more jobs require continuous additions to knowledge . . . and the application of that knowledge to practical purposes. Science provides no panacea for individual, social, and economic ills. But without scientific progress, no amount of achievement in other directions can insure our health, prosperity, and security as a nation in the modern world.”65

    Praising the far-reaching effects of Bush’s report, Harvard University president Neil Rudenstine wrote in a recent commentary, “We have pursued this path over the past 50 years, and our nation’s health, prosperity and security have benefitted enormously as a result. . . . [I]n our drive to bring the federal budget closer to balance, we must keep in mind that our short-term choices will have profound long-term effects. . . . In the past 50 years, we have built a research enterprise that is the pride of the world. If we damage it, it will not be easily mended. And, in the long run, it will cost far more to rebuild something that has been allowed to slip into disrepair than to keep a strong and productive enterprise running well.”66

    In conclusion, whether we are concerned with cardiovascular disease as basic researchers, healthcare providers, clinical investigators, or epidemiologists and statisticians, it is crucial that we maintain a united front in calling for increased public health efforts to combat the current epidemic in the United States and the emerging pandemic of cardiovascular disease. It is equally critical that a steady flow of funding be ensured for the promising new frontiers of research that will greatly aid our understanding of the causes—and our ability to prevent and treat—cardiovascular disease.

    In this vein, the words of Benjamin Franklin seem as important and timely today as at the signing of the Declaration of Independence on July 4, 1776: “We must all hang together, or assuredly we shall all hang separately.”67

    Presented as the Lewis A. Conner Memorial Lecture at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10, 1996.

    Table 1. Sources of Evidence in Identifying Risk Factors for Cardiovascular Disease

    Basic research
    Epidemiological research
    Case-control studies
    Cohort studies
    Randomized trials

    Table 2. Causal and Preventive Risk Factors for Cardiovascular Disease

    Cigarette smokingLow-dose aspirin?
    Elevated cholesterolEstrogen replacement therapy in women?
    HypertensionAntioxidant vitamins?
    Physical inactivity

    Table 3. Potential New Risk Factors for Cardiovascular Disease

    Atherosclerotic and/or ThromboticGenetic
    Plasma fibrinogenMTHFR gene
    Factor VIIACE gene
    Endogenous tissue-type plasminogen activatorAngiotensinogen
    Plasminogen activator inhibitorVenous
    d-DimerFactor V mutation


    Correspondence to Charles H. Hennekens, MD, DrPH, Eugene Braunwald Professor of Medicine and Professor of Ambulatory Care and Prevention, Harvard Medical School, Chief, Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA.


    • 1 Conner LA. The American Heart Journal. Am Heart J.1925; 1:115–116.CrossrefGoogle Scholar
    • 2 Statistical Abstract of the United States: 1995. Washington, DC: US Department of Commerce; 1995.Google Scholar
    • 3 Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown & Co; 1987.Google Scholar
    • 4 Total Population Death Rate for CVD, by Age, per 100 000, US, 1979–93. Dallas, Tex: American Heart Association; 1996.Google Scholar
    • 5 Health, United States, 1994. Hyattsville, Md: National Center for Health Statistics; 1995.Google Scholar
    • 6 Johnson LD, Bachman JG, O’Malley PM. Cigarette Smoking Continues to Rise Among American Teenagers in 1996. Ann Arbor, Mich: University of Michigan News and Information Services; December 19, 1996.Google Scholar
    • 7 Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents. Arch Pediatr Adolesc Med.1995; 149:1084–1091.Google Scholar
    • 8 Physical Activity and Health: A Report of the Surgeon General. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1996.Google Scholar
    • 9 Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability From Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, Mass: Harvard University Press; 1996.Google Scholar
    • 10 Murray CJL, Lopez AD. The Global Burden of Disease: Summary. Cambridge, Mass: Harvard University Press; 1996.Google Scholar
    • 11 Cairns J. The treatment of diseases and the war against cancer. Sci Am.1985; 253:51–59.CrossrefMedlineGoogle Scholar
    • 12 Hennekens CH, Buring JE. Observational evidence. In: Warren KS, Mosteller F, eds. Doing More Good than Harm: The Evaluation of Health Care Interventions. Ann N Y Acad Sci.1993; 703:18–24.CrossrefMedlineGoogle Scholar
    • 13 MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease, 1: prolonged differences in blood pressure—prospective observational studies corrected for the regression dilution bias. Lancet.1990; 335:765–774.CrossrefMedlineGoogle Scholar
    • 14 Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke, and coronary heart disease, 2: short-term reductions in blood pressure: overview of randomized drug trials in their epidemiologic context. Lancet.1990; 335:827–838.CrossrefMedlineGoogle Scholar
    • 15 Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med.1993; 153:578–581.CrossrefMedlineGoogle Scholar
    • 16 Doll R, Hill AB. Smoking and carcinoma of the lung: preliminary report. BMJ.1950; 2:739–748.CrossrefMedlineGoogle Scholar
    • 17 Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of 684 proved cases. JAMA.1950; 143:329–336.CrossrefMedlineGoogle Scholar
    • 18 Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DS: US Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control; 1964. PHS publication No. 1103.Google Scholar
    • 19 Hennekens CH, Buring J, Mayrent SL. Smoking and aging in coronary heart disease. In: Bosse R, Rose C, eds. Smoking and Aging. Lexington, Mass: DC Heath; 1984:95–115.Google Scholar
    • 20 Hennekens CH, Gaziano JM, Manson JE, Buring JE. Antioxidant vitamin-cardiovascular disease hypothesis is still promising, but still unproven: the need for randomized trials. Am J Clin Nutr.1995; 62:1337S–1380S.CrossrefMedlineGoogle Scholar
    • 21 Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY, Yu Y, Liu Bq, Tangrea J, Sun Yh, Liu F, Fraumeni JF, Zhang YH, Li B. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst.1993; 85:1483–1492.CrossrefMedlineGoogle Scholar
    • 22 Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med.1994; 330:1029–1035.CrossrefMedlineGoogle Scholar
    • 23 Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Branhard S, Hammar S. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med.1996; 334:1150–1155.CrossrefMedlineGoogle Scholar
    • 24 Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med.1996; 334:1145–1149.CrossrefMedlineGoogle Scholar
    • 25 Worth RM, Kato H, Rhoads GG, Kagan A, Syme SL. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: mortality. Am J Epidemiol.1975; 102:481–490.CrossrefMedlineGoogle Scholar
    • 26 Manson JE, Tosteson H, Ridker PM, Satterfield S, Hebert P, O’Connor GT, Buring JE, Hennekens CH. The primary prevention of myocardial infarction. N Engl J Med.1992; 326:1406–1416.CrossrefMedlineGoogle Scholar
    • 27 Heller RF, Chinn S, Tunstall Pedoe HD, Rose G. How well can we predict coronary heart disease? Findings in the United Kingdom Heart Disease Prevention Project. BMJ.1984; 288:1409–1411.CrossrefMedlineGoogle Scholar
    • 28 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol.1971; 231:232–235.CrossrefMedlineGoogle Scholar
    • 29 Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation.1989; 80:749–756.CrossrefMedlineGoogle Scholar
    • 30 Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged anti-platelet therapy. BMJ.1988; 296:320–332.CrossrefMedlineGoogle Scholar
    • 31 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet treatment, I: prevention of vascular death, myocardial infarction and stroke by prolonged antiplatelet therapy in different categories of patients. BMJ.1994; 308:81–106.CrossrefMedlineGoogle Scholar
    • 32 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet.1988; 2:349–360.MedlineGoogle Scholar
    • 33 Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med.1989; 321:129–135.CrossrefMedlineGoogle Scholar
    • 34 Buring JE, Hennekens CH, for the Women’s Health Study Research Group. The Women’s Health Study: summary of the study design. J Myocardial Ischemia.1992; 4:27–29.Google Scholar
    • 35 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses’ Health Study. N Engl J Med.1991; 325:756–762.CrossrefMedlineGoogle Scholar
    • 36 Rich-Edwards J, Manson JE, Hennekens CH, Buring JE. Primary prevention of coronary heart disease in women. N Engl J Med.1995; 332:1758–1766.CrossrefMedlineGoogle Scholar
    • 37 Braunwald E. Foreword. In: Fuster V, Verstraete M, eds. Thrombosis and Cardiovascular Disease. Philadelphia, Pa: WB Saunders; 1992.Google Scholar
    • 38 Ridker PM, Hennekens CH. Hemostatic risk factors for coronary heart disease. Circulation.1991; 83:1098–1100.CrossrefMedlineGoogle Scholar
    • 39 Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA.1992; 7:878–881.Google Scholar
    • 40 Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow MR, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation.1996; 94:2410–2416.CrossrefMedlineGoogle Scholar
    • 41 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med.1984; 311:501–505.CrossrefMedlineGoogle Scholar
    • 42 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet.1986; 2:533–537.CrossrefMedlineGoogle Scholar
    • 43 Goldbourt U, Behar S, Reicher-Reiss H, Agmon J, Kaplinsky E, Graff E, Kishon Y, Caspi A, Weisbort J, Mandelzweig L. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Study). Am J Cardiol.1993; 71:909–915.CrossrefMedlineGoogle Scholar
    • 44 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.1997; 336:973–979.CrossrefMedlineGoogle Scholar
    • 45 Van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJH, Evenberg AJM, de Groot ER, Jansen J, Gallati H, Büller HR, ten Cate JW, Aarden LA. Elimination of interleukin-6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med.1994; 179:1253–1259.CrossrefMedlineGoogle Scholar
    • 46 Hardardottir I, Grunfeld C, Feingold KR. Effects of endotoxin and cytokines on lipid metabolism. Curr Opin Lipidol.1994; 5:207–215.CrossrefMedlineGoogle Scholar
    • 47 Ioamoto GK, Konicel SA. Cytomegalovirus immediate early genes upregulate interleukin-6 gene expression. J Invest Med.1997; 45:175–182.MedlineGoogle Scholar
    • 48 Örtqvist Å, Hedlund J, Wretling B, Carlström A, Kalin M. Diagnostic and prognostic values of interleukin-6 and C-reactive protein in community-acquired pneumonia. Scand J Infect Dis.1995; 27:457–462.CrossrefMedlineGoogle Scholar
    • 49 Cohen HJ, Pieper CF, Harris TB, Rao KMK, Currie MS. Associations of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol Med Sci. In press.Google Scholar
    • 50 Hotamisgil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor-necrosis factor-α in human obesity and insulin resistance. J Clin Invest.1995; 95:2409–2415.CrossrefMedlineGoogle Scholar
    • 51 Takahashi K, Takashiba S, Nagai A, Takigawa M, Myoukai F, Kurihara H, Murayama Y. Assessment of interleukin-6 in the pathogenesis of periodontal disease. J Periodontal Res.1994; 65:147–153.CrossrefGoogle Scholar
    • 52 Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med.1995; 332:848–854.CrossrefMedlineGoogle Scholar
    • 53 Meydani M, Evans WJ, Handelman G, Biddle L, Fielding RA, Meydani SN, Burrill J, Fiatarone MA, Blumber JB, Cannon JG. Protective effect of vitamin E on exercise-induced oxidative damage in young and older adults. Am J Physiol.1993; 264:R992–R998.MedlineGoogle Scholar
    • 54 DeRijk R, Michelson D, Karp B, Petrides J, Galliven E, Deuster P, Paciotti G, Gold PW, Sternberg EM. Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1β, IL-6, and tumor necrosis factor-α production in humans: high sensitivity of TNF-α and resistance of IL-6. J Clin Endocrinol Metab.1997; 82:2182–2191.MedlineGoogle Scholar
    • 55 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.1994; 344:1383–1389.MedlineGoogle Scholar
    • 56 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Primary Prevention Study Group. N Engl J Med.1995; 333:1301–1307.CrossrefMedlineGoogle Scholar
    • 57 Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med.1996; 335:1001–1009.CrossrefMedlineGoogle Scholar
    • 58 Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. JAMA.1997; 278:313–321.CrossrefMedlineGoogle Scholar
    • 59 LaCroix AZ, Lang J, Scherr P, Wallace RB, Cornoni-Huntley J, Berkman L, Curb JD, Evans D, Hennekens CH. Smoking and mortality among older men and women in three communities. N Engl J Med.1991; 324:1619–1625.CrossrefMedlineGoogle Scholar
    • 60 Manson JE, Stampfer MJ, Hennekens CH, Willett WC. Body weight and longevity: a reassessment. JAMA.1987; 257:353–358.CrossrefMedlineGoogle Scholar
    • 61 Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, Hennekens CH, Speizer FE. Body weight and mortality among women. N Engl J Med.1995; 333:677–685.CrossrefMedlineGoogle Scholar
    • 62 Willett WC, Manson JE, Stampfer MJ, Colditz GA, Rosner B, Speizer FE, Hennekens CH. Weight and weight change in relation to risk of coronary heart disease in women: a 14-year follow-up. JAMA.1995; 273:461–465.CrossrefMedlineGoogle Scholar
    • 63 Women’s top health risks. U S A Today. May 18, 1995:1-D.Google Scholar
    • 64 Breslow J. Presidential address. Presented at the American Heart Association 69th Scientific Sessions, November 10, 1996, New Orleans, La.Google Scholar
    • 65 Bush V. Science: the endless frontier: a report to the President by Vannevar Bush, director of the Office of Scientific Research and Development. Washington, DC: US Government Printing Office; July 1945.Google Scholar
    • 66 Rudenstine NL. Don’t slash funding for scientific research. The Boston Globe. July 11, 1995.Google Scholar
    • 67 Bartlett J. Famous Quotations: A Collection of Passages, Phrases, and Proverbs Traced to Their Sources in Ancient and Modern Literature. 16th ed. Boston, Mass: Little, Brown and Co; 1992:310.Google Scholar


    eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

    Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.