(Circulation. 1995;92:3350-3360.)
© 1995 American Heart Association, Inc.
Articles |
Clinical Misconceptions Dispelled by Epidemiological Research
Presented as the Ancel Keys Lecture at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.
From the Department of Medicine, Boston (Mass) University School of Medicine/Framingham Heart Study.
Correspondence to William B. Kannel, MD, Department of Medicine, Section of Preventive Medicine and Epidemiology, Evans Memorial Research Foundation, Boston University School of Medicine/Framingham Heart Study, Boston, MA 02118.
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Abstract |
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 Top Abstract IntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Abstract The epidemiological approach to investigation of cardiovascular disease was innovated in 1948 by Ancel Keys' Seven Countries Study and T.R. Dawber's Framingham Heart Study. Conducted in representative samples of the general population, these investigations provided an undistorted perception of the clinical spectrum of cardiovascular disease, its incidence and prognosis, the lifestyles and personal attributes that predispose to cardiovascular disease, and clues to pathogenesis. The many insights gained corrected numerous widely held misconceptions derived from clinical studies. It was learned, for example, that the adverse consequences of hypertension do not derive chiefly from the diastolic pressure, left ventricular hypertrophy was not an incidental compensatory phenomenon, and small amounts of proteinuria were more than orthostatic trivia. Exercise was considered dangerous for cardiovascular disease candidates; smoking, cholesterol, and a fatty diet were regarded as questionable promoters of atherosclerosis. The entities of sudden death and unrecognized myocardial infarction were not widely appreciated as prominent features of coronary disease, and the disabling and lethal nature of cardiac failure and atrial fibrillation was underestimated. It took epidemiological research to coin the term "risk factor" and dispel the notion that cardiovascular disease must have a single origin. Epidemiological investigation provided health professionals with multifactorial risk profiles to more efficiently target candidates for cardiovascular disease for preventive measures. Clinicians now look to epidemiological research to provide definitive information about possible predisposing factors for cardiovascular disease and preventive measures that are justified. As a result, clinicians are less inclined to regard usual or average values as acceptable and are more inclined to regard optimal values as "normal." Cardiovascular events are coming to be regarded as a medical failure rather than the first indication of treatment.
Key Words: epidemiology • risk factors • prevention
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Introduction |
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There has been skepticism expressed concerning the validity and utility of epidemiological research on risk factors for the development of cardiovascular disease.1 2 3 4 This report examines the accomplishments of epidemiological research into the evolution of cardiovascular disease over the past half-century, emphasizing the insights and clinical misconceptions dispelled by knowledge gained from prospective epidemiological investigations.
The era of an epidemiological approach to unraveling the causes of atherosclerotic cardiovascular disease began in 1948, approximately two decades after coronary heart disease (CHD) reached the awareness of physicians in the United States in 1923. Until the advent of epidemiological studies, the inciting causes were speculative based on selected pathological studies, animal experiments, and clinical impressions. Investigations comprised descriptive case reports and case-control comparisons of small samples because electronic computers and calculators were unavailable. The net and joint effects of predisposing factors could not be estimated precisely because multivariate analysis techniques and computers to rapidly count and sort large amounts of data did not exist. This state of affairs led to many misconceptions about the nature and causes of atherosclerotic disease.
Because they were population-based and prospective, epidemiological studies were less subject to distortion of selection bias. Routine periodic observation of more representative general population samples allowed discernment of the full clinical spectrum of cardiovascular events, including then-overlooked sudden deaths and unrecognized myocardial infarctions. By means of long-term and more complete surveillance, studies provided a more accurate appraisal of the prognostic implications of overt disease and seemingly innocuous predisposing conditions such as high "normal" blood pressures, cholesterol values, fibrinogen, left ventricular hypertrophy (LVH), weight, and cigarette smoking. They changed concepts of "normal" for these biological variables from usual to optimal and emphasized continuous graded effects rather than the false perception of critical values. They also emphasized the multifactorial cause of atherosclerotic cardiovascular disease.
This report attempts to illustrate the influence of epidemiological research on current medical thinking and practice with Framingham Heart Study data used to provide examples of misconceptions that have been corrected. Because the Framingham study spans >40 years of continuous surveillance of a general population sample and its data have been widely used and cited in clinical cardiology, such a historical perspective is possible.
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Origins of Cardiovascular Epidemiology |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Several epidemiological population studies implemented in the 1950s were undertaken to ferret out factors capable of predicting the development of coronary heart disease (CHD).5 6 7 8 9 10 These prospective studies closely observed population samples to determine the incidence of CHD and any factors that may be related to its development. Included among these were the Framingham study, which followed a general population sample of men and women; the Albany study of male civil servants; the Los Angeles study of male civil servants; the Chicago Western Electric and Peoples Gas studies; and a study of Minneapolis professional and businessmen.5 6 7 8 9 The individual and pooled data from these studies established the relevance of a number of major cardiovascular risk factors and stimulated the application of this approach to unraveling the population and individual determinants of cardiovascular disease incidence around the world.5 As a result, epidemiology has become the basic science of preventive cardiology.
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Medical Trivia |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Although physicians agreed on the necessity for early diagnosis and treatment of diseases such as atherosclerotic cardiovascular disease (which were not considered preventable), opinions on the need to detect and treat asymptomatic abnormalities such as hypertension or elevated cholesterol differed.10 11 The perception prevailed that it was meddlesome to label, alarm, and treat persons with these asymptomatic conditions, particularly when they were within the usual range of values found in the apparently healthy population. However, an examination of the way in which cardiovascular disease evolved in the general population revealed that much of the premature mortality from CHD and stroke occurs with little warning in populations generally prone to atherosclerosis and in relation to identified risk factors present well in advance of symptoms.12 A preventive approach is essential because more than half the CHD deaths are unexpected, occurring suddenly outside the hospital.13 Only 20% of myocardial infarctions are preceded by chronic angina, and most strokes occur unheralded by transient ischemic attacks. Atherosclerotic cardiovascular events must be dealt with on their way to happening if substantial inroads are to be made against the continuing epidemic of cardiovascular disease.
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Hypertension |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Before data emerged from epidemiological investigations of the hazards of hypertension, the most common variety of hypertension was characterized as "benign essential hypertension." Opinions differed on the indications for or value of treatment of essential hypertension, the level of pressure at which treatment should be instituted, or the age at which therapy should be prescribed. There was also no sound basis for selecting those hypertensive persons most likely to develop cardiovascular sequelae.
At the initiation of the Framingham study, it was considered
appropriate to ignore labile and systolic elevations of blood
pressure.14 Clinicians tended to disregard casual blood
pressure elevations in favor of basal pressures.14 15
Isolated systolic hypertension was rarely taken
seriously.16 Those features of hypertension began to lose
their aura of innocence when epidemiological investigation revealed
that an average of a series of pressures determined risk, regardless of
how labile it is.17 Isolated systolic hypertension
was shown to be a powerful predictor of cardiovascular
disease,18 and casual office pressures have been found to
be highly predictive of subsequent occurrence of all the major
atherosclerotic cardiovascular diseases (Fig 1
).19
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Before epidemiological insights were provided, hypertension was considered to be less dangerous in the elderly and women. Because blood pressure tended to increase with age, higher pressures were accepted as more "normal" in the elderly than in the middle-aged population.20
Epidemiological data corrected this clinical misconception by
demonstrating that risk ratios did not diminish greatly with age
and that the hazard of a given elevation of pressure in the elderly was
actually higher than the same pressure in the
middle-aged.21 Although women have a lower incidence
of cardiovascular events than men with the same blood
pressure, the risk ratio in women has been shown to be just as great as
in men (Fig 1
).
Epidemiological investigation also pointed out that the hazard of
hypertension does not depend solely on blood pressure elevation but is
markedly influenced by the cardiovascular risk factors
that tend to accompany hypertension (Fig 2). It is clear
that accepted teachings about hypertension that were based on case
studies and clinical impressions did not stand the test of prospective
epidemiological investigation. Physicians have corrected many of these
misconceptions because of the epidemiological insights
provided.15 16 22
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Blood Lipids |
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When epidemiological studies were begun, there was a substantial body of evidence connecting serum total cholesterol to the occurrence of atherosclerosis. Animal experiments had shown a relation between the production of elevated serum cholesterol and the development of atherosclerosis. Clinical studies demonstrated that average cholesterol values of persons with CHD were significantly higher than those of control subjects. However, it remained for the prospective epidemiological studies to demonstrate a relation between preexisting elevation of serum cholesterol and the subsequent development of CHD.5 23
Despite the abundant evidence incriminating serum cholesterol, there has been much confusion about its importance. Unfortunately, uncertainty about the mechanism responsible for the elevation of serum cholesterol often obscured its importance as a predictor and contributor to the development of CHD.23 24 25 26 27
As the technology for measuring blood lipids evolved, triglyceride levels and the various lipoprotein-cholesterol fractions were investigated as atherogenic factors predisposing to CHD.25 Gofman and associates28 maintained that the lipoproteins were more fundamental than the serum total cholesterol, a claim that proved correct despite early skepticism.
HDL Cholesterol
Cardiovascular epidemiologists, in concert
with
clinicians, had by 1966 arrived at a consensus that total plasma
cholesterol was for practical purposes as useful for
predicting CHD as any other lipid or lipoprotein
measure.26 This ignored a substantial study by Barr et
al27 and some other reports in the 1950s and
1960s,26 that indicated that persons with high HDL levels
were less likely to have CHD than persons with low HDL levels. It also
ignored prospective data from Gofman et al28 showing that
HDL was related to the incidence of CHD. It was only after
case-control studies of the Cooperative Lipoprotein Phenotyping
Study25 and prospective data from the Framingham
study29 were published that HDL cholesterol
was widely accepted as an important lipid feature of
atherogenesis.
Blood lipids are now conceded to be fundamental to atherogenesis. Epidemiological data demonstrating the hazards of dyslipidemia, coupled with recent evidence of the efficacy of controlling blood lipids by diet and pharmaceuticals, have stimulated interest in the detection and treatment of elevated cholesterol and LDL. Federal guidelines were promulgated for the detection and treatment of dyslipidemia.30 Epidemiological data indicate that implementation of these guidelines will require the evaluation and treatment of a large proportion of the adult population unless more efficient lipid profiles are used in conjunction with a comprehensive cardiovascular risk profile.30 31 32
Epidemiological investigation has shown that elevated cholesterol and LDL cluster with other major cardiovascular risk factors that are metabolically linked.32 Only 20% of individuals with elevation of these lipids are free of one or more other risk factors that greatly affect the risk.32 Serum total cholesterol has been shown to reflect two-way traffic of cholesterol entering and leaving the arterial intima, so it is important to ascertain the LDL and HDL fractions.32 Epidemiological investigation has demonstrated that at any serum total cholesterol, risk for CHD is markedly affected by the associated HDL cholesterol so that, unless it is measured, it is possible to falsely reassure or needlessly alarm those patients screened with serum total or LDL cholesterol alone.32 The ratio of total to HDL cholesterol has been shown to be a practical indicator of the atherogenic potential of serum lipids. A ratio of 3.5, which corresponds to half the North American risk of coronary events, would appear optimal32
Because the risk associated with
blood lipids is markedly affected by
often-accompanying cardiovascular risk factors, it
is important to consider blood lipids as a component of a comprehensive
cardiovascular risk profile (Fig 3).
This is now possible with epidemiological data that have been
formulated into American Heart Association (AHA)–distributed
multivariate risk profile scoring
systems.33
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Diabetes |
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Before data from epidemiological research became available, clinicians believed that only overt diabetes posed a threat of accelerated atherogenesis.34 It is now evident that any degree of impairment of glucose intolerance is a hazard.35 Four decades of epidemiological research now indicate that glucose intolerance is a powerful independent predisposing factor for atherosclerotic cardiovascular disease in general and coronary disease in particular.35 36 37 Diabetes has been shown to increase the incidence of atherosclerotic cardiovascular twofold for men and threefold for women (Table 1
). Epidemiological research established that
contrary to clinical impression, diabetes has a greater impact on
women, eliminating their advantage over men. It also established that
diabetes was metabolically linked to other atherogenic
cardiovascular risk factors that are labeled the
insulin-resistance syndrome (Table 2).
Epidemiological research established that dyslipidemia and
other risk factors that accompany diabetes actually precede the
appearance of diabetes.38 Thus, it established diabetes as
a complex metabolic disorder, whereas the clinical
perception was that the dyslipidemia and hypertension
occurred only as a consequence of uncontrolled diabetes.
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Epidemiological research has also established that the
cardiovascular risk in diabetics is not uniform; it
varies widely, depending on the intensity of the
metabolically linked atherogenic risk factors (Fig 4). Because
the high risk of
cardiovascular sequelae in diabetics is concentrated in
those patients with one or more associated risk factors, physicians are
now alerted to the fact that "control" of diabetes involves more
than normalization of blood sugar.
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Homocysteine |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Homocystinemia was linked to atherothrombotic disease by McCully39 in 1969. This was done in autopsy studies of children with distinct inborn errors of metabolism, resulting in a marked accumulation of homocysteine in the blood and urine. A later review of 20 retrospective case-control studies indicated that moderate hyperhomocystinemia was an independent risk factor for premature CHD, stroke, and peripheral artery disease.40 Two large prospective epidemiological studies recently showed that there is a graded increase in risk of myocardial infarction with the level of homocysteine after adjustment for cardiovascular risk factors.41 42 Data from the Framingham study further showed that multivariable odds of extensive carotid atherosclerosis increased twofold with high versus low homocysteine quartiles.43
Data from the Framingham study also indicated that nearly two thirds of the cases of moderate hyperhomocystinemia in the elderly were associated with reduced intakes of folic acid and vitamin B6 and decreased plasma status of folate, peridoxial 51 phosphate (active B6), and B12.44 This has major preventive implications. Hence, what was clinically regarded as a genetic curiosity has been shown by epidemiological research to be a fairly common atherogenic consequence of vitamin deficiency.
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Cigarette Smoking |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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In 1956, the AHA issued a statement on smoking and cardiovascular disease that among other things indicated that the available evidence was insufficient to justify concluding that there is a cause-and-effect relation between cigarette smoking and increased death rates from CHD.45 In reviewing the problem in 1960, Dawber46 concluded that increased cigarette smoking is clearly related to death rates from CHD but that it had not been possible to clearly link cigarette smoking to coronary morbidity. Just 4 years after the 1956 AHA statement, the Framingham study, based on 6 years of follow-up, reported an association between cigarette smoking and incidence of CHD that owing to lack of numbers, was not statistically significant.47
Thus, except for reports from the Albany Cardiovascular Health Center and the Framingham study in 1959 and 1961,47 reliable information relating CHD to tobacco use had not been published, and even the AHA was reluctant to indict it.45 Both studies presented data that suggested a relation, but the events were too few in each to permit a definitive assessment. To remedy this, information on smoking habits and incidence of CHD was combined in these two large prospective studies. Heavy cigarette smokers were found to experience a threefold increase in incidence of myocardial infarction compared with nonsmokers, pipe and cigar smokers, and former cigarette smokers.47 Cigarette smoking appeared unrelated to angina pectoris, and former smokers had morbidity and mortality from CHD similar to those who never smoked.
Thus, prospective epidemiological investigation of the relation of cigarette smoking to the development of atherosclerotic cardiovascular disease established smoking as a major hazard to cardiovascular health. The risk of CHD was shown to be related to the number of cigarettes smoked each day, regardless of the duration of the smoking habit. This, and the fact that quitting smoking was found to promptly decrease the risk by half compared with persons who continued to smoke, served to give smoking abatement a high priority among prevention-minded physicians.
As we approach the end of the 20th century, smoking continues to decline in the United States, with fewer than one in four adults reporting that they use cigarettes on a regular basis. At the beginning of the 1950's, cigarette smoking was nearly universally accepted and enjoyed widespread social appeal. The prevalence of smoking among physicians and dentists was equal to and even exceeded that seen in the general population of men. Today, <10% of physicians or dentists smoke.
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Obesity |
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By the end of the 19th century, the life insurance industry recognized that overweight is associated with premature mortality attributable chiefly to greater susceptibility to cardiovascular disease.48 49 The insurance companies were persuaded not only that overweight leads to excess mortality but also that weight reduction by overweight people leads to a reduction in mortality.
However, there have been dissent and continuing controversy concerning optimal weights and the independent contribution of obesity to cardiovascular disease.50 51 52 This issue has not been completely resolved by epidemiological research, although research has provided some clues to pathogenesis such as the insulin-resistance syndrome. Controversy continues about the influence of patterns of obesity and the benefits of weight reduction.53
However, obesity, or excessive body fat, has been established as a significant contributor to atherosclerotic cardiovascular disease and the risk factors that predispose to its occurrence.53 More recently epidemiological research has indicated that the pattern of obesity is important, with centralized or abdominal obesity being particularly hazardous.53 54 This android variety of obesity has been linked to occurrence of cardiovascular disease, hypertension, dyslipidemia, and insulin resistance.55 56
Obesity has also been shown to be a contributor to cardiac failure, particularly in women, both directly and by promoting hypertension, LVH, insulin resistance, and dyslipidemia. Weight gain has been shown to be an important determinant of the general population burden of cardiovascular risk factors.53 Despite this, it has been puzzling to find that weight reduction and leanness are associated with an apparent excess of cardiovascular and overall mortality.57 Recent epidemiological investigation indicates that this is a result of involuntary weight loss and confounded by cigarette smoking.57
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Fibrinogen |
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Clinically, fibrinogen values within the "normal" range were not considered pathological. However, mounting epidemiological data support a causal connection between high-normal fibrinogen and atherosclerotic cardiovascular disease. In both men and women, there is a consistent significant relation of fibrinogen to cardiovascular disease in general and CHD in particular.58 The average fibrinogen values were found to be higher in persons with other risk factors, including hypertension, cigarette smoking, diabetes, obesity, and elevated hematocrit. However, epidemiological investigation indicates an independent contribution of fibrinogen to atherosclerotic cardiovascular disease on adjustment for these coexisting risk factors, and fibrinogen enhances risk in persons who have these other risk factors.58 Seven prospective epidemiological studies document an excess of cardiovascular events in persons with high-normal fibrinogen values (Fig 5
).58 59 60 61 62 63
Each SD
increase in fibrinogen is associated with 30% and 40% increases in
CHD events in men and women, respectively.58
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Fibrinogen appears to be a marker for unstable atherosclerotic lesions that are fissuring, undergoing subintimal hemorrhage or inflammatory lipid infiltration.58
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Leukocyte Count |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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A number of epidemiological studies consistently called attention to the fact that a significant relation exists between leukocyte count and the occurrence of CHD and stroke.63 64 65 66 67 68 69 Once again, attention is called to the concept that what is regarded clinically as within the "normal" range is not necessarily optimal. High-normal leukocyte counts have been shown to have a powerful influence on risk of CHD.63 64 65 66 67 68 69 The interaction with cigarette smoking needs further clarification.64 Among other possible pathogenetic mechanisms, the likelihood exists that like fibrinogen such mild leukocytosis indicates active atherogenesis.
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Physical Activity |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Before epidemiological data were available, physical exercise was not recommended for candidates for cardiovascular disease. In fact, even minimal exertion was discouraged. Epidemiological research, beginning with the work of Morris et al,70 called attention to the benefits of exercise. A number of epidemiological studies followed that demonstrated that men in active occupations requiring greater exertion appeared to have lower rates of fatal coronary disease than those in sedentary occupations.70 71 72 73 This argument was weakened by evidence of differences in body build and obesity that might have led to selection of the different occupations.73 Later epidemiological investigations clearly demonstrated that physical inactivity is a risk factor for CHD, even with other risk factors, including obesity, accounted for.74 75 76 Initially, only vigorous exercise of the sort needed to achieve a trained effect was deemed necessary for benefit; now it is recognized that even moderate exercise is beneficial.77 78
However, recent reports have confirmed clinicians' long-held suspicion that vigorous exertion can trigger a coronary attack.74 75 Importantly, it has been shown that regular moderate exercise provides protection against this triggering effect of strenuous exercise.74
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Left Ventricular Hypertrophy |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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The ECG pattern of LVH was long recognized as an important clinical diagnostic entity, but before epidemiological investigation in 1969 there were no prospective data allowing a precise assessment of the incidence and significance of this finding in the general population.80 Before this, it was thought that LVH was a compensatory phenomenon in response to the increased workload imposed by hypertension or valvular disease or the need to offset loss of heart muscle after myocardial infarction. There was even fear that removal of this hypertrophy would be detrimental.
Epidemiological research has shown that LVH is an ominous harbinger of overt disabling and lethal cardiovascular disease and not an asset.81 Echocardiographic evaluation of the impact of LVH indicated grave consequences, with a continuous graded effect proportional to the degree of increased left ventricular mass. No critical value where compensatory hypertrophy ends and pathological hypertrophy begins could be identified.82
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Atrial Fibrillation |
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Although atrial fibrillation was recognized as an important hazard for the occurrence of a stroke, the magnitude of the problem was not appreciated until data on its prognostic significance were reported by epidemiological surveys.83 84 Atrial fibrillation is the most frequently encountered serious arrhythmia in clinical practice and the most common arrhythmia responsible for hospital admission in the United States.
Epidemiological investigation has identified and quantified cardiovascular precursors.85 The prognostic outlook, based on clinical impression, was believed to depend chiefly on the associated cardiac disease, but epidemiological investigation indicated that its appearance added greatly to the hazard of the underlying cardiac disease.86 Atrial fibrillation not associated with overt cardiac disease was thought to be benign and not related to excess mortality.87 The prognosis of such lone atrial fibrillation is currently in dispute.88 89
In the past, and even as late as 1986, the risk of embolism in atrial fibrillation was not considered excessive unless the rhythm disturbance was intermittent or associated with obstructed emptying of the left atrium.90 Epidemiological data revealed that chronic, sustained atrial fibrillation is actually more dangerous than the paroxysmal variety.86
As a result of epidemiological data documenting the hazards of chronic atrial fibrillation, trials have been undertaken to determine the benefit of anticoagulant therapy.91 Physicians now take chronic atrial fibrillation much more seriously than in the past. Chronic atrial fibrillation without valvular heart disease used to be considered relatively innocuous. Now chronic atrial fibrillation in the absence of rheumatic valvular heart disease is recognized as a major hazard for stroke. Whereas most cardiologists agreed that atrial fibrillation in mitral stenosis was a clear indication for prophylactic anticoagulation, there was considerable doubt about its indication in the elderly with nonvalvular atrial fibrillation.
Clinical Manifestations of CHD
Increasingly reliable
estimates of the prevalence, incidence, and
clinical manifestations of CHD from prospective epidemiological studies
emphasized the importance of this disease as a lethal and disabling
health hazard. By means of routine periodic ECG examination of general
population samples, it was possible to learn that one in three
myocardial infarctions went unrecognized,92 a fact not
widely recognized from clinical studies. In addition, on the basis of
clinical studies, it was believed that angina pectoris occurs
predominantly in men,93 whereas general population data
from Framingham indicated that if all cases of angina are ascertained
rather than only those presenting for medical care, angina is as
common in women as in men.94 95 Only angina
associated
with myocardial infarction was more common in men.
It was widely accepted that sudden death was usually the result of CHD and that it may be the only manifestation of CHD. It was not possible until epidemiological data became available to determine how often sudden death occurs as the initial manifestation of CHD. One in six coronary attacks was found to present with sudden death as the first, last, and only symptom. It was found, including prehospital and hospital mortality, that the first prolonged attack of ischemic chest pain carries a 34% fatality rate.96
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Misconceptions About Stroke |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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In 1955, Cecil and Loeb's Textbook Dexter noted that "there is little or no correlation between the height of the blood pressure and symptoms, rate of progression and development of complications".97 In 1951, Denny-Brown,98 a prominent neurologist, concluded about treatment of transient ischemic attacks that "it would, therefore, appear logical to raise systemic blood pressure.
Prospective epidemiological studies have clearly demonstrated that the incidence of all varieties of stroke, including atherothrombotic brain infarction, is directly related to blood pressure.99 Since 1970, numerous trials of drug treatment of hypertension have consistently shown that for stroke prevention the benefits are substantial. Meta-analysis of trials indicate that a 42% reduction in stroke incidence can be expected.100
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Cardiac Failure |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Before epidemiological investigation of cardiac failure, there were conflicting data on the incidence, frequency of predisposing cardiac diseases, and prognosis for this end-stage cardiac event.101 Virtually all clinical studies of cardiac failure were hampered by a lack of consistent diagnostic criteria and complete extended follow-up. Clinical studies underestimated the contribution of hypertension to the occurrence of cardiac failure because of inconsistent recording of blood pressure and a lack of concern among physicians about hypertension in their patients.22
Because medication often effected a gratifying reversal of signs of cardiac failure, the long-term outlook of the disease was viewed with greater optimism than justified. Epidemiological investigation in the Framingham study revealed that its clinical course and prognosis were surprisingly grim, not much better than for cancer.101 Epidemiological data also indicated that sudden death was a common feature of CHF mortality, with heart failure rates five times the rate of the general population.102
Epidemiological investigation has provided the means for identifying
high-risk candidates for cardiac failure from a
multivariate cardiovascular risk
profile made up of systolic pressure, LVH, blood lipids, vital
capacity, heart rate, and cardiac enlargement on roentgenogram (Fig
6). This allows detection and preventive management of
candidates for cardiac failure before the heart has used up all its
reserve and compensatory mechanisms.
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Peripheral Artery Disease |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Before epidemiological research, clinicians' concerns about peripheral artery disease focused on the danger to the limbs and symptoms. Epidemiological research has produced useful insights into the risk factors that promote peripheral artery disease and its prognostic implications.103 104 105 Identification of patients at high risk of intermittent claudication also points out those at increased risk of other atherosclerotic cardiovascular events and mortality. Thus, measures taken to avoid peripheral artery disease also should improve the outlook for other cardiovascular events and mortality. At the time of diagnosis of intermittent claudication, about one third of patients have evidence of overt cardiovascular disease.103 Whereas the prognosis for the limbs has been shown to be good, the outlook for cardiovascular morbidity and mortality is distinctly ominous.103
The same primary risk factors that promote CHD also predict
intermittent claudication, including blood pressure, diabetes,
cigarette smoking, cholesterol, and ECG
LVH.106 The most powerful risk factors for
peripheral artery disease are cigarette smoking and
diabetes.106 Risk of intermittent claudication increases
with the burden of atherogenic risk factors (Fig 7).
Risk profiles for estimating the conditional probability of developing
peripheral artery disease from the identified risk factors
can and should be made possible.
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The Elderly |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Cardiovascular disease is the leading cause of death and a prominent cause of disability, which takes the joy out of reaching a venerable stage of life. Before epidemiological research, atherosclerotic cardiovascular disease was considered a degenerative wear-and-tear phenomenon of aging that was virtually inevitable. However, mortality data have shown that death rates from CHD and stroke have declined dramatically over the past three decades and that the elderly have shared in the decline. Evidently, cardiovascular morbidity and mortality are not inevitable, and risk factor modification has potential even for the elderly.
Epidemiological investigation has provided a more optimistic outlook for the prevention of cardiovascular disease in the elderly. The primary cardiovascular risk factors have been shown to apply in the elderly and the middle-aged, including hypertension, dyslipidemia, impaired glucose tolerance, physical indolence, and cigarette smoking.107 These risk factors have been shown to be highly prevalent in the elderly but not an inevitable consequence of aging or genetic makeup.107 With aging, there is a longer exposure to risk factors and perhaps a diminished capacity to cope with them, resulting in a doubled incidence of cardiovascular sequelae at any level of risk factors compared with younger candidates for cardiovascular disease.
The predisposing modifiable risk factors for cardiovascular disease in general and coronary disease, stroke, cardiac failure, and peripheral artery disease in particular are virtually the same in young and old candidates for cardiovascular disease.95 Multivariate cardiovascular risk profiles have been shown to predict cardiovascular disease as efficiently in the elderly as in the young. Although proof of efficacy of modifying the risk factors in older persons is limited to hypertension control, there is little justification for the pessimism of many clinicians about the value of implementing preventive measures in the elderly.
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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When the prospective epidemiological longitudinal investigations were first initiated, it was believed that a single origin for the atherosclerotic cardiovascular diseases would be discovered to be essential and, in most instances, sufficient to induce the pathological process.108 However, four decades of epidemiological research have indicated that each of the atherosclerotic cardiovascular diseases is distinctly multifactorial, with some nontrivial differences in their individual risk factor effects.
The risk factor multivariable concept formulates that certain lifestyles promote atherogenic traits in genetically susceptible persons that, after prolonged exposure, result in a compromised arterial circulation and finally clinical events. Thus, it is now acknowledged that atherosclerotic cardiovascular disease is a multifactorial process involving a variety of metabolically linked predisposing risk factors, each of which is best conceptualized as an ingredient of a cardiovascular risk profile.
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Epidemiological Focus on New Risk Factors |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Over the past four decades, prospective epidemiological investigations at Framingham and elsewhere have documented the importance of a number of primary risk factors that predispose to atherosclerotic cardiovascular disease. Continued clinical, metabolic, and epidemiological research has expanded the number of risk factors and introduced further refinements of those already established. Thus, the atherogenic-lipid connection now is concerned with the apoprotein makeup of the atherogenic LDL cholesterol and protective HDL cholesterol, subfractions of these lipoprotein-cholesterol moieties, and lipoprotein(a). The epidemiological data linking diabetes and glucose intolerance now focus on the atherogenic potential of insulin resistance and its interrelation with lipoprotein lipase, hyperinsulinemia, hypertriglyceridemia, reduced HDL cholesterol, obesity, and hypertension. Researchers studying the connection between hypertension and risk of cardiovascular disease now focus on isolated systolic hypertension, circadian rhythm, and ambulatory monitoring. Detection of a compromised coronary circulation is now possible by exercise ECG examination and ambulatory ECG monitoring to detect silent ischemic attacks.
The epidemiological data demonstrating the ominous cardiovascular implications of ECG LVH have led to more specific and sensitive measures of anatomic hypertrophy with the echocardiogram. Preliminary data from Framingham using the roentgenogram and ECG indicate that both versions contribute independently to risk, suggesting different pathogenetic mechanisms. The benefits of reversion of ECG LVH to normal or improvement in echocardiograph-determined left ventricular mass are under active investigation.
Fibrinogen and elevated white blood cell count have emerged as possible indicators of active, inflammatory atherosclerotic lesions. Fibrinogen is the most solidly established of the thrombogenic risk factors under investigation. It rivals cholesterol in potency as a cardiovascular risk factor. Each 1000-cell increase in white blood cell count has been shown to be associated with 32% and 17% increases in cardiovascular risk in men and women, respectively, with a puzzling interaction with cigarette smoking.
Epidemiological investigations to date indicate that atherosclerotic cardiovascular disease derives from a complex interaction of multiple risk factors. These include living habits that promote atherogenic traits, genetic susceptibility to these traits, indicators of active lesions, and indications of a compromised arterial circulation. Optimal assessments of cardiovascular risk are obtained by multivariate risk profiles made up of the relevant independent risk factors. These profiles have been developed and are being refined and extended from CHD and stroke to cardiac failure and peripheral artery disease.
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Preventive Implications |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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Because overt cardiovascular disease is often lethal and, once manifest, does not allow the heart to be restored to full function, a preventive approach is required. Prospects for prevention are good because epidemiological research has identified and documented modifiable predisposing lifestyles and personal attributes, some of which, when corrected, have been shown to reduce the risk of cardiovascular disease. Multivariate risk profiles have been formulated that facilitate efficient selection of high-risk candidates for preventive measures by physicians. Public health measures also can be implemented to improve the average level of the primary risk factors in the general population. The public can be educated to make better choices in living habits to protect their own health. With these strategies, it should be possible to achieve further improvements in cardiovascular morbidity and mortality. For the candidate at high risk of cardiovascular disease, optimal preventive management requires more than normalization of any particular risk factor; only improvement of the multivariate risk profile has great potential for risk reduction.
The potential for more effective preventive measures continues to expand as epidemiological research uncovers more risk factors such as abdominal obesity, insulin resistance, fibrinogen, high-normal leukocyte count, lipoprotein(a), and homocystinemia. More trials are needed to determine the efficacy of risk factor correction in the elderly, women, and blacks.
However, based on epidemiological research and the preventive efforts they have stimulated, great strides have been made in reducing cardiovascular mortality in countries making aggressive efforts to reduce known risk factors. These examples should encourage those persons lacking in resolve to implement preventive programs based on existing knowledge. As a result of the epidemiological insights provided, clinicians are beginning to regard overt cardiovascular events as medical failures rather than the first indication for treatment.
Despite strong opinions to the contrary,1 2 3 4 a substantial body of evidence exists that the epidemiological approach to unraveling the causes of atherosclerotic cardiovascular disease has produced considerable enlightenment. This research discipline has achieved a great deal in providing insights into the preclinical and clinical spectrum of atherosclerotic cardiovascular disease. Epidemiological research has stimulated basic laboratory research and profited from advances in our ability to measure relevant variables. Cohort studies have repeatedly confirmed the utility of risk factor profiles for predicting atherosclerotic cardiovascular events.
Epidemiology has emerged as the basic science of preventive cardiology. It can justifiably claim credit for the role it has played in helping to achieve the primary declines in CHD and stroke mortality over the past two decades through changes in lifestyle and medical care stimulated by epidemiological research. Epidemiological investigation has stimulated clinical trials, influenced the practice of medicine, helped formulate public health policy, and provided needed information for health education. The integration of epidemiology in the current multidisciplinary approach to understanding the atherosclerotic cardiovascular diseases will undoubtedly make further changes in the clinical appraisal of candidates for these diseases and continue to correct clinical misconceptions.
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Acknowledgments |
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This work was supported by NIH grants N01-HV-92922 and N01-HV-52971 and the Visiting Scientist Program.
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References |
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TopAbstractIntroductionOrigins of Cardiovascular...Medical Trivia Hypertension Blood Lipids Diabetes Homocysteine Cigarette Smoking Obesity Fibrinogen Leukocyte Count Physical Activity Left Ventricular Hypertrophy Atrial Fibrillation Misconceptions About Stroke Cardiac Failure Peripheral Artery Disease The Elderly Multivariate Risk Formulation Epidemiological Focus on New...Preventive Implications References |
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1. Stehbens WE. The quality of epidemiological data in coronary heart disease and atherosclerosis. J Clin Epidemiol. 1993;46:1337-1346. [Medline] [Order article via Infotrieve]
2.
Comar C. Bad science and social
penalties. Science. 1978;200:1225.
3. LeRiche WH. Is the age of unreason upon us? Can Med Assoc J. 1978;119:5-6. [Medline] [Order article via Infotrieve]
4.
Stehbens WE. Limitations of the
epidemiological method in coronary heart disease.
Int J Epidemiol. 1991;20:818-820.
5. The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to the incidence of major coronary events: final report of the pooling project. J Chronic Dis. 1978;31:201-306. [Medline] [Order article via Infotrieve]
6. Dawber TR, Moore FE, Mann GV. Coronary heart disease in the Framingham study. Am J Public Health. 1957;47:4-24.
7. Doyle JT, Heslin SA, Hilleboe HE, Formel PF, Korns RF. A prospective study of cardiovascular disease in Albany: report of three years' experience: ischemic heart disease. Am J Public Health. 1957;47:25-32.
8.
Keys A, Taylor HL, Blackburn HB, Brozek J, Anderson
JT, Simonson E. Coronary heart disease among Minnesota
business and professional men followed 15 years.
Circulation. 1963;28:381-395.
9. Chapman JM, Goerke LS, Dixon W, Loveland DB, Phillips E. Measuring the risk of coronary heart disease in adult population groups, IV: clinical status of a population group in Los Angeles under observation for two-three years. Am J Public Health. 1957;47:33-42.
10. Werko L. Risk factors and coronary heart disease: facts or fancy? Am Heart J. 1976;91:87-91. [Medline] [Order article via Infotrieve]
11.
Oliver M. Dietary cholesterol,
plasma cholesterol and coronary heart
disease. Br Heart J. 1976;38:214-218.
12.
Gordon T, Kannel WB. Premature mortality from
coronary heart disease: the Framingham study.
JAMA. 1971;215:1617-1625.
13. Kannel WB, Barry P, Dawber TR. Immediate mortality in coronary heart disease: the Framingham study. In: Proceedings of the IV World Congress of Cardiology, Mexican Intl Soc Cardiol. 1963;IV-B:176-188.
14. Smirk FH, Veale Amo, Alstad KS. Basal and supplemental blood pressures in relationship to life expectancy and hypertension symptomatology. N Z Med J. 1959;58:711. [Medline] [Order article via Infotrieve]
15. Vaisrub S. Labile and systolic hypertension: a reappraisal. JAMA. 1981;245:1250. Editorial.
16. Koch-Weser J. The therapeutic challenge of systolic hypertension. N Engl J Med. 1973;289:481-482.
17.
Kannel WB, Sorlie P, Gordon T. Labile
hypertension: a faulty concept? The Framingham study.
Circulation. 1980;61:1183-1187.
18.
Kannel WB, Dawber TR, McGee DL. Perspectives
on systolic hypertension: the Framingham study.
Circulation. 1980;61:1179-1182.
19. Dawber TR, Kannel WB, Revotskie N, Stokes J III, Kagan A, Gordon T. Some factors associated with the development of coronary heart disease: six years' follow-up experience in the Framingham study. Am J Public Health. 1959;49:1349-1356.
20. Kannel WB, Schwartz MJ, McNamara PM. Blood pressure and risk of coronary heart disease: the Framingham study. Dis Chest. 1969;56:43-52. Critical review.
21. Kannel WB. Rationale for treatment of hypertension in the elderly. Am J Geriatr Cardiol. 1994;3:33-45. [Medline] [Order article via Infotrieve]
22. Frohlich ED, Emmott C, Hammarsten JE, Linehan M, Pollack D, Horsley AW. The disregard of abnormal arterial pressure in randomly selected hospitalized patients. Clin Res. 1970;18:629.
23. Kannel WB. Lipid profile and the potential coronary victim. Am J Clin Nutr. 1971;24:1074-1081. [Medline] [Order article via Infotrieve]
24. Smith RL. Diet, Blood Cholesterol and Coronary Heart Disease: A Critical Review of the Literature. Santa Monica, Calif: Vector Enterprises Inc; 1991:2.
25.
Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland
MC, Hulley SB, Kagan A, Zukel WJ. HDL cholesterol
and other lipids in coronary heart disease: the Cooperative
Lipoprotein Phenotyping Study.
Circulation. 1977;55:767-772.
26. Gordon T; Gotto AM Jr, Miller NE, Oliver MF, eds. High Density Lipoproteins and Atherosclerosis: Comments on the Epidemiological Background in High Density Lipoproteins and Atherosclerosis. 1978:121-125.
27. Barr DP, Russ EM, Eder HA. Protein-lipid relationships in human plasma, II: in atherosclerosis and related conditions. Am J Med. 1951;11:480-493. [Medline] [Order article via Infotrieve]
28.
Gofman JW, Young W, Tandy R. Ischemic
heart disease, atherosclerosis and longevity.
Circulation. 1966;34:679-697.
29. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease: the Framingham study. Am J Med. 1977;62:707-714. [Medline] [Order article via Infotrieve]
30.
Expert Panel on the Detection, Evaluation and
Treatment of High Blood Cholesterol in Adults. Summary of
the second report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of
High Blood Cholesterol in Adults. JAMA. 1993;269:3015-3023.
31.
Wilson PWF, Christianson JC, Anderson KM, Kannel
WB. Impact of national guidelines for cholesterol
risk factors screening: the Framingham Offspring Study.
JAMA. 1989;262:41-44.
32. Kannel WB, Wilson PWF. Efficacy of lipid profiles in the prediction of coronary disease. Am Heart J. 1992;124:768-774. [Medline] [Order article via Infotrieve]
33. Anderson KM, Wilson PWF, Odell PM, Kannel WB. Updated coronary risk profile. Circulation. 1991;83:357-363.
34. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Cardiovascular complications in diabetics. Adv Metab Disorders. 1973;suppl 2:493-499.
35. Wilson, PWF, Cupples LA, Kannel WB. Is hyperglycemia associated with cardiovascular disease? The Framingham study. Am Heart J. 1991;121:586-590. [Medline] [Order article via Infotrieve]
36. Kannel WB, Hjortland MC, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34:29-34. [Medline] [Order article via Infotrieve]
37. Kannel WB, McGee DL. Diabetes and glucose intolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care. 1979;2:120-126. [Abstract]
38.
Wilson PWF, McGee DL, Kannel WB. Obesity, very
low density lipoproteins and glucose intolerance over fourteen
years. Am J Epidemiol. 1981;114:697-704.
39. McCully KS. Vascular pathology of homocysteinemia: implications for pathogenesis of atherosclerosis. Am J Pathol. 1969;56:111-128. [Medline] [Order article via Infotrieve]
40. Ueland PM, Refsum H, Brattstrom LA. Plasma homocysteine and cardiovascular disease. In: Francis RBJ, ed. Atherosclerotic Cardiovascular Disease: Hemostatis and Endothelial Function. New York, NY: Marcell Dekker Inc. 1992:182-236.
41.
Stampfer MJ, Malinow MR, Willett WC, Newcomer LM,
Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective
study of plasma homocysteine and risk of myocardial infarction in US
physicians. JAMA. 1992;268:877-881.
42. Arnesen E, Refsum H, Bonaa KH. The Tromso study: serum total homocysteine and myocardial infarction, a prospective study. Abstract presented at the Third International Conference on Preventive Cardiology; 1993; Oslo, Norway.
43. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PWF, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Plasma homocysteine and extracranial carotid stenosis in the Framingham Heart Study. N Engl J Med. 1995;332:287-291.
44.
Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg
IH. Vitamin status and intake as primary determinants of
homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.
45. American Heart Association Committee on Smoking and Cardiovascular Disease, 1956. Cigarette smoking and cardiovascular diseases: report of the American Heart Association. Circulation. 1960:22(suppl 12):160-166.
46. Dawber TR, Kannel WB, Revotskie N, Stokes J III, Kagan A, Gordon T. Some factors associated with the development of coronary heart disease. Am J Public Health. 1959;49:1349-1356.
47. Doyle JT, Dawber TR, Kannel WB, Heslin AS, Kahn HA. Cigarette smoking and coronary heart disease: combined experience of the Albany and Framingham studies. N Engl J Med. 1962;266:796-801.
48. Build and Blood Pressure Study. Chicago, Ill: Society of Actuaries; 1959;1.
49. Marks HH. Influence of obesity on morbidity and mortality. Bull N Y Acad Med. 1960;36:296-312. [Medline] [Order article via Infotrieve]
50. Mann GV. The influence of obesity on health. N Engl J Med. 291:178-185(pt 1);291:226-232.
51. Keys A. Overweight, obesity, coronary heart disease and mortality. Nutr Rev. 1980;38:297-307. [Medline] [Order article via Infotrieve]
52. Andres R, Elahi D, Tobin JD, Muller DC, Brant L. Impact of age on weight goals. Ann Intern Med. 1985;103:1030-1033.
53. Higgins M, Kannel WB, Garrison R, Pinsky J, Stokes J III. Hazards of obesity: the Framingham experience. Acta Med Scand Suppl. 1988;723:23-36. [Medline] [Order article via Infotrieve]
54. Gillum RF. The association of body fat distribution with hypertension, hypertension heart disease, coronary heart disease, diabetes and cardiovascular risk factors in men and women aged 18-79 years. J Chron Dis. 1987;40:421-428. [Medline] [Order article via Infotrieve]
55. Peiris AN, Sothmann MS, Hoffmann RG, Heanes MI, Wilson CR, Gustafson AB, Kissebah AH. Adiposity, fat distribution and cardiovascular risk. Ann Intern Med. 1989;110:864-872.
56. Haffner SM, Fong D, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia, upper body adiposity and cardiovascular risk factors in non-diabetics. Metabolism. 1988;37:333-345.
57.
Garrison RJ, Feinlib M, Castelli WP, McNamara
PM. Cigarette smoking as a confounder of the relationship
between relative weight and long-term mortality: the Framingham
Heart Study. JAMA. 1983;249:2199-2203.
58. Kannel WB, D'Agostino RB, Belanger AJ. Update on fibrinogen as a cardiovascular risk factor. Ann Epidemiol. 1992;2:457-466. [Medline] [Order article via Infotrieve]
59. Wilhelmsen L, Svardsudd 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;34:501-505.
60. Stone MC, Thorp JM. Plasma fibrinogen: a major coronary risk factor. J R Coll Gen Pract. 1985;35:565-569. [Medline] [Order article via Infotrieve]
61. Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol. 1990;43:913-919. [Medline] [Order article via Infotrieve]
62. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines RP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principle results of the Northwick Park Heart Study. Lancet. 1986;2:533-637. [Medline] [Order article via Infotrieve]
63. Yarnell JWG, Baker IA, Sweetnam PM, Bainton D, O'Brien JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity and white blood cell count are major risk factors for ischemic heart disease: the Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation. 1991;84:836-844.
64. Friedman GD, Klatsky AL, Siegalub AB. The leukocyte count as a predictor of myocardial infarction. N Engl J Med. 1974;290:1275-1278.
65. Zalokar JB, Richard JL, Claude JR. Leukocyte count, smoking and myocardial infarction. N Engl J Med. 1981;304:465-468. [Medline] [Order article via Infotrieve]
66.
Prentice RL, Szatrowski JP, Fujikura T, Kato H, Mason
MW, Hamilton HH. Leukocyte counts and coronary heart
disease in a Japanese Cohort. Am J Epidemiol. 1982;116:496-509.
67.
Grimm RH Jr, Neaton JD, Ludwig W. Prognostic
importance of the white blood cell count for coronary, cancer
and all-cause mortality. JAMA. 1985;254:1932-1937.
68.
Phillips AN, Neaton JD, Cook DG, Grimm RH, Shaper
AG. Leukocyte count and risk of major coronary disease
events. Am J Epidemiol. 1992;136:59-70.
69. Kannel WB, Anderson K, Wilson PWF. White blood cell count and cardiovascular disease. JAMA. 1992;261:1253-1256.
70. Morris JN, Raffle PAB, Roberts CG, Parks JW. Coronary heart disease and physical activity of work. Lancet. 1953;2:1053-1057.
71. Morrison SL. Occupational mortality in Scotland. Br J Industr Med. 1957;14:130-132. [Medline] [Order article via Infotrieve]
72. Kahn HA. The relationship of reported coronary disease mortality to physical activity of work. Am J Public Health. 1963;53:1058-1067.
73. Morris JN, Heady JA, Raffle PAB. Physique of London busmen: epidemiology of uniforms. Lancet. 1956;2:569-570.
74.
Curfman GD. Is exercise beneficial—or
hazardous—to your heart? N Engl J
Med. 1993;329:1730-1731.
75.
Curfman GD. The health benefits of exercise: a
critical appraisal. N Engl J Med. 1993;328:574-576.
76.
Paffenbarger RS Jr, Wing AL, Hyde RT. Physical
activity as an index of heart attack risk in college alumni.
Am J Epidemiol. 1978;108:161-175.
77.
Berlin JA, Colditz GA. A meta analysis
of physical activity in the prevention of coronary heart
disease. Am J Epidemiol. 1990;132:612-628.
78.
Loon AS, Connett J, Jacobs DR Jr, Rauramaa R.
Leisure-time physical activity levels and risk of coronary
heart disease and death: the Multiple Risk Factor Intervention
Trial. JAMA. 1987;258:2388-2395.
79. Kannel WB. Habitual physical activity and risk of coronary heart disease. Can Med Assoc J. 1967;96:811-812. [Medline] [Order article via Infotrieve]
80. Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence and mortality in the Framingham study. Ann Intern Med. 1969;71:89-105.
81. Kannel WB, Cobb J. Left ventricular hypertrophy and mortality: results from the Framingham study. Cardiology. 1992;81:291-298. [Medline] [Order article via Infotrieve]
82. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561-1566. [Abstract]
83.
Gajewski J, Singer RB. Mortality in an insured
population with atrial fibrillation. JAMA. 1981;245:1540-1544.
84. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med. 1982;306:1018-1022. [Abstract]
85.
Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB,
Belanger AJ, Wolf PA. Independent risk factors for atrial
fibrillation in a population-based cohort: the Framingham Heart
Study. JAMA. 1994;271:840-844.
86. Kannel WB, Abbott RD, Savage DD, McNamara PM. Coronary heart disease and atrial fibrillation: the Framingham study. Am Heart J. 1983;106:389-396. [Medline] [Order article via Infotrieve]
87. Neufeld HN, Wagenvoort CA, Burchell HB, Edwards JE. Idiopathic atrial fibrillation. Am J Cardiol. 1961;8:193-197. [Medline] [Order article via Infotrieve]
88.
Brand FN, Abbott RD, Kannel WB, Wolf PA.
Characteristics and prognosis of lone atrial fibrillation: 30-year
follow-up in the Framingham study. JAMA. 1985;254:3449-3453.
89. Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR, Istrup DM, Frye AL. Atrial fibrillation: a population-based study over three decades. N Engl J Med. 1987;317:669-674. [Abstract]
90.
Treseder AS, Sastry BSD, Thomas TDL, Yates MA,
Pathy MSJ. Atrial fibrillation and stroke in elderly
hospitalized patients. Age Aging. 1986;15:89-92.
91. Singer DE. Randomized trials of warfarin for atrial fibrillation. N Engl J Med. 1992;327:1451-1453. Editorial. [Medline] [Order article via Infotrieve]
92. Kannel WB, Abbott RD. Incidence and prognosis of unrecognized myocardial infarction: an update from the Framingham study. N Engl J Med. 1984;311:1144-1147. [Abstract]
93. Friedberg CK. Diseases of the Heart. 2nd ed. Philadelphia, Pa: WB Saunders; 1956:455.
94. Kannel WB, Feinleib M. Natural history of angina pectoris in the Framingham study: prognosis and survival. Am J Cardiol. 1972;29:154-163.[Medline] [Order article via Infotrieve]
95. Kannel WB, Vokonas PS. Demographics of the prevalence, incidence and management of coronary heart disease in the elderly and in women. Ann Epidemiol. 1992;2:5-14. [Medline] [Order article via Infotrieve]
96. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coll Cardiol. 1985;5:141B-149B.
97. Dexter L, Cecil RL, Loeb RF, ed. A Textbook of Medicine. 9th ed. Philadelphia, Pa: WB Saunders; 1955:1256.
98. Denny-Brown D. Symposium on specific methods of treatment: treatment of recurrent cerebrovascular symptoms and the questions of `vasospasm.' Med Clin North Am. 1951;35:1457-1474. [Medline] [Order article via Infotrieve]
99.
Wolf PA. Contributions of
epidemiology to the prevention of
stroke. Circulation. 1993;88:2471-2478.
100. 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 epidemiological context. Lancet. 1990;335:827-838. [Medline] [Order article via Infotrieve]
101. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441-1446.
102. Kannel WB, Plehn JF, Cupples LA. Cardiac failure and sudden death in the Framingham study. Am Heart J. 1988;115:869-875. [Medline] [Order article via Infotrieve]
103.
Kannel WB, Skinner JJ, Schwartz MJ, Shurtleff
D. Intermittent claudication: incidence in the Framingham
study. Circulation. 1970;41:875-883.
104.
Smith GD, Shipley MJ, Rose G. Intermittent
claudication: heart disease risk factors and mortality: the Whitehall
Study. Circulation. 1990;82:1925-1931.
105. Revnanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand. 1982;211:249-256. [Medline] [Order article via Infotrieve]
106. Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham study. J Am Geriatr Soc. 1985;33:13-18. [Medline] [Order article via Infotrieve]
107. McCormick J. The multifactorial etiology of disease, a dangerous delusion. Prospect Biol Med. 1988;32:103-108.
108.
Wolf PA, D'Agostino RB, Belanger AJ, Kannel
WB. Probability of stroke: a risk profile from the Framingham
study. Stroke. 1991;22:312-318.
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 M. Kerkeni, F. Addad, M. Chauffert, A. Myara, M. Ben Farhat, A. Miled, K. Maaroufi, and F. Trivin Hyperhomocysteinemia, Endothelial Nitric Oxide Synthase Polymorphism, and Risk of Coronary Artery Disease Clin. Chem., January 1, 2006; 52(1): 53 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Vasan, L. M. Sullivan, P. W.F. Wilson, C. T. Sempos, J. Sundstrom, W. B. Kannel, D. Levy, and R. B. D'Agostino Relative Importance of Borderline and Elevated Levels of Coronary Heart Disease Risk Factors Ann Intern Med, March 15, 2005; 142(6): 393 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M G Colombo, M G Andreassi, U Paradossi, N Botto, S Manfredi, S Masetti, G Rossi, A Clerico, and A Biagini Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298->Asp polymorphism) to the presence, extent, and severity of coronary artery disease Heart, June 1, 2002; 87(6): 525 - 528. [Abstract] [Full Text] [PDF]
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|
|
 |
|
 E.-R. Rietzschel, E. Boeykens, M. L. De Buyzere, D. A. Duprez, and D. L. Clement A Comparison Between Systolic and Diastolic Pulse Contour Analysis in the Evaluation of Arterial Stiffness Hypertension, June 1, 2001; 37 (6): e15 - e22. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. C. Swan The Framingham offspring study: A commentary J. Am. Coll. Cardiol., April 1, 2000; 35(5_Suppl_B): 13B - 17B. [PDF]
|
|
|
|
 |
|
 C. Lenfant Conquering Cardiovascular Disease: Progress and Promise JAMA, December 1, 1999; 282(21): 2068 - 2070. [Full Text] [PDF]
|
|
|
|
 |
|
 C. T Sempos, K. Liu, and N. D Ernst Food and nutrient exposures: what to consider when evaluating epidemiologic evidence Am. J. Clinical Nutrition, June 1, 1999; 69 (6): 1330S - 1338S. [Abstract] [Full Text] [PDF]
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|
|
|
|
H. J. C. Swan The Framingham Offspring Study: a commentary J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1136 - 1140. [Full Text] [PDF]
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|
|
 |
|
 G. Fager and O. Wiklund Cholesterol Reduction and Clinical Benefit : Are There Limits to Our Expectations? Arterioscler. Thromb. Vasc. Biol., December 1, 1997; 17(12): 3527 - 3533. [Abstract] [Full Text]
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