Epidemiologic Reviews
1
Copyright © 2000 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
DISEASES AND HEALTH PROBLEMS
Coronary Heart Disease Epidemiology in the 21st Century
Herman A. Tyroler
INTRODUCTION
Knowledge of the determinants, distribution, and
sequelae of coronary heart disease (CHD) in popula-
tions of the world's developed nations is extensive, is
growing rapidly, and extends from the molecular level
of individual persons to total societies. Lifestyle
changes as well as public health and medical care
advances in the prevention and treatment of CHD from
the 1950s to the 1980s were accompanied by a 50 per-
cent decline in CHD mortality in countries such as the
United States (1). CHD nevertheless remains the lead-
ing cause of death in developed nations and is predicted
to achieve that status worldwide within decades (2).
The clinical manifestations, morbidity, and mortality
of CHD are end-stage events triggered after decades of
progression of asymptomatic, subclinical coronary
atherosclerosis. The determinants of both the subclini-
cal and clinical stages of the disease are numerous and
varied, including risk factors for individual persons,
group characteristics of entire populations, and envi-
ronmental exposures. Broad, multilevel categories of
CHD determinants and their interrelations are illus-
trated in figure 1. In this conceptualization, the deter-
minants are categorized as follows: inherited genes
and culture; biomedical, lifestyle, and psychosocial
risk factors at the individual level; social, political, and
economic factors at the group and aggregate levels;
and social, medical care, physicochemical, and bio-
logic exposures at the environmental level. Each inter-
actively influences population levels of and trends in
CHD over time. CHD susceptibility is transmitted
intergenerationally, is conditioned environmentally,
evolves and is manifest clinically over the time scale
of each individual person's life, and is expressed in
population rates of CHD during societies' histories.
Received for publication May 3, 1999, and accepted for publica-
tion February 10, 2000.
Abbreviation: CHD, coronary heart disease.
From the Department of Epidemiology, School of Public Health,
University of North Carolina, Chapel Hill, 137 East Franklin Street,
Suite 306, Chapel Hill, NC 27514 (e-mail: htyroler@aol.com).
(Reprint requests to Dr. Tyroler at this address).
Vol. 22, No.
Printed in U.S.A.
In this paper, no attempt is made to detail the wealth
of current information on the CHD determinants in
each category shown in figure 1; rather, a brief
overview of the contemporary status of general knowl-
edge at each level is presented and is illustrated with
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selected examples. Based on this synopsis, the
prospects for CHD epidemiology in the 21st century
within and across these spatial and temporal biosocial
levels are addressed.
ACUTE ISCHEMIC EPISODES AND THEIR
CLINICAL EPIDEMIOLOGY
The incidence of angina, acute myocardial infarc-
tion, and sudden death, the major clinical manifesta-
tions of CHD assessed epidemiologically, varies
according to risk factors, age, gender, and ethnicity at
the individual level and among countries, regions, and
social strata within countries at the population level,
and it has varied markedly over time (3). Unstable
angina, acute myocardial infarction, and acute ischemic
episodes result from sudden, life-threatening, impaired
blood supply to the myocardium and are usually pre-
cipitated by lumen-obstructing thrombi that are super-
imposed on lipid-rich coronary artery plaques after
they rupture (4). Until recently, the "natural history" of
coronary atherosclerosis at these advanced stages of
the disease was resistant to therapeutic intervention; it
now can be converted to a favorable clinical course
modifiable by medical intervention, which is the sub-
ject matter of clinical CHD epidemiology and its clin-
ical trials (5). Often, infarctions can be aborted, their
extension and severity reduced, and progression from
unstable angina to myocardial infarction prevented,
given prompt medical intervention. In-hospital case
fatality rates have declined (6), initially in parallel with
the development of coronary care units and subse-
quently with the development of medical and surgical
techniques for thrombolysis and coronary artery revas-
cularization. Advances in diagnosis and treatment,
both in and out of hospital, have contributed to the
decline in CHD mortality, but how much of the
improved in-hospital prognosis is attributable to treat-
8 Tyroler

Coronary Heart Disease

in Individuals
Inheritance
Culture - Genes
Risk Factors
Environments Established - Emerging Time Scales
Social Subclinical Coronary Atherosclerosis Social Historical
Economic Fatty streaks - Plaques - Complicated Lesions Intergenerational
Political Life Course
Clinically Manifest Coronary Heart Disease
Medical Care Angina, Myocardtal Infarction, Sudden Death Physiological
and Public Health and Biochemical
Physical
Chemical
Biological

Coronary Heart Disease

in Populations
Prevalence, Incidence,

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Case Fatality, Mortality Rate

FIGURE 1. Multilevel, interacting determinants of levels of and trends in coronary heart disease in populations.

ment, admission of less severe cases, or more favor-
able risk factor profiles of cases is unclear (7-9).
There has been differential use of diagnostic,
medical, and surgical procedures such as angiogra-
phy, thrombolytic therapy, and coronary artery
bypass surgery in relation to ethnicity, socio-
economic status, and gender; these procedures are
used less frequently for women and in minority and
socioeconomically disadvantaged strata of the US
population (10). Additionally, use of simple adjunc-
tive medication such as aspirin and beta blockers of
proven efficacy in clinical trials, during and after
acute ischemic episodes, varies across regions of the
United States (11). Furthermore, there are complex
interactive associations of CHD severity, treatment,
and prognosis with supraindividual group and popu-
lation characteristics.
Improved in-hospital survival of acute ischemic
episodes can be expected to increase the prevalence in
populations of persons more susceptible to recurrent
episodes and chronic cardiovascular disease complica-
tions such as congestive heart failure. Regardless of
extent, reduced hospital mortality cannot prevent most
CHD deaths, since the majority (approximately 60 per-
cent of all deaths attributed to CHD) occur out of hos-
pital. It is difficult to obtain valid estimates of the lev-
els of and trends in sudden CHD deaths in and out of
hospital; however, available US data indicate increas-
ing inequalities in relation to the socioeconomic status
of persons and the social environment of populations
(12). Thus, organization and use of the medical care
system, which offers preventive and therapeutic treat-
ments in and out of hospital, is becoming an increas-
ingly important environmental determinant of the dis-
tribution of CHD in populations.
SUBCLINICAL ATHEROSCLEROSIS
Despite its marked increase with age, and in contrast
to earlier beliefs, atherosclerosis resulting in CHD is
not a degenerative, inevitable consequence of aging.
Atherosclerosis begins early in life, and it results from
endothelium injury and repair as well as from active
subintimal inflammatory, immunologic, metabolic,
and hemostatic processes involving multiple systems
and cell types (13). It progresses in stages from depo-
sition of hpid-laden macrophages (foam cells) to fatty
streaks and fibrous plaques with lipid core and calcium
deposits; complicated lesions result from endothelium
disruption, hemorrhage, and occlusive thrombosis (14,
15). Autopsy studies disclose geographic variation in
atherosclerosis prevalence and severity associated
with population mortality rates and association of ath-
erosclerosis with the established risk factors, even at
young ages (16). Many of the pathologic cellular, his-
tologic, gross structural, and functional changes in
arteries can now be assessed in population studies by
measuring circulating markers of cell biology
processes and by using noninvasive imaging and func-
tional techniques.
Results of ultrasound imaging of superficial arteries,
such as the carotids, presently serve as a marker of sys-
Epidemiol Rev Vol. 22, No. 1, 2000

temic atherosclerosis. Carotid intima-media wall
thickness provides reliable and valid estimates of the
presence and extent of local atherosclerosis, is corre-
lated with angiographic coronary atherosclerosis, is
related to the established risk factors, and predicts
prevalent and incident CHD (17, 18). Thickness of this
wall also varies strongly and inversely with socioeco-
nomic status (19). Indices of atherosclerosis in the
arterial beds supplying the lower extremities are
obtained from the ratio of ankle to brachial artery
blood pressure. This index also is related to the estab-
lished CHD risk factors and to prevalent CHD (20).
More direct epidemiologic assessment of the coronary
arteries may be provided by quantitative radiologic
estimation of calcium deposition. Coronary calcium
scores predict the extent of angiographic disease and
CHD case prognosis and are correlated with estab-
lished risk factor levels (21); research currently is
under way to evaluate their predictive utility in large
population studies. New imaging, functional, and
marker tests move epidemiologic studies of athero-
sclerosis to earlier stages, enable testing of mecha-
nisms at multiple levels, and are applicable over the
life course of persons in populations.
RISK FACTORS
Risk factors are central to CHD epidemiology. The
term risk factor is used here to denote attributes of per-
sons that are predictive of incident CHD with evidence
of probable causality; in contrast, the term risk indica-
tor denotes a statistical predictor whose causal role is
uncertain (more than 200 have been identified). Risk
factors include biomedical, behavioral, and lifestyle
characteristics. Those firmly established, for example,
serum total and low density lipoprotein cholesterol,
blood pressure, smoking, diabetes, and diet, are sup-
ported by results of numerous observational epidemio-
logic and genetic, clinical, and pathophysiologic
investigations and animal experiments (22, 23).
Clinical trials of serum total and low density lipopro-
tein cholesterol lowering, which reduced occurrence of
clinical events and progression of atherosclerosis by
amounts consistent with quantitative estimates from
observational epidemiologic studies, have confirmed
their causal significance (24).
Most of the established risk factors are continuously
distributed in populations, and their risk functions are
monotonic. Most cases of CHD do not occur in per-
sons with very high risk factor values but in persons
whose values are closer to the population statistical
norm. Therefore, both population and individual high-
risk perspectives are mandatory in the study of risk
factors. Scores, based on the aggregated values of the
established risk factors, can rank order persons by risk
Epidemiol Rev Vol. 22, No. 1, 2000
Coronary Heart Disease in the 21st Century 9
of incident disease. The CHD risk for women and men
whose scores are in the upper quintile is 10-20 times
higher than for those whose scores are in the lowest
quintile (25). The major risk factors are similarly pre-
dictive of CHD for men and women (26) and appear so
for minorities (27, 28). Although extensive quantita-
tive data currently are lacking for groups other than
White men, large-scale observational studies and clin-
ical trials are under way for women. (29). Life-course
study indicates tracking of risk factor levels over time
(30), and levels are associated with subclinical athero-
sclerosis in adolescents and young adults (16).
Risk summary scores based on the established risk
factors in one population rank order CHD risk for per-
sons in other populations with different CHD rates, but
they usually do not predict absolute incidence rates
across socially diverse populations. The aggregate
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level of established major risk factors for persons does
not completely explain differences in CHD mortality
levels even among developed nations (31). When dif-
ferences among socially defined subpopulations are
explained statistically, inclusion of additional fac-
tors—such as dietary components and physical activ-
ity at the behavioral level; hostility and anger at the
psychological level; indices of obesity and body fat
distribution at the anthropometric level; serum fibrino-
gen at the hemostatic level; and serum high density
lipoprotein cholesterol, lipoprotein(a), triglycerides,
insulin, and homocysteine at the metabolic and bio-
chemical levels—improves quantitative predictiveness
more than is achieved by considering the major estab-
lished risk factors only (32).
A large number of studies have reported on the asso-
ciation of certain chronic bacterial and viral infections
with atherosclerosis and clinical manifestations of
CHD, although causality remains uncertain (33). The
etiologic role of organisms such as Chlamydia pneu-
moniae may be clarified by the results of clinical trials
of ongoing antibiotic treatment for secondary preven-
tion of CHD (34). Among the emerging risk factors,
markers of inflammation and acute-phase reactants,
circulating cytokines, C-reactive protein, white blood
cell count, serum albumin, and fibrinogen are predic-
tors of incident CHD and recurrent acute myocardial
infarction, but it is presently uncertain whether they
reflect the consequences or the causes of atherosclero-
sis and its clinical sequelae (35, 36).
INHERITANCE OF CHD SUSCEPTIBILITY
Family history of CHD is associated with each of the
following stages in the development of the disease in
probands: risk factor elevation (37), subclinical ather-
osclerosis (38), and clinically manifest CHD (39).
Aggregation of the major risk factors present in fami-
10 Tyroler
lies does not totally account for the within-family
aggregation of CHD. Furthermore, occurrence of CHD
in families usually does not follow the pattern of sim-
ple Mendelian inheritance, leading to the aphorism
that CHD aggregates but does not segregate within
families. Inheritance of increased susceptibility to
CHD results from the intergenerational transmission of
cultural, lifestyle, and shared environmental determi-
nants of CHD (40) as well as multiple susceptibility
genes. Parental socioeconomic status is a strong deter-
minant of the adult socioeconomic status of offspring,
and CHD-relevant lifestyle, behavioral, dietary, and
smoking practices may thereby aggregate within fam-
ilies and be expressed as adult CHD risk (41, 42).
A large number of genes associated with increased risk
of CHD have been identified, generally by their relation
to the known risk factors. For example, numerous bio-
chemical steps in the metabolism of serum lipids (43)
and physiologic steps in the regulation of blood pressure
(44) are known to be influenced by genes and therefore
influence CHD risk. Thus, although a few genetic disor-
ders of large, single gene effects exist, such as familial
hypercholesterolemia, CHD and its major risk factors
generally involve many genes, each having a relatively
small effect. Regarding lipids, for example, lipoprotein
receptors, apolipoproteins and Upases, and structural and
functional gene product proteins have been identified as
influencing each of the large number of biochemical
steps involved in absorption of dietary fatty acids and
cholesterol and in synthesis, transport, and metabolism
of serum lipoproteins. Numerous mutant alleles have
been found for genes identified to date. Given the large
number of susceptibility genes and their mutant alleles,
each responsible for only a small effect, and the general
modification of genes' effects in different environments
and in the presence of other genes, CHD is classified as
a complex genetic disorder. Gene-by-environment and
gene-by-gene interactions invalidate meaningful
attempts to estimate the relative importance of genes
versus environment or the independent effect of a single
gene or single risk factor under all circumstances.
Multiple interdependent steps are involved in mainte-
nance of physiologic and biochemical homeostasis of
levels of the risk factors and mediators. Although each
step is influenced by the genotype, mapping of the sus-
ceptibility genotypes to risk factor levels and to subclin-
ical and clinical CHD phenotypes, modified as they are
by internal and external environments, presents formi-
dable theoretical and methodological challenges (45).
BEHAVIORAL, PSYCHOSOCIAL, AND SOCIAL
ENVIRONMENTAL DETERMINANTS
Studies reporting the association of psychosocial
factors, such as hostility, depression, low social sup-
port, social isolation, job instability, and powerless-
ness, with CHD have variously been summarized as
inadequate, conflicting, or inconclusive for women
(46) and conversely as strong enough to enable clinical
trials to be undertaken of the efficacy of modifying
some of these factors (47, 48). In contrast, strong, con-
sistent evidence exists of the association of CHD risk
behavior, risk factors, subclinical atherosclerosis, and
clinically manifest CHD with individual socioeco-
nomic status (49). Levels of and long-term trends in
CHD also vary according to the social environmental
characteristics of nations and of geopolitical units
within nations (50). CHD mortality rates increased dur-
ing the transition of rural, agrarian, and economically
underdeveloped societies to urbanized, industrialized,
and modernized societies. Socioeconomic status was
related positively to CHD during the ascending limb of
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the epidemic; currently, during the descending limb of
the epidemic in countries such as the United States and
Great Britain, socioeconomic status at the individual
and societal level is becoming increasingly inversely
associated with CHD (51).
The quantity of knowledge about CHD determi-
nants, ability to change behavior, availability of pre-
ventive and therapeutic resources, salience of health
compared with other concerns, and preventive and
therapeutic resources in communities of residence is
greater as socioeconomic status increases. All stages in
the development of CHD over the life course—that is,
CHD-relevant knowledge, attitudes, and beliefs; risk
behaviors; biomedical risk factors; preventive medical
care; subclinical atherosclerosis; clinical incidence;
therapeutic medical care; prevalence; secondary pre-
ventive medical care; prognosis; and mortality—are
related to social organization and social exposures
(52).
The social characteristics of geopolitically defined
regions, for example, levels of income, education, and
types of occupations, are related at the aggregate level
to their residents' CHD mortality rates (53).
Additionally, and conceptually distinct, measures of
the distribution per se of these attributes within popu-
lations may be related to CHD. Income inequality, a
characteristic of the population and not the individual
person, as the unit of study reportedly is associated
with CHD mortality across nations and among states in
the United States (54).
CHD EPIDEMIOLOGY IN THE NEAR FUTURE
Given the global increase in life expectancy and the
greater risk of CHD with increasing age, worldwide
increases in CHD are predictable, with CHD as the
leading single cause of death. However, limitations in
long-term forecasting of population levels of and
Epidemiol Rev Vol. 22, No. 1, 2000

trends in CHD is illustrated by the failure to predict, or
even in retrospect to explain adequately, the onset of
the decline of CHD mortality rates in the United States
and most western industrialized nations in the 1960s.
To date, controversy remains regarding the relative
contribution of decreasing incidence and decreasing
case fatality to the subsequent decline in CHD mortal-
ity in these countries (55, 56). The failure to predict
trends in CHD risk-related factors also is illustrated by
the unanticipated current worldwide increase in obe-
sity. In addition, mortality differences are widening
among ethnic and socioeconomic groups in the United
States, and recent trend analyses suggest flattening of
the CHD decline for the aggregate population despite
increasing epidemiologic knowledge, educational pro-
grams, and public health and medical care efforts.
Similar uncertainty exists about the causes of the
presently high and rising rates of CHD in nonmarket-
economy, industrialized countries of eastern Europe.
Cohort studies in these settings indicate they are only
partially explained by elevated levels of some of the
established risk factors, such as hypertension and
smoking (57).
CHD rates appear to be rising in developing nations
(58), although comprehensive and valid epidemiologic
data in these settings are scarce. Prediction of future
patterns of CHD epidemics for these nations can be
based on earlier experiences of now-developed nations.
For example, a decrease in the burden of infectious dis-
eases and undernutrition can be expected, with an
increase in life expectancy and the numbers of older
persons. The transition from poor, predominantly rural
agrarian, hard-manual-labor societies with stable, tradi-
tional cultural and social values to more affluent,
urbanized, industrialized societies with minimal physi-
cal activity demands, diets rich in calories and saturated
fats, increased smoking, and new psychosocial stresses
will prime their populations for the development of ath-
erosclerosis throughout life and for the emergence of
clinical CHD sequelae in large numbers of persons at
older ages. Thus, despite increases in biomedical
knowledge about CHD, the disease can be expected to
increase in frequency and importance worldwide as a
consequence of changes in population composition and
societal organization and of technologic advances.
In the early 21st century, as a simple extrapolation of
ongoing trends, one can confidently predict a marked
increase in knowledge at each of the CHD epidemiol-
ogy levels shown in figure 1 and described in mis paper.
Typing of the entire genome plus indices derived from
presently established and emerging risk factors—sim-
ply, reliably, validly, and inexpensively measurable
many times over the life course—will make it possible
to characterize and identify high-risk persons earlier in
Epidemiol Rev Vol. 22, No. 1, 2000
Coronary Heart Disease in the 21 st Century 11
life. Modifying a person's CHD risk with lifestyle
interventions and medical treatments will be more effi-
cacious and potentially more effective. Continuing
advances in treatment of ischemic episodes will result
in increasing survival and decreased morbidity but with
consequent increases in prevalence of the disease.
Study of the emerging risk factors will increase knowl-
edge about mechanisms responsible for atherosclerosis
and its clinical complications. Technologic innovations,
which permit noninvasive assessment of the structure
and function of the coronary arteries and heart in pop-
ulation studies, combined with methodological and
analytical advances in information processing, will
enable extended epidemiologic investigations of all
stages from clinical CHD and subclinical coronary ath-
erosclerosis to risk factors and their determinants
beginning early and continuing over a person's life.
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Despite the present and predicted future expanding
wealth of epidemiologic and biomedical knowledge
about the determinants of the disease in persons within
populations, the increasing worldwide epidemic of CHD
presents an urgent public health challenge. A shift in the
distribution of the established risk factors to lower val-
ues for populations with currently high levels of CHD
would greatly reduce the public health burden of this
disease. Evidence indicates that primordial prevention,
that is, preventing populations from developing deleteri-
ous levels and distributions of the established coronary
risk factors, would remove CHD as the leading cause of
death. This goal will be achieved with increasing recog-
nition of the different theoretical and methodological
requirements for epidemiologic studies at different lev-
els of biosocial organization; epidemiology will focus
on populations and their attributes as the units of study
in addition to the study of persons within populations
(59). The challenge will be to integrate studies of char-
acteristics of individual persons with those of their social
organizations and environments, providing perspectives
that explain the epidemiology of CHD both within and
among populations, thereby enabling the epidemic to be
controlled further and eventually eradicated.
ACKNOWLEDGMENTS
The author thanks Dr. Gerardo Heiss for critical review of
the manuscript and Marilyn Knowles for preparing the figure.
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