AJH 1999;12:92S–95S
Coronary Heart Disease is a Multifactorial
Disease
N. Poulter
Coronary heart disease (CHD) is the leading cause of
death in the Western World. For effective treatment
and prevention strategies to be put in place, the
major risk factors associated with this disease must
be identified. Data show that almost 300 variables are
statistically associated with CHD. However, evidence
suggests that the vast majority of coronary events can
be explained on the basis of blood pressure, lipids,
smoking, and diabetes. Laboratory, experimental, and
epidemiologic data identify dyslipidemia as a pivotal
CHD risk factor, in the absence of which other risk
factors cease to produce any important increase in
absolute risk of events. For example, in populations
with relatively low levels of low-density lipoprotein
cholesterol, such as China and Japan, the incidence
of CHD remains low even when smoking and
hypertension are highly prevalent.
Observational data have clearly established that
CHD risk factors tend to cluster in individuals.
The impact of coexisting risk factors is greater than
additive, and indeed is usually multiplicative. The
implications of such an interactive effect are that
O
ur understanding of the pathogenesis of
coronary heart disease (CHD) continues
to improve as new findings from clinical,
experimental, and epidemiologic research
emerge. Despite this, CHD is still the leading cause of
From the Cardiovascular Studies Unit, Department of Clinical
Pharmacology, Imperial College School of Medicine at St. Mary’s
Campus, London, United Kingdom.
Address correspondence and reprint requests to Professor N.
Poulter, Cardiovascular Studies Unit, Department of Clinical Phar-
macology, Imperial College School of Medicine at St. Mary’s Cam-
pus, Paddington, London W2 1PG, U.K.
© 1999 by the American Journal of Hypertension, Ltd.
Published by Elsevier Science, Inc.
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relatively normal levels of two or more risk factors
in coexistence may have a profound impact on
risk. Despite these findings, in the past most
treatment algorithms have viewed risk factors
separately and have recommended discrete
treatment targets. More recent guidelines have
taken a broader view and provide simple, yet
accurate, methods of evaluating absolute risk
based on the consideration of several risk factors.
Coronary heart disease is clearly a multifactorial
disease with risk factors that tend to cluster and
interact in an individual to determine the level of
coronary risk. The current trend towards a more
holistic approach in CHD risk evaluation and
preventive management appears logical based on
evidence from animal-experimental, observational,
and clinical trial evidence. Am J Hypertens 1999;
12:92S–95S © 1999 American Journal of
Hypertension, Ltd.
KEY WORDS: Coronary heart disease, risk-factor
clustering, dyslipidemia.
death in the Western World. It is imperative, therefore,
that effective diagnostic, preventive, and therapeutic
strategies are put in place. For this to be possible, it is
essential to identify the major risk factors associated
with cardiovascular disease.
RISK FACTORS
Almost 300 variables have been shown to be statisti-
cally associated with CHD.1 It is not possible to prove
which, if any, of these variables actually cause CHD,
but rather a judgment has to be made based on an
overview of available epidemiologic, experimental,
and clinical evidence. The criteria recommended to
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AJH–OCTOBER 1999 –VOL. 12, NO. 10, PART 2 CHD IS A MULTIFACTORIAL DISEASE 93S

TABLE 1. FROM ASSOCIATION TO CAUSE:

SUGGESTED CRITERIA

• Strength
• Dose response
• Temporal sequence
• Independence
• Consistency
• Coherence (plausible)
• Predictive
• Reversible

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help make that judgment are shown in Table 1. Al-
though almost no variables satisfy all of these criteria,
for a limited number of variables the data do appear to
be sufficiently robust to conclude that they are caus-
ally associated with CHD (Table 2).
Taken in isolation, for each of these variables— or FIGURE 1. Coronary heart disease mortality rates in different
risk factors—there is a limited ability to predict which countries from 1988 to 1991 (data taken from reference 6). Indi-
individuals will or will not develop a CHD event. viduals were aged from 30 to 69 years.
There are several reasons for the lack of predictive
power of any single factor. These include the impact of
events observed among this cohort of 4473 middle-
protective factors (eg, high intake of fresh fruit and
aged British men had at least one of the following:
vegetables), genetic susceptibility, and the fact that
serum total cholesterol ⱖ 6 mmol/L, current cigarette
risk factors tend to cluster in individuals, as well as the
smoking, or a systolic blood pressure ⱖ 148 mm Hg or
fact that when risk factors coexist, their impact on risk
diastolic blood pressure ⱖ 93 mm Hg. The remaining
tends to be multiplicative or even greater. Further-
five patients were either exsmokers or had a past
more, levels of risk factors evaluated by single or even
medical history of CHD.
several assessments are unlikely to accurately reflect
Further focus on the key risk factors for CHD arises
the lifetime exposure of risk factors for a chronic de-
from the huge cohort of 356,222 middle-aged Ameri-
generative disease such as CHD, the first signs of
can men screened for the MRFIT study.5 Among the
which appear in the early years of life2 and may
2.2% (7948 men) of those screened who satisfied five
originate even earlier.3
criteria, the CHD mortality rates were 8/10,000 per
It is most unlikely that the list of variables shown in
annum, which is lower than for age-matched men in
Table 2 is complete, but several pieces of evidence
Japan, where the lowest CHD rates in the industrial-
suggest that the major risk factors for CHD have been
ized world prevail (Figure 1).6 The criteria were no
identified and are shown in Table 2. For example, after
previous history of acute myocardial infarction; non-
4 years’ follow-up in the British Regional Heart Study
diabetic; nonsmoker; serum total cholesterol in the
(BRHS),4 197 of the 202 patients with major coronary
lowest quintile; and systolic and diastolic blood pres-
sure in the lowest quintiles.
Consequently, it appears that the vast majority of
TABLE 2. MODIFIABLE AND NONMODIFIABLE
the CHD epidemic currently prevalent in the Western
RISK FACTORS FOR CHD
World can be explained on the basis of blood pressure,
Modifiable lipids, smoking, and diabetes. This is, however, de-
High LDL-C Diabetes (⫾ glucose intolerance) pendent upon defining each risk factor appropriately.
High blood pressure Left ventricular hypertrophy For example, data from the BRHS and MRFIT studies
Smoking Central obesity show that blood pressure and total cholesterol are
Low HDL-C Clotting factors
considered risk factors at levels that do not conven-
Lack of exercise Oral contraceptives
tionally define patients as hypertensive and dyslipide-
Homocysteine
mic, respectively.
Nonmodifiable
Age Family history/genetics DYSLIPIDEMIA: THE PIVOTAL CHD
Gender Birth weight (?) RISK FACTOR
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipopro- At the risk of further oversimplifying the list of vari-
tein cholesterol. ables shown in Table 2, there are various sets of data
94S POULTER
TABLE 3. NI-HON-SAN STUDY: CHD RATES AND
RISK FACTORS IN JAPANESE MEN IN THREE
SOCIETIES*
Japan Hawaii California
Acute myocardial
infarction rate/1000 7.3 13.2 31.4
Hypertensive heart
disease/1000 9.3 1.4 4.6
Nonsmokers (%) 26.0 57.0 64.0
Serum total cholesterol
(mmol/L) 4.7 5.6 5.9
* Data taken from reference 9.
that identify dyslipidemia as the pivotal CHD risk
factor, in the absence of which other risk factors cease
to produce any important increase in absolute risk of
CHD. Supporting evidence for this theory comes from
laboratory, experimental, and epidemiologic data.
In 1941, when reviewing the animal-experimental
data on the etiology of atherosclerosis, Leary summa-
rized, “Excess cholesterol is always present in the
active stages of human atherosclerosis. It can be iden-
tified in the lesions as definitely as can the bacterial or
other parasitic agents producing infections. Human
arterial lesions can be reproduced experimentally by
its use with more exactness than the lesions of many
human infections can be reproduced by the introduc-
tion into susceptible animals of their recognized
causal agents.”7 In essence, the presence of dietary
saturated fat or cholesterol is sufficient to produce
atherosclerosis in an experimental model. In the same
model, no other agent or activity (including chain-smok-
ing, severe hypertension, and stress) can produce ath-
erosclerosis in the absence of dietary fat or cholesterol.
Supportive epidemiologic evidence has arisen from
China and Japan, where, despite very high rates of
smoking and hypertension, CHD rates are very low.8
Even in Japanese patients who are diabetic, CHD
death rates are relatively low. The results of the Ni-
Hon-San study9 (Table 3) suggested that the increase
in CHD rates observed in Japanese migrants to the
United States was due to a worsened lipid profile, in
conditions of reduced hypertensive heart disease and
smoking. It could be argued that the implications of
these observations in Japanese populations cannot be
generalized and may be critically dependent on the
Japanese genotype. However, similar (though less for-
mally evaluated) data are available from other parts of
the world, including parts of Africa and the Carib-
bean. In these areas, as in Japan, hypertension and
smoking are common but CHD rates are (relatively or
absolutely) very low. These populations, in common
with the Japanese, have very low levels of low-density
lipoprotein cholesterol (LDL-C); it seems most un-
likely that this finding is a coincidence.
AJH–OCTOBER 1999 –VOL. 12, NO. 10, PART 2
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FIGURE 2. Body weight and its relation to other risk factors.
Figure adapted with permission from Assmann G: Lipid Metabo-
lism and Atherosclerosis. Schattauer, Stuttgart, New York, 1982.
Along with the animal-experimental data, these ep-
idemiologic data are convincing evidence that serum
total cholesterol (which reflects LDL-C) is the risk
factor that is the major determinant of the baseline
level of CHD events in a population. However, in
modern Westernized societies the vast majority of the
population have sufficient circulatory LDL-C to pro-
duce atherosclerosis. Hence, in the evaluation of CHD
risk, dyslipidemia is quite correctly considered one of
several important risk factors.10 –12
RISK-FACTOR CLUSTERING
Observational data have clearly established that risk
factors tend to cluster in individuals. For example,
dyslipidemia is more common in hypertensives than
in normotensives,13 and hypertension is more com-
mon in diabetics than nondiabetics.14 A further exam-
ple of clustering is shown in Figure 2,15 which shows
the increasing prevalence of several risk factors asso-
ciated with increasing levels of obesity.
It is clear from observational data that when risk
factors coexist, the impact on CHD risk is greater than
additive and indeed is usually multiplicative or even
greater (Figure 3).16 The implications of such an inter-
active effect are that relatively normal levels of two or
more risk factors in coexistence may have a profound
impact on CHD risk, without any of the individual
risk factors being at levels that are usually considered
abnormal and requiring intervention. Hence, the role
of the classic risk factors should not be undervalued.
Given the observations that CHD risk factors cluster
in individuals and interact to determine levels of risk,
it seems reasonable to conclude that individual risk
factors should be neither considered nor managed in
isolation. Despite this, until recent years, most treat-
ment algorithms have taken a blinkered view of each
separate risk factor and have recommended discrete
AJH–OCTOBER 1999 –VOL. 12, NO. 10, PART 2
FIGURE 3. Levels of coronary heart disease risk associated with
combinations of smoking, hypertension, and hypercholesterolemia.
Figure reproduced with permission of The McGraw-Hill Compa-
nies from Genest et al, Hypertension, Physiopathology and Treat-
ment. McGraw Hill, New York, 1977.
didactic thresholds and targets for their treatment,
irrespective of coexisting problems. More recently,
some guidelines have taken a broader view and pro-
vided simple and yet reasonably accurate, easy-to-use
methods of evaluating absolute risk based on consid-
eration of several risk factors. The New Zealand
Guidelines on the management of mild hypertension
are an excellent example of this approach.17
It must be admitted that randomized trial evidence
supporting a multifactorial approach to preventing
CHD is, to date, relatively limited. However, some of
the data, such as that arising from the Oslo Diet Heart
Study,18 suggest that this approach is appropriate.
CONCLUSIONS
In summary, CHD is clearly a multifactorial disease,
with risk factors that tend to cluster and interact in
individuals to determine the level of CHD risk. The
current trend towards a more holistic approach in
CHD risk evaluation and preventive management ap-
pears logical based on evidence from animal-experi-
mental, observational, and clinical trial evidence. Sim-
ple ways of putting the theory into practice are
increasingly important if we are to reduce the current
burden of CHD in Western societies.
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