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International Journal of Epidemiology2001;30:S66S72
The a pproach t o prevent ion o f cardiova scular disease (CVD) is
rapidly cha nging because of new and better methods of risk
prediction,1 efficacious th erapies such as lipid-low ering drugs,2
anti-hypertensive therapy,3 development of new technology
to measure subclinical CVD4 and methods of measuring host
susceptibility, i.e. genetics.5 Risk prediction has improved because
major advances in molecular biology and biochemistry make it
possible to evaluate not only total cholesterol levels, but also
lipoproteins, apoproteins, enzymes related to the metabolism of
the lipoproteins a nd their specific receptors. These n ew tech-niqu es are now being applied in both longitudina l studies of
CVD an d in clinical trials.6
Recent clinical trials of lipid-lowering d rugs, both in primary
and secondary prevention of CVD, ha ve clearly show n efficacy
in reducing low density lipoprotein cholesterol (LDLc) levels
and have resulted in substantial declines in coronary heart
disease (CHD), stroke and total mortality.7 The in troduction of
the statin drugs has had a major impact on CVD prevention.
These drugs a ppear to be very safe a nd efficacious. The critical
question now is at w hat level of LDLc and risk of CHD should
an individual be treated w ith drug therapy to low er their LDLc?
The w idespread use of lipid-low ering drug th erapies in
preventive medicine has been limited primarily by the cost of
drugs and concern about their long-term adverse effects.8,9
The n ew techno logies for mea suring subclinical athero-sclerosis have provided the first approaches for epidemiologists
to study the determinants of atherosclerosis in vivo, the
progression of disease and the relationship of subclinical
atherosclerosis to risk of clinical CVD.10 These new measures of
atherosclerosis include ultrasound measurement of carotid
intimal-media w all thickness, an kle-brachial blood pressure,
echocardiography and MRI of the heart , electron-beam
computed tomography (EBCT) and spiral CT to measure the
extent of coronary atherosclerosis, measures of vascular
stiffness, compliance and pulse characteristics and endothelial
International Epidemiological Association 2001 Printed in Great Britain
Prevention of cardiovascular disease and thefuture of cardiovascular disease epidemiologyLew is H Kull er
Background Coron ary h eart disease is preventa ble. The improv ed interpreta tion of risk
factors, in vivonon-invasive measuring of arteries, brain and heart, and proven
efficacy o f both non-pharm acological an d pha rmaceutical therapies provides the
model for both cardiova scular prevention programmes and new epidemiological
studies.
Methods Risk factors can be subdivided into those related to the development of athero-
sclerosis with relatively lon g incubation periods, and risk factors that m oderate
the changes in a therosclerotic plaq ue, th rombosis and fibrinolysis, i.e. th ose w ith
short incubation periods, or proximate risk factors.
Results The level of ApoB conta ining lipoproteins, low density lipoprotein (LDL) and
very low density lipoprotein (VLDL) are th e primary determina nts of ath ero-sclerosis. Using no n-inva sive meth ods of measuring at hero sclerosis, w e can
evaluate the efficacy of intervention to both prevent the development of athero-
sclerosis an d th e progression of disease. The im portan ce of proxim ate risk factors,
especially inflammatory markers, is less estimated than long incubation period
factors. It is possible that a combination of measures of subclinical atherosclerosis
and proximate risk factors may provide the best estimate of the risk of clinical
disease, especially among higher risk older individuals.
Conclusions The m easuremen t of subclinical disease an d new proximat e risk factors
(i.e. inflammation , fibrinolysis) may be useful for comparing reported d ifferences
in rates of clinical disease am ong populations an d m onitoring the emerging epi-
demic of cardiovascular disease in countries that currently have low death ra tes
due to cardiova scular disease.
Keywords Corona ry heart disease, lipids, subclinical d isease, inflamma tion, thrombo sis
Accepted 28 February 2001
University of Pittsburgh, Department of Epidemiology, G SPH, Pittsburgh, PA,
USA.
Correspondence: Lew is H Kuller, Department of Epidemiology, G SPH, 130
DeSoto Street, Pittsburgh, PA 15261, USA. E-mail: [email protected]
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PRE VENTION OF CARDI OVASCU LAR DISEASE S67
function.4,11 The ext ent of subclinical mea sures such as carotid
intimal w all thickness, decreased an kle-brachial blood pressure,
and the increased amounts of arterial coronary calcium are
clearly pow erful predictors of t he risks of clinical CVD.1216
These new measures of subclinical disease can be u sed to
evalua te the relation ships betw een specific risk factors and
measures of atherosclerosis in vivo,17 particularly important in
you nger individuals wh ere long-term follow -ups to clinicaloutcom es wo uld be difficult. It is now possible to compare the
extent of a therosclerosis within a nd across populations in
relation to both genetic and lifestyle factors. We can determine
variables that relate to the progression of atherosclerosis and
identify higher-risk individuals based on the extent of
subclinical disease. Measures of subclinical disease have been
especially valuable in the study of older individuals.4 The
epidemiological studies have further substant iated the pow erful
role of tra ditional cardiov ascular risk factors, especially levels of
LDLc, cigarette smo king, elevated blood pressure, w aist cir-
cumference, diabetes, triglyceride levels, an d low high den sity
lipoprotein cholesterol (HDLc) levels, on the extent of
subclinical disease in both younger and older individuals.17
More recently, studies have also utilized these non-invasivemethods to evaluate short-term effects of pharmacological and
non-pharmacological interventions such as the effects of lipid
lowering and anti-hypertensive drug therapy on carotid
intimal-media w all thickness.7,11
Host susceptibility, i.e. genetic factors, in part, determines
both the levels of risk factors (phenotype), and the relationship
of risk factors to atherosclerosis and to clinical disease. In the
past, most genetic studies primarily focused on fa mily history a s
a predictor of the risk of CVD. A critical qu estion w as w heth er
family history w as an independent risk factor for CHD. Early
genetic metabolic studies focused primarily on major single-
gene disorders such a s familial hy percholesterolaemia. The so-
called genetic revolution has changed the concept of host
susceptibility. It is likely tha t ma ny genes w ill be identified thatmodify the levels of specific risk factors. Most of these new ly
identified genetic polymorphisms w ill likely ha ve a relatively
small effect on a ny risk factor level, but in combina tion w ith
lifestyle or environm ental fa ctors w ill be of considerable
importan ce in determin ing levels of risk factors, phen otypes an d
the risk of CVD. Of specific interest for prevention in the future
w ill be the study of gene-lifestyle and gen e-drug interactions,
i.e. pharma cogenetics. Individuals w ill vary in their response to
various dietary or lifestyle factors, i.e. the amount of saturated
fat o r cholesterol in th e diet and levels of LDLc, as w ell as in
their response to specific drug therapy, such as anti-
hypertensive drugs, and in the reduction in blood pressure
levels an d risk of disease. It is extremely unlikely, ho w ever, that
w e w ill ever reach th e point tha t genetic analysis w ill divide thepopulation into those who are likely to develop a heart attack
over t heir lifetime, irrespective of lifestyle exposures, an d th ose
w ho are immune.18
Development of atherosclerosis
The preva lence of a therosclerosis is very high in most in dus-
trialized populations.19,20 Post-mortem pathology studies and,
more recently, in vivo studies using EBCT have c lear ly
docum ented the very high prevalence of ath erosclerosis w ith
increasing age, especially in population s that consume relatively
high a mou nts of satu rated fa t an d cholesterol. The critical step
from subclinical atherosclerosis to clinical events, i.e. myo-
cardial infarction or sudden CHD death, is likely determined in
part by the characteristics of coronary plaque morphology, such
as rupture, haemorrhage, erosion of the plaques, and by
secondary thrombosis.5,18 There a re three h ypoth eses related to
the development of atherosclerosis.21
First, the response toinjury hypothesis, originally developed by Russell Ross, prop-
osed that injury to the endothelium and smooth muscles was
the initiating event and downplayed, to some degree, the
importan ce of lipoproteins. These injuries included in fectious
agen ts, toxic chem icals an d hy pertension. The oxida tive hypo-
thesis proposed that oxidative modification of LDLc and
secondary inflammation is the critical step in the development
of a therosclerosis. The response to retention hy pothesis prop-
osed that ApoB containing lipoproteins, LDL and VLDL (very
low density lipoprotein), a re primary determinan ts of a thero-
sclerosis. Four key factors are responsible for the development
of atherosclerosis: the plasma concentration of the atherogenic
lipoproteins, the difference betw een the arterial w all influx a nd
efflux of the atherogenic lipoproteins, modification of the lipo-proteins w ithin the arterial wall and the inflammatory response
to mo dified LDL. The last hy poth esis includes major com pon ents
of the first two an d is probably the m ost supported at the pres-
ent time. The on ly variables tha t can be relatively easily meas-
ured in epidemiological studies are the levels of LDLc, VLDLc,
ApoB, LDL particle size, genetic characteristics such as ApoE
polymorphisims and, to a limited degree, oxidized LDL and
other lipoproteins such as HDLc and VLDLc, size distributions,
and apolipoproteins. Elevated ApoB lipoproteins are required
for the development of atherosclerosis irrespective of the
presence or a bsence of oth er risk factors.21,22 The h ypo th esis is
also consistent w ith the linear relation ship betw een blood
cholesterol levels and risk of CHD, as w as no ted in the M ultiple
Risk Facto r Interv ent ion Trial screenees,23 and the linearassociation betw een the avera ge blood cholesterol level and the
extent of coronary atherosclerosis found in pathology studies. 24
The recent report from the Pa tho biology Determina nts of
Atherosclerosis in Youth (PDAY) studies show ed th at a t a n
average age of 34, 20% of men a nd 8% of wom en w ho h ad died
primarily from trau matic causes had 40% stenosis of their left
anterior descending coronary artery at the post-mortem
exam.19,20 The risk of stenosis w as directly related t o levels of
no n-HDLc, i.e. ApoB-conta ining lipoproteins. The h ypoth esis
also suggests that other factors may determine the extent of
atherosclerosis at any ApoB lipoprotein level. In post-mortem
examination, the average levels of LDLc and atherosclerosis are
strongly and positively correlated. At any level of LDLc, how-
ever, there is substantial variation in the extent of coronaryatherosclerosis. Part of this variation is likely due to the
meta bolism w ithin th e arterial w all, genetic susceptibility, the
secondary inflammatory response, and growth factors which
may be determined, in part, by other risk factors such as blood
pressure levels or cigarette smoking.24
Prevention of cardiovascular disease
Stam ler recently reported tha t, in three relatively yo ung coho rts,
primarily 1839 years of age, follow ed for up to 22 yea rs, there
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S68 INTERNATIONAL JO URNAL OF EPID EMI OLOG Y
w as a linear relationship betw een serum cholesterol levels
and deaths from CHD. In one of the cohorts (Multiple Risk
Facto r Interv ent ion Trial, MRFIT, screenees) th e rate o f CHD
death w as only 2.3 per 1000 persons/year for m en w ith
cholesterols 160 mg% as compared to 27.3, over a 10-fold
difference, for men w ith cholesterols 280 mg% at baseline.
Unfortunately, 10% of the men had serum cholesterol levels
160 mg%.25,26
Further evaluation of th e MRFIT screeneesby Stamler et al . demon strated tha t it wa s possible to identify
men a t very low risk of CHD based on a low serum cholesterol
level, non-cigarette smoking and systolic blood pressure
120 mmHg.25 Unfortunately, there are very few men in this
very low risk stratum , at least in the US. A recent report from
the Nurses Health Study in th e US has also show n tha t it is
possible to identify w omen at very low risk of disease even
w ithou t including biochemical measurements. Thu s, a hea lthy
diet, non-cigarette smoking, higher levels of physical activity,
moderate alcohol, and not being overweight and obese was
associated w ith a v ery low risk of CHD. Unfortuna tely, only 3%
of the n urses were in this low risk category.27 The se studies
from both the Nurses and MRFIT as w ell as others strongly
suggest that CHD is preventa ble but that, a t least in th e US, veryfew ind ividuals have ado pted lifestyles tha t are associated w ith
low risk of CHD. The ma jority of individuals in most cou ntries
that have h igh ra tes of CHD are not in th is low risk category
and, therefore, require some type of preventative approach to
reduce their risk of CHD.
The efficacy of reducing LDLc and hen ce the risk of heart
disease has now been established by the results of statin trials.
Previous dietary trials, such as th e Oslo Trial, demon strated
similar ben efits of dietary intervention . These drug t rials, in
both primary a nd secondary prevention settings, have demo n-
strated about a 25% reduction of the risk of heart attack asso-
ciated w ith proba bly a 3040% reduction in LDLc levels. The
efficacy of therapy has now been demonstrated even in rela-
tively low risk population s with a n av erage LDL level of150 mg%: not much higher than tha t of the US population
overall142 mg%. Approximately one-third of the US adult
population m ight be candidates for lipid-low ering therapies and
a similar high percenta ge in oth er countries. The cost of w ide-
spread use of lipid-low ering therapies an d potent ial long-term
adverse effects have raised concerns in the US and other countries
abou t such w idespread use, especially as a replacement for m ore
aggressive, non-pharmacological dietary interventions.7
Risk prediction equations have been developed from
Framingha m an d other studies and have been used to estimate
the long-term risk of coronary artery disease (CAD) based on a
combination of risk factors, age and sex. Several committees in
the US and Europe are attempting to determine what level of
risk, i.e. 15, 20 or 30% over 10 years, m ight be con sidered highrisk in primary prevention and therefore provide candidates for
specific drug therapy.28,29 Most now agree that individuals
who have already had a heart attack are candidates for lipid-
low ering thera py to reduce their LDLc levels below 100 mg%.
A basic problem w ith th e high risk approach, i.e. 20 or 30%
risk, is that the majority of heart attacks occur among
individuals w ho a re not in th is high risk category, i.e. 20%
risk over 10 years, except for older individuals. In the MRFIT
screenees, age 3539 follow ed over 16 yea rs, 56% of th e heart
atta cks occurred amon g men w ith baseline serum cholesterols
between 160239 mg% and only 14% among th ose with
cholesterols 280 mg%. Thu s, focusing only on the h igh risk
population fo r aggressive drug therapy w ill likely hav e only a
small effect on reducing the population burden of clinical
CHD.25
The current dietary a pproaches for reducing LDLc are n ot
nearly as efficacious as drug therapy w ith statins.30 However,
new evolving dietary approaches may provide a much moresuccessful method of reducing LDLc or VLDL, ApoB and the
subsequent risk of heart attack.31 Jenkins estimated that an
increase in viscous fibres, soy proteins, a nd plan t sterols as well
as a decrease in saturated fat and cholesterol and a modest,
10-pound, w eight loss w ould result in a reduction in LDLc of
abou t 35%, similar to tha t obta ined from lipid-lowering statin
therapy. 32 It is uncertain, however, whether the current small
reductions in m an y dietary trials of LDLc, perhaps only 510%,
w ill ha ve an y appreciable effect on the individua l risk of heart
attack.33 The poten tial benefits of other n utrients in th e pre-
vention of CAD are currently being evaluated in clinical, epi-
demiological an d an imal experiment al studies. There is
considerable interest in the potential value of antioxidant
nu trients such as vitamin E, flavinoids, omega -3 fatty acids, folicacids and soy proteins.
The contin ued low er CHD incidence an d morta lity rates in
parts of southern Europe do not appear to be explained by the
differences in the amount of saturated fat and cholesterol and
total fat in the diet. However, it is important to note that any
data regarding incidence and mortality in older age groups born
prior to World War II may reflect prior lifestyles and a specific
cohort effect.34 Cha nges in lifestyles, especially diet, m ay be less
apparent in older age groups than younger age groups and
similarly, the dietary changes may have less of an effect in
individuals w ith exten sive atherosclerosis. Steinberg suggested
that antioxidants, such as vitamin E, may have their primary
effect early in the progression of atherosclerosis or in the
prevention of atherosclerosis and have less of an effect inindividuals wh o already ha ve extensive ath erosclerosis.35 We
have previously reported that the CHD mortality rates for ages
3544 are still relatively low in south ern Euro pe, especially
France, Italy, and Spain, but are now also low in former high
rate cardiovascular countries such as in Finland. 36
If the reported large differences in incidence and mortality
due to CHD a mon g countries persists, even in the yo unger post-
World War II birth cohorts, then it wo uld be very importan t to
determine w hether such differences are consistent w ith the
extent of atherosclerosis measured in vivoby such techniques as
EBC T. There a re severa l possible optio ns. For ex am ple, the
extent of ath erosclerosis, especially in these post-World War II
birth cohorts, ma y be substantially low er in southern European
countries than in other parts of Europe in spite of the apparentincreases in risk factor levels and higher consumption of
satura ted fat a nd cho lesterol follow ing World War II. On the
other hand, the extent of atherosclerosis across these
populations may be similar and the differences in morbidity and
mortality, i.e. incidence, may be related to endothelial function,
inflammation, or thrombosis. Other risk factors than diet and
lipoprotein B levels ma y d etermine clinical disease.
One of th e most interesting observations has come from the
Leon Diet Heart Study, a secondary prevention diet trial that
ha s show n th at increases in alpha-linolenic acid, as w ell as
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decreases in dietary cholesterol and saturated fat, but little
chan ge in blood cho lesterol levels, were associated w ith a
substantial reduction in the risk of recurrent coronary events.37
We have recently evaluated changes in CHD mortality and
CVD mortality over time among young men in Japan, age
3544.38 There h as been a substantia l chan ge in risk factors in
post-World War II birth cohorts in Japan including an increase
in total fat and saturated fat in the diet, increases in LDLc, asubstantial increase in cigarette smoking, and a decrease in
blood pressure levels. The levels of LDLc an d blood pressure are
very similar now to US men in the age ran ge 3544 years and
smoking rates are much higher in men. In spite of these
substantial changes in risk factors, there appears to be only a
small increase in CHD mortality, even after a careful evaluation
of the quality of the information on the death certificates. On
the other hand, there has been a substantial increase in CHD
morta lity in youn ger men in Korea. The poten tial protective
effects in Japanese lifestyles may include higher intakes of soy
proteins, fish and omega-3 fatty a cids and high alcohol intake
an d the continued relatively low preva lence of obesity. Furth er
studies evaluating the development and progression of athero-
sclerosis in these young cohorts in relationship to specificlifestyles and risk factors will provide importa nt info rmat ion
about potential beneficial lifestyles and dietary factors that can
then be applied to oth er populations. The a ddition of th e study
of a therosclerosis to tra ditional, clinical studies of risk factors of
heart a ttacks may provide important a nd interesting new infor-
mation to explain the marked geographical variations across
population s, especially in post-World War II birth cohorts.39
The low er risk of CHD, as no ted, in south ern Europe ha s also
been attributed to higher alcohol intake, especially in countries
such as France, Northern Italy a nd Spain . The increased alcohol
intake is clearly a ssociated w ith higher levels of HDLc in th ese
populations and may also have some effect on clotting and
thrombosis. Studies in the US have clearly documented that
modera te alcohol inta ke is associated w ith reduced risk of CHDin both m en an d w omen. Although higher levels of HDLc are
associated with low er risks of heart a ttack in most populations,
evidence tha t raising the level of HDLc will reduce the risk of
heart attack is limited. Several trials have used fibrate drugs for
raising HDLc to reduce th e risk of CAD. The results ha ve n ot
been consistent w ith the VA HIT trial demonstrating a sub-
stantial reduction in CHD and the Bezofibrate Intervention
(BIP) trial show ing no effect.40,41 Part of the differences in the
results of the trials appear to be related to the levels of LDLc,
prevalence of diabetes and elevated blood triglycerides.
The role of oxida tion of LDLc and a ntioxida nts is also a
research topic of great interest. Results, to date, are not con-
sistent w ith benefits from an tioxidant th erapy. There are
continued attempts to identify n ew and novel risk factors foratherosclerosis. Some of them may help to explain the geo-
graphical variation in CHD incidence and mortality that are
unaccounted for by traditional cardiovascular risk factors.4245
Inflammation, thrombosis and fibri nolysis
Pathology studies have demonstrated inflammation within
plaqu es, such a s infiltration of m acropha ges an d T-cells. Ele-
vated levels of inflamma tory m arkers such a s C-reactive protein,
IL6, TNF, higher wh ite blood cell count s, and sedimentation
rate h ave a ll been associated w ith increased risk of initial heart
attack and recurrent heart atta ck.4649
Higher levels of fibrinogen ha ve been associated w ith an
increased risk of heart attack. Whether the measure of
fibrinogen is a m arker of inflamma tion or o f an increased risk
of t hrom bosis is not certain. The a ssociation of specific measures
of clotting or thrombosis, platelet function and fibrinolysis and
risk of CAD ha ve been less consistent. How ever, studies hav eclearly show n relationsh ips betw een higher levels of PAI-1 and
TPA an tigen levels and risk of CAD as w ell as betw een m eas-
ures of fibrinolysis, D-dimer and risk of CAD. Recent emphasis
has focused on markers of soluble adhesion molecules, such
as intercellular adhesion molecule-1 (ICAM-1) and vascular
cell adhesion mo lecule-1 (VCAM-1) as well as e-selectin an d
p-selectin. These ha ve also been sho w n to be related to th e risk
of CHD in some, bu t no t all, studies. Therapies focused on th e
prevention o f throm bosis, such as aspirin an d low -dose
w arfarin, ha ve also demon strated benefit in reducing th e risks
of CHD.
The poten tial effects of inflamm ation , throm bosis, an d
fibrinolysis on the risk of CAD occur primarily in the context of
significant a therosclerosis. Most individuals wh o die from CHDhave extensive coronary atherosclerosis. Whether these meas-
ures provide a marker for the identification of vulnerable
plaques likely to rupture and lead to thrombosis and a clinical
event is a much debated and unresolved hypothesis. It is
possible that the inflammatory markers are an indirect measure
of the extent of atherosclerosis or the characteristics of the
plaque but have little role in the pathogenesis of the clinical
disease. On the other hand, it is also possible that these meas-
ures of inflammation play a key role in the progression from
atherosclerosis to clinical disease.18
Future epidemiological studies that can combine measures of
subclinical atherosclerosis, perhaps using MRI or other tech-
niques to characterize the atherosclerotic plaque a long w ith
measures of thrombosis, fibrinolysis and inflammation mayidentify specific lifestyle factors, such as nutrients, physical
activity, etc., that may modify these proximate risk factors for
heart attack.
Impl ications for the future
Prevention of the initial development of atherosclerosis and
progression over time w ith age must be the number one goal of
any cardiovascular disease prevention programm e. Populations
w ith a low prevalence of atherosclerosis do not h ave endemic
clinical CHD.
In many countries the prevalence of atherosclerosis,
especially in older ages, is so h igh tha t individua lized preventive
effort s require substa nt ial resources. The level of LDLc is theprimary determinant o f the extent of atherosclerosis. The a moun t
of saturated fat and cholesterol in th e diet remain the primary
factors determin ing th e population levels of LDLc. The d evelop-
ment and progression of atherosclerosis is not a function of
ageing, but primarily determined by the distribution of cardio-
va scular risk factor s related to specific lifestyles. Thu s, preven-
tion is possible by modification of specific lifestyles.
The primary prevention of a therosclerosis must begin ea rly in
life an d focus on facto rs that w ill low er the LDLc, probably
below 100 mg%, an d possibly a lso VLDL (ApoB) lipoproteins. A
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second major goal must be the prevention of the rise in LDLc
w ith increasing age. The effects of oth er dietary m odifications,
such as specific polyunsaturated fatty acids, viscous fibre, and
plant sterols in modifying both the LDLc level and perhaps
atherosclerosis need further evaluations.50,51
It is very important to monitor trends in LDLc levels and
other risk factors among populations that continue to h ave low
incidence of CHD an d likely a low prevalence of at herosclerosis.It is probable that in these populations, as the LDLc begins to
rise abov e 100130 mg%, there w ill be an in crease in a thero-
sclerosis and over time development of CHD.52 The lo ng
incubation period from the time of the development of
atherosclerosis to the onset of clinical heart disease may delude
investigators into thinking that the rising LDLc level is not
associated w ith an y increase in CHD in the population . This is
most likely a mistake and in futu re years these population s will
ha ve epidemic CHD. Thus th e mon itoring of these populations
in tran sition sh ould include measures of LDLc as w ell as oth er
cardiovascular risk factors, especially in younger age groups to
look at specific cohort effects and second arily, the mon itoring of
the extent of atherosclerosis using new, non-invasive measures
in defined population samples. Only later, and perhaps too late,in terms of developmen t of cardiov ascular disease will incidence
and mortality rates increase.
In populat ions in w hich th e level of LDLc is already elevated,
i.e. above 100130 mg/% or total cholesterol is over 200,
atherosclerosis is prevalent. A multifaceted approach is
necessary. First, the public hea lth approa ch shou ld lower th e
population LDLc level. Second, other lifestyle risk factors may
enhance the progression of atherosclerosis and the risk of
clinical disease.5355
Weight gain during young adult l i fe is an important
determina nt in th e rise in LDLc. The prevent ion o f increases in
w eight, w hich is primarily due to a m ore calorically dense diet,
as w ell as decreased physical activity, is an importa nt deter-
minant of the evolution of early atherosclerosis and elevatedLDLc levels.56 However, not all populations w ith a high
prevalence of obesity, necessarily have high LDLc levels or
increased prevalence of ath erosclerosis. The com position of th e
diet also plays a critical role.57
A major challenge for epidemiological and prevention
research is to document th at non-pharmaceutical interventions,
i.e. diet modification, can successfully reduce th e LDLc in w ay s
tha t w ill prevent th e progression of at herosclerosis. At the
present time w e hav e no good ev idence in recent studies in
primary prevention that non-pharmacological therapies will
reduce or delay the progression of atherosclerosis among
individuals w ith modera tely elevated LDLc, i.e. in the ran ge
130160 mg%, etc.
The a vailability of n on-invasive metho ds of measuringatherosclerosis provides an interesting opportunity to test
alternative dietary and drug therapies in relation to the
progression of a thero sclerosis. This w ill be particularly
important in evaluating not only the traditional methods of
reducing LDLc, i.e. satu rated fa t, cholesterol, but a lso th e effects
of different polyunsatura ted fats, an tioxidants in the diet, fibre
an d possibly the effects of w eight loss, as w ell as the effects of
dietary interven tions on oth er risk factors, i.e. low ering blood
pressure through reduction of total fat, increase in fruit and
vegetables, low salt diet, w eight reduction, etc.57
In the older age group, 65+ , w e have a unique problem. Life
expectancy has increased for these older individuals, and active
life expectancy, i.e. functional status, can now be as much as
over 20 years for women and perhaps 15 or so years for men.
The preva lence of ath erosclerosis is very high, a nd a s noted,traditional measures such as lipoprotein levels do not predict
the extent of a therosclerosis very w ell. There a re three po ssible
choices to deal w ith thera pies in these older ages: (1) to
presume that practically every relatively healthy person over 65
ha s significant a therosclerosis and w ould benefit from lipid-
lowering therapy and other pha rmacological therapies, i.e. to
provide pharmacological therapy universally except w here
there is major disability or contraindications to such therapy;
(2) to use non-invasive methods of measuring atherosclerosis,
i.e. coronary calcium, carotid, ankle/brachial blood pressure,
major ECG abnormalities, MRI of brain, to stratify older
individuals w ith regard to th e extent of a therosclerosis and risk
of disease and then provide therapy for those w ith moderate to
high levels of subclinical atherosclerosis; and (3) to treat veryfew of the elderly a nd limit treatment to those older individuals
w ho a lso ha ve diabetes, hy pertension, and /or cigarette smokers
and /or moderate sym ptomato logy associated w ith early
corona ry hea rt disease. How ever, this approach w ill result in a
substantia l number of older individuals being treated w ith lipid-
low ering drugs since about 20% of the population of o lder
individuals w ill be diabetic and proba bly 60% or so ha ve systolic
hypertension.3,58
Recently lipid-lowering thera py has been show n to also
redu ce the risk of ischa emic stroke. The inciden ce of stroke,
especially amon g w omen, is practically th e same as th at of
myocardial infarction in the older age groups, and disability
from stroke especially the development of post-stroke dementia
can be even more devastating than that from coronary heartdisease amon g older individuals. Thu s, the decision to treat w ith
lipid-low ering drugs in older individuals should include no t
only t he risk of my ocardial infarction, bu t also the risk of stroke.
The ma intena nce of plaq ue stability an d the prevention of
thrombosis can also have an immediate and important role in
delaying th e onset of hea rt atta ck and stroke. The identification
of the proxima te risk factors and interven tions are less well
established tha n tha t regarding lipid-lowering thera py, an ti-
hypertensive therapy, etc.59,60
Clinical trials w hich specifically focus on mod ifying
inflammatory markers are probably the only way to provide
definitive information on w hether these markers hav e a role in
a specific causal path w ay to risk of disease, or wh ether they a re
just measures of inflammation in th e plaqu e and th e burden ofath erosclerosis, i.e. are expensive sedimenta tion mea surements.
National programmes to reduce incidence and mortality due
to CHD and stroke should be a major component of all public
hea lth programm es. The objective evalua tion of such program mes
in terms of reduction in incidence and mo rtality w ill require
innovative epidemiological approaches to surveillance and
measures of both clinical events and subclinical atherosclerosis.
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PRE VENTION OF CARDI OVASCU LAR DISEASE S71
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