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7/27/2019 Pencegahan Cardio

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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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The know ledge of key risk factors, measurement of atherosclerosis and efficacy of both pharma cological and non-

pharma cological therapies provide a strategy to substantially reduce cardiovascular m orbidity an d m ortality.

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