Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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Aspartame hydrolyzes slowly at the low pH values

characteristic of soft drinks. Therefore, products con-

taining exclusively aspartame become less sweet on

prolonged storage.

0015 When aspartame is substituted for sugar in food

products, the sugar bulk must be replaced. Although

gums can be used as a thickening agent, modified

food starch may be a better choice.

0016 Sucrose can be replaced in nondiet carbonated soft

drinks by aspartame–glucose syrup formulations,

which mimic sucrose properties in soft drinks. Prod-

ucts containing this blend are liked as much as, or

more than, all-sucrose drinks by consumers. They are

also significantly cheaper since aspartame has a lower

per-unit sweetness than sucrose.

0017 Aspartame may be used as total sugar replacements

in whey beverages, resulting in a significant reduction

in the amount of carbohydrate present. The amount

required to produce a sweetness level equal to that of

a beverage containing 10.5 g per 100 ml of invert

sugar is 0.25 g l

1

. When used together with acesul-

fame-K, synergism results in a 25% reduction in the

total amount of sweetener required.

Stability

0018 In the dry state (e.g., table top sweetener, powdered

drinks, dessert mixes), aspartame is quite stable.

However, when used in aqueous solutions or inter-

mediate moisture systems, it is susceptible to hy-

drolysis, other chemical reactions, and microbial

degradation, thus limiting its shelf-life.

0019 In aqueous solution, aspartame undergoes decom-

position and racemization, forming a variety of prod-

ucts. Degradation is also significantly affected by the

pH, temperature, and storage period of the food or

beverage. These factors cause a degradation reaction

of first-order kinetics.

0020 Aspartame is stable in the pH range of 3–5, which

is characteristic of most foods. At 25



C, the max-

imum stability is reported at pH 4.3. The good stabil-

ity observed during refrigerated storage of yogurt is

due to its pH, which ranges from 4.0–4.5. A frozen

dairy dessert may have a pH ranging from 6.5 to 7.0,

but, because of the frozen state, the rate of reaction is

dramatically reduced.

0021 The influence of temperature on aspartame depends

on the composition and water activity of the food.

Maximal stability is observed in the lower tempera-

ture range used for refrigerated and frozen storage.

The activation energy decreases above and below the

isoeletric point, pH 5.4. Aspartame can withstand the

heat processing used for dairy products and juices,

aseptic processing, and other processes in which high-

temperature short-time and ultrahigh temperature

conditions are used. However, under conditions of

excessive heat, aspartame may hydrolyze or cyclize,

limiting its applications. An encapsulated form of

aspartame is now available to improve heat stability.

0022The initial microbial load and subsequent growth

of contaminants in yogurt and milk chocolate can

affect the rate of aspartame degradation. The stability

of aspartame has been observed to be similar for

different strains of Lactobacillus bulgaricus and

Streptococcus thermophilus, suggesting that strain

differences do not affect stability. To improve stabil-

ity, aspartame should be added to yogurt after fer-

mentation.

0023Aspartame can react with aldehydes, which are the

principal flavor compounds used in chewing gums

and in some soft drinks. However, the reactivity

varies with aldehyde type, owing to differences in

reaction pathway.

0024Nonenzymatic browning via the Maillard reaction

is another important pathway for aspartame degrad-

ation in foods. Owing to its dipeptide structure,

aspartame can react with reducing sugars in the pres-

ence of water. This reaction is favored at alkaline pH

values, because nonprotonated amine groups on the

molecule are more available. This interaction may

result in off-flavors, loss of sweetening power or

undesirable color changes. Another example of

carbonyl-amino reactions has been shown for vanil-

lin, resulting in the loss of vanilla flavor. Both tem-

perature and water content during storage can affect

reaction rates, which have been observed to follow

zero-order kinetics.

Decomposition Products

0025As indicated in Figure 2, aspartame decomposition

[1] results in hydrolysis of the methylester with loss

of methanol forming 3,6-dioxo-5-phenylmethyl-2-

piperazineacetic acid – diketopiperazine. This com-

pound is then hydrolyzed [2], yielding aspartylphenyl-

alanine, which is eventually hydrolyzed [3] to the free

amino acids aspartic acid and phenylalanine. At acid

pH values [4], products such as phenylalanine methyl

ester and aspartic acid are formed. The first

is hydrolyzed [5], forming phenylalanine and metha-

nol. Another degradative pathway involves base-

catalyzed hydrolysis with loss of methanol [6]

forming a-aspartylphenylalanine, which undergoes

further hydrolysis [3] to give phenylalanine and

aspartic acid. Racemization of a-aspartame [7] and

its degradation products has also been observed.

0026The major degradation products are diketopipera-

zine and aspartylphenylalanine. None of the decom-

position products have a sweet taste or aftertaste.

Therefore, when these compounds are formed in the

334 ASPARTAME

food, a loss of sweetness is perceived. Several investi-

gators have monitored aspartame in different food

products in the market and observed that levels varied

from 52 to 107% of the value declared on the label.

Metabolism

0027 Metabolism studies in numerous species, including

humans, demonstrated that aspartame is rapidly and

completely metabolized to its individual constituents

phenylalanine, aspartic acid, and methanol. Conse-

quently, it has the same caloric value of proteins –

4 kcal g

1

. However, because of its intense sweetness,

the amount of aspartame used in foods is small

enough for the sweetener to be virtually nonnutritive,

providing negligible energy. It is noncariogenic and

produces little glycemic response.

0028 Aspartame may be absorbed and metabolized in

one of three ways (Figure 3). It may be hydrolyzed

in the intestinal lumen by proteolytic and hydrolytic

enzymes to form aspartate, phenylalanine, and

methanol. These hydrolysis products are absorbed

from the intestinal lumen and reach the systemic cir-

culation in a manner similar to that of amino acids,

peptides and methanol arising from the digestion of

dietary proteins and polysaccharides. Aspartame may

be absorbed directly into mucosal cells by one of

the peptide transporter systems, with subsequent

hydrolysis within the epithelial cells to aspartate,

phenylalanine, and methanol. Aspartame may also

be de-esterified in the intestinal lumen to yield metha-

nol and aspartylphenylalanine, which is taken up by

enterocytes via a peptide transport system and further

hydrolyzed to aspartate and phenylalanine. Once

absorbed, these components are metabolized, util-

ized, and/or excreted by the body through similar

pathways as when they are derived from any other

dietary source.

Diketopiperazine (DKP)

α-Aspartame (α-APM) β-Aspartame (β-APM)

Phenylalanine methyl ester (PMe)

[5]

[7]

[4]

[1]

[6]

[2]

[3]

β-Aspartylphenylalanine

(β-AP)

α-Aspartylphenylalanine

(α-AP)

Aspartic acid (Asp)

artic acid (As

)

Phenylalanine (Phe)

fig0002 Figure 2 Decomposition products of aspartame.

INTESTINAL LUMEN MUCOSAL CELL

PORTAL BLOOD

Aspartame Aspartame

Aspartate Aspartate

Aspartate

Phenylalanine

Phenylalanine Phenylalanine

Methanol Methanol Methanol

esterases

peptidasespeptidases

fig0003 Figure 3 Diagram of aspartame metabolism. From Burini RC and Caballero B (1992) Metabolismo do aspartame em humanos.

Cadernos de Nutri

c¸ a

o 4: 38–47, with permission.

ASPARTAME 335

Safety

0029 Aspartame has been the subject of extensive investi-

gation in animals and humans. Prior to the marketing

of aspartame, numerous studies were done to evalu-

ate its metabolism and tolerance in healthy subjects

and various subpopulations, including phenylketon-

uric heterozygotes, children, lactating and pregnant

women, and individuals with renal and liver disease.

Postmarketing, numerous additional studies were

performed, including the evaluation of alleged sensi-

tivity to aspartame. The results of extensive scientific

research investigating these allegations did not

show any causal relationship between aspartame

and adverse effects.

0030 Aspartame has undergone extensive clinical testing

prior to its regulatory approval, including acute and

long-term studies in the general population and in

populations that may be extensive users of a high-

intensity sweetener, such as diabetics and obese sub-

jects. In addition, pharmacokinetic and metabolism

studies, including radiolabeled studies, were carried

out in normal subjects, subjects with a somewhat

reduced capacity to metabolize phenylalanine (i.e.,

heterozygotes for phenylketonuria), and subjects

with an almost complete inability to metabolize

phenylalanine (i.e., phenylketonurics). Following

the approval of aspartame, additional studies were

undertaken to further evaluate the safety of aspar-

tame in special populations.

0031 The safety of aspartame has been extensively tested

in animal and human studies. Undoubtedly, it is the

most thoroughly studied of the high-intensity sweet-

eners. Its safety has been affirmed by numerous scien-

tific bodies and regulatory agencies, including the

Joint Expert Committee on Food Additives (JECFA)

of the Codex Alimentarius (Food and Agriculture and

World Health Organizations), the Scientific Com-

mittee for Food of the Commission of European

Communities, the United States Food and Drug

Administration, and the regulatory agencies of

more than 100 other countries around the world.

0032 On the basis of the results of comprehensive safety

studies, a no observed-effect level of more than 2000–

4000 mg per kilogram of body weight was established

for aspartame. Based on this information, an accept-

able daily intake (ADI) of 40 mg per kilogram of body

weight per day for aspartame was set by JECFA. On

the basis of both animal and human data, the United

States Food and Drug Administration set an ADI for

aspartame of 50 mg per kilogram of body weight per

day. An ADI value of 7.5 mg per kilogram of body

weight was given for its metabolite diketopiperazine.

The use of aspartame appears to be unanimously

authorized in different foods and beverages.

0033However, products containing aspartame have to

be labeled to warn people with phenylketonuria.

Methanol released from aspartame does not consti-

tute an excessive metabolic load. Numerous studies

have shown that aspartame and diketopiperazine

are not associated with any serious adverse health

effects.

Estimation of Consumption

0034Aspartame has been the subject of extensive post-

marketing surveillance of consumption. Data from

surveys in the USA indicate that approximately 40%

of the population is consuming aspartame-containing

products. From 1984 to 1992, the 90th percentile 14-

day average consumption of aspartame in the general

population ranged from 1.6 to 3.0 mg per kilogram

per day. This is approximately 5–10% of the US ADI.

The consumption by children aged 2–5 years and

from all age groups ranged from 2.6 to 5.2 and from

5.2 to 8.5 mg per kilogram per day, respectively. As-

partame consumption by diabetics ranged from 2.1 to

3.4 mg per kilogram per day. Therefore, persons with

diabetes who would likely be frequent users of aspar-

tame consume quantities well below the ADI.

0035In Canada, three different methods to estimate

potential aspartame intake have been used. In the

first method, it was estimated that aspartame con-

sumption would be 11 mg per kilogram per day if it

replaced per-capita disappearance of sugar. In the

second method, it was estimated that aspartame con-

sumption would be approximately 4 mg per kilogram

per day if it replaced sugar in major types of foods on

a per-capita disappearance basis. In the third method,

based on a 24-h dietary recall survey of food con-

sumption in over 13 000 individuals, it was estimated

that potential aspartame use in these foods would

result in an intake ranging from 3.2 to 7.4 mg

per kilogram per day. In a survey with over 5000

individuals in 1987, it was observed that 45% of the

individuals consumed products with aspartame.

Consumption at the 90th percentile for the general

population was 5.5 and 5.9 mg per kilogram per day

during the winter and summer months, respectively.

Intake by diabetics was 5.5 and 11.4 mg per kilogram

per day during the winter and summer months, re-

spectively. In addition, the consumption by all age

groups of children was below 10 mg per kilogram

per day.

0036In the UK, in a study based on the consumption of

saccharin, it was estimated that aspartame consump-

tion by diabetics would be approximately 5.5 mg per

kilogram per day at the 90th percentile. In another

study, potential aspartame intake in children from

soft-drink consumption would be approximately

336 ASPARTAME

6.6–6.8 mg per kilogram per day at the 90th per-

centile.

0037 Nearly 73% of the diabetic children surveyed in

Finland consumed aspartame-containing products

with a mean intake of 1.15 mg per kilogram per day.

Aspartame intake in France from 1991 to 1992 was

0.6 mg per kilogram per day and in Germany, con-

sumption in 1988–1989 was 2.75 mg per kilogram

per day at the 90th percentile. The average intake of

aspartame among Italian teenagers users of diet

products was 0.03 mg per kilogram per day, with a

maximum of 0.39 mg per kilogram per day.

0038 In Brazil, data on potential intake of aspartame

have been based on questionnaires to users of sweet-

ener in the cities of Campinas, state of Sa

o Paulo, and

Curitiba, state of Parana

, during the winter of 1990

and summer of 1991. Data showed that 40% of the

population consumed aspartame alleging reasons

of weight-control diet (36%), diabetes (35%), and

weight loss (23%). Table-top sweeteners were the

major source, followed by soft drinks. The median

daily intake by users represented 2.9% of the ADI.

Diabetics had a much higher intake within the studied

population.

0039 Although survey methodologies differed among

these evaluations, aspartame intake is remarkably

consistent across studies and well below the IDA.

0040 Because aspartame is metabolized to common diet-

ary components – aspartate, phenylalanine, and

methanol – it is useful to evaluate the impact of its

consumption on the normal dietary intake of these

components. At the current 90th percentile 14-day

average levels of consumption, aspartame contributes

approximately 1.5 and 3% of an adult’s daily dietary

intake of aspartate (80 mg per kilogram per day)

and phenylalanine (52 mg per kilogram per day),

respectively.

0041 Aspartame yields approximately 10% methanol by

weight. This amount is well below the normal dietary

exposure to methanol from many fruits, vegetables,

and juices. Therefore, normal diets provide several

times more methanol than that from foods sweetened

with aspartame. For example, tomato juice provides

approximately six times more methanol than an

equal volume of aspartame-sweetened beverage.

Whereas methanol exposure at the 90th percentile

of chronic aspartame consumption is 0.3 mg per kilo-

gram per day, the FDA has established acceptable

levels of exposure to methanol at 7.1–8.4 mg per

kilogram per day for 60-kg adults.

Methods of Analysis

0042 Many analytical procedures have been proposed

to check food labeling or to measure the degree of

aspartame decomposition during manufacturing and

storage of food products. Several types of methods

have been described for the analysis of aspartame,

including spectrophotometric, enzymatic, titrimetric,

capillary isotachophoretic, thin-layer chromatog-

raphy, and liquid and gas chromatographic methods.

0043HPLC is by far the most frequently used technique

to monitor aspartame, intermediates formed during

its synthesis, and decomposition products formed

during manufacture and storage of food products. It

is also used to check for amounts declared on food

labels.

Sample Preparation

0044Sample preparation generally depends on the type of

food matrix. Samples can be directly injected into

the HPLC or after minimal pretreatment. However

extraction, clean-up, and/or purification might be

necessary, depending on the complexity of the matrix,

in order to eliminate any interference.

0045Clarification with Carrez solutions can be used to

eliminate any interfering compounds. Purification,

isolation, or concentration of the extract can also be

performed by solid-phase extraction with C8 or C18.

Sep-Pak C18 cartridges can be used for the separation

of aspartame from its degradation products. The use

of ion-exchange cartridges, such as Bond Elut SCX,

Bond Elut C18, and Amberlite CG-120, has also been

described.

Separation of Aspartame from Other Sweeteners

0046During HPLC analysis of aspartame, the most com-

monly used stationary phase is reverse-phase C18.

Two main types of mobile phase have been used: an

alcohol (methanol or isopropanol) associated with

acetate or phosphate buffer or acetonitrile associated

with phosphate buffer. In both cases, the pH is

adjusted to 3.0–4.5. Ion-pair chromatography has

also been used to separate aspartame from other

sweeteners.

Separation of Aspartame from Synthesis

Intermediates, Stereoisomers and Degradation

Products

0047The most commonly used stationary phase for the

separation of aspartame from synthesis intermedi-

ates, stereoisomers and degradation products, is the

reverse-phase C18 column. The main type of mobile

phase used is a phosphate buffer at a pH ranging from

2.5 to 5.0, associated with acetonitrile. Reverse-phase

HPLC with gradient elution of acetonitrile in phos-

phate buffer has also been used.

0048Ion-pair chromatography has also been used to

separate aspartame from synthesis intermediates and

ASPARTAME 337

degradation products. The method using sodium

hexanesulfonate and gradient elution to separate

aspartame from two decomposition products and

seven related synthesis byproducts has been used rou-

tinely for the control of aspartame synthesis and as a

check for the purity of both finished bulk and mother

liquor. Chiral chromatography can also be used to

obtain the resolution of stereoisomers from aspar-

tame, its precursors, and its degradation products.

Detection Systems

0049 Aspartame has been quantified by UV detection (254,

200–217 nm). However, because aspartame has a

relatively low extinction at 254 nm, quantification

at lower wavelengths provides an increased response.

Detection can also be performed with increased spe-

cificity by fluorescence after postcolumn derivatiza-

tion with o-phthaldehyde. In order to improve the

detection sensitivity, aspartame can also be separated

by HPLC as a fluorescent derivative. Fluorescamine

derivatives are separated on LiChrosorb RP-8 using

acetonitrile in 50 mM acetate buffer, pH 6, 22:78, v/v

or on Spherisorb S5 ODS-2 RP using 0.2 M phos-

phate buffer (pH 9):acetonitrile:methanol, 2:1:1, v/v.

Detection is performed at 397 nm excitation and

482 nm emission.

See also: Acesulfame/Acesulphame; Browning:

Nonenzymatic; Chromatography: High-performance

Liquid Chromatography; Saccharin; Sweeteners:

Intensive; Others

Further Reading

Burini RC and Caballero B (1992) Metabolismo do aspar-

tame em humanos. Cadernos de Nutric¸a

o 4: 38–47.

Butchko HH and Stargel WW (2001) Aspartame: scientific

evaluation in the postmarketing period. Regulatory

Toxicology and Pharmacology 34(3): 221–233.

Duffy VB and Anderson GH (1998) Position of the Ameri-

can Dietetic Association: use of nutritive and nonnutri-

tive sweeteners. Journal of the American Dietetic

Association 98(5): 580–587.

FDA (1981) Aspartame: commissioner’s final decision. Fed-

eral Drug Administration Register 46: 38285–38308.

FDA (1984) Food additives permitted for direct addition to

food for human consumption; aspartame. Federal Drug

Administration Register 49: 6672–6682.

Glo

ria MBA (2000) Intense sweeteners and synthetic color-

ants. In: Nollet LML (ed.) Food Analysis by HPLC,

pp. 523–573. New York: Marcel Dekker.

Grenby TH (1991) Intense sweeteners for the food industry:

an overview. Trends in Food Science and Technology 2:

2–6.

JECFA (1980) Aspartame. Evaluation of certain food addi-

tives. FAO/WHO Technical Report Series 653: 20–21.

Sherlock JC (1986) The estimation of intake. In: Inter-

national Aspartame Workshop Proceedings. Marbella,

Spain. Washington, DC: International Life Sciences

Institute – Nutrition Foundation.

Tschanz C, Butchko HH, Stargel WW and Kotsonis FN

(1996) The Clinical Evaluation of a Food Additive –

Assessment of Aspartame. Boca Raton, FL: CRC Press.

Assays See Immunoassays: Principles; Radioimmunoassay and Enzyme Immunoassay; Analysis of Food

ATHEROSCLEROSIS

A H Lichtenstein, Jean Mayer USDA Human Nutrition

Research Center on Aging at Tufts University, Boston,

MA, USA

Introduction

0001 Atherosclerosis is the leading cause of death and

disability in developed countries and its rates are

rising rapidly in developing countries. The disorder

is characterized by the thickening of artery walls.

There are three major types of atherosclerotic lesions;

fatty streaks, fibrous plaques, and complicated

lesions. The latter two are raised and because they

are on the surface of a blood vessel they result in

decreased lumen size and impeded blood flow (ische-

mia). The blood vessel involved, location of the

lesion(s), and extent of ischemia determine the clin-

ical manifestations of the disorder. Primary risk

factors for atherosclerosis include elevated low-dens-

338 ATHEROSCLEROSIS

ity lipoprotein (LDL) cholesterol levels, male gender,

increased age, positive family history, current cigar-

ette smoking, hypertension, diabetes mellitus, and

low high-density lipoprotein (HDL) cholesterol

levels. This article emphasizes dietary modification

as a nonpharmacological approach to treating the

major risk factor for atherosclerosis, elevated LDL

cholesterol levels. The topics discussed include satur-

ated fat, omega-3 fatty acids, trans fatty acids, dietary

cholesterol, and soluble fiber.

0002 The term atherosclerosis describes a subgroup of

arteriosclerotic disorders characterized by the pres-

ence of fatty plaque (atheromas) within the intima

and media of medium and large arteries. The word

atherosclerosis is derived from a combination of the

Greek words athere, gruel, and skleros, hardening.

The World Health Organization defines athero-

sclerosis as a ‘variable combination of changes in

the intima of the arteries involving focal accumula-

tions of lipids and complex carbohydrates with blood

and its constituents accompanied by fibrous tissue

formation, calcification and associated changes in

the media.’ The American Heart Association defines

atherosclerosis as ‘a process that leads to a group

of diseases characterized by a thickening of artery

walls.’

Incidence

0003 In the late 1990s, 15 million deaths were attributed to

cardiovascular disease worldwide. This accounted for

about 30% of all the deaths reported. In industrial-

ized countries, the rate of cardiovascular disease has

been declining for a number of years. However, it still

accounts for about 50% of all deaths. In developing

countries and eastern Europe, the rate of cardio-

vascular disease has been increasing. It accounts for

about 25% and 60% of all deaths, respectively. As

compiled by the American Heart Association from

World Health Organization data, the mortality rates

for coronary heart disease, stroke, and total cardio-

vascular disease, relative to total deaths, are shown in

Table 1.

Pathology

0004 The development of atherosclerotic lesions is rela-

tively slow and the etiology has yet to be fully eluci-

dated. Evidence suggests that there are multiple

factors which independently impinge on lesion pro-

gression. Atherosclerotic lesions are frequently sub-

divided into three categories: fatty streaks, fibrous

plaque, and complicated lesion. The first to appear,

fatty streaks, are flat or slightly raised accumulations

of lipid-rich macrophages and smooth-muscle cells.

Fatty streaks are ubiquitous in humans and appear

early in life. They rarely impede blood flow and their

presence goes largely unnoticed. Although some fatty

streaks can progress to fibrous plaque, their distribu-

tion suggests this is not always the case.

0005Fibrous (atherosclerotic) plaque is made up of

macrophages which have accumulated lipid and are

transformed into what are commonly referred to as

foam cells. These lesions are elevated and composed

of a core of cholesteryl ester, cellular debris, and

cholesterol crystals, and a fibrous cap made up of

smooth muscle and foam cells, collagen, and lipid.

Due to their raised nature, fibrous plaques frequently

obstruct the arterial lumen and impede blood flow.

Rupturing of the cap may lead to clot formation and

occlusion of the artery.

0006Fibrous plaquefrequently progresses to complicated

lesions. Complicated lesions severely or even com-

pletely obstruct the arterial lumen, with consequent

ischemia or infarction. They are frequently associated

with mural thrombosis (frequently leading to com-

plete obstruction), ulceration, hemorrhage into the

lesion, and calcification.

0007There are a number of theories on how and why

both fibrous plaques form and progress to compli-

cated lesions. The lipid hypothesis suggests that per-

sistent hypercholesterolemia leads to LDL infiltration

of the epithelial cells, smooth-muscle cells, and

macrophages. This hypercholesterolemia not only

leads to cholesterol accumulation but also activates

protein growth factors which stimulate smooth-

muscle cell proliferation into the media and subse-

quent lipid uptake. The response to injury hypothesis

suggests that injury results from mechanical factors,

chronic hypercholesterolemia, toxins, viruses, or

immune reactions and leads to monocyte aggregation

and adherence at the site of injury. Injury causes

the release of growth factors which may arise from

endothelial cells, monocytes, macrophages, plate-

let, smooth-muscle cells, and T cells. Monocytes

and smooth-muscle cells carry ‘scavenger’ receptors

which bind oxidized but not native LDL in a nonsa-

turable fashion. Uptake of oxidized LDL converts

macrophages and smooth-muscle cells into foam

cells. The immunological hypothesis suggests that an

autoimmune reaction, potentially to oxidized LDL,

precipitates a chain of events which results in lipid

accumulation and the development of fibrous plaque.

Clinical Events

0008Atherosclerosis is a disorder that is slow to be

detected, primarily because it is silent throughout

most of its natural history. Its stealthy presentation is

explained by the fact that under normal circumstances

ATHEROSCLEROSIS 339

tbl0001 Table 1 Death rates for coronary heart disease, stroke, total cardiovascular disease, and all causes in selected countries

State Totalcardiovascular disease

Coronaryheart disease

Stroke

2000 1940 2000 1940 2000 1940

Rank

Death rate Rank

Death rate

Alabama 43 414.3 47 202.2 19 157.5 27 80.7 37 68.4 45 31.3

Alaska 7 316.0 4 137.7 4 124.9 5 62.0 41 69.3 25 25.5

Arizona 10 322.9 13 147.4 17 157.1 15 72.2 9 56.7 10 22.8

Arkansas 47 420.8 42 198.1 47 208.1 46 102.6 51 86.1 51 36.7

California 19 347.5 15 153.7 28 176.3 20 76.2 26 63.2 29 26.3

Colorado 4 305.7 2 131.5 6 130.6 4 60.3 1.1 57.1 5 22.1

Connecticut 17 345.4 16 154.3 16 156.8 11 69.8 6 52.5 3 21.4

Delaware 30 375.6 31 174.9 22 162.5 23 78.2 4 52.5 12 23.4

District of Columbia 33 383.9 50 206.4 7 131.3 9 67.2 29 64.2 47 33.5

Florida 15 339.5 17 155.2 35 184.8 30 82.7 5 52.5 8 22.6

Georgia 45 417.6 46 200.6 25 168.0 31 84.1 47 75.8 48 34.0

Hawaii 1 295.7 6 139.2 1 110.7 2 53.1 14 60.0 30 26.3

Idaho 9 322.7 7 141.5 18 157.3 19 75.4 34 65.6 23 25.1

Illinois 34 389.9 34 180.1 42 199.0 38 90.8 33 64.9 35 27.4

Indiana 40 401.6 37 183.7 43 204.3 44 98.2 44 71.1 39 28.7

Iowa 24 356.3 24 157.9 32 180.8 29 82.5 21 62.3 16 24.2

Kansas 21 352.6 20 156.6 24 166.1 21 77.8 25 63.0 19 24.9

Kentucky 46 420.0 43 198.9 45 205.7 48 104.2 39 68.7 38 28.5

Louisiana 44 415.5 45 200.1 30 177.8 39 90.9 40 69.2 44 30.8

Maine 23 354.8 27 160.8 29 177.5 32 85.3 10 56.9 9 22.6

Maryland 27 360.5 29 167.5 15 154.8 12 71.4 20 61.8 28 26.1

Massachusetts 12 324.7 10 144.7 20 159.3 17 73.4 2 50.9 2 20.0

Michigan 39 399.1 36 182.7 40 197.6 37 89.5 31 64.7 34 26.9

Minnesota 5 305.9 3 134.9 10 140.4 8 67.0 32 64.8 20 24.9

Mississippi 52 474.8 52 235.5 34 184.3 42 97.3 46 71.8 49 34.2

Missouri 42 408.9 41 188.5 51 220.4 47 104.1 35 65.7 36 27.4

Montana 8 319.2 9 144.0 5 129.8 7 64.7 22 62.8 21 25.0

Nebraska 25 359.3 25 158.0 14 154.2 15 72.4 16 60.5 17 24.3

Nevada 35 390.9 39 183.8 11 141.9 10 67.6 30 64.3 33 26.8

New Hampshire 28 360.9 19 156.4 33 181.1 26 80.2 24 63.0 13 23.7

New Jersey 29 364.5 28 163.1 41 197.6 34 86.7 3 51.8 7 22.5

New Mexico 6 311.6 5 138.0 2 112.4 1 50.4 8 55.5 6 22.2

New York 41 402.2 35 180.2 52 253.1 52 108.4 1 44.2 1 19.5

North Carolina 37 394.3 40 187.4 37 188.5 41 95.6 49 79.6 46 33.4

North Dakota 16 340.7 14 153.1 26 168.2 25 80.0 27 63.8 24 25.4

Ohio 38 399.1 38 183.7 46 206.0 43 97.6 19 61.5 26 25.7

Oklahoma 49 427.8 44 199.6 50 219.7 51 107.2 43 70.2 41 29.4

Oregon 14 334.3 11 145.7 13 152.0 13 72.0 48 77.5 43 29.7

Pennsylvania 36 391.5 33 179.2 38 190.7 36 88.9 15 60.2 22 25.0

Puerto Rico

3 304.7 22 157.2 9 139.0 18 73.9 12 59.7 40 29.2

Rhode Island 20 351.8 23 157.4 44 205.1 40 91.5 7 53.3 4 21.4

South Carolina 48 423.7 51 208.1 39 192.2 45 99.6 52 88.5 52 39.3

South Dakota 18 345.4 18 155.9 31 178.0 33 86.3 18 61.4 15 23.9

Tennessee 51 433.4 49 204.9 49 215.5 49 104.4 50 81.9 50 34.8

Texas 32 380.4 30 174.4 36 187.1 35 87.9 38 68.5 37 28.2

Utah 2 299.9 1 128.2 3 124.7 3 56.6 23 63.0 14 23.8

Vermont 26 360.5 26 158.0 23 164.2 22 77.8 13 59.9 11 23.1

Virginia 31 379.3 32 175.3 21 160.5 24 79.2 45 71.4 42 29.5

Washington 11 324.5 8 141.6 8 138.5 6 63.5 42 69.5 31 26.5

West Virginia 50 430.6 48 202.5 48 214.8 50 105.1 17 61.0 27 25.8

Wisconsin 22 354.7 21 157.1 27 174.7 28 81.4 36 67.7 32 26.5

Wyoming 13 328.1 12 146.0 12 151.2 16 73.1 28 64.1 18 24.4

Total USA 375.1 171.5 186.5 86.3 63.0 26.3

Total cardiovascular disease is defined here as ICD/9 390–459.

Coronary heart disease is defined here as ICD/9 410–414.

Stroke is defined here as ICD/9 430–438.

Rank is lowest to highest.

Cardiovascular disease data for Puerto Rico are for major cardiovascular disease (390–448) and for 1996–97 only.

Source: NCHS compressed mortality file for the years 1994 to 1997. Age adjustments are based on the 2000 and 1940 standards. Reproduced from American

HeartAssociationwebsitehttp://www.americanheart.orgwithpermission.

340 ATHEROSCLEROSIS

unobstructed arteries have an excess capacity for

blood flow, even under conditions of high demand,

for example during prolonged physical exertion.

Therefore, the gradual progression of the disease

can go undetected until fibrous or complicated lesions

form and blood flow is impeded to a significant

extent. Because lesion development is silent, a surro-

gate measure of lesion progression, elevated LDL

cholesterol levels, is used as a guide to determine

whether individuals are at increased risk of develop-

ing atherosclerosis and whether the elevated levels,

frequently in combination with other established risk

factors, warrant treatment. Treatment of asymptom-

atic individuals with established hyperlipoproteine-

mia has been demonstrated to delay or prevent the

onset of atherosclerotic events.

0009 There are a number of disorders that are classified

under the generic rubric of atherosclerosis. Angina

pectoris (chest pain) is attributed to myocardial

ischemia, at times precipitated by increased physical

activity, accompanied by increased oxygen demand of

the heart. A myocardial infarction describes a com-

plete or near complete obstruction of a coronary

vessel by thrombosis, hemorrhage, or ulceration of

an atherosclerotic plaque or spasm of an artery, and

usually involves vessels that are already partially ob-

structed. The result can be damage to the myo-

cardium or sudden death. Cerebral ischemia refers

to compromised blood flow to the brain due to ath-

erosclerosis and can involve the carotid, subclavian,

or vertebral arteries, as well as intracranial vessels.

Clinical manifestations can include episodic cerebral

ischemia with motor function, monocular blindness,

or loss of consciousness. A complete occlusion results

in ischemia due to thrombosis, embolism, and hem-

orrhage (either intracerebral or subarachnoid) of a

cerebral artery and can result in neurologic defi-

ciency. Atherosclerosis of the renal artery can lead

to the development of hypertension. Occlusive

atherosclerosis of the femoral, popliteal, and tibial

arteries is associated with intermittent claudication

and eventually gangrene. The presence of these

lesions tends to correlate with atherosclerosis in

other parts of the vascular tree.

Etiology

0010Both observational and interventional data indicate

that the major contributing factors to the etiology of

atherosclerosis are elevated LDL cholesterol levels,

male gender, increased age, positive family history,

current cigarette smoking, hypertension, diabetes

mellitus, and low HDL cholesterol levels (Table 2).

It is difficult to rank the relative contribution to each

to the natural progression of the disease because the

relative importance of each depends on severity and

likely varies from individual to individual. Additional

factors, albeit not always independent factors, such as

elevated levels of homocysteine, lipoprotein (a)

(Lp(a)), triglyceride, physical inactivity, and obesity

also likely determine the course of development and

rate of progress of atherosclerotic lesion formation.

For this reason, the importance of devising individu-

alized treatment plans when counseling patients

cannot be overstated.

Primary Risk Factors

Nonmodifiable Risk Factors

0011Age Major prospective epidemiological investiga-

tions have provided strong evidence that the risk of

developing atherosclerosis is increased with advan-

cing age. These observations are consistent with

what is known about the etiology of atherosclerotic

lesions and the latency period between the appear-

ance of fatty lesions and development of complicated

plaque. In developed countries atherosclerosis

tbl0002 Table 2 Risk factors

Positive risk factors

Age

Male 45 years

Female 55 years or premature menopause without estrogen replacement therapy

Family history of premature coronary heart disease

Myocardial infarction or sudden death before 55 years or 65 years of age in parent or first-degree relative, male or female,

respectively

Current cigarette smoking

Hypertension

Blood pressure 140/90 mmHg (should be confirmed) or taking antihypertension medication

Low high-density lipoprotein (HDL) cholesterol (< 40 mg dl

1

(1.0 m mol l

1

))

Diabetes mellitus

Negative risk factor (subtract one positive risk factor)

High HDL cholesterol (60 mg dl

1

(1.6 mmol

1

))

ATHEROSCLEROSIS 341

becomes the leading cause of death in males during

the fourth decade of life and in females during the

sixth decade of life. Males above the age of 45 years

and females above the age of 55 years (or premature

menopause without estrogen replacement therapy)

are considered to be a positive risk factor.

0012 Family history of premature coronary heart disease

(genetics) Early studies have identified a trend to-

wards familial aggregation of atherosclerosis among

the relatives of individuals with established disease

compared to those without disease. Similarly, studies

of monozygotic and dizygotic twins provide support-

ive evidence for the heritability of atherosclerosis

through comparisons of concordance rates of clinical

events. Offspring of patients with a premature myo-

cardial infarction have been reported to have higher

circulating cholesterol levels than age-matched off-

spring of patients without a premature myocardial

infarction. Familial combined hyperlipidemia is one

of the major genetic causes of atherosclerosis within

families. Numerous genetic mutations associated

with different risks of developing atherosclerosis

have been identified. As the methodology for

screening advances, a greater understanding of how

individual mutations alter the clinical progression of

this multifactorial disease will emerge.

Modifiable Risk Factors

0013 Elevated LDL cholesterol levels Elevated LDL chol-

esterol levels are currently considered to be the

primary risk factor for the development of athero-

sclerosis. LDL levels below 2.57 mmol l

1

are classi-

fied as desirable, 2.58–3.34 mmol l

1

are classified in

the near or above optimal, 2.35–4.41 mmol l

1

are

classified in the borderline high, 4.12–4.89 mmol l

1

are classified in the high and above 4.91 mmol l

1

are

classified as very high (Table 3). There are three cat-

egories of risk that determine LDL cholesterol lowing

goals (Table 4). Risk category is determined on the

basis on the presence of existing coronary heart dis-

ease (CHD) and CHD risk equivalents (other clinical

forms of atherosclerotic disease such as peripheral

arterial disease, abdominal aortic aneurysm, and

symptomatic carotid artery disease; diabetes; or mul-

tiple risk factors that confer a 10-year risk for

CHD > 20%) or the number risk factors (Table 2).

Ten-year risk for CHD can be estimated using the

criteria presented in Table 5. The higher the estimated

risk for CHD the lower the LDL cholesterol goals.

Cross-cultural comparisons have clearly identified a

positive relationship between LDL cholesterol levels

and the incidence of atherosclerosis. Similar observa-

tions have been made within populations. Migration

studies which have resulted in elevations in LDL

cholesterol levels, presumably due to environmental

factors (diet and lifestyle), have supported these ob-

servations. Primary prevention trials resulting in de-

creased LDL cholesterol levels have led to reduced

rates of atherosclerosis. More recent interest has

centered on the potential for regression of athero-

sclerotic lesions by nonpharmacological means.

Efforts in this area have been hampered by the lack

of a safe, noninvasive, inexpensive, and accurate

measure of atherosclerotic plaque. The primary non-

pharmacological approach to reducing LDL choles-

terol levels is to limit saturated fat, trans fatty acids,

and cholesterol, increased physical activity, and

maintain a healthy body weight. The goals for

lowering LDL cholesterol levels as established by the

National Cholesterol Education Program are shown

in Table 5.

0014Current cigarette smoking A dose-dependent

relationship has been observed between cigarette

smoking and atherosclerotic events. The cessation of

cigarette smoking is associated with a precipitous

drop in the risk of a clinical event. This observation

suggests that cigarette smoking, per se, may act as a

triggering agent that results in a series of reactions

culminating in an atherosclerotic event. Physiological

responses associated with cigarette smoking include

undesirable effects on platelet adhesiveness and

clotting factors, increased heart rate, catecholamine

levels, and myocardial oxygen demand, and de-

creased oxygen-carrying capacity of the blood. Simi-

lar effects of pipe and cigar smoking are not normally

observed.

tbl0003 Table 3 Classification on the basis of total and LDL cholesterol

levels

Total cholesterol;

200 mg/dl ( 5.2 mmol/L) Desirable

201–239 mg/dl (5.2–6.2 mmol/L) Borderline–high

240 mg/dl (6.2 mmol/L) High

LDL cholesterol;

<100 mg/dl (<2.57 mmol/L) Optimal

100–129 mg/dl (2.58–3.34 mmol/L) Near or above optimal

130–159 mg/dl (2.35–4.11 mmol/L) Borderline high

160–189 mg/dl (4.12–4.89 mmol/L) High

190 mg/dl (4.91 mmol/L) Very high

tbl0004Table 4 Categories of risk and LDL cholesterol goal

Category LDLGoal

CHD and CHD risk equivalents <2.59 mmol/L

Multiple (2 or more) risk factors <3.36 mmol/L

0–1 risk factors <4.14 mmol/L

342 ATHEROSCLEROSIS

tbl0005 Table 5A Estimate of 10-Year Risk for Men (Framingham Point

Scores)

Age, y Points

20–34 9

35–39 4

40–44 0

45–49 3

50–54 6

55–59 8

60–64 10

65–69 11

70–74 12

75–79 13

To t a l

Cholesterol,

mg/dL

Points

Age

20^39 y

Age

40^49 y

Age

50^59 y

Age

60^69 y

Age

70^79 y

<160 0 0 0 0 0

160–199 4 3 2 1 0

200–239 7 5 3 1 0

240–279 9 6 4 2 1

280 11 8 5 3 1

Points

Age

20^39 y

Age

40^49 y

Age

50^59 y

Age

60^69 y

Age

70^79 y

Nonsmoker 0 0 0 0 0

Smoker 8 5 3 1 1

HDL, mg/dL Points

60 1

50–59 0

40–49 1

<40 2

Systolic BP,

mm Hg

If Untreated If Treated

<120 0 0

120–129 0 1

130–139 1 2

140–159 1 2

160 2 3

PointTotal 10 -YearRisk,

<0 <1

10 6

11 8

12 10

13 12

14 16

15 20

16 25

17 30

tbl0006Table 5B Estimate of 10-Year Risk for Women (Framingham

Point Scores)

Age, y Points

20–34 7

35–39 3

40–44 0

45–49 3

50–54 6

55–59 8

60–64 10

65–69 12

70–74 14

75–79 16

Total

Cholesterol,

mg/dL

Points

Age

20^39 y

Age

40^49 y

Age

50^59 y

Age

60^69 y

Age

70^79 y

<160 0 0 0 0 0

160–199 4 3 2 1 1

200–239 8 6 4 2 1

240–279 11 8 5 3 2

280 13 10 7 4 2

Points

Age

20^39 y

Age

40^49 y

Age

50^59 y

Age

60^69 y

Age

70^79 y

Nonsmoker 0 0 0 0 0

Smoker 9 7 4 2 1

HDL, mg/dL Points

60 1

50–59 0

40–49 1

<40 2

Systolic BP,

mm Hg

If Untreated If Treated

<120 0 0

120–129 1 3

130–139 2 4

140–159 3 5

160 4 6

PointTotal 10 -Year Risk,

<9 <1

10 1

11 1

12 1

13 2

14 2

15 3

16 4

17 5

18 6

19 8

20 11

21 14

22 17

23 22

24 27

25 30

ATHEROSCLEROSIS 343