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

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The copper intake of nurses was roughly estimated at

between 5.3 and 32 mg copper, and the dose of 5.3 mg

copper day

1

has been adopted by some authorities

as the ‘lowest observed no-effect level’. Other author-

ities have suggested 0.21–0.5 mg kg

1

,orupto30mg

of copper in a 60-kg person, as the maximum toler-

able daily total intake for copper. Proposals for the

maximal allowable amount of copper in drinking

water are in the range of 1–2mg l

1

, but based on

copper poisoning in children, the safe amount for

children may be as low as 0.2 mg l

1

. This wide

range of estimates is attributed to insufficient data,

lack of understanding by toxicologists and regulatory

authorities that copper is an essential nutrient, lack of

awareness that humans are exposed to copper from

both foods and beverages, and concern about copper

toxicosis syndromes such as childhood cirrhosis.

Regulations for copper intakes and copper in drink-

ing water are summarized in Table 7.

0033 Indian childhood cirrhosis was a common killer

until the early 1990s when it became preventable

and treatable. The disease generally occurs between

the ages of 6 months and 5 years, and is characterized

by increased hepatic, urinary, and serum copper

concentrations. Symptoms include nonspecific com-

plaints such as abdominal distension, irregular fever,

excessive crying, and altered appetite. Jaundice is

usually a late feature. If left untreated, the illness

progresses rapidly within a few months and is associ-

ated with liver failure and possibly death. The source

of the dietary copper appears to be milk boiled in

copper or brass (an alloy with about 70% copper

and 30% zinc) vessels that have been used extensively

in India, particularly by traditional Hindu families.

Some investigators also believe that a genetic disorder

enhances susceptibility to this toxicity syndrome

associated with excessive dietary exposure to copper.

Public health campaigns in India designed to discon-

tinue the use of copper-containing vessels markedly

reduced the incidence of this disease.

0034Contamination of drinking from copper plumbing

has emerged as a public health concern. Copper-

associated liver diseases in infants and children, simi-

lar to the condition seen in India, have now appeared

in parts of Europe. The source of copper appears to

be drinking water. Treatment for this liver disease

involved d-pencillamine (a copper chelator) and in

a few cases a liver transplant was conducted. In an

investigation in Wisconsin (USA), one water system

involved had an alkaline pH of 7.2–7.4 that would

not be expected to be corrosive. However, phosphate

was added to sequester iron, and this may have pre-

vented calcium and magensium from depositing on

the inner surface of the copper pipes and providing

a protective coating. Thus, copper was more easily

leached into the water from the pipes. Homes built or

remodeled within the past 10 years had the highest

concentrations of copper in the water. In a second

location, symptoms began after installation of new

copper pipes in a mobile-home park and the water

was naturally corrosive and very low in mineral con-

tent. In both areas, the symptoms were nausea, diar-

rhea, abdominal cramps, and headaches. The copper

concentration of the water associated with toxicity

was up to 3.6 mg l

1

. Flushing the faucet for 1 min

decreased the copper content to below 0.25 mg l

1

The authors suggested that owners of homes with

new copper pipes should be informed about the risks

of copper-contaminated drinking water and have their

water tested. They also recommended that copper

intoxication be included in the differential diagnosis

for those presenting with chronic or intermittent

tbl0007 Table 7 Regulations regarding total intakes of copper and copper content of drinking water

Agency Upper limit Rationale

Water content

World Health Organization (WHO) 2.0 mg l

1

Attempt to keep contribution of water to no more than 10% of total

copper intake

European Commission (EC) None Suggested guide of 0.1 mg l

1

at water treatment plant, and 3 mg l

1

after water has stood in pipes for 12 h

US Environmental Protection Agency (EPA) 1.3 mg l

1

Based on a ‘lowest observed adverse-effect level’ of 5.3 mg in

humans (nurses, study), consumption of 2 l water daily, and

addition of safety factors

1.0 mg l

1

Nonenforcible concentration of 1 mg l

1

based on taste

considerations

Total intake

Food and Agricultural Organization/World

Health Organization (FAO)/WHO)

0.5 mg kg

1

Based on no-observed-effect level of 5 mg kg

1

in dogs

US National Academy of Science 10 mg day

1

European Commission 10 mg day

1

Risk of nausea and vomiting increases when this dose is exceeded

Reproduced from Johnson MA (1998) Copper: physiology, dietary sources and requirements. In: Encyclopedia of Human Nutrition. Academic Press, with

permission.

1646 COPPER/Physiology

gastrointestinal upsets, particularly when these symp-

toms can be linked with a change in the water supply.

Infants may be particularly sensitive to high intakes of

copper and some investigators have recommended

that drinking water contain no more than 0.2 mg l

1

See also: Copper: Properties and Determination; Dietary

Reference Values

Further Reading

Failla ML, Johnson MA and Prohaska JR (2001) Copper.

In: Bowman BA and Russell RM (eds) Present Know-

ledge in Nutrition, 8th edn., pp. 373–383. Washington,

DC: ILSI Press.

Food and Nutrition Board (2001) Copper. In: Dietary Ref-

erence Intakes for Vitamin A, Vitamin K, Arsenic,

Boron, Chromium, Copper, Iodine, Iron, Manganese,

Molybdenum, Nickel, Silicon, Vanadium, and Zinc,

pp. 224–257. National Academy of Sciences. Washing-

ton DC: National Academy Press.

Hardorn H-B (1999) Copper-associated liver diseases in

children. Introduction. European Journal of Medical

Research 4: 212–213.

Harris ZL and Gitlin JD (1996) Genetic and molecular

basis for copper toxicity. American Journal of Clinical

Nutrition 63: 836S–841S.

Harris ED (1997) Copper. Chapter 8. In: O’Dell BL and

Sunde RA (eds) Handbook of Nutritionally Essential

Mineral Elements. pp. 231–273. New York: Marcel

Dekker.

Johnson MA (1998) Copper: physiology, dietary sources

and requirements. In: Encylopedia of Human Nutrition,

pp. 442–450. London: Academic Press.

Johnson MA, Smith MM and Edmonds J (1998) Copper,

iron, zinc and manganese in dietary supplements, infant

formulas, and ready-to-eat breakfast cereals. American

Journal of Clinical Nutrition 67: 1035S–1042S.

nnerdal B (1998) Copper nutrition during infancy and

childhood. American Journal of Clinical Nutrition 67

(suppl.): 1046S–1053S.

Olivares M and Uauy R (1996) Limits of metabolic

tolerance to copper and biological basis for present

recommendations and regulations. American Journal of

Clinical Nutrition 63: 846S–852S.

Pandit A and Ghave S (1996) Present interpretation of the

role of copper in Indian childhood cirrhosis. American

Journal of Clinical Nutrition 63: 830S–835S.

Scheinberg IH and Sternlieb I (1996) Wilson disease and

idiopathic copper toxicosis. American Journal of Clin-

ical Nutrition 63: 842S–845S.

Turnlund JR (1999) Copper. Chapter 12. In: Shils ME,

Olson JA, Shike M and Ross AC (eds) Modern Nutrition

in Health and Disease, 9th edn, pp. 241–252. Baltimore,

MD: Williams & Wilkins.

CORONARY HEART DISEASE

Contents

Etiology and Risk Factor

Antioxidant Status

Intervention Studies

Prevention

Etiology and Risk Factor

F G Huffman, S Koutoubi and S Nath, Florida

International University, Miami, FL, USA

Background

0001 Our understanding of the biology and pathophysiol-

ogy of cardiovascular medicine and pathogenesis of

coronary heart disease (CHD), a multifactorial dis-

ease with a complex pathophysiology, continues to

expand as new horizons in epidemiological, experi-

mental, clinical, and genetic research are required.

Even so, CHD remains the leading cause of death,

accounting for more than 7 million of all cases of

mortality, and is responsible for chronic disability

and much of the healthcare costs worldwide. The

World Health Organization predicts that CHD will

prevail as the primary cause of morbidity and mortal-

ity worldwide until the year 2020.

0002No single risk factor consummates the ‘cause

and effect’ relationship. That the presence of any

one isolated risk factor cannot predict which individ-

ual will develop CHD. To date, data from myriad

CORONARY HEART DISEASE/Etiology and Risk Factor 1647

research have documented several hundred risk

factors that are statistically associated with the devel-

opment of CHD. Experts in cardiovascular research

often agree to classify these etiological factors as

major and minor risk factors or modifiable and non-

modifiable risk factors (Table 1). The majority of the

CHD epidemic in developed countries are associated

with the presence of smoking, high blood pressure,

high blood cholesterol, and impaired glucose toler-

ance. Most often, these common risk factors tend to

cluster in individuals who eventually develop CHD

events.

0003 Atherosclerosis, hardening of the arterial wall,

commences in childhood and, after decade-long cellu-

lar, molecular, and biochemical changes, culminates in

a heart attack, a well-known indication of CHD. In

1973, the ‘response-to-injury’ hypothesis of athero-

sclerosis was first outlined, underlining that the ath-

erosclerosis results from an arterial response to

chronic injury. Commonly chronic endothelial cell

injury is initiated by tobacco toxins (smoking), high

blood pressure, diabetes, oxidized low-density-lipo-

protein (LDL) cholesterol, as well as free radicals

resulting from oxidation of homocysteine (Hcy), and

infection (e.g., chlamydia). In response to an injury to

endothelial cells, there is a downregulation of protect-

ive mechanisms and upregulation of several factors

leading to atherosclerosis. For example, at the site of

endothelial injury, there is downregulation of the

potent endogenous vasodilator nitric oxide (NO),

tissue plasminogen activator (tPA), and prostacycline,

leading to a hyperprothrombic environment charac-

terized by upregulation of platelet aggregation and

leukocyte adhesion. At the initial stage, circulating

monocytes are attracted to the vascular intima, the

battleground of the atherosclerotic process. It is

worth mentioning that vascular cell adhesion mol-

ecule, usually expressed on the surface of endothelial

cells due to an inflammatory process, always precedes

the binding of monocytes. Monocytes then squeeze

through the tight junctions of the endothelial cells,

enter the subendothelial layer of the intima and are

transformed to phagocytic state macrophage. Macro-

phages engulf oxidized LDL cholesterol and form the

foam cells, the integral part of the ‘fatty streak.’ At one

stage, smooth muscles cells from the tunica media

migrate to the intima and release an extracellular

matrix. Monocytes, lymphocytes, platelets, endothe-

lial cells, and smooth muscle cells liberate numerous

factors, such as platelet-derived growth factors (a, b),

fibroblast growth factor, insulin-like growth factor-1,

interleukins (IL)-1, -2, -6, and -8, tissue necrosis factor

(TNF), which influence further cellular migration and

proliferation. The size of the fatty streak increases

with the accumulation of different types of cells and

lipids. Eventually, calcium is deposited and forms an

atherosclerotic plaque (Figures 1 and 2).

0004The following subsections detail each risk factor as

it relates to CHD.

Age, Gender, and Menopausal Status

0005The absolute risk of CHD increases with age, as there

is a progressive accumulation of coronary athero-

sclerosis with aging. Coronary heart disease is most

common after the age of 65 years, irrespective of

gender. Men however have a greater risk of CHD

than women; with men developing atherosclerotic

lesions 20 years earlier than women. Behavioral and

physiological differences between men and women

such as prolonged exposure to smoking, dislipidemia

and hormonal differences may partly explain the

gender difference. Among premenopausal women,

CHD is rare (except among smokers and oral contra-

ceptive users). However, the CHD risk is precipitous

among postmenopausal women, approaching that

for men.

Family History

0006Based on genetic data, twin studies, and phenotypes

(measurable traits) linked by inheritance, a positive

family history of CHD is one of the most potent

etiological influences on CHD independent of other

major risk factors such as smoking, high blood

tbl0001 Table 1 Etiology of coronary heart disease (CHD)

Nonmodifiable risk factors

Age and gender (men 45 years; women 55 years)

Family history of premature CHD (CHD in male first-degree

relative <55 years; CHD in female first-degree relative <65

years)

Modifiable risk factors

Cigarette smoking

Atherogenic diet

Physical inactivity

High blood pressure (140/90 mmHg)

Obesity

Diabetes mellitus

High blood total cholesterol (200 mg dl

1

)

High blood low-density lipoprotein cholesterol (130 mg dl

1

)

Low blood high-density lipoprotein cholesterol (< 40 mg dl

1

)

High blood triglycerides (150 mg dl

1

)

Thrombogenic factors

Inflammation or infection

Cytomegalovirus

Chlamydia pneumoniae

Helicobacter pylori

Herpes simplex

C-reactive protein

Serum amyloid A protein

Others

High blood homocysteine

Angiotensin II

1648 CORONARY HEART DISEASE/Etiology and Risk Factor

pressure, diabetes, and high LDL cholesterol. For

example, a single gene mutation (genetic variation)

in lipid metabolism is well documented in the devel-

opment of CHD. Plasma lipoprotein(a), Lp(a), is a

new risk factor for CHD. In normal population, the

variability of the apo(a) gene accounts for 90% of the

variability of plasma Lp(a). African Americans have a

higher levels of Lp(a) than white Americans. French

Canadians also have a higher level than expected due

to relative genetic homogeneity, also known as

‘founder effects.’ Familial combined hyperlipidemia,

another well-known lipid disorder, may cause CHD

before the age of 60 years, with a prevalence of about

2%.

0007 The risk of CHD increases in an individual with a

history of CHD in a first-degree relative (parent,

brother, sister, son, or daughter). The family history

is considered positive if clinical CHD or sudden

death can be documented in first-degree male rela-

tives before the age of 55 or in first-degree female

relatives before the age of 65.

Smoking

0008 Cigarette smoking is one of the most important risk

factors for the development and progression of CHD.

It has been estimated that smoking is responsible for

about 30% of CHD-related deaths. Coronary heart

disease events and deaths are attributable to cigarette

smoking in both a dose- and duration-dependent

fashion. Coronary heart disease risk is two to four

times higher in smokers than in non-smokers. Inhaled

cigarette smoke contains thousands of substances,

many of which are toxic to cells. For example, the

extensively studied chemical nicotine appears to

be involved in endothelial cell death, diminished

endothelial cell mitosis rate, and inhibition of NO

synthesis. Detrimental effects of smoking on the car-

diovascular system include an acute increase in vas-

cular resistance and blood pressure, impaired oxygen

transport, constriction of coronary vessel walls, ac-

celeration of LDL cholesterol oxidation, decreased

HDL cholesterol, increased platelet aggregation, and

increased fibrinogen production. Smoking also acts

synergistically with other etiological factors for

CHD, thereby substantially increasing the risk. Pas-

sive smoking or environmental exposure also carries a

substantial risk in the development of CHD. Like

first-hand smoke, environmental smoke contains

many toxins, such as carbon monoxide, benzopyrene,

and hundreds of other chemicals. Many of these

substances are toxic to arterial walls and may cause

endothelial dysfunction and substantially reduce

coronary microcirculation, an early process of

atherosclerosis.

Diabetes mellitus

Tobacco use by-products

Interventional therapies

Infections

Hypercholesterolemia

Homocysteine-derived

free radicals

Other free radicals

Chronic endothelial injury

Increased LDL

permeability

Lumon

Intima

Oxidized

LDL uptake

Media

Adverbha

Smooth muscle cell

and fibroblast migration

Enhanced monocyte

adhesion and

migration

Fibrous cap

formation

Matrix

degradation

Metalloprotease

Atherosclerotic

plaque

Vasoconstriction C.Lynm

Local increase in:

Thromboxane A

Serotonin

ADP

Thrombin

PAF

Free radicals

Tissue factor

Endothelin

Extracellular lipid core

and

Cellular debris formation

Platelet aggregation

and

Thrombus development

Form cell

Growth

factors

Chromatactic

factors

Smooth muscle

cell proliferation

Ulceration

fissure

Decreased endothelial

production of

NO, tPA, PGI

fig0001 Figure 1 (see color plate 39) Mechanisms in the initiation and progression of atherosclerosis. Endothelial injury results from a

variety of factors such as smoking, high blood cholesterol and homocysteine, and ulceration of atherosclerotic plaques, etc. (see text).

At the site of endothelial injury, there is a downregulation of endothelial-derived nitric oxide (NO), tissue plasminogen activator (tPA),

and prostacyclin (PGl

) with increased adhesion of platelets and leukocytes, increased permeability to lipoproteins, and vasoconstric-

tion. ADP, adenosine diphosphate; LDL, low-density lipoprotein; PAF, platelet activating factor. From Lefkowitz RJ and Willerson JT

(2001) Prospects for cardiovascular research. Journal of the American Medical Association 285: 581–587 with permission.

CORONARY HEART DISEASE/Etiology and Risk Factor 1649

Psychosocial Risk Factors

0009 There is mounting evidence that exposure to environ-

mental stressors and psychological reactions to stress,

an individual’s personality prototype (type A), lack of

social support, depression, and low socioeconomic

condition are associated with increased CHD risk.

Type A behavior is of special interest since it is associ-

ated with a two- to threefold higher risk for acute

myocardial infarction, as documented by substantial

prospective and case-control studies. A comprehen-

sive explanation of the effects of psychosocial factors

on CHD risk factors (e.g., high blood pressure) has not

yet been established. Psychosocial factors may act in

different ways. For example, they may be related to

risky behaviors or lifestyle factors such as smoking,

poor diet, physical inactivity, or excessive alcohol con-

sumption, which in turn influence the development of

CHD. However, the essential role of the psychosocial

factors in developing CHD event is mediated by a

neuroendocrine mechanism that alters catecholamine

levels. Excessive adrenergic (sympathetic) activity

may cause platelet aggregation, leading to occlusive

arterial thrombus formation. It is also hypothesized

that psychosocial stress may also increase circulating

IL-6, which in turn acts on the hypothalamic–pituit-

ary–adrenal axis, releasing many hormones that even-

tually result in abdominal obesity, insulin resistance,

and various lipid disorders, the risk factors for CHD.

Atherogenic Diet

0010Many decades of research have established that diet

plays a key role in atherosclerosis and subsequent

events such as myocardial infarction. The rates

of CHD are strongly associated with atherogenic

diets, which influence other biological factors such

as high blood pressure, LDL cholesterol, HDL chol-

esterol, thrombogenic factors, and obesity. The diet

also affects CHD in other ways: high-calorie, high-

saturated-fat (especially 12–16 carbon atoms) diets,

combined with physical inactivity or a sedentary life-

style, may lead to obesity, diabetes, and high blood

pressure. Experimental models have proved that diet-

ary saturated fat may cause atherosclerotic changes

even in the absence of other classical etiological

Nomenclature and

main histology

Main

growth

mechanism

Growth

mainly

by lipid

accumu-

lation

Accelerated

smooth

muscle

and

collagen

increase

Thrombosis,

hematoma

Earliest

onset

From

first

decade

From

third

decade

From

fourth

decade

Clinical

corre-

lation

Clinically

silent

Clinically

silent

overt

Sequences in progression

Type I (initial) lesion

isolated macrophage

foam cells

Type II (fatty streak) lesion

mainly intracellular

lipid accumulation

Type III (intermediate) lesion

Type II changes and small

extracellular lipid pools

Type IV (atheroma) lesion

Type II changes and core

extracellular lipid

Type V (fibroatheroma) lesion

lipid core and fibrotic layer,

or multiple lipid cores and fibrotic

layers, or mainly calcific,

or mainly fibrotic

Type VI (complicated) lesion

surface defect,

hematoma-hemorrhage,

thrombus

III

fig0002 Figure 2 Flow diagram of the progression of atherogenesis. Roman numerals indicate histological characteristics of lesions. Loop I

to loop IV illustrates the morphological changes in the lesion due to lipid accumulation. The loop between V and VI illustrates how

lesions increase in thickness when thrombotic deposits form on their surface. From Stary HC et al. (1995) A definition of advanced

types of atherosclerotic lesions and a histological classification of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology

15: 1512–1531 with permission.

1650 CORONARY HEART DISEASE/Etiology and Risk Factor

factors for CHD. In contrast, substitution of saturated

fat with isocaloric unsaturated fatty acids and com-

plex carbohydrates, especially soluble fiber, lowers

LDL cholesterol. Partial hydrogenation of polyunsat-

urated fatty acids (e.g., margarine) increases LDL

cholesterol. Dietary cholesterol has a small effect on

elevating LDL cholesterol. A diet high in protein can

substantially limit carbohydrate intakes. Proteins

from animal sources are generally higher in fat, satur-

ated fat, and cholesterol and are considered athero-

genic. Excessive salt intake is associated with high

blood pressure in susceptible persons. Dietary supple-

mentation of b-carotene (20 mg per day), a precursor

of vitamin A,mayincreasecardiovascularmortalityby

12–26%, especially among male smokers. Many epi-

demiological studies have shown a J- or U-shaped rela-

tionship between alcohol consumption and all-cause

mortality. Excessive alcohol consumption is associated

with increased CHD, possibly because of an increase in

blood pressure and cardiac arrhythmias. In contrast,

light to moderate alcohol consumption is cardiopro-

tective, since it increases HDL cholesterol and apoli-

poprotein A1, and has favorable effects on markers of

inflammation (e.g., C-reactive protein and IL-6).

Physical Inactivity

0011 Prospective epidemiological studies have shown that

both physical inactivity and a sedentary lifestyle are

independent etiological factors and predictive of in-

creased CHD risk. It is, however, difficult to quantify

the association between the amount of physical activ-

ity and CHD. Results from meta-analyses have con-

cluded that physical activity may lower the rate of

CHD events by 50%. The positive benefits of physical

activity on CHD outcomes may be partially mediated

by lowering high blood pressure, decreasing triglycer-

ides and LDL cholesterol, increasing HDL choles-

terol, and increasing insulin sensitivity by lowering

blood glucose levels.

High Blood Pressure

0012 Although high blood pressure or hypertension is de-

fined as a systolic blood pressure of 140 mmHg or

greater and a diastolic blood pressure of 90 mmHg

or greater, this definition is arbitrary. Several large-

scale epidemiological studies have consistently dem-

onstrated a positive, strong, continuous, graded, and

independent relationship between high blood pressure

and the etiology of CHD. The prevalence of high blood

pressure is approximately 50% in the persons aged 65

years or older in many countries. High blood pressure

promotes the atherogenesis process by several mech-

anisms: increased endothelin production, increased

leukocyte adherence, impaired endothelium-derived

relaxant factor production, increased endothelium-

derived contractile substances, and increased vascular

permeability to lipoproteins. It has been shown that in

essential hypertension, endothelial damage inhibits

NO production, and there is production of endothelin

a potent vasoconstrictor from the activated endothe-

lium. In addition, high blood pressure may also cause

structural remodeling of vascular walls (cell prolifer-

ation) and accumulation of smooth muscle cells in the

tunica intima, which in turn initiates a series of cas-

cades leading to atherogenesis.

Obesity

0013Obesity, particularly central or abdominal obesity, is

considered one of the prime etiological risk factors for

CHD, since the adverse effects of obesity on CHD

risk factors (blood pressure, lipid profiles, and glu-

cose tolerance) are numerous. Central obesity is de-

fined as a waist-to-hip ratio of > 102 cm in men and

> 88 cm in women. Among the several adverse effects

of obesity in mediating CHD, the most profound

effect is high blood pressure. It has been estimated

that more than 75% of high blood pressure is directly

attributed to obesity. It is well documented in medical

literature that blood pressure increases with weight

gain and decreases with weight loss. Another signifi-

cant negative effect of obesity is on lipid metabolism;

obesity increases triglycerides and LDL cholesterol,

and decreases HDL cholesterol. Although it is diffi-

cult to establish the exact contribution of obesity

to glucose intolerance or insulin resistance, the role

of excess body fat, particularly abdominal fat, is posi-

tively correlated with insulin resistance.

Diabetes Mellitus

0014Individuals with either type 1 (insulin-dependent dia-

betes mellitus) and type 2 (noninsulin-dependent

diabetes mellitus) are at higher risk for CHD than

nondiabetic individuals. Atherosclerosis is responsible

for more than 75% of all mortality among diabetics.

Silent myocardial ischemia commonly occurs in pa-

tients with diabetes. Data from longitudinal

epidemiological studies suggest that diabetes or hyper-

glycemia (random plasma glucose concentration

200 mg dl

1

or fasting plasma glucose concentration

125 mg dl

1

) is an independent and well-established

etiological factor for CHD. Diabetes, especially type 2

diabetes, is a strong CHD risk factor in women which

increases CHD-related mortality by 400%.

0015The relationship between diabetes and CHD risk is

complex, poorly understood, and yet to be elucidated.

Diabetes alters endothelial cell function by contrib-

uting several mechanisms such as smooth muscle cell

proliferation and extracellular matrix production, ele-

vation of endothelin and angiotensin II, enhance plate-

let adhesion, and decrease in tPA. All these changes

CORONARY HEART DISEASE/Etiology and Risk Factor 1651

result in the progression of atherosclerosis. In the case

of type 2 diabetes, the hyperinsulinemic state exerts

mitogenic effects on the smooth muscle cells, leading

to an alteration of endothelial structure. In addition,

in the pathogenesis of atherosclerosis process, hyper-

glycemia and other CHD risk factors such as smoking,

high blood pressure, hyperlipidemia, obesity, physical

inactivity, and insulin resistance are interrelated and

intertwined and continue to act independently in pa-

tients with diabetes. The majority of patients with

type 2 diabetes have insulin resistance, which indeed

predisposes then to CHD. There are other factors such

as abdominal obesity, elevated triglycerides and LDL

cholesterol, low HDL cholesterol, high blood pres-

sure, and alterations in coagulation mechanisms that

tend to cluster among type 2 diabetics, collectively

known as metabolic syndrome. Elevated plasminogen

activator inhibitor-1 (PAI-1) concentration, a novel

risk factor of CHD, is another potentially important

thrombogenic factor in this syndrome.

Blood Lipids

0016 The essential roles of blood cholesterol and triglycer-

ides in the etiology of CHD are well established. There

is a continuous and graded risk between total blood

cholesterol and CHD in population-based studies.

However, on an individual basis, total cholesterol

may be used as a risk factor in determining CHD. In

fact, most of the lipid-related risk is explained by the

LDL cholesterol levels, and the positive association

between high LDL cholesterol (160 mg dl

1

) and

the risk of CHD is applicable to individuals with or

without established CHD, in both men and women.

In epidemiological studies, LDL cholesterol increases

as total cholesterol increases. Low-density lipopro-

teins increase with age, weight gain, and atherogenic

diets. Genetic factors such as the heterozygous form of

familial hypercholesterolemia further increase LDL

cholesterol in the general population. The oxidized

form of LDL is the main culprit in atherogenesis.

Scavenging macrophages engulf oxidized LDL par-

ticles, resulting in the formation of lipid-laden foam

cells. Subsequently, in combination with smooth

muscle proliferation, the lipid-laden foam cells are

transformed to a fatty streak, as mentioned earlier.

Oxidized LDL cholesterol also inhibits relaxation

factors and promotes contraction factors leading to

modification of vascular tone, which eventually leads

to vasospasm and thrombus formation.

0017 A low level of HDL cholesterol is a strong independ-

ent etiological factor for CHD. Low HDL cholesterol is

defined as a level of < 40 mg dl

1

(Table 2). High-

density lipoprotein cholesterol levels are negatively

influenced by cigarette smoking, overweight/obesity,

physical inactivity, and type 2 diabetes. It has been

hypothesized that cholesterol efflux from athero-

sclerotic lesions is promoted by HDL cholesterol via a

receptor-mediated mechanism.

0018A meta-analysis of prospective studies has indi-

cated that elevated triglycerides, or hypertriglyceride-

mia (200 mg dl

1

), is an independent risk factor for

CHD after controlling for LDL and HDL cholesterol.

Several factors contribute to the development of high

triglyceride levels such as cigarette smoking, obesity

and overweight, physical inactivity, type 2 diabetes,

excess alcohol consumption, and genetic disorders

(e.g., familial hypertriglyceridemia). The proposed

potential mechanisms by which elevated triglycerides

contribute to CHD include increased thrombo-

genicity, increased chylomicron and very low-density

lipoprotein (VLDL) remnant particles, increased LDL

and decreased HDL cholesterol, and altered meta-

bolic processes involved in triglyceride transport.

0019Lp(a) is a cholesterol ester- and apolipoprotein

B-containing particle with the presence of glycoprotein

apo(a) that can promote atherogenesis by enhancing

oxidation of LDL cholesterol, promoting cholesterol

deposition in tunica intima, and interfering with

fibrinolysis. The level of Lp(a) appears to be genetically

determined.

Thrombogenic Risk Factors and Homeostasis

0020Both case-control and prospective studies have shown

that thrombogenic factors (fibrinogen, blood clot-

ting factor VII, tPA and, PAI-1) independently and

tbl0002Table 2 Classification of total, LDL, HDL cholesterol, and

triglycerides (mg dl

1

)

Lipid fraction Classification

Total cholesterol

< 200 Low

200–239 Borderline high

240 High

LDL cholesterol

< 100 Optimal

100–129 Near optimal/above optimal

130–159 Borderline high

160–189 High

190 Very high

HDL cholesterol

< 40 Low

60 High

Tr i g l y c e r i d e s

< 150 Optimal

150–199 Borderline high

200–499 High

500 Very high

HDL, high-density lipoprotein; LDL, low-density lipoprotein.

From (2001) Third Report of the National Cholesterol Education Program

(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood

Cholesterol in Adults (Adult Treatment Panel III) Executive Summary.NIH

Publication No. 01–3670. Bethesda, MD: National Heart, Lung, and Blood

Institute.

1652 CORONARY HEART DISEASE/Etiology and Risk Factor

consistently increase the risk of CHD. Coronary

thrombosis is generally present in most cases of

acute myocardial infarction. Increased platelet counts

and platelet aggregation are also associated with re-

current CHD. PAI-1 activity or antigen inhibits fibri-

nolysis, and increased concentrations of fibrinogen

promote platelet aggregation, which in turn induces

blood clotting. Several factors elevate fibrinogen,

notably increasing age, smoking, obesity and dia-

betes, use of oral contraceptive pills, and genetic

polymorphism. Blood clotting factor VII plays a piv-

otal role in coagulation initiation and may also be

predictive of myocardial infarction. Plasma concen-

trations of factor VII again are influenced by both

environmental and genetic polymorphism. PAl-

1 regulates the rate of tPA synthesis by the endothelial

cells. Several studies have shown that the levels of

PAl-1 and tPA mass concentrations are predictive of

initial and subsequent myocardial infarction. Ele-

vated plasma fibrinogen, a consistent procoagulant

risk factor for CHD, has several mechanisms;

notably, it increases fibrin formation, platelet aggre-

gation, and plasma viscosity. Other markers such as

the d-dimer, plasmin-a-antiplasmin complex, are in-

dicators of activation of the fibrinolytic system.

Inflammation and Infectious Agents

0021 There is a considerable body of evidence indicating

that inflammation and infection are responsible in the

pathogenesis of CHD as potential etiological factors.

C-reactive protein (CRP) is of special interest. Both

experimental and clinical studies have documented

that elevation of plasma CRP, a marker of low-grade

inflammation, can predict an increased risk of CHD

event in healthy persons independent of other risk

factors. Although the definitive mechanism of actions

of CRP that triggers low-grade inflammatory response

in atherosclerosis is still under further investigation,

possible indirect roles have been as follows: (1) CRP

may act as a procoagulant, (2) it binds avidly with

neutrophils, (3) it facilitates uptake of oxidized LDL

cholesterol by macrophages, (4) it induces comple-

ment activation, (5) it is chemotactic for monocytes,

and (6) it impairs endothelial functions and enhances

tissue injury. Other low-grade markers of inflamma-

tion, notably amyloid A protein, albumin, IL-6, TNF-

a, transforming growth factor b1, and leukocytes may

also be involved in the atherogenesis process. In the

development of coronary event, the proposed mech-

anisms of IL-6 include alterations in insulin sensitivity,

increased hepatic release of fibrinogen, procoagulant

effects on platelets, and increased release of adhesion

molecules. TNF-a inhibits lipoprotein lipase, stimu-

lates lipolysis, and influences endothelial function

leading to a procoagulant state. Recently, chronic

infections by several microorganisms, especially

herpes simplex viruses, cytomegalovirus, Chlamydia

pneumoniae, and Helicobacter pylori, have attracted

interest in the potential roles in the pathogenesis of

atherosclerosis leading to CHD.

Homocysteine

0022There is substantial evidence supporting elevated

plasma levels of Hcy (> 15 mmol l

1

) as an independent

etiological factor for premature atherosclerotic

lesions. Hcy is a metabolite of methionine as a product

of many S-adenosylmethionine-dependent trans-

methylation reactions that require several enzymes

(cystathionine b-synthase, g-cystathionase, betaine-

homocysteine methyltransferase, methionine syn-

thase, 5,10-methyltetrahydeofolate reductase) and

vitamins (folic acid, B

). Enzymatic defects or

vitamin deficiencies cause Hcy accumulation, which

causes (1) direct toxic effects to the endothelium, (2) in-

creased adhesiveness of platelets, (3) oxidation of LDL

cholesterol, (4) proliferation of smooth muscle, (5)

inhibition of nitric oxide formation, and (6) increased

thromboxane formation. Meta-analyses document

that as much as 10% of the CHD risk may be attribut-

able to elevated Hcy, and each 5 mmol l

1

increment of

Hcy is associated with a 60–80% increase in CHD.

Homocystinuria is a rare autosomal recessive genetic

disorder that is associated with a 10-fold increase of

blood Hcy levels.

Emerging Risk Factors

0023Accumulating evidence suggests that the renin–angio-

tensin II system plays an integral role in the multiple

processes critically implicated in the pathogenesis of

atherosclerosis. The inflammatory response of angio-

Psychosocial

stress

Catech-

olamines

Smoking (Central)

obesity

Pollution

migration

infection

HPA

axis

+ve

−ve

Genotype

programming

CRP

Insulin

resistance

Hyper

tension

Dys-

lipidemia

Endothelial

dysfunction

Coagulation

CHD

Interleukin-6

fig0003Figure 3 Possible mechanisms of action of IL-6 in the patho-

genesis of CHD. From Atherosclerosis 148(2): 209–214 with

permission.

CORONARY HEART DISEASE/Etiology and Risk Factor 1653

tensin II on endothelium is mediated by the release of

platelet-derived growth factor, insulin-like growth

factor, IL-1, IL-6, and IL-8. Angiotensin II may also

alter the structural integrity of endothelium, antagon-

ize NO synthesis, increase the growth and migration of

smooth muscle cells and fibroblasts, and promote LDL

cholesterol oxidation and deposition in the intimal

layer. IL-6 may also initiate the atherosclerotic process

by changing metabolic, endothelial, and coagulant

mechanisms. The possible mechanisms of action of

IL-6 in CHD pathogenesis are illustrated in Figure 3.

0024 The multifactorial etiology of CHD and the contri-

bution of these factors, individually or in combin-

ation, to the risk of developing a CHD event in

future is of prime importance in terms of both pri-

mary and secondary prevention.

See also: Atherosclerosis; Cholesterol: Role of

Cholesterol in Heart Disease; Coronary Heart Disease:

Antioxidant Status; Intervention Studies; Prevention;

Diabetes Mellitus: Secondary Complications; Exercise:

Metabolic Requirements; Hypertension: Physiology;

Hypertension and Diet; Obesity: Etiology and Diagnosis;

Smoking, Diet, and Health; Vitamin B

: Properties and

Determination