Ch15.pdf

Alterations in Blood Flow

Disorders of the Arterial Circulation

Hyperlipidemia

Lipoproteins

Hypercholesterolemia

Atherosclerosis

Risk Factors

Pathology and Pathogenesis

Clinical Manifestations

Aneurysms and Dissection

Aortic Aneurysms

Aortic Dissection

The Vasculitides

Arterial Disease of the Extremities

Acute Arterial Occlusion

Atherosclerotic Occlusive Disease

Thromboangiitis Obliterans

Raynaud’s Disease and Phenomenon

Disorders of the Venous Circulation

Venous Circulation of the Lower Extremities

Varicose Veins

Chronic Venous Insufﬁciency

Venous Thrombosis

Disorders of Blood Flow Caused by

Extravascular Forces

Compartment Syndrome

Pressure Ulcers

Mechanisms of Development

Prevention

Staging and Treatment

trients to the tissues and in the removal of waste products

from the tissues. Unlike disorders of the respiratory sys-

tem or central circulation that cause hypoxia and impair oxy-

genation of tissues throughout the body, the effects of blood

vessel disease usually are limited to local tissues supplied by a

particular vessel or group of vessels.

Disturbances in blood flow can result from pathologic

changes in the vessel wall ( i.e. , atherosclerosis, vasculitides),

acute vessel obstruction caused by thrombus or embolus,

vasospasm ( i.e. , Raynaud’s phenomenon), abnormal vessel di-

lation ( i.e. , arterial aneurysms or varicose veins), or compres-

sion of blood vessels by extravascular forces ( i.e. , tumors,

edema, or ﬁrm surfaces such as those associated with pressure

ulcers).

DISORDERS OF THE

ARTERIAL CIRCULATION

The arterial system distributes blood to all the tissues in the

body. There are three types of arteries: large arteries, includ-

ing the aorta and its distal branches; medium-size arteries,

such as the coronary and renal arteries; and small arteries and

arterioles that pass through the tissues. Each of these different

types of arteries tends to be affected by different disease

processes.

Pathology of the arterial system affects body function by

impairing blood flow. The effect of impaired blood flow on

the body depends on the structures involved and the extent of

altered flow. The term ischemia ( i.e. , holding back of blood)

denotes a reduction in arterial ﬂow to a level that is insufﬁcient

to meet the oxygen demands of the tissues. Infarction refers to

an area of ischemic necrosis in an organ produced by occlu-

sion of its blood supply. The discussion in this section focuses

on hyperlipidemia, atherosclerosis, arterial aneurysms, vas-

culitides, and arterial disease of the extremities.

Hyperlipidemia

Hyperlipidemia with elevated cholesterol levels is a major

cause of atherosclerosis with its attendant risk of heart attack

and stroke. An estimated 41.3 million Americans have high

254

CHAPTER

B lood vessels function in the delivery of oxygen and nu-

Chapter 15: Alterations in Blood Flow

255

KEY CONCEPTS

DISORDERS OF THE ARTERIAL CIRCULATION

Low

density

Chylomicrons

80% 90% triglycerides,

2% protein

■

The arterial system delivers oxygen and nutrients to

the tissues. Disorders of the arterial circulation pro-

duce ischemia owing to narrowing of blood vessels,

thrombus formation associated with platelet adhe-

sion, and weakening of the vessel wall.

VLDL

55% 65% triglycerides,

10% cholesterol,

5% 10% protein

■

Atherosclerosis is a progressive disease characterized

by the formation of ﬁbrofatty plaques in the intima

of large and medium-sized arteries, producing a de-

crease in blood ﬂow due to a narrowing of the vessel

lumen.

LDL

10% triglycerides,

50% cholesterol,

25% protein

■

Aneurysms represent an abnormal localized dilatation

of an artery due to a weakness in the vessel wall. As

the aneurysm increases in size, the tension in the wall

of the vessel increases, predisposing it to rupture.

HDL

5% triglycerides,

20% cholesterol,

50% protein

High

density

serum cholesterol levels that could contribute to a heart

attack, stroke, or other cardiovascular event associated with

atherosclerosis. 1

Lipoproteins

Because cholesterol and triglyceride are insoluble in plasma,

they are encapsulated by special fat-carrying proteins called

lipoproteins for transport in the blood. There are ﬁve types of

lipoproteins, classiﬁed by their densities as measured by ultra-

centrifugation: chylomicrons, very–low-density lipoprotein

(VLDL), intermediate-density lipoprotein (IDL), low-density

lipoprotein (LDL), and high-density lipoprotein (HDL) (see

Fig. 15-1).

Each type of lipoprotein consists of a large molecular com-

plex of lipids combined with proteins called apoproteins . 2,3 The

major lipid constituents are cholesterol esters, triglycerides,

nonesteriﬁed cholesterol, and phospholipids. The insoluble

cholesterol esters and triglycerides are located in the hydro-

phobic core of the lipoprotein macromolecule, surrounded

by the soluble phospholipids, nonesteriﬁed cholesterol, and

apoproteins (Fig. 15-2). Nonesteriﬁed cholesterol and phos-

pholipids provide a negative charge that allows the lipoprotein

to be soluble in plasma. The apoproteins control the inter-

actions and ultimate metabolic fate of the lipoproteins. Some

of the apoproteins activate the lipolytic enzymes that facilitate

the removal of lipids from the lipoproteins; others serve as a

reactive site that cellular receptors can recognize and use in

the endocytosis and metabolism of the lipoproteins.

There are two sites of lipoprotein synthesis: the small intes-

tine and the liver. The chylomicrons, which are the largest of

the lipoprotein molecules, are synthesized in the wall of the

small intestine. They are involved in the transport of dietary

triglycerides and cholesterol that have been absorbed from the

gastrointestinal tract. Chylomicrons transfer their triglycerides

to the cells of adipose and skeletal muscle tissue. The remnant

chylomicron particles, which contain cholesterol, are then

taken up by the liver, and the cholesterol is used in the synthe-

sis of VLDL or excreted in the bile.

■ FIGURE 15-1 ■ Lipoproteins are named based on their protein

content, which is measured as density. Because fats are less dense

than proteins, as the proportion of triglycerides decreases, the

density increases.

The liver synthesizes and releases VLDL and HDL. The VLDLs

contain large amounts of triglycerides and lesser amounts

of cholesterol esters. 4 They provide the primary pathway for

transport of the triglycerides produced in the liver, as opposed

to those obtained from the diet. Like chylomicrons, VLDLs

carry their triglycerides to fat and muscle cells, where the tri-

glycerides are removed. The resulting IDL fragments are re-

duced in triglyceride content and enriched in cholesterol. They

Cholesterol

esters

Apoproteins

Triglycerides

Phospholipids

■ FIGURE 15-2 ■ General structure of a lipoprotein. The cholesterol

esters and triglycerides are located in the hydrophobic core of the

macromolecule, surrounded by phospholipids and apoproteins.

256

Unit Four: Alterations in the Cardiovascular System

are taken to the liver and recycled to form VLDL, or converted

to LDL in the vascular compartment. The pathways for triglyc-

eride and cholesterol transport are shown in Figure 15-3.

LDL, sometimes called the bad cholesterol , is the main carrier

of cholesterol. The IDLs are the main source of LDL. The LDL

is removed from the circulation by either LDL receptors or by

scavenger cells such as monocytes or macrophages. Approx-

imately 70% of LDL is removed by way of the LDL receptor-

dependent pathway. 4 Although LDL receptors are widely dis-

tributed, approximately 75% are located on hepatocytes; thus

the liver plays an extremely important role in LDL metabolism.

Tissues with LDL receptors can control their cholesterol intake

by adding or removing LDL receptors.

The scavenger cells, such as the monocytes and macro-

phages, have receptors that bind LDL that has been oxidized or

chemically modiﬁed. The amount of LDL that is removed by

the “scavenger pathway” is directly related to the plasma cho-

lesterol level. When there is a decrease in LDL receptors or

when LDL levels exceed receptor availability, the amount of

LDL that is removed by scavenger cells is greatly increased. The

uptake of LDL by macrophages in the arterial wall can result in

the accumulation of insoluble cholesterol esters, the formation

of foam cells, and the development of atherosclerosis.

HDL is synthesized in the liver and often is referred to as the

good cholesterol . Epidemiological studies show an inverse relation

between HDL levels and the development of atherosclerosis. 5 It

is thought that HDL, which is low in cholesterol and rich in sur-

face phospholipids, facilitates the clearance of cholesterol from

atheromatous plaques and transports it back to the liver, so that

it can be excreted in the bile. HDL also is believed to inhibit the

uptake of LDL into the arterial wall. It has been observed that reg-

ular exercise and moderate alcohol consumption increase HDL

levels. Smoking and diabetes, which are in themselves risk factors

for atherosclerosis, are associated with decreased levels of HDL. 4

Hypercholesterolemia

The Third Report of the National Cholesterol Education Pro-

gram (NCEP) Expert Panel on Detection, Evaluation, and Treat-

ment of High Blood Cholesterol in Adults has published a

classiﬁcation system for hyperlipidemia that list the laboratory

values for optimal to very high levels of LDL cholesterol, desir-

able to high levels of total cholesterol, and low and high levels

of HDL cholesterol (see Table 15-1). 6 The NCEP recommends

that all adults 20 years of age and older should have a fasting

lipoprotein proﬁle (total cholesterol, LDL cholesterol, HDL

cholesterol, and triglycerides) measured once every 5 years. 6 If

testing is done in the nonfasting state, only the total cholesterol

and HDL are considered useful. A follow-up lipoprotein proﬁle

should be done on persons with nonfasting total cholesterol

levels

≥

200 mg/dL or HDL levels

Dietary

triglycerides

and cholesterol

Bile acid

and cholesterol

HDL

Intestine

HDL

Receptor

dependent

pathway

Nonreceptor

dependent

pathway

Extrahepatic

tissue

LDL

receptor

Liver

Chylomicron

LDL

Cholesterol

VLDL

Chylomicron

fragments

IDL

Triglycerides

Blood vessels

Adipose and skeletal muscle tissue

■ FIGURE 15-3 ■ Schematic representation

of the exogenous and endogenous pathways

for triglyceride and cholesterol transport.

40 mg/dL. Lipoprotein mea-

surements are particularly important in persons at high risk for

the development of coronary heart disease (CHD).

Chapter 15: Alterations in Blood Flow

257

NCEP Adult Treatment

Panel III Classification of LDL,

Total, and HDL Cholesterol

dependent mechanisms, blood cholesterol levels are markedly

elevated in persons with this disorder. The disorder is probably

one of the most common of all mendelian disorders; the fre-

quency of heterozygotes is 1 in 500 persons in the general pop-

ulation. 2 Although heterozygotes commonly have an elevated

cholesterol level from birth, they do not experience symptoms

until adult life, when xanthomas ( i.e. , cholesterol deposits) de-

velop along the tendons and atherosclerosis occurs (Fig. 15-4).

Myocardial infarction before the age of 40 years is common.

Homozygotes are much more severely affected; they develop

cutaneous xanthomas in childhood and may experience myo-

cardial infarction by the age of 20 years. 2

Secondary causes of hyperlipoproteinemia include diets

high in saturated fats and cholesterol, obesity caused by high-

calorie intake, and diabetes mellitus. Diets that are high in tri-

glycerides and saturated fats increase cholesterol synthesis and

suppress LDL receptor activity. Excess ingestion of cholesterol

reduces the formation of LDL receptors and thereby decreases

LDL removal. In diabetes mellitus, metabolic derangements

cause an elevation of lipoproteins. 7

The management of hyperlipidemia focuses on dietary and

lifestyle modiﬁcations; when these are unsuccessful, pharma-

cologic treatment may be necessary. Lifestyle modiﬁcation in-

cludes increased emphasis on physical activity, dietary mea-

sures to reduce LDL cholesterol levels, and weight reduction for

people who are overweight. The aim of dietary therapy is to re-

duce total and LDL cholesterol levels and increase HDL levels.

Three dietary elements affect serum cholesterol and its lipopro-

tein fractions: excess calorie intake, saturated fats, and choles-

terol. High-calorie diets increase the production of VLDL, with

triglyceride elevation and high conversion of VLDL to LDL.

Saturated fats and cholesterol in the diet tend to increase LDL

cholesterol levels.

The third report of the NCEP continues to identify reduction

in LDL cholesterol as the primary target for cholesterol-lowering

therapy, particularly in people at risk for CHD. 6 Lipid-lowering

drugs work mainly by decreasing cholesterol absorption from

the intestine, decreasing cholesterol synthesis by the liver, or

Cholesterol Level (mg/dL) Classiﬁcation

LDL Cholesterol

<100

Optimal

100–129

Near optimal/above optimal

130–159

Borderline high

160–189

High

≥ 190

Very high

Total Cholesterol

<200

Desirable

200–239

Borderline high

≥ 240

High

HDL Cholesterol

<40

Low

≥ 60

High

National Institutes of Health Expert Panel. (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) .

(NIH publication no. 01-3670). Bethesda, MD: National Institutes of

Health.

Causes. Three factors—genetics, nutrition, and metabolic

diseases—contribute to an increase in blood lipid levels. Many

types of hyperlipidemia have a genetic basis. There may be a de-

fective synthesis of the apoproteins, a lack of LDL receptors, de-

fective LDL receptors, or defects in the intracellular handling of

cholesterol. 2 The LDL receptor is deﬁcient or defective in the ge-

netic disorder known as familial hypercholesterolemia . This auto-

somal dominant type of hyperlipoproteinemia results from

a mutation in the gene specifying the receptor for LDL. Because

most of the circulating cholesterol is removed by receptor-

■ FIGURE 15-4 ■ Xanthomas in the skin and tendons

( A, C, D ). Arcus lipoides represents the deposition of

lipids in the peripheral cornea ( B ). (Rubin E., Farber

J.L. [1999]. Pathology [3rd ed., p. 506]. Philadelphia:

Lippincott Williams & Wilkins)

TABLE 15-1

258

Unit Four: Alterations in the Cardiovascular System

inhibiting VLDL release. Drugs that act directly to decrease cho-

lesterol levels also have the beneﬁcial effect of further lowering

cholesterol levels by stimulating the production of additional

LDL receptors. Because many of these drugs have signiﬁcant ad-

verse effects, they usually are used only in persons with signif-

icant hyperlipidemia that cannot be controlled by other means,

such as diet.

clude age, male gender, and family history of premature coro-

nary heart disease.

The tendency to develop atherosclerosis appears to run in

families. Persons who come from families with a strong his-

tory of heart disease or stroke caused by atherosclerosis are at

greater risk for developing atherosclerosis than are those with

a negative family history. Several genetically determined al-

terations in lipoprotein and cholesterol metabolism have

been identified, and it seems likely that others will be identi-

fied in the future. The incidence of atherosclerosis also increases

with age. Other factors being equal, men are at greater risk for

coronary heart disease than are premenopausal women, prob-

ably because of the protective effects of natural estrogens.

After menopause, the incidence of atherosclerotic-related dis-

eases in women increases, and by the 7th to 8th decade of life,

the frequency of myocardial infarction in the two sexes tends

to equalize. 4

The major risk factors that can be affected by a change in

health behaviors include hyperlipidemia, cigarette smoking,

hypertension, and diabetes mellitus. These risk factors can

often be modified or controlled by a change in diet, exercise,

health care practices, or medications. The presence of hyper-

lipidemia is the strongest risk factor for atherosclerosis in per-

sons younger than 45 years of age. Both primary and secondary

hyperlipidemia increase the risk. Cigarette smoking is closely

linked with coronary heart disease and sudden death. Cessa-

tion of smoking reduces the risk substantially. High blood pres-

sure produces mechanical stress on the vessel endothelium. It

is a major risk factor for atherosclerosis in all age groups and may

be as important or more important than hypercholesterolemia

after the age of 45 years. Both systolic and diastolic pressures are

important in increasing risk. Diabetes mellitus (type 2) typically

develops in middle-aged persons and those who are overweight.

Diabetes elevates blood lipid levels and otherwise increases the

risk of atherosclerosis (see Chapter 32). Controlling other risk

factors, such as hypertension and hypercholesterolemia, is par-

ticularly important in persons with diabetes.

Other factors, known as “soft” risk factors, are not as con-

vincing as the established risk factors. These include insufﬁcient

physical activity, a stressful lifestyle, and obesity. These “soft”

risk factors commonly are linked with the established and

other contributing risk factors. For example, obesity and phys-

ical inactivity often are observed in the same person. Both con-

ditions are reported to bring about elevations in blood lipid

levels. Likewise, major risk factors such as cigarette smoking are

closely associated with stress and personality patterns.

There are a number of other less well-established risk factors

for atherosclerosis, including high serum homocysteine levels,

elevated serum C-reactive protein, and infectious agents. 9,10

Homocysteine is derived from the metabolism of dietary me-

thionine, an amino acid that is abundant in animal protein.

Homocysteine inhibits elements of the anticoagulant cascade

and is associated with endothelial damage, which is thought

to be an important first step in the development of athero-

sclerosis. 10 Factors tending to increase plasma levels of homo-

cysteine include lower serum levels of folate and vitamins B 6

and B 12 ; genetic defects in homocysteine metabolism; renal im-

pairment; malignancies, increasing age; male gender; and female

menopause. 11 C-reactive protein (CRP) is a serum marker for

systemic inﬂammation. Several prospective studies have indi-

cated that elevated CRP levels are associated with vascular dis-

Atherosclerosis

Atherosclerosis is a type of arteriosclerosis or hardening of the

arteries. The term atherosclerosis , which comes from the Greek

words atheros (meaning “gruel” or “paste”) and sclerosis (mean-

ing “hardness”), denotes the formation of ﬁbrofatty lesions in

the intimal lining of the large and medium-size arteries such as

the aorta and its branches, the coronary arteries, and the large

vessels that supply the brain. Atherosclerosis contributes to

more mortality and more serious morbidity than any other dis-

order in the western world. 4 The major complications of ather-

osclerosis, including ischemic heart disease, stroke, and periph-

eral vascular disease, account for more than 40% of the deaths

in the United States. 8

Risk Factors

The cause or causes of atherosclerosis have not been determined

with certainty. However, epidemiologic studies have identiﬁed

predisposing risk factors, which are listed in Chart 15-1. 2,4

Some risk factors can be affected by a change in health behav-

ior and others cannot. Risk factors that cannot be changed in-

CHART 15-1 Risk Factors in Coronary Heart

Disease Other Than Low-Density Lipoproteins

Positive Risk Factors

Age

Men: ≥ 45 years

Women: ≥ 55 years or premature menopause without

estrogen replacement therapy

Family history of premature coronary heart disease (deﬁnite

myocardial infarction or sudden death before 55 years of

age in father or other male ﬁrst-degree relative, or before

65 years of age in mother or other female ﬁrst-degree

relative)

Current cigarette smoking

Hypertension ( ≥ 140/90 mm Hg* or on antihypertensive

medication)

Low HDL cholesterol (<40 mg/dL*)

Diabetes mellitus

Negative Risk Factor

High HDL cholesterol ( ≥ 60 mg/dL)

HDL, high-density lipoprotein.

* Conﬁrmed by measurements on several occasions.

(Modiﬁed from National Institute of Health Expert Panel [2001]. Third

Report of the National Cholesterol Program [NCEP] Expert Panel on

Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults

[Adult Treatment Panel III]. [NIH Publication No. 01-3670]. Bethesda,

MD: National Institutes of Health.)

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