408
U N I T 5
Circulatory Function
be elevated as a result of an increase in any of the
lipoproteins. For example, two persons with the same
total serum cholesterol of 275 mg/dL may have very
different lipid profiles.
11
One person may have a favor-
able lipid profile with an HDL of 110 mg/dL, a triglyc-
eride level of 175 mg/dL, and an LDL of 130 mg/dL,
whereas another person with an HDL of 40 mg/dL, a
triglyceride level of 150 mg/dL, and an LDL cholesterol
of 205 mg/dL would be at much greater risk for cardio-
vascular disease.
Management of Hyperlipidemia.
A reduction in LDL
cholesterol continues to be the primary target for choles-
terol-lowering therapy, particularly in people at risk for
coronary artery disease (CAD). The major risk factors
for CAD, exclusive of LDL cholesterol levels, include
cigarette smoking, hypertension, family history of pre-
mature CAD in a first-degree relative, age (men
≥
45
years; women
≥
55 years), an HDL cholesterol level less
than 40 mg/dL, and diabetes mellitus.
6,11,12
Guidelines
recommend that persons with none of the major risk
factors should have an LDL cholesterol goal of 160 mg/
dL or less; those with two or more of the major risk fac-
tors should have an LDL cholesterol goal of less than
130 mg/dL; persons with
high-risk
factors (i.e., those
with CAD, other forms of atherosclerotic disease, or
diabetes) should have an LDL cholesterol goal of less
than 100 mg/dL; and persons with
very–high-risk
fac-
tors (i.e., acute coronary syndromes or CAD with other
risk factors) should have an LDL cholesterol goal of less
than 70 mg/dL.
13
It is also recommended that persons
with a greater than 20% 10-year risk of experiencing
myocardial infarction or coronary death, as determined
by the risk assessment tool developed from Framingham
Heart Study data, should have an LDL cholesterol
goal of less than 100 mg/dL (to calculate a risk score,
go to
.
asp?usertype=prof )
The management of hypercholesterolemia focuses on
dietary and therapeutic lifestyle changes; when these are
unsuccessful, pharmacologic treatment may be neces-
sary. Therapeutic lifestyle changes include an increased
emphasis on physical activity, dietary measures to reduce
LDL levels, smoking cessation, and weight reduction for
people who are overweight.
Several dietary elements affect cholesterol and its
lipoprotein fractions: (1) excess calorie intake, (2)
saturated and trans fats, and (3) cholesterol.
12
Excess
calories consistently lower HDL and less consistently
elevate LDL. Saturated fats in the diet can strongly
influence cholesterol levels. Depending on individual
differences, they raise VLDL and LDL levels. Trans
fats, which are manufactured from vegetable oils and
are used to enhance the taste and extend the shelf
life of fast foods, are more atherogenic than satu-
rated fats. Dietary cholesterol tends to increase LDL
cholesterol.
Lipid-lowering drugs work in several ways, includ-
ing decreasing cholesterol production, decreasing cho-
lesterol absorption from the intestine, and removing
cholesterol from the bloodstream. Drugs that act to
directly decrease cholesterol levels also indirectly lower
cholesterol levels by stimulating the production of addi-
tional LDL receptors. There currently are five major
types of medications available for treating hypercho-
lesterolemia: 3-hydroxy-3-methyl-glutaryl coenzyme A
(HMG-CoA) reductase inhibitors (statins), bile acid–
binding resins, cholesterol absorption inhibitor agents,
niacin and its congeners, and the fibrates.
9,12
Inhibitors
of HMG-CoA reductase, a key enzyme in the choles-
terol biosynthetic pathway, can reduce or block the
hepatic synthesis of cholesterol and are the corner-
stone of LDL-reducing therapy. Statins also reduce
triglyceride levels. The bile acid–binding resins bind
and sequester cholesterol-containing bile acids in the
intestine. This leads to increased production of LDL
receptors by the liver, with resulting increased removal
of cholesterol from the blood for synthesis of new bile
acids. The cholesterol absorption inhibitor (ezetimibe)
interferes with the absorption of cholesterol. Nicotinic
acid, a niacin congener, blocks the synthesis and
release of VLDL by the liver, thereby lowering not only
VLDL levels but also IDL and LDL levels. Nicotinic
acid also increases HDL concentrations up to 30%.
The fibrates decrease the synthesis of VLDL by the
liver and also enhance the clearance of triglycerides
from the circulation.
Atherosclerosis
Atherosclerosis is a condition in which an artery wall
thickens as a result of the accumulation of fatty mate-
rials. The term atherosclerosis, which comes from the
Greek words atheros (“gruel” or “paste”) and sclerosis
(“hardness”), denotes the formation of fibrous plaque in
the intimal lining of the large and medium-sized arteries
such as the aorta and its branches, the coronary arter-
ies, and the cerebral arteries that supply the brain (Fig.
18-6). The disorder, which remains a leading cause of
coronary artery disease, stroke, and peripheral artery
disease, can begin in the late teens, but usually takes
decades to cause symptoms. Some people experience
rapidly progressing atherosclerosis during their 30s,
others during their 50s or 60s.
Epidemiology and Risk Factors
Atherosclerosis is a complex disorder. Although its exact
cause is unknown, epidemiologic studies have identi-
fied predisposing risk factors (Chart 18-1).
1,2,6,11
Some
of these are constitutional and cannot be changed, but
others are affected by lifestyle and can be modified. The
major risk factor, hypercholesterolemia, has both con-
stitutional and lifestyle components.
Constitutional risk factors such as increasing age,
male gender, and family history of premature coronary
artery disease cannot be changed. The tendency toward
the development of atherosclerosis appears to run in
families. Persons who come from families with a strong
history of heart disease or stroke due to atherosclerosis
are at greater risk for developing atherosclerosis than
those with a negative family history. Several genetically
