Atherosclerosis Friday, November 7, 2003

1
AtherosclerosisFriday, November 7, 2003

• Reading-
• PDF handouts

2
Pathogenesis of Thrombosis
Thrombosis is the activation of hemostasis at an
inappropriate time and in an inappropriate blood
vessel.   Virchow's triad (1845) postulated that
thrombosis results from alterations in vessel
wall, blood flow, and properties of
blood. Thrombosis occurs when there is a
breakdown in the balance between thrombogenic
factors and protective mechanisms.
3
Atherosclerosis
No disease in the U.S. is responsible for more
deaths and has engendered more controversy than
atherosclerosis (AS).   Characterized by
plaques called atheromas that protrude into the
lumen, weaken the underlying media, and undergo a
series of complications that predispose to
overlying thrombosis.   Coronary
atherosclerosis induces ischemic heart disease
(IHD) and when lesions are complicated by
thrombosis, myocardial infarction (MI) accounts
for many deaths in the U.S.
4
Atherosclerosis (contd)
Atherosclerosis is the principle source
of   --cerebral and myocardial infarction,
--gangrene of the extremities, and --loss of
function of organs and/or tissues. Atheroscleros
is appears to be a chronic inflammatory condition
that is converted to an acute clinical event by
the induction of plaque rupture, which in turns
leads to thrombosis and death.
5
Atherosclerosis
Definition- Atherosclerosis is a process that
impairs blood flow to various organs.
Atherosclerosis is from the Greek words,
refers to the thickening of the arterial intima
(sclerosis, hardening) and accumulation of
lipid (athere, gruel) that characterize the
typical lesion. Atherosclerosis narrows
arteries, a process that causes ischemia,
infarction, and necrosis.
6
Atherosclerosis (contd)
Is a disease of the arterial intima leading to
the formation of fibrous (atheromatous)
plaques- proliferation of smooth muscle cells and
the accumulation of lipids. Complicated
plaques are raised plaques into the lumen of the
vessel
7
Normal Artery Structure
Normal Vessel Architecture All blood vessels have
a number of structural features in common, but
remember that they are structurally adapted to
their specific physiological requirements.
8
Atherosclerosis--Basic Mechanisms
Lesions of atherosclerosis represent a
specialized form of a protective, inflammatory
(fibroproliferative) response to forms of
insult to the artery wall.   Depending upon the
nature and duration of the insult, the protective
response may become excessive and over many years
in its excess become a disease process.   This
is called the response-to-injury hypothesis.
9
Response-to-Injury Theory of Atherosclerosis
10
Response-to-Injury Hypothesis for Development
of Atherosclerosis
11
Response-to-Injury Hypothesis for Development
of Atherosclerosis
12
Response-to-Injury Hypothesis for Development
of Atherosclerosis
13
Response-to-Injury Hypothesis for Development
of Atherosclerosis
14
Response-to-Injury Hypothesis for Development
of Atherosclerosis
15
Response-to-Injury Hypothesis for Development
of Atherosclerosis
16
Expression of Atherosclerosis
Thrombus nearly occluding the lumen of the
carotid artery
17
Expression of Atherosclerosis (contd)
18
Expression of Atherosclerosis (contd)
19
Examples of Atherosclerosis of Human Arteries
This is a normal coronary artery with no
atherosclerosis and a widely patent lumen that
can carry as much blood as the myocardium
requires.
Fatty streaks in a relatively normal adult aorta.
Coronary artery with mild athero-sclerosis and
some fatty streaks.
20
Examples of Atherosclerosis of Human Arteries
The degree of atherosclerosis is much greater in
this coronary artery, and the lumen is narrowed
by half. A small area of calcification is seen
in the plaque at the right.
A coronary thrombosis is seen microscopically
occluding the remaining small lumen of this
coronary artery.
21
Examples of Atherosclerosis of Human Arteries
Microscopically, the aortic atheromatous plaque
is thicker than the remaining media at the right.
The plaque contains amorphous pink material with
slit-like "cholesterol clefts" of lipid material.
There is overlying recent hemorrhage at the
left. Thrombus may form on top of such a plaque.
At higher magnification, many foam cells
(macrophages full of lipid material) and a
cholesterol cleft are seen in this atheromatous
plaque.
22
Risk Factors
Prevalence and severity of the disease are
related to many factors, some constitutional but
others are acquired and potentially controllable.
  Constitutional factors are age, sex, and
genetics   Age. Clinically significant disease
rises with each decade, even into advanced age.
  Sex. Males are much more prone to AS than
females. Females are sheltered from disease
from AS until menopause. Genetics. Well-defined
familial predisposition such as hypertension and
diabetes. Genetic derangements in lipoprotein
metabolism, prototype is familial
hypercholesterolemia.
23
Risk Factors (contd)
Hyperlipidemia is acknowledged to be a major
risk factor for AS. Most evidence implicates
hypercholesterolemia low-density lipoprotein
(LDL-C).   Inverse relationship between
symptomatic AS and high-density lipoprotein (HDL
or HDL-C) levels. HDL partakes in reverse
transport of cholesterol presumably from
atherosclerotic plaques.   Hypertension is a
major risk factor for atherosclerosis and may
well be more important than hypercholesterolemia
after age 45.   Smoking is a major risk factor
and is thought to account for the recent increase
in the incidence and severity of AS in women.
Diet in the U.S., and now more so in Europe-
obesity and over-eating.
24
(No Transcript)
25
Obesity Trends Among U.S. AdultsBRFSS, 1985
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
26
Obesity Trends Among U.S. AdultsBRFSS, 1986
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
27
Obesity Trends Among U.S. AdultsBRFSS, 1987
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
28
Obesity Trends Among U.S. AdultsBRFSS, 1988
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
29
Obesity Trends Among U.S. AdultsBRFSS, 1989
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
30
Obesity Trends Among U.S. AdultsBRFSS, 1990
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
31
Obesity Trends Among U.S. AdultsBRFSS, 1991
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
32
Obesity Trends Among U.S. AdultsBRFSS, 1992
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
33
Obesity Trends Among U.S. AdultsBRFSS, 1993
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
34
Obesity Trends Among U.S. AdultsBRFSS, 1994
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
35
Obesity Trends Among U.S. AdultsBRFSS, 1995
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
36
Obesity Trends Among U.S. AdultsBRFSS, 1996
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
37
Obesity Trends Among U.S. AdultsBRFSS, 1997
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
38
Obesity Trends Among U.S. AdultsBRFSS, 1998
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
39
Obesity Trends Among U.S. AdultsBRFSS, 1999
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
40
Obesity Trends Among U.S. AdultsBRFSS, 2000
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
41
Obesity Trends Among U.S. AdultsBRFSS, 2001
Source Mokdad A H, et al. J Am Med Assoc
199928216, 200128610.
42
Mechanism of Cholesterol-lowering Drugs
Cholesterol is generally thought to be the major
contributor to atherosclerosis. If we have
these deposits of cholesterol, the lipoproteins
are modified, and so forth and so forth.
Lowering cholesterol, especially LDL-C (so
called bad cholesterol), is clearly a good
thing. Lowering LDL-C helps prevent and may
even reverse atherosclerosis, and it may even
decrease the risk of heart attacks and strokes.
43
Statins
Inhibit 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase Catalyzes conversion of
HMG-CoA to mevalonate, an early step in the
synthesis of cholesterol a rate-limiting step in
cholesterol production. Inhibit that step and
you inhibit your ability to make cholesterol!
Statins lower serum LDL-C concentrations by
up-regulating LDL-receptor activity and by
reducing entry of LDL into the circulation.
Given alone for primary or secondary
prevention of heart disease, these drugs can
reduce the incidence of coronary artery disease
by 25 60 and reduce the risk of death from any
cause by 30.
44
Statins (contd)
One of the drugs used today is shown below next
to HMG-CoA
HMG-CoA (3-Hydroxy-3-methylglutaryl-CoA)
45
Statins (contd)
46
(No Transcript)