ATHEROSCLEROSIS (ATH)
Atherosclerosis affects the intima of arteries of the systemic circulation.
It is characterized by intimal lesions called atheromas, or atheromatous,
Atherosclerosis
or fibrofatty or atherosclerotic plaques which protrude into and obstruct
vascular lumens.
MORPHOLOGY
It may lead to serious complications
More than any other disorder in the Western world, ATH contributes to
EPIDEMIOLOGY & RISK FACTORS
approximately half or more of all deaths (and causes serious morbidity)
PATHOGENESIS
Global in distribution, it has reached epidemic proportions in
economically developed societies
MORPHOLOGY OF ATHEROSCLEROSIS
" The key processes in ATH are intimal thickening and lipid accumulation.
" Fatty streaks are the earliest lesions of atherosclerosis. They are composed of
lipid-filled foam cells. They are not significantly raised and thus do not cause any
disturbance in blood flow. Fatty streaks begin as multiple yellow, flat spots less than
Atherosclerosis
1 mm in diameter. They contain T lymphocytes and extracellular lipid in smaller
amounts than in plaques.
MORPHOLOGY
Photomicrograph of fatty streak demonstrating
intimal, macrophage-derived foam cells (arrow).
Aorta with fatty streaks
(arrows)
MORPHOLOGY OF ATHEROSCLEROSIS
MORPHOLOGY OF ATHEROSCLEROSIS
An atheroma (derived from Greek word for gruel) is an essential lesion.
" Fatty streaks appear in the aortas of some children younger than 1 year It consists of a raised focal lesion within the intima, having a soft, yellow core of
lipid (mainly cholesterol and cholesterol esters) phagocytized by myocytes and
old and all children older than 10, regardless of geography, race, sex,
macrophages (yellow plaque). Then covered by a firm, white fibrous cap (white
or environment.
plaque)
Atheromatous plaques vary in size from approximately 0.3 to 1-2 cm in diameter
" Coronary fatty streaks begin to form in adolescence and at anatomic sites
Atherosclerotic lesions usually only partially involve the circumference of the arterial
that may be prone to develop plaques.
wall (focal lesions). Focal and sparsely distributed at first, atherosclerotic lesions
become increasingly numerous and diffuse as the disease progresses.
" The relationship of fatty streaks to atherosclerotic plaques is complex:
Atherosclerotic plaques develop primarily in elastic arteries
Fatty streaks are related to the known risk factors of atherosclerosis in
(e.g., aorta, carotid arteries) and large and medium-sized
adults and some experimental evidence supports the concept of the muscular arteries (e.g. coronary and popliteal arteries).
evolution of fatty streaks into plaques.
Although fatty streaks may be precursors of plaques, not all fatty streaks
Gross view of atherosclerosis in the aorta - mild atherosclerosis
are destined to become fibrous plaques or more advanced lesions.
composed of yellow and white plaques, one of which is denoted
by the arrow.
1
MORPHOLOGY OF ATHEROSCLEROSIS
MORPHOLOGY OF ATHEROSCLEROSIS
Atherosclerotic plaques have three principal components:
In the characteristic distribution of atherosclerotic plaques in humans the
1. cells, including SMCs, macrophages, and other leukocytes;
abdominal aorta is usually much more involved than the thoracic aorta, and
2. ECM, including collagen, elastic fibers, and proteoglycans; and
lesions tend to be much more prominent around the origins (ostia) of major
3. intracellular and extracellular lipid
branches.
5 These components occur in varying proportions and configurations in different lesions.
In descending order (after the lower abdominal aorta -1),
4
" Typically, the superficial fibrous cap is composed of SMCs and relatively dense ECM.
the most severely affected vessels are the:
Beneath and to the side of the cap is a cellular area consisting of macrophages, SMCs,
coronary arteries - 2,
and T lymphocytes.
2
popliteal arteries - 3,
" Deep to the fibrous cap is a necrotic core, containing a disorganized mass of lipid
(primarily cholesterol and cholesterol esters), cholesterol clefts, debris from dead cells,
internal carotid arteries - 4,
1
foam cells, fibrin, variably organized thrombus, and other plasma proteins. Foam cells are
the vessels of the circle of Willis - 5.
large, lipid-laden cells that derive predominantly from blood monocytes (tissue macrophages).
Finally, particularly around the periphery of the lesions, there is usually evidence of
Vessels of the upper extremities are usually spared,
neovascularization (proliferating small blood vessels).
as are the mesenteric and renal arteries, except at their ostia.
Nevertheless, in an individual case, the severity
3
of atherosclerosis in one artery does not predict
the severity in another.
Schematic depiction of
the major components of
Moreover, in any given vessel,
well-developed intimal
lesions at various stages often coexist.
atheromatous plaque.
MORPHOLOGY OF ATHEROSCLEROSIS
MORPHOLOGY OF ATHEROSCLEROSIS
ATH plaques generally continue to change and progressively enlarge through:
cell death and degeneration,
synthesis and degradation (remodeling) of ECM, and
Atherosclerotic plaques are susceptible to the following
organization of thrombus.
clinically important changes:
Atheromas often undergo calcification
" Rupture, ulceration, or erosion of the intimal
surface of atheromatous plaques exposes the blood
to highly thrombogenic substances and induces
thrombosis.
Such thrombosis can partially or completely occlude
the lumen and lead to downstream ischemia. If the
patient survives the initial thrombotic occlusion, the clot
may become organized and incorporated into the
growing plaque.
Overall architecture demonstrating fibrous cap (F)
Higher-magnification photomicrograph at the
and a central necrotic (largely lipid) core (C). The
junction of the fibrous cap and core, showing
lumen (L) has been moderately narrowed. In this
scattered inflammatory cells, calcification
section, collagen has been stained blue (Masson's
(broad arrow), and neovascularization (small
trichrome stain).
arrows)
MORPHOLOGY OF ATHEROSCLEROSIS
MORPHOLOGY OF ATHEROSCLEROSIS
" Hemorrhage into a plaque.
Rupture of the overlying fibrous cap, or
of the thin-walled vessels in the areas of
" Aneurysm formation.
neovascularization, can cause intra-
Atherosclerosis-induced
plaque hemorrhage; a contained
pressure or ischemic atrophy
hematoma may expand the plaque or
of the underlying media, with
induce plaque rupture. loss of elastic tissue, causes
weakness resulting in
aneurysmal dilation and
" Atheroembolism.
potential rupture
Plaque rupture can discharge
atherosclerotic debris into the
bloodstream, producing microemboli.
Abdominal aortic aneurysm.
A, External view, gross photograph of a large aortic aneurysm that ruptured;
B, Opened view. The wall of the aneurysm is exceedingly thin, and the lumen is filled by a large quantity
from: http://www.aorte.ru/heart-attack.php
of layered but largely unorganized thrombus.
2
Atherosclerosis
EPIDEMIOLOGY & RISK FACTORS
American Heart Association classification of human atherosclerotic lesions from the fatty dot
(type I) to the complicated type VI lesion. The diagram also includes growth mechanisms and
clinical correlations. (Modified from Stary HC, et al: A definition of advanced types of atherosclerotic
lesions and a histological classification of atherosclerosis. Circulation 92:1355, 1995.)
EPIDEMIOLOGY OF ATHEROSCLEROSIS
EPIDEMIOLOGY OF ATHEROSCLEROSIS
Despite the ongoing health impact of ATH-related diseases,
" ATH causes far more morbidity and mortality (roughly half of all
significant progress has been made over the last decades
deaths) in the Western world than any other disorder.
in the US and elsewhere.
Between 1963 (the peak year) and 2000 there was an approximately
" Because ischemic heart disease (IHD) is an important manifestation of
50% decrease in the death rate from IHD.
the disease, epidemiologic data on ATH is usually presented in terms
Three factors contribute to this impressive improvement:
of frequency of the number of deaths caused by IHD.
1. primary prevention- prevention of ATH through changes in
lifestyle, including reduced cigarette smoking, altered dietary habits with
" ATH is virtually ubiquitous among the population of North America,
reduced consumption of cholesterol and saturated animal fats, and
Europe, Australia, New Zealand and other developed nations and
control of hypertension;
much less prevalent in Central and South America, Africa, and Asia.
2. improved methods of treatment
of myocardial infarction and other complications of IHD; and
" The mortality rate for IHD in the US is among the highest in the world
(e.g. is approximately five times higher than that in Japan)
3. secondary prevention- prevention of recurrences in patients who
have previously suffered serious atherosclerosis-related clinical events.
ATH- EPIDEMIOLOGY AND RISK FACTORS
RISK FACTORS FOR ATHEROSCLEROSIS
The risk factors that predispose to ATH and resultant IHD have been identified by
means of number of studies in well-defined population groups e.g. Framingham
CONSTITUTIONAL (NONMODIFIABLE)
(Massachusetts) Study, Multiple Risk Factor Intervention Trial
AGE
RISK FACTORS FOR ATHEROSCLEROSIS
MAJOR
LESSER, UNCERTAIN, OR
" Age is a dominant influence.
NONQUANTITATED
Nonmodifiable
Increasing age " Although ATH is not usually clinically evident until middle age
Male gender Obesity
or later, it is slowly progressive disease that begins in
Family history Physical inactivity
childhood and develops slowly over decades.
Genetic abnormalities Stress
High carbohydrate intake
Potentially Controllable
" Death rates from IHD rise with each decade even into
Hyperlipidemia Lipoprotein (a)
advanced age. For example, from age 40 to 60, there is a
Hypertension Hardened (trans)unsaturated fat intake
greater than five-fold increase in the incidence of MI
Cigarette smoking Chlamydia pneumoniae
Diabetes
C-reactive protein
3
RISK FACTORS FOR ATHEROSCLEROSIS
RISK FACTORS FOR ATHEROSCLEROSIS
CONSTITUTIONAL (NONMODIAFIABLE)
CONSTITUTIONAL (NONMODIAFIABLE)
SEX
GENETICS
" Males are more prone to ATH and its consequences than females.
" Family history is the most significant independent risk factor for ATH
" MI and other complications of ATH are uncommon in
" Many mendelian disorders associated with atherosclerosis, such as
premenopausal women unless they are predisposed by diabetes,
hyperlipidemia, or severe hypertension. familial hypercholesterolemia have been characterized.
E.g. between 35 and 55 years, the mortality rate of IHD
Nevertheless, these genetic diseases account for only a small
for women is one fifth that for men
percentage of cases.
" The well-established familial predisposition to ATH and IHD is
" After menopause, however, the incidence of ATH-related diseases
usually multifactorial, relating to inheritance of various genetic
increases, probably owing to decrease in natural estrogen levels.
polymorphisms, and familial clustering of other established risk
The frequency of MI becomes the same in both sexes by
factors, such as hypertension or diabetes
the seventh to eighth decade of life
RISK FACTORS FOR ATHEROSCLEROSIS
RISK FACTORS FOR ATHEROSCLEROSIS
POTENTIALLY CONTROLLABLE (MODIFIABLE)
POTENTIALLY CONTROLLABLE (MODIFIABLE)
HYPERLIPIDEMIA
HYPERLIPIDEMIA
" HL is a major risk factor for ATH.
" The major component of serum cholesterol associated with increased
" Most of the evidence specifically implicates hypercholesterolemia. risk is low-density lipoprotein (LDL) cholesterol-"bad cholesterol"
LDL cholesterol is the form of cholesterol that is delivered to
peripheral tissues.
Elevated levels of serum cholesterol are sufficient to
stimulate lesion development, even if other risk factors
" In contrast, high-density lipoprotein (HDL)-"good cholesterol is
are absent.
believed to mobilize cholesterol from developing and existing
atheromas and transport it to the liver for excretion in the bile
Therefore, higher levels of HDL correlate with reduced risk.
RISK FACTORS FOR ATHEROSCLEROSIS
OPTIMAL -
CH total < 200 mg/dl CH LDL <150mg/dl CH HDL > 40mg/dl
" There is a great interest in dietary, pharmacologic, and behavioral
POTENTIALLY CONTROLLABLE (MODIAFIABLE)
methods of lowering serum LDL and raising serum HDL
HYPERTENSION
" Ä™! LDL - high dietary intake of cholesterol and saturated fats, such
" Hypertension is a major risk factor for atherosclerosis at all ages.
as those present in egg yolks, animal fats, and butter.
" “! LDL - diet low in cholesterol and low in the ratio of saturated-to- " Both systolic and diastolic levels are important in increasing
polyunsaturated fats . risk.
“! HDL - obesity and smoking ;
" Men between ages 45 and 62 whose blood pressure exceeds
Ä™! HDL - exercise and moderate consumption of ethanol
169/95 mmHg have a more than 5-fold greater risk of IHD
than those with blood pressures of 140/90 mmHg or lower.
Omega-3 fatty acids, abundant in fish oils, are likely beneficial,
whereas hardened (trans)unsaturated fats produced by artificial
" Antihypertensive therapy reduces the incidence of atherosclerosis-
hydrogenation of polyunsaturated vegetable fats and used in baked
related diseases, particularly strokes and IHD.
goods and margarine may adversely affect cholesterol profiles and
contribute to atherosclerosis.
4
RISK FACTORS FOR ATHEROSCLEROSIS
RISK FACTORS FOR ATHEROSCLEROSIS
POTENTIALLY CONTROLLABLE (MODIFIABLE)
POTENTIALLY CONTROLLABLE (MODIFIABLE)
DIABETES MELLITUS
CIGARETTE SMOKING
" Diabetes mellitus induces hypercholesterolemia and a markedly
increased predisposition to atherosclerosis.
" Cigarette smoking is a well-established risk factor
" Other factors being equal, the incidence of MI is twice as high in
" Smoking one or more packs of cigarettes per day for several
diabetics as in nondiabetics.
years increases the death rate from IHD by up to 200%.
" There is also an increased risk of strokes and, even more striking,
" Cessation of smoking reduces the increased risk substantially. perhaps a 100-fold increased risk of atherosclerosis-induced
gangrene of the lower extremities.
RISK FACTORS FOR ATHEROSCLEROSIS RISK FACTORS FOR ATHEROSCLEROSIS
POTENTIALLY CONTROLLABLE (MODIFIABLE)
OTHER FACTORS ELEVATED PLASMA HOMOCYSTEINE
INFLAMMATION as marked by C-reactive protein
" Patients with homocystinuria, a rare inborn error of metabolism resulting in
" While a number of markers of inflammation correlate with IHD risk,
high levels of circulating homocysteine (>100 µmol/L) and urinary
CRP has emerged as one of the simplest and most sensitive
homocysteine, have premature vascular disease.
" When CRP is secreted from cells within the atherosclerotic intima, it
" Beyond these individuals, clinical and epidemiologic studies have shown a
can activate local endothelial cells and induce a prothrombotic state
more general relationship between total serum homocysteine levels and
and also increase the adhesiveness of endothelium for leukocytes.
coronary artery disease, peripheral vascular disease, stroke, and venous
thrombosis.
" It strongly and independently predicts the risk of MI, stroke,
peripheral arterial disease, and sudden cardiac death, even among
" Hyperhomocystinemia can potentially be caused by low folate and
apparently healthy individuals. Indeed, CRP levels have recently
vitamin B intake, and recent evidence suggests that folate and vitamin B6
been incorporated into risk stratification algorithms.
ingestion beyond conventional dietary recommendations may reduce the
incidence of cardiovascular disease. However, this remains to be firmly
" Interestingly, although there is as yet no direct evidence that
established
lowering CRP directly reduces cardiovascular risk, smoking
cessation, weight loss, and exercise all reduce CRP
RISK FACTORS FOR ATHEROSCLEROSIS
RISK FACTORS FOR ATHEROSCLEROSIS
Multiple risk factors may have a multiplicative effect; two major risk factors increase
the risk approximately 4-fold. When three risk factors are present (e.g., hyperlipidemia,
hypertension, and smoking), the rate of myocardial infarction is increased 7 times.
Estimated 10-year risk of coronary artery
disease according to various combinations of
risk factor levels, expressed as the probability
of an event in 10 years. (From Kannel WB, et
al: An update on coronary risk factors. Med
Clin North Am 79:951, 1995.)
5
ATHEROSCLEROSIS- PATHOGENESIS
The overwhelming importance of ATH has stimulated enormous efforts to discover its cause.
Historically, two hypotheses for atherogenesis were dominant:
One emphasized cellular proliferation in the intima as a reaction to insudation of
plasma proteins and lipids from the blood
Other postulated that organization and repetitive growth of thrombi
resulted in plaque formation.
Atherosclerosis
The current view of the pathogenesis of ATH incorporates elements of both
older theories and accommodates the risk factors previously discussed.
PATHOGENESIS
This concept, called the response to injury hypothesis ,
considers ATH to be a chronic inflammatory response of the arterial wall
initiated by some form of injury to the endothelium.
Moreover, lesion progression is sustained by interaction between modified
lipoproteins, monocyte-derived macrophages, T lymphocytes, and the
normal cellular constituents of the arterial wall
Evolution of arterial wall changes in the response
ATHEROSCLEROSIS- PATHOGENESIS
to injury hypothesis.
RESPONSE TO INJURY HYPOTHESIS
1. Normal.
Central to this thesis are the following:
" chronic endothelial injury, usually subtle, with resultant endothelial dysfunction,
such as increased permeability, leukocyte adhesion, and thrombotic potential
2. Endothelial injury with adhesion of monocytes
and platelets.
" accumulation of lipoproteins, mainly LDL, with its high cholesterol content,
in the vessel wall and modification of lesional lipoproteins by oxidation
" adhesion of blood monocytes (and other leukocytes) to the endothelium,
3. Migration of monocytes (from the lumen) and
followed by their migration into the endothelium, and their transformation into
smooth muscle cells (from the media) into the
macrophages and foam cells
intima.
" adhesion of platelets
" release of factors from activated platelets, macrophages, or vascular cells
that cause migration of SMCs from media into the intima
4. Smooth muscle cell proliferation in the intima.
" proliferation of SMCs in the intima, and elaboration of extracellular matrix, leading
to the accumulation of collagen and proteoglycans
" enhanced accumulation of lipids both within cells (macrophages and SMCs) and
extracellularly
5. Well-developed plaque
ATH- PATHOGENESIS ATH- PATHOGENESIS
THE ROLE OF INFLAMMATION
THE ROLE OF ENDOTHELIAL INJURY
" The normal endothelium does not support binding of white blood cells.
" Chronic or repetitive endothelial injury forms the basis for the response-to-injury
hypothesis.
However, early in atherogenesis arterial endothelial cells begin to express on their
surface selective adhesion molecules that bind various classes of leukocytes.
" The specific cause of endothelial dysfunction in early atherosclerosis is unknown:
potential culprits include circulating derivatives of cigarette smoke, homocysteine, " Vascular cell adhesion molecule-1 (VCAM-1) binds the types of leukocytes found
and possibly viruses and other infectious agents. in early human and experimental atheroma, the monocyte and T lymphocyte.
" However, there are two most important determinants of endothelial alterations: " After monocytes adhere to the endothelium, they: 1. migrate between ECs to
- hemodynamic disturbances and adverse effects of hypercholesterolemia. localize in the intima, largely stimulated by chemokines; and 2. transform into
macrophages and engulf lipoproteins, largely oxidized LDL.
" In support of a hemodynamic effect is the well-defined tendency for plaques to
occur at ostia of the vessels arising from the aorta, branch points, and along the " Macrophages produce IL-1 and TNF, which increase adhesion of leukocytes.
posterior wall of the abdominal aorta where there are disturbed flow patterns. Several chemokines generated by macrophages, including monocyte chemotactic
Areas of disturbed, turbulent flow are prone to atherosclerosis while those with protein-1 (MCP-1), may recruit more leukocytes into the plaque.
smooth, laminar flow seem protected.
6
ATH- PATHOGENESIS
ATH- PATHOGENESIS THE ROLE OF LIPIDS
The mechanisms by which hyperlipidemia contributes to atherogenesis include the
THE ROLE OF INFLAMMATION
following:
Chronic hyperlipidemia, particularly hypercholesterolemia, may directly impair EC
function through increased production of oxygen free radicals
The activated leukocytes and intrinsic arterial cells can
With chronic hyperlipidemia, lipoproteins accumulate within the intima at sites of
release fibrogenic mediators, including a variety of peptide
increased endothelial permeability.
growth factors that can promote replication of SMCs and
Chemical change of lipid induced by free radicals generated in macrophages or
contribute to elaboration by these cells of a dense extracellular ECs in the arterial wall yields oxidized (modified) LDL.
matrix characteristic of the more advanced atherosclerotic
Oxidized LDL
(1) is ingested by macrophages, thus forming foam cells;
lesion.
(2) increases monocyte accumulation in lesions;
(3) stimulates release of growth factors and cytokines; and
(4) is cytotoxic to ECs and SMCs.
ATH- PATHOGENESIS
THE ROLE OF SMOOTH MUSCLE CELLS.
Schematic diagram of
hypothetical sequence of
" SMCs migrate from the media to the intima, where they proliferate and deposit
cellular interactions in
atherosclerosis.
ECM components, converting a fatty streak into a mature fibrofatty atheroma, and
contribute to the progressive growth of atherosclerotic lesions.
" Several growth factors have been implicated in the proliferation of SMCs, including
PDGF (released by platelets adherent to a focus of endothelial injury, and by
" Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting in adhesion of platelets and
macrophages, ECs, and SMCs), FGF, and TGF-Ä….
monocytes and release of growth factors, including platelet-derived growth factor (PDGF), which lead to smooth
muscle cell migration and proliferation.
" Foam cells of atheromatous plaques are derived from both macrophages and smooth muscle cells-from
macrophages via lipoproteins modifications.
" SMCs synthesize extracellular matrix molecules (notably collagen) that stabilize
" Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of
atherosclerotic plaques. hypercholesterolemia, and also from degenerating foam cells.
" Cholesterol accumulation in the plaque reflects an imbalance between influx and efflux, and high-density lipoprotein
(HDL) likely helps clear cholesterol from these accumulations.
" Smooth muscle cells migrate to the intima, proliferate, and produce extracellular matrix, including collagen and
proteoglycans.
ATHEROSCLEROSIS (ATH)
Myocardial infarction, cerebral infarction (stroke), aortic aneurysms, and peripheral vascular
disease are the major consequences of atherosclerosis.
In small arteries, atheromas can occlude lumens, compromise blood flow to distal organs, and
cause ischemic injury. Plaques can undergo disruption and precipitate thrombi that further
obstruct blood flow.
Schematic summary of the natural history, morphologic features, main pathogenetic events, and
clinical complications of atherosclerosis in the coronary arteries.
7
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