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major cause of death and premature

disability in developed societies
CNS provokes strokes and transient
cerebral ischemia
PNS intermittent claudication and
gangrene and can jeopardize limb viability
splanchnic circulation mesenteric
renal artery stenosis

apoptosis - death of mononuclear

phagocytes results in formation of the lipidrich center of more complicated
atherosclerotic plaques - called the necrotic
core of the lesion

Atheroma Formation

Fatty Streak Formation

represents the initial lesion of
focal increases in the content of
lipoproteins within regions of the intima
lipoprotein accumulation and modification
(oxidation and enzymatic glycosylation)
Leukocyte Recruitment
recruitment of leukocytes monocytes and
lymphocytes occurs as a second step in
formation of the fatty streak
adhesion molecules or receptors for
leukocytes expressed on the surface of the
arterial endothelial cell
o vascular cell adhesion molecule
(VCAM) 1
o intercellular adhesion molecule
(ICAM) 1
o P-selectin (a member of a distinct
family of leukocyte receptors
known as selectins)
Foam-cell Formation
mononuclear phagocytes differentiate into
macrophages and transform into lipid-laden
foam cells
requires the uptake of lipoprotein particles
by receptor-mediated endocytosis
atheroma, ensues if the amount of lipid
entering the artery wall exceeds that
exported by mononuclear phagocytes or
other pathways

Atheroma Evolution and Complications

ATP binding cassette (ABC) transporters
macrophages may play a vital role in the
dynamic economy of lipid accumulation in
the arterial wall during atherogenesis
death of mononuclear phagocytes results in
the formation of the lipid-rich center, often
called the necrotic core
IL-1 and TNF- formation of PDGF,
fibroblast growth factors, and others
o may contribute to plaque evolution
and complication

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Plaque Rupture, Thrombosis and Healing

atherosclerotic plaques also accumulate
osteocalcin, osteopontin, and bone
morphogenetic proteins
Plaque Evolution
complex balance between entry and egress
of lipoproteins and leukocytes, cell
proliferation and cell death, extracellular
matrix production, and remodeling, as well
as calcification and neovascularization


A. Arterial remodeling during atherogenesis

B. Rupture of the plaque's fibrous cap causes
C. When the clot overwhelms the endogenous
fibrinolytic mechanisms, it may propagate
and lead to arterial occlusion
D. The subsequent thrombin-induced fibrosis
and healing causes a fibroproliferative
response that can lead to a more fibrous
lesion that can produce an eccentric plaque
that causes a hemodynamically significant
abundant plexuses of microvessels develop
in connection with the artery's vasa
provide an abundant surface area for
leukocyte trafficking
may serve as the portal for entry and exit of
white blood cells from the established
may also furnish foci for intraplaque
may be friable and prone to rupture and
can produce focal hemorrhage
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epidemiologic data support a relationship
between hypertension and atherosclerotic
pharmacologic treatment of hypertension
can reduce the risk of stroke, heart failure,
and CHD events
Diabetes Mellitus, Insulin Resistance, and the
Metabolic Syndrome
diabetic dyslipidemia
o low HDL and elevated triglyceride
elevated cardiovascular risk in patients with
type 2 diabetes
"tight" glycemic control may increase
adverse events in patients with type 2
diabetes, lending even greater importance
to aggressive control of other aspects of risk
in this patient population

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Male Sex/Postmenopausal State

excess coronary risk in men compared with
premenopausal women
After menopause, coronary risk accelerates
in women
Estrogen therapy lowers LDL cholesterol
and raises HDL cholesterol reduces
coronary risk
Dysregulated Coagulation or Fibrinolysis
Thrombosis provoked by atheroma rupture
and subsequent healing may promote
plaque growth
fibrinogen levels correlate with coronary
risk and provide information about
coronary risk independent of the
lipoprotein profile
balance between fibrinolytic factors
(plasmin) and inhibitors of the fibrinolytic
system (plasminogen activator inhibitor 1
Aspirin reduces CHD events in several

Lifestyle Modification
optimize risk factor profiles long before
atherosclerotic disease manifests
assess and minimize cardiovascular risk
counsel patients about the health risks of
tobacco use and provide guidance and
resources regarding smoking cessation
prudent dietary and physical activity habits
for maintaining ideal body weigh
at least 30 minutes of moderate-intensity
physical activity per day


Libby P. Chapter 241. The Pathogenesis,

Prevention, and Treatment of
Atherosclerosis. In Longo DL, Fauci AS,
Kasper DL, Hauser SL, Jameson JL, Loscalzo
J. (2012). Harrisons Principles of Internal
Medicine, 18th ed. USA: McGraw-Hill.

accumulation correlate with thrombosis
and with coronary risk
plasma levels of CRP, as measured by a
high-sensitivity assay (hsCRP)
o also correlate with the outcome in
patients with acute coronary
o validated biomarker of risk but
probably not as a direct contributor
to pathogenesis

Evidence from the JUPITER study that both

LDL-lowering and anti-inflammatory
actions contribute to the benefit of statin
therapy in primary prevention

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