Transcript الشريحة 1 - bums.ac.ir

Harisson 2012 1983-1991
Dr.Toba kazemi
Associate Professor of Cardiology
BUMS-BCRC
24 Farvardin 1391
Introduction:
of blood vessels – large arteries.
 Modern life style disease… *
 Major cause of IHD, MI, Stroke & Aortic
disease - Major cause of death &
disability.
 Incidence is decreasing since 1995 - West
 Better understanding & Change in life
style.
 Disease
Definition:
“Chronic inflammatory disorder of
intima of large arteries
characterised by formation of
fibrofatty plaques called atheroma”.
Hardening of arteries Arteriosclerosis
Etiology:
Exact cause is unknown 
 Variation in severity & distribution.
 Starts with endothelial injury.
 Genetic/Familial
 Risk Factors…



Age, Htn, DM, Smoking – endothelial
damage.
Obesity, lifestyle, economic status, - lipid.
Activation of Platelet / Coagulation.
 Oxidised
LDL.
Lipoprotiens - LDL & HDL
• Good and Bad Fats?
• Lower LDL, Increase HDL
• Mono unsaturated fats
• Poly unsaturated fats
• Omega-3 fatty acids (Fish)
• LDL indicate Positive lipid
balance, HDL – negative.
Risk Factors:





Non modifiable
Age
Male Sex,
Genetic - Hyperchol.
Family history





Potentially Modifiable
Hyperlipidemia –
HDL/LDL ratio.
Hypertension.
Smoking.
Diabetes.
Pathogenesis:






intimal injury
Inflammation, Necrosis
Lipid – Cholesterol accumulation (soft.a)
Fibrosis, smooth muscle proliferation (hard.a)
Extension of lesion and destruction of vessel
Complications - Thrombosis, embolism,
aneurism, dissection & rupture.
Structure of Atheroma:
Fibrous Cap
Necrotic center
Cholesterol Cry.
Macrophages
Pathogenesis-stages






Type I – Fatty dots - Foam cells
Type II – Fatty streak
Type III – Extracellular lipid pool
Type IV – Atheroma – Core of lipid
Type V – Fibroatheroma – Fibrotic layer
Type VI – Complicated – Ulcer, Ca+

Hemorrhage, thrombus, embolism, aneurysm.
Development of
Coronary Atherosclerosis:
Complications:
 Thrombosis,
Thrombo-embolism
 Rupture – Haemorrhage
 Aneurysm
 Fibrosis & Calcification
 Ischemia / Infarction – end organ damage.
 Stroke, Myocardial Infarctions, Renal
infarction, Mesentric vein thrombosis,
intermittent claudication, gangrene etc.
Coronary Atheorsclerosis
Left Coronary Artery.•
Anterior Descending (LAD)•
Left Circumflex (LCx)•
Right Coronary •
Artery.
LCx
LAD
Coronary
Thrombosis
With Infarction
Coronary Angioplasty:
Atheroma - Objectives 1
Definition of atheroma
 Macroscopic appearances
 Microscopic appearances
 Effects

Atheroma

Definition
Atheroma is the accumulation of
intracellular and extracellular lipid in the
intima of large and medium sized arteries
Atherosclerosis
Definition
The thickening and hardening of arterial
walls as a consequence of atheroma
 The thickening of the walls of arteries and
arterioles usually as a result of
hypertension or diabetes mellitus

Atheroma - Macroscopic
Features
Fatty streak
 Simple plaque
 Complicated plaque

Atheroma - The Fatty Streak
Lipid deposits in
intima
 Yellow, slightly
raised

Atheroma - The Simple
Plaque




Raised yellow/white
Irregular outline
Widely distributed
Enlarge and
coalesce
Atheroma - The Complicated
Plaque




Thrombosis
Haemorrhage into
plaque
Calcification
Aneurysm formation
Atheroma - Common Sites
Aorta - especially abdominal
 Coronary arteries
 Carotid arteries
 Cerebral arteries
 Leg arteries

Normal Arterial Structure
Endothelium
 Sub-endothelial c.t.
 Internal elastic
lamina
 Muscular media
 External elastic
lamina
 Adventitia

Atheroma - Microscopic
Features

Early changes
proliferation of smooth muscle cells
 accumulation of foam cells
 extracellular lipid

Endothelium
Smooth muscle cell
Lipid
Matrix
Atheroma - Microscopic
Features

Later changes
fibrosis
 necrosis
 cholesterol clefts
 +/- inflammatory cells

Atheroma - Microscopic
Features

Later changes
disruption of internal elastic lamina
 damage extends into media
 ingrowth of blood vessels
 plaque fissuring

Atheroma - Coronary Artery
Atheroma - Clinical Effects

Ischaemic heart disease
sudden death
 myocardial infarction
 angina pectoris
 arrhythmias
 cardiac failure

Atheroma – cerebral infarction
Atheroma – Abdominal Aortic
Aneurysm
Atheroma - Pathogenesis







Age
Gender
Hyperlipidaemia
Cigarette smoking
Hypertension
Diabetes mellitus
Infection
Atheroma

Age
slowly progressive throughout adult life
 risk factors operate over years


Gender
women protected relatively before
menopause
 presumed hormonal basis

Atheroma

Hyperlipidaemia
high plasma cholesterol associated with
atheroma
 LDL most significant
 HDL protective

Atheroma-Infection
Chlamydia pneumoniae
 Helicobacter pylori
 Cytomegalovirus

Atheroma - Other Risk Factors
Lack of exercise
 Obesity
 Stress
 Familial predisposition well known

Atheroma - Pathogenesis
Thrombogenic theory
 Insudation theory
 Monoclonal hypothesis
 Reaction to injury hypothesis

Atheroma - Thrombogenic
Theory

1852 Karl Rokitansky
plaques formed by
repeated thrombi
 lipid derived from
thrombi
 overlying fibrous cap

Atheroma - Insudation Theory

1856 Rudolf
Virchow
endothelial injury
 inflammation
 increased
permeability to
lipid from plasma

Atheroma - Reaction to Injury
Hypothesis

1972 Ross and Glomset
 plaques
form in response to endothelial injury
 hypercholesterolaemia leads to endothelial
damage in experimental animals
 injury increases permeability and allows
platelet adhesion
 monocytes penetrate endothelium
 smooth muscle cells proliferate and migrate
Atheroma - Reaction to Injury
Hypothesis

1986 Ross
endothelial injury may be very subtle and
be undetectable visually
 LDL, especially oxidised, may damage
endothelium

Atheroma - The Monoclonal
Hypothesis

Benditt and Benditt
crucial role for smooth muscle proliferation
 each plaque is monoclonal
 might represent abnormal growth control
 is each plaque a benign tumour?
 could atheroma have a viral aetiology?

Atheroma - The Processes
Involved
Thrombosis
 Lipid accumulation
 Production of intercellular matrix
 Interactions between cell types

Atheroma - The Cells Involved
Endothelial cells
 Platelets
 Smooth muscle cells
 Macrophages
 Lymphocytes
 Neutrophils

Atheroma - A Unifying
Hypothesis 1


Endothelial injury due to
 raised LDL
 ‘toxins’ eg cigarette smoke
 hypertension
 haemodynamic stress
Endothelial injury causes
 platelet adhesion, PDGF release, SMC proliferation
and migration
 insudation of lipid, LDL oxidation, uptake of lipid by
SMC and macrophages
 migration of monocytes into intima
Atheroma - A Unifying
Hypothesis 3
Stimulated SMC produce matrix material
 Foam cells secrete cytokines causing

further SMC stimulation
 recruitment of other inflammatory cells

Atheroma - Prevention
No smoking
 Reduce fat intake
 Treat hypertension
 Not too much alcohol
 Regular exercise/weight control


BUT some people will still develop
atheroma!
Atheroma - Intervention
Stop smoking
 Modify diet
 Treat hypertension
 Treat diabetes
 Lipid lowering drugs

pathogenesis
 Atherosclerosis:
major cause of death &
premature disability in developed society
 By 2020 :CVD is the leading global cause
of total disease burden
 Atherosclerosis affect various region of
circulation: although its risk factors are
systemic or generalized
pathogenesis
 Atherosclerosis
of coronary A. :MI, angina
pectoris
 Atherosclerosis of CNS:TIA , stroke
 Atherosclerosis of peripheral A :
intermittent claudication ,gangrene
 Atherosclerosis of splanchnic circulation;.
Mesentric ischemia
 Atherosclerosis of kidney:renal art.
Stenosis, emboli to Renal A.
CEREBRAL FORM OF ATHEROSCLEROSIS
THROMBOSIS OR 
EMBOLISM ON ULCERED PLAQUE
ISCHEMIC INFARCTION
Hemorrhage within
The brain
53
RENAL FORM OF
ATHEROSCLEROSIS

Acute form may be as
infarction

Chronic form is called
Atherosclerotic
Nephrosclerosis or
Primary contracted
kidney
54
Intestinal form of atherosclerosis

Acute form may be as
gangrenous necrosis
of the intestine

Chronic form may be
as ischemic
enterocolitis
55
Extremity form of atherosclerosis
 Acute
form may be as gangrenous
necrosis.
56
atherosclerosis in arterial bed
 Occur
focally
 At branching point: disturbed blood flow
 coronary A. :proximal of LAD
 Atherosclerosis renal artery: proximal
portion
 Extra cranial circulation: carotid
bifurcation
 Not always stenotic: ectasia, aneurysm
 Nonocclosive diffuse intimal irregularity
:IVUS , postmortem
 Atherosclerosis
in human: occure over a
period( years / decades)
 Growth of Atherosclerosis:not smooth or
linear / but quiesence
rapid evolution
chronic:
 clinically
expression of AT
acute:
AMI ,SCD,stroke

never
experience clinical manifestation
Silent:befo
re
clinically
expressio
n
Chronic:
Stable
angina
clinically
expression
of
AT
Never
symptom
acute:
AMI, SCD,
stroke
Pathogenesis of Atherosclerosis
According
to injury hypothesis
considers atherosclerosis to be a
chronic inflammatory Response of
the arterial wall initiated by injury:
60
Pathogenesis of Atherosclerosis
chronic endothelial injury
 2 insudation of lipoproteins [LDL]
 3 modification of lipoproteins by
oxidation
 4 adhesion of blood monocytes
 5 adhesion of platelets
1
61
Pathogenesis of Atherosclerosis
6 migration of smooth muscle cells
from the media into the intima
7 proliferation of smooth muscle cells
in the intima
8 enhanced accumulation of intra and
extra cellular lipids
62
atherosclerotic plaque
It has three principle components:
 1 cells –smooth muscle cells, macrophages
other leukocytes
2 Extra cellular matrix- collagen, elastic fibers,
proteoglycans
3 Intra cellular and extra cellular lipids

63
atherosclerotic plaque
 There
are two types of atherosclerotic
plaque
1
vulnerable
2 stable
64
atherosclerotic plaque

1 vulnerable
2 STABLE
THERE ARE
A LOT OF LIPIDS
65
Pathogenesis

Fatty streak: initial lesion
 Mechanism: lipoprotein in intima (not simply
from permeability or leakiness )
 Lipoprotein bind to extracellular matrix
(glycoseaminoglycans )
residence time
of lipid rich particle= slow regress of this particle
 Oxidative modification of lipoproteins








Chronic inflammatory response of the vascular
wall to endothelial injury or dysfunction
Elevated plasma LDL levels causing the deposit
of LDL in the subendothelium of blood vessels
Oxidation of transmigrated LDL
Activation of endothelial cells
Recruitment of monocytes/macrophages which
ingest oxLDL through scavenger receptors
Formation of foam cells – fatty streaks
Proliferation of smooth muscle cells
Deposition of extracellular matrix proteins
Monocyte Recruitment
lumen
intima
LDL
Formation of Atherosclerotic Plaques
lumen
neointima
Lipid Core
Plaque Rupture and Thrombosis
Tissue Factor
Platelet Aggregation
Lipid Core
 Atherosclerosis
is the buildup of plaque on
the inside walls of arteries. Plaque is made
up of low density lipoprotein (LDL),
macrophages, smooth muscle cells,
platelets, and other substances. It may
narrow the lumen of a blood vessel and
restrict blood flow. Plaque rupture can
induce the formation of thrombus (blood
clot) and block blood flow. This will result
in ischemic stroke or heart attack.
Formation of foam cells
 The
first stage in the development of
atherosclerosis is the formation of foam cells
(macrophages with ingested oxidized LDL). The
process begins with trap of LDL in the intima,
which lies just below the endothelium (the
monolayer of cells lining the arterial wall).
Trapped LDL could be oxidized, triggering
recruitment of monocytes into the intima.
Several adhesion molecules are involved,
including vascular-cell adhesion molecule
(VCAM), integrin, selectin, and others. After
Formation of plaque
 As
atherosclerosis progresses, T
lymphocytes, platelets and smooth muscle
cells also join foam cells, expanding the
plaque size. This involves cytokines to
activate T lymphocytes and growth factors to
promote proliferation of smooth muscle cells.
Platelets can also release cytokines and
growth factors to enhance migration and
proliferation of smooth muscle cells. During
this stage, a fibrous cap is formed to
Thrombosis
 Thrombosis
(formation of thrombus) arises
from plaque rupture. Macrophages may
release metalloproteinases and other
proteolytic enzymes to degrade fibrous
cap, making it susceptible to rupture.
Plaque rupture activates platelets, leading
to formation of blood clots at the site of
lesion
NO)
 Molecular
mechanisms for the production
of nitric oxide (NO) by exercise leading to
the protection of atherosclerosis.
Emerging anti-inflammatory therapies in clinical atherosclerosis.
Klingenberg R , Hansson G K Eur Heart J 2009;30:28382844
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2009. For permissions please email: [email protected]
Leukocyte diversity in atherosclerosis.
Klingenberg R , Hansson G K Eur Heart J 2009;30:28382844
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2009. For permissions please email: [email protected]
Prognostic role of clinical risk scores and biomarkers of cardiovascular risk.
Kaski J C Eur Heart J 2010;31:274-277
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2009. For permissions please email: [email protected]
Risk modifiers influence atherogenesis through effects on inflammation as reflected by
biomarkers of the acute phase response.
Libby P , Crea F Eur Heart J 2010;31:777-783
Framingham Ten Year Risk
Men
Women
Framingham Ten Year Risk
0
Framingham Ten Year Risk
0
3
0
Non-Smoker
Framingham Ten Year Risk
0
3
0
1
HDL = 43
Framingham Ten Year Risk
0
3
0
SBP = 119, untreated
1
0
4
Framingham Ten Year Risk
0
3
0
1
0
4
‫سطح ايده ال‪LDL‬و ‪Non HDL‬در افراد مختلف‬
‫‪HDL‬‬
‫‪non‬هدف‬‫(‪) mg/dl‬‬
‫شروع رژیم‬
‫شروع دارو غذایی و فعالیت‬
‫كمتر از ‪100‬‬
‫‪≤ 70‬‬
‫‪≤ 70‬‬
‫‪LDL‬هدف‬
‫)‪(mg/dl‬‬
‫كمتر از‬
‫‪70‬‬
‫میزان ریسک‬
‫وضعیت بیمار‬
‫‪Very High‬‬
‫بيماري عروق كرونر و ديابت يا چند‬
‫ريسك فاكتور قلبي‬
‫كمتر از ‪130‬‬
‫‪≤ 100‬‬
‫‪≤ 100‬‬
‫كمتر از ‪100‬‬
‫‪High‬‬
‫كمتر از ‪130‬‬
‫‪≤ 130‬‬
‫‪≤ 130‬‬
‫كمتر از ‪100‬‬
‫‪Moderately‬‬
‫‪High‬‬
‫كمتر از ‪160‬‬
‫‪≤ 160‬‬
‫‪≤ 130‬‬
‫كمتر از ‪130‬‬
‫‪Moderate‬‬
‫كمتر از ‪190‬‬
‫‪≤ 190‬‬
‫‪≤ 160‬‬
‫كمتر از ‪160‬‬
‫‪low‬‬
‫بيماري عروق كرونر يا معادالت‬
‫آن‪‬‬
‫≤‪2‬ريسك فاكتور قلبي و احتمال‬
‫بيماري كرونر در ‪10‬سال آینده بین‪-20‬‬
‫‪%10‬‬
‫≤ ‪2‬ريسك فاكتور قلبي و‬
‫احتمال بيماري كرونر در‬
‫‪10‬سال آینده کمتر از ‪%10‬‬
‫يك ريسك فاكتور ويا كمتر‬
TREATMENT
‫باتشكر از صبر وحوصله شما‬
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