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ATHEROSCLEROSIS

DR.S.ARUN
DNB CARDIOLOGY PG
Atherosclerosis
"athero," meaning gruel, or wax,
corresponding to the necrotic core area at the
base of the atherosclerotic plaque, and

"sclerosis" for hardening, or induration,
referring to the fibrous cap of the plaque's
luminal edge.
3
RUDOLF VIRCHOW
Inflammation-based
arterial changes as a
mechanism of primary
importance in
atherogenesis
mid 19th century
Lamond, B. The American Journal of Pathology. 2008
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Atherosclerosis

Start from very young
To Old age ?
HISTORY
Virchow- viewed atherosclerosis as a
proliferative disease.

Rokitansky- believed that atheroma
derived from healing and resorption of
thrombi.
Normal Blood Vessel Wall
Three concentric
layers: intima,
media, and
adventitia
These are present to
some extent in all
vessels but are most
apparent in larger
arteries and veins.
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Normal Blood Vessel Wall
Blood vessel walls
a) Tunica intima
(1) Endothelium
(2) Subendothelial layer
b) Tunica media
(1) Smooth muscle
(2) Elastin
c) Tunica adventitia (externa)
(1) CT(Connective tissue) surrounding TM(Tunica Media)
(2) Arterioles in larger vessels
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Normal Blood Vessel Wall
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Normal Blood Vessel Wall
Arterial walls are
thicker than
corresponding
veins at the same
level of branching
to accommodate
pulsatile flow and
higher blood
pressure.
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Classes of Arteries
Arteries
a) Elastic arteries large arteries near heart
b) Muscular (distributing) arteries thick tunica
media

Atherosclerosis affects mainly elastic and
muscular arteries and hypertension affects
small muscular arteries and arterioles.

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Endothelial progenitor cells(EPCs)
Population of rare cells that circulate in the
blood with the ability to differentiate
into endothelial cells VASCULOGENESIS.
Endothelial progenitor cells can be marked
using the Inhibitor of DNA Binding 1 (ID1)
EPCs are mobilized after a MI, and that they
function to restore the lining of blood vessels
that are damaged during the heart attack.
Those with a higher burden of risk factors for
atherosclerosis have fewer EPCs.
EPC number may correlate with prognosis in
atherosclerotic patients
More aged individuals may have impaired
EPC numbers and hence less ability to repair
breaches in intimal integrity.

Transplantation of Progenitor Cells and
Regeneration Enhancement in Acute
Myocardial Infarction - TOPCARE-AMI

- POSSIBLE ROLE IN FUTURE.

Arterial Smooth Muscle Cells
These cells contract and relax and thus control
blood flow through the various arterial beds.
SMCs synthesize the bulk of the complex arterial
ECM that plays a key role in normal vascular
homeostasis as well as the formation and
complication of atherosclerotic lesions.


These cells also can migrate and proliferate,
contributing to the formation of intimal
hyperplastic lesions.

Death of SMC may promote destabilization of
atheromatous plaques or favor ectatic remodeling
and ultimately aneurysm formation.
Atherosclerosis
Atherosclerosis is a disease of large and
medium-sized muscular arteries and is
characterized by
endothelial dysfunction,
vascular inflammation, and
the buildup of lipids, cholesterol, calcium, and
cellular debris within the intima of the vessel
wall.
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Theories of atherogenesis

Lipid hypothesis.
Thrombogenetic hypothesis.
Mesenchymal hypothesis.
Monoclonal hypothesis.
Response to injury hypothesis.
Response-to-retention hypothesis
Oxidative modification hypothesis

ENDOTHELIUM
Endothelial junctions loosen.
Increasing the permeability to fluid, lipids,
and leukocytes
Lipoprotein particles, and especially low-
density lipoprotein (LDL), enter the arterial
wall and undergo oxidation.
OXIDISED LDL ANTIGENIC
THE FATTY STREAK
First signs of atherosclerosis that are visible
without magnification
lipid-containing foam cells in the arterial wall
just beneath the endothelium.
appears as a yellow discoloration in the
artery's inner surface and occurs in the aorta
and coronary arteries of most people by age
20.
FIBROUS CAP ATHEROMA
INTRAPLAQUE HEMORRHAGE
Leakage from intraplaque microcapillaries.
Free hb inactivates NO
Hb-Hp complex.
CD-163 receptor on macrophages scavenge
hb-hp complex.
When exceeds its capacity more free hb-
more oxidative stress.

MECHANISM OF PLAQUE RUPTURE
Fibrous cap degradation by MMPs
High shear stress
Macrophage and SMC death
Microcalcification and iron accumulation within
fibrous cap.

Luminal thrombus at site of rupture : platelet rich
At prox and distal sites red thrombus.


ADAPTIVE INTIMAL THICKENING
(AHA I)

Several layers of SMCs with little/no
inflammatory cells.
35% neonates
At birth intima/media ratio =0.1 (0.3 by 2 yrs)
SMCs low proliferative activity and
antiapoptotic phenotype.

FATTY STREAK (AHA-II)

Lesion not raised
Abundant foamy macrophages.
Reversible lesion.
PATHOLOGIC INTIMAL THICKENING
(AHA III)
Earliest progressive irreversible lesion
Proliferation of SMCs near lumen with an
underlying lipid pool.
Lipid pool devoid of SMCs. Rich in ECM.
In advanced form foamy macrophages near
lumen.
FIBROATHEROMA (AHA-IV)
Acellular necrotic cores.
Hyaluran and proteoglycan degraded by
MMPS.
Defective phagocytic clearance of apoptotic
cells.
Increasing necrotic core and plague
progression.

EARLY : Focally express proteoglycans
esp.towards media.

LATE : Necrotic core devoid of ECM.
POSITIVE CORONARY ARTERY REMODELLING:
Occurs to preserve lumen.
Occurs at > 40% of luminal narrowing.

THIN CAP FIBROATHEROMA
Vulnerable plaque
Large necrotic core with overlying thin fibrous
cap contain mainly type I collagen with few
SMC
Cap < 65 m highly vulnerable
Rupture usually at the shoulder of the plaque.
CALCIFIED NODULE
Lesion with underlying calcification.
Resembles an eruptive nodule protruding into
lumen accompanied by platelet rich thrombus
which is usually non-occlusive.
Small necrotic core
MC in older person
Carotids > Coronaries.
HEALED PLAQUE
Silent plaque rupture for many years.
Repair occurs by formation of new cap.
Further luminal narrowing. (HPR)

8% lesions with < 20% diameter.
19% lesions with 21-50% diameter.
73% lesions with > 50% diameter.



CALCIFIED STABLE PLAQUES
Source of calcium : apoptotic SMCs, macroph
Varies from pt to pt
BMP, Osteopontin, bone sialoprotein,
osteoblast specific transcription factor highly
expressed.

Modified AHA Consensus
Classification Based on Morphologic
Descriptions
Nonatherosclerotic intimal lesions
1) Intimal thickening :
Normal accumulation of SMCs in the intima in
the absence of lipid or macrophage foam cells
2) Intimal xanthoma :
Superficial accumulation of foam cells without a
necrotic core or fibrous cap; based on animal
and human data, such lesions usually regress
Progressive atherosclerotic lesions:
Pathologic intimal thickening:
SMC-rich plaque with proteoglycan matrix and
focal accumulation of extracellular lipid
Fibrous cap atheroma :
Early necrosis: focal macrophage infiltration into
areas of lipid pools with an overlying fibrous
cap
Late necrosis: loss of matrix and extensive
cellular debris with an overlying fibrous cap
Thin cap fibroatheroma:
A thin, fibrous cap (< 65 m) infiltrated by
macrophages and lymphocytes with rare or
absence of SMCs and a relatively large
underlying necrotic core; intraplaque
hemorrhage/fibrin may be present
Lesions with acute thrombi
Plaque rupture:
Fibroatheroma with fibrous cap disruption; the
luminal thrombus communicates with the
underlying necrotic core
Plaque erosion :
Plaque composition, as above; no communication
of the thrombus with the necrotic core; can occur
on a plaque substrate of pathologic intimal
thickening or fibroatheroma
Altered Vessel Function
Vessel change
Plaque narrows lumen
Wall weakened

Thrombosis

Breaking loose of
plaque
Loss of elasticity
Consequence
Ischemia, turbulence
Aneurysms, vessel
rupture
Narrowing, ischemia,
embolization
Athero-embolization

Increase systolic blood
pressure
Morphologies in acute MI
Thin fibrous cap atheroma
Plaque rupture 60-75%
Plaque erosion 30-40%
Calcified nodules 2-7%
Prox. LAD 43%, Prox.RCA 20%, LCX-18%
INTERESTING QUESTIONS
CAN ATHEROSCLEROSIS BE REVERSED ?


CAN ATHEROSCLEROSIS BE CURED?

CAN WE DO SURGERY FOR
ATHEROSCLEROSIS?

Off Pump Endartrectomy Of Individual
Coronary Branches
CAN WE PREDICT THE DISEASE PROCESS
STAGE?
GENOMICS & PROTEOMICS
Mendelian genetics
Autosomal Dominant Hypercholesterolemia
LDLR, APOB, PCSK9
Familial Thoracic Aortic Aneurysm and
Dissection syndromes:
FBN1, TGFBR1, TGFBR2, ACTA2, MYH11,
NOTCH

Genetic markers for CAD
Chromosome 9p21/ANRIL
KIF6
Recent Developments in CAD Genetics
Lusis A, Trends
Cardio Med, 2003;
13:309-16.
Genes
contributing to
CAD susceptibility
Chromosome 9p21 & ANRIL
9p21 confined to 58K bp region
Risk associated with MI and CAD independent of known
risk factors
50% of individuals heterozygous for allele
15-20% increased risk of CAD
25% of individuals homozygous for allele
30-40% increased risk of CAD
High-risk CAD 9p21 haplotype overlaps with exons 13-
19 of ANRIL


HIGH AMOUNTS OF THESE PROTEINS
INDICATE INCREASED RISK
LOW AMOUNTS OF THESE PROTEINS
INDICATE INCREASED RISK
Soluble tumour necrosis factor-like weak
inducer of apoptosis
Rho GDP
Integrin II
Platelet activating factor acetylhydrolase
Apolipoprotein D
Heat shock protein 27
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BIOCHEMICAL PARAMETER FOR
ENDOTHELIAL DYSFUNCTION
- vWF
- Thrombomodulin
- E-Selection
- ICAM-1
- VCAM-1
- NO
- Microalbuminuria
- PAI-1
(D. Sargowo)

- Ox LDL MDA F2 - Isoprostane
- LP PLA2
- Lyso-PC OxFA
BIOCHEMICAL PARAMETER FOR
ENDOTHELIAL DYSFUNCTION
- vWF
- Thrombomodulin
- E-Selection
- NO
- Microalbuminuria
- PAI-1
- Ox LDL MDA F2 - Isoprostane
- LP PLA2
- Lyso-PC OxFA
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INFLAMMATORY MARKERS AS
PREDICTORS OF CARDIOVASCULAR RISK
Adhesion molecules
Cytokines
Acute-phase reactants
Fibrinogen
SAA
CRP
WBC count
Erytrocyte sedimentation rate
(Pearson et al, 2003)
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SURREGATE BIOMARKERS FOR ACS
HS CRP
MMP
Stromelysin
Kalogenase
Elastase
INFj, TNF, IL1
Gelatinase

LDH
CPK
MBCK
Troponin T-I
Fibrinogen
Albuminuri