Pathophysiology of

Atherosclerosis
and Vulnerable Plaque
Greg L. Kaluza, MD, PhD, FACC


Director of Research
Skirball Center for Cardiovascular Research
Cardiovascular Research Foundation
New York, NY
Disclosure Statement of Financial Interest
I have no actual or apparent conflict of
interest in regard to this presentation.

CAMs
ET PDGF
LDL
TF
MMPs
Moreno PR, Sanz J, Fuster V. JACC 2009; 53: 2315
Atherothrombosis:
Failure of Defense Mechanisms
Intimal Thickening (IT)
Pathologic Intimal Thickening (PIT)
Smooth Muscle Cell Apoptosis +
Lipid Pool + Proteoglycans +
Microcalcification
Smooth Muscle Cells +
Proteoglycans
media intima media
Microcalcifications
Von Kossa stain
media
Lipid Pool
Adaptive IT Pathological IT
?
Adaptive Intimal Thickening
(Usually Eccentric)
Slide (Modified) Courtesy of Dr. Renu Virmani
Early Atherosclerosis
Adaptive
Intimal
Thickening
Intimal
Xanthoma
Pathologic
Intimal
Thickening
LP
Human Coronary Atherosclerosis Development
Extracellular lipid
Necrotic core
Cholesterol clefts
Calcified plaque
Healed thrombus
Macrophage foam cells Hemorrhage
Thrombus
Smooth muscle cells
Collagen
From Plaque to Artery:
Positive Remodeling
Normal
Vessel
Minimal CAD Moderate CAD Severe CAD
Expansion Overcome:
Lumen Narrows
Compensatory Expansion
Maintains Consistent Lumen
Glagov S et al NEJM 1987;316:1371-5
Pathologic Intimal Thickening
Fibroatheroma
CD68
NC
CD68
PIT to Fibroatheroma Transition
LP LP
Abbreviations: LP = lipid pool; NC = necrotic core
Slide Courtesy of Dr. Renu Virmani
LP Early
Early foam cell apoptosis
(via Endoplasmic Reticulum
stress path)
Clearance by phagocytosis.
CD68
Engulfment
NC
Early NC = Macrophages (CD 68+) within the lipidic pool
Virmani R. JACC 2006 Apr 18;47(8 Suppl):C13-8
Mechanisms of Early Necrotic Core
Formation in Human Atherosclerosis
Adaptive
Intimal
Thickening
Intimal
Xanthoma
Pathologic
Intimal
Thickening
LP
NC
Fibrous
Cap Atheroma
Human Coronary Atherosclerosis Development
Extracellular lipid
Necrotic core
Cholesterol clefts
Calcified plaque
Healed thrombus
Macrophage foam cells Hemorrhage
Thrombus
Smooth muscle cells
Collagen
FC = fibrous cap
LP = lipid pool
NC = necrotic core

REMODELING!!!!
NEOVESSELS!!!!
Neovessels and Disease Progression
Neovessels & macrophages, analyzed by plaque severity and diabetes:
2. Increased in plaques in patients with diabetes
3. Increased in lipid-rich and ruptured plaques
1. Neovascularization is associated with Inflammation
Moreno PR. Circulation: 2004;110:2032-38
Moreno PR. Circulation: 2006;113:2245-52
CAMs
1. EPC Failure to Repair
Incompetent Bone Marrow
ET
3. Vasa Vasorum
Neovascularization
PDGF
LDL
2. Inflammation &
Macrophages
Moreno PR, Sanz J, Fuster V.
JACC 2009; 53: 2315
Mechanisms of Late Necrotic Core
Formation in Humans
Late
Excess foam cell apoptosis
Defective phagocytosis
1) Fas ligand
2) Transglutaminase-2
3) Lactadherin
4) Mer receptor Tyr Kinase

CD68
NC
Excess
Free cholesterol
Free hemoglobin (Hb)
Macrophages
Efferocytosis

ICAM
Hemorrhagic
Free-
Chol
CD163
Hp-2
NC
Defective
engulfment
CAMs
1. EPC Failure to Repair
Incompetent Bone Marrow
ET PDGF
LDL
2. Inflammation &
Macrophages
TF
MMPs
Apoptosis
Thrombosis
Moreno PR, Sanz J,
Fuster V. JACC 2009;
53: 2315
3. Vasa Vasorum
Neovascularization
Sirius Red Sirius Red with Polarized Light
Plaque Rupture & Healing = Progression
Type III
Type I
Disruption
Burke AP. Circulation. 2001 Feb 20;103(7):934-40
Mean % Stenosis Increases
with Number of Prior Rupture Sites
M
e
a
n

%

s
t
e
n
o
s
i
s

Number of prior ruptures,
Healed rupture sites
0
10
20
30
40
50
60
70
80
90
1 2 3 4
A
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4
Number of prior ruptures,
Acute rupture sites
M
e
a
n

%

s
t
e
n
o
s
i
s

B
Only 11% of plaque rupture is de novo
Plaque progresses through repeated rupture
Burke AP. Circulation. 2001 Feb 20;103(7):934-40
Adaptive
Intimal
Thickening
Intimal
Xanthoma
Pathologic
Intimal
Thickening
LP
NC
Fibrous
Cap Atheroma
Thin-Cap
Fibroatheroma
NC
FC
Human Coronary Atherosclerosis Development
Extracellular lipid
Necrotic core
Cholesterol clefts
Calcified plaque
Healed thrombus
Macrophage foam cells Hemorrhage
Thrombus
Smooth muscle cells
Collagen
FC = fibrous cap
LP = lipid pool
NC = necrotic core

REMODELING!!!!
NEOVESSELS!!!!
Accepted Histological Definition of a
TCFA or Vulnerable Plaque
Thin Cap Fibro-Atheroma (TCFA)
Presence of large necrotic core
Thin fibrous cap (< 65 mm)
Cap infiltrated by macrophages and lymphocytes
Cap composition type I collagen with few or absent SMCs
NC
Is the TCFA Always the Precursor Lesion
of Plaque Rupture?
TCFA
NC
Thin fibrous
cap
Th
Plaque Rupture
NC
Ruptured
cap
Th
*
Cap = Collagen type I with few SMC
Cap infiltrated by macrophages
Lipid rich necrotic core
Thin fibrous cap (<65 um)
60 to 70%

Vulnerable plaque after 2003 (broad clinical-
pathologic definition derived from currently available
knowledge and recognizing retrospective and
prospective aspects):
Any thrombosis-prone plaque or plaque at a risk of
rapid progression, with potential of becoming a
culprit lesion and triggering an ACS independent of
its specific morphology (although TCFA is still
believed to be the most prevalent lesion type in 60-
70% of cases).
Vulnerable Plaque Consensus :
Clinical Definition
Circulation 2003; 108: 1664-1672
Circulation 2003; 108: 1664-1672
Morphologic Variants of Vulnerable Plaque
Circulation 2003; 108: 1664-1672
Morphologic Variants of Vulnerable Plaque
Most Complex Lesions Feature
Positive (Expansive) Remodeling
I
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L
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A.
5
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3
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1
0
-1
-2
-3
Medial SMC
apoptosis
NC
Medial SMC loss
Slide Courtesy of Dr. Renu Virmani
Plaque Subtype and the Genesis of Plaque
Progression, Rupture and Thrombosis
Modified after Insull W. Am J Med (2009) 122,S3-S14
Stable lesion
Ruptured plaque
Thr
Thr
NC
NC
NC
FC
NC
FC
Ca
++

Ca
++

NC
f
Thin cap fibroatheroma
Not All Plaques Develop Similarly
Images Courtesy of Dr. Renu Virmani
Falk et al Circulation 1995; 92: 657-671
Fuster et al. JACC 2005; 46 (6): 937-945
Lesions in Different Stages and with
Different Morphology Coexist in the Same
Patient and Even in the Same Artery
Coronary bifurcation
Fibrofatty Lipid-rich, ruptured,
Non-occlusive thrombus
Plaque Rupture
Asymptomatic
TCFA
Quiescent State
Healing
Asymptomatic
Symptomatic or
Asymptomatic
Plaque Thrombosis= ACS
Mostly Symptomatic
Accelerated Plaque Progression
Symptomatic or Asymptomatic
Plaque Rupture and
Atherosclerosis Progression
TCFA Presence is the Focal Manifestation of a
Systemic Disease
Cheruvu P et al. J Am Coll Cardiol 2007;50:940-9
Plaque Rupture PIT Thin Cap Fibroatheroma
LAD
LCX
RCA
Longitudinal sections
from 50 autopsy hearts
10.9 meters examined from
148 coronary arteries
PROSPECT: Imaging Summary
Per-Patient Incidence of VH-TCFAs
28.4% of pts have 1 VH-TCFA
Mean 0.42 0.78 VH-TCFAs per pt.
Range 0 5 per pt
Total 266 lesions in 616 pts.
N lesions/pt per coronary tree:
Slide Courtesy of Dr. Gregg Stone
PROSPECT: VH-TCFA and
Non Culprit Lesion Related Events
Lesion HR 3.84 (2.22, 6.65) 6.41 (3.35, 12.24) 10.77 (5.53, 21.00) 10.81 (4.30, 27.22)
P value <0.0001 <0.0001 <0.0001 <0.0001
Prevalence* 51.2% 17.4% 11.0% 4.6%


*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA
Stone GW et al. NEJM 2011;364:226-35
Summary: Atherosclerosis
Pathological Intimal Thickening is the most accepted
lesion precursor of complex fibro-atheroma formation.
Plaques appear to progress through necrotic core
expansion, intraplaque hemorrhage and repeated ruptures
which lead to severe luminal narrowing either by plaque or
thrombus, although not always symptomatic.
Rupture of TCFA is believed to account for 60-70% of
ACS; other 30% are due to erosion and calcific nodule
breakage.
TCFA can be effectively detected and characterized
using several clinically available imaging modalities.
However, natural history of the malignant transformation
of TCFA into plaque rupture is still poorly understood.