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
Dec 26, 2015
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
Me
an
% s
ten
osis
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
Me
an
% s
ten
osis
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
IEL
-Ex
pe
cte
d I
EL
(/p
laq
ue a
rea
)
Ero
sio
n
Sta
ble
Th
in c
ap
ath
ero
ma
Pla
qu
e h
em
orr
ha
ge
Ac
ute
ru
ptu
re
He
ale
d r
up
ture
To
tal o
cc
lus
ion
A. 5
4
3
2
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.