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.