Badimon

NATURAL HISTORY OF ATHEROTHROMBOTIC PLAQUES IN DIFFERENT ARTERIAL DISTRICTS April 2013

Lina Badimon Barcelona Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau

•MEDITERANEAN LEAGUE AGAINST THROMBOSIS (MLTD) •MLTD FOUNDATION PRESIDENT: Lina Badimon EDUCATIONAL COURSES Coordinator: S. Coccheri BIANNUAL MEETING: Valencia, Spain 14-17 May 2014

NO CONFLICT OF INTEREST ON THE TOPIC OF MY LECTURE

Atherothrombosis

atherotrombosis

Acute ischemic syndromes

Major Clinical Manifestations of Atherothrombosis plaques plaques

• Transient ischemic attack • Ischemic stroke • Angina pectoris (stable, unstable) • Myocardial infarction

Ischemic sudden death

• Claudication plaques

• Critical limb ischemia, rest pain, gangrene, necrosis

Life Expectancy of Patients with Atherothrombosis First PAD

16 13.9

First MI

8.8

First IS PAD patients with:

1.8

Later MI Later IS

1.5

MI patients with: Second MI

0.4

Later IS

0.4

IS patients with:

3.9

Later MI

4.2

Second IS 0

5

10

15

Years P Wolf, Boston University, from Framingham Database (with the courtesy of Prof. Wolf)

20

General Metabolic Disorders:

Local Factors:

Obesity - Diabetes

Lesion Severity Lesion Consistency Lesion Atheroma-size Lesion geometry Flow-rheology (shear stress)

Systemic Conditions:

Genetics:

Hyperlipidemia Hypercoagulability Hypofibrinolysis Hypertensión…

Traits Gender Age

Endothelial Dysfunction Normal artery

Fat Streak

Intermediate lesion

atheroma

Fibrous atheroma

Ruptured atheroma

Plaquetas PLATELETS

Atherosclerotic Progression

20 years

30 years

Lipids-inflammation-fibrous tissue…..

40 years Thrombus Formation

Risk Factors for Plaque Destabilization Systemic Factors

Local Factors Cap Fatigue

Smoking Inflammation Cholesterol

Atheromatous Core (size/consistency) Cap Thickness/ Consistency Cap Inflammation

Diabetes Mellitus

Homocysteine

Plaque Rupture

HTA Fibrinoge n Impaired Fibrinolysis

Risk Factors and Atherothrombosis ATHEROGENESIS

Family/Genes Gender Age (menopause) Diet Hypertension Obesity Sedentarism others

THROMBOSIS

Diabetes Hyperlipidemia

Inflammation Apoptosis Shear rate Stress Depression CRP

Smoking Cathecholamines Fibrinogen Lp(a)/Homocysteine Factor V Leiden Platelet polymorph.

Hypercoagulability Hypofibrinolysis Genetic Protein Deficiencies

CULPRIT LESION AND DIFFUSE DISEASE

Thrombosis

Clinical Signal

Atherosclerosis

Silent Disease Variable risk

Inflammation

LBM/CRC-2013

Athero-thrombosis: An unifying concept?

Coronary disease:

vulnerable lesions (lipid-rich) non-stenotic

Carotid disease:

heterogenous lesions (complex) – highly stenotic

Coronary disease: disruption of a vulnerable/eroded lesion with acute thrombus formation Carotid disease:  ulcerated carotid lesion leading to thrombosis or thromboembolic complications

Athero-thrombosis: An unifying concept? Ischemic strokes have an atherothrombotic origin: •An aortic or carotid thrombus embolize to the brain.

•Similar RF’s than those in CHD except for % stenosis •Same agents are effective in preventing events (antithrombotic, statins) Stroke patients are different from MI patients in: •They are older •They have a higher risk for a new stroke than for MI.

VESSEL WALL

BLOOD

. PROTHROMBOTIC STATE (?)

THROMBOSIS

.GENETICS clotting and fibrinolytic factors

.SEVERELY DAMAGED ruptured/eroded .MILDLY DAMAGED .ECM composition -endothelial function-

. CYTOKINES (septic shock)

FLOW

High vs low shear conditions Laminar vs Turbulent Local geometry Spasm

ADHESION PROTEINS Fibrinogen Fibronectin vWF Thrombospondin Vitronectin P-selectin GPIIb/IIIa

PLATELET MICROPARTICLES

COAGULATION FACTORS Factor V and XI PAI-1 Plasminogen Protein S GAS 6

Adhesive molecules Proinflammatory factors

GROWTH FACTORS PDGF PDGF TGF-?

TGF-?

EGF EGF bFGF bFGF

CYTOKINE-LIKE FACTORS

ENDOTHELIUM

CHEMOKINES RANTES RANTES MIP-1??

MIP-1 PDGF PDGF PF4 PF4 IL-8 IL-8 ENA-78 ENA-78

?-thromboglobulina ?-thromboglobulina IL-1?

IL-1?

CD40L CD40L

ACTIVATED PLATELET

Monocyte recruitment Oxidized lipoprotein uptake and retention

IL- 8 MCP-1

VCAM-1 ICAM-1 E-selectin ROS TF IL- 6

SUDDEN DEATH CASE

L. Badimon et al. Atlas de Cardiopatia Isquemica, 2004

Acute Coronay Syndromes (ACS) Atherothrombosis 70 % Plaque rupture

30% Plaque erosion

Oriol J, Badimon L. Sudden Death Eulalia Study. A H J 2012

Composition of plaques prone to rupture vs. erosion

rupture

necrotic core /thin fibrous plaque lipid core inflammatory cells smooth muscle cells collagen fibers

structural failure

plaque DISRUPTION Copyright Š2005 BMJ Publishing Group Ltd.

Composition of plaques prone to rupture vs. erosion Badimon L, et al. Atlas de Cardiopatia Isquémica. 2004

erosion

smooth muscle cells

Copyright ©2005 BMJ Publishing Group Ltd.

proteoglycans collagen fibers number of inflammatory cells

•Deendothelization •Prothrombotic SMC

Apoptosis SMC phenotype differentiation*

Badimon L, Llorente- Cortes V, Padro T et al. 2002-2007

Plaque erosion compared to plaque rupture as the basis of ACS Patient

Lesion

rupture – 45% ACS



under 50 years



women



cigarette smoking



eccentric (82% eroded plaques)



less % stenosis



infrequently calcified

erosion – 55% ACS

Virmani R et al. JACC 2006

Atherothrombosis and Microcirculation

Plaque rupture

Embolization

Microvascular obstruction

CAROTID ATHEROSCLEROTIC PLAQUES

plaque

carotid

CAROTID ATHEROSCLEROTIC PLAQUES

ulcerated

fibrotic

calcic

LBM/CRC-2013

0,8 0,7 0,6 (relativo a GUS)

mRNA-CRP expression

PLAQUE CRP-GENE EXPRESSION MICROFLUIDITY CARD PLATFORM

0,5 0,4

*

0,3 0,2 0,1

#

0 UNC

fibrotic

p=0,01*, p=0,001#

Krupinski J et al Stroke 2006; 37:1200-1204.

UC

IDENTIFICATION OF DIFFERENTIAL PROTEIN EXPRESSION ASSOCIATED WITH DEVELOPMENT OF USTABLE HUMAN CAROTID PLAQUES

Protein microarray platform

Slevin M, Baset A, Miguel M, Krupinsky J, Badimon L and Gaffney J

American Journal of Pathology 1648, 3, 1004-1021, 2006

nt o

INFLAMMATION AND THROMBOSIS ON PLAQUES

TF TF

+FVIIa TF

TF:VIIa Xa + Va X macrophages Xa:Va

proteolysis Prothrombin

Thrombin

TF TF TF

*

1000 800 600 400 200 0

INT

GRADO TF 1

TF

Plaque Thrombos unstability

is

6 /cm 2

TF

deposici贸n plaquetar x 10

Tissue Factor

TF AND THROMBOGENICITY

CR

FC

TM

ADV LRC

1

2

2

2

3

Toschi et al. Circulation 1997

control

TFPI-treated

TF

rupture

thrombosis

Badimon et al Circulation 1999

ROLE OF LOCAL HEMODYNAMICS AND LESION TYPE ON THE CHARACTERISTICS OF MURAL THROMBUS LOCAL RHEOLOGICAL CONDITIONS 1700/S

212/S

L

L

L

L

LL

PLATELETS: RED FIBRIN: GREEN (200X)

MILD ARTERIAL DAMAGED

SEVERE ARTERIAL DAMAGED

Badimon et al 2001

Thrombus Composition: Immunohistochemical Analysis RUPTURED PLAQUES IMH:

fibrin

platelets

ruptured plaques

ERODED PLAQUES fibrin

platelets

eroded plaques

Sato, Y et al. Heart 2005;91:526

CAROTID PLAQUE UNSTABILITY, INFLAMMATION,THROMBOSIS Balance between inflammation and repair: •Apoptosis of SMCs, proteolysis

30

•Proliferation od SMCs, collagen

Interaction Bar Plot for CRP Effect: DISLIPEMIA * SINTOMATOLOGIA * placa/estabilitad Error Bars: ± 1 Standard Error(s)

25

Cell Mean

20 a-estable

15

b-inestable

10

Interaction Bar Plot for D-dim er/plasma

+ -

+

D-DIMER Effect: placa/estabilitadIN PLASMA 900

6 5 Cell Mean

600 Cell Mean

Interaction Bar Plot for D-dimer/placa Effect: placa/estabilitad Error Bars: ± 1 Standard Error(s)

Cell

7

700

500 400 300

4 3 2

200

1

100

Krupinski J , Badimon L Stroke 2006

-

D-DIMER IN PLAQUE

Error Bars: ± 1 Standard Error(s)

800

0

b-no, b- sense

SYMPTOMS

+ +

b-no, a- simptomàtic

DYSLIPEMIA

a-si, b- sense

0

a-si, a- simptomàtic

5

a-estable

b-inestable Cell

0

a-estable

b-inestable Cell

ANTITHROMBOTICS ANTICOAGULANTS

STATINS

Diversity of atherosclerotic plaque types in the three coronaries of a 39-year old man who died from Sudden Death

PLAQUES AT RISK FOR CLINICAL COMPLICATION

Lesion Heterogeneity 1- Have a thin fibrous cap

2- Contain a large lipid core 3- Show outward vessel remodelling 4- Have increased content of inflammatory cells 5- Have reduced collagen content

L. BADIMON L. CASANI P. CATALINA J. CRESPO R. FERRER M. GARCIA-ARGUINZONIS R. HERNANDEZ O. JUAN V. LLORENTE R. LUGANO B. MOLINS B. OÑATE T. PADRO E. PEÑA I. RAMAIOLA E. SEGALES R. SUADES G. VILAHUR

BARCELONA CARDIOVASCULAR RESEARCH CENTER (CSIC-ICCC) HSCSP-UAB