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