Imunopatogeneza aterosclerozei

Dr. Alexandru Schiopu Clinica de Cardiologie Spitalul Universitar Malm Suedia

Atheroscleroza - definitie
Boala inflamatorie cronica a arterelor de marime mare si mijlocie, caracterizata de acumularea de lipide si tesut fibros in peretele arterial Leziunea caracteristica Placa de aterom Placa de aterom ingrosare focala a peretelui arterial avand ca si consecinta ingustarea lumenului si perturbarea fluxului sanguin

Placa de aterom

Placa de aterom

Manifestari clinice ale aterosclerozei

Afectiuni coronariene

Angina stabila, angina instabila, infarct miocardic, moarte subita

Afectiuni cerebrovasculare

Stroke (infarct cerebral), accident vascular cerebral ischemic tranzitoriu

Afectiuni vasculare periferice

Claudicatie intermitenta

Importanta globala
Infarctul miocardic si infarctul cerebral principalele cauze de deces global

Deces datorat afectiunilor coronariene 1.95 milioane (2002) Deces datorat infarctului cerebral 1.28 milioane (2002)

Rata mortalitatii datorata afectiunilor cardiovasculare egala cu rata totala a mortalitatii datorata urmatoarelor 5 cauze de deces (cancer, boli respiratorii cronice, accidente, viroze respiratorii, pneumonie) Estimat 20 milioane decese in 2020

Factori de risc
Modificabili
Dislipidemie

Nemodificabili
Varsta Sex Ereditate

Colesterol total crescut LDL crescut HDL scazut TG crescute

Fumat Hipertensiune arteriala Diabet

Obezitate
Sedentarism Dieta

Etiopatogeneza aterosclerozei

Afectarea peretelui vascular de catre factorii de risc (colesterol, hipertensiune, fumat, diabet, etc)
Inflamatie Inflamatia cauzeaza fibroza

Fibroza cauzeaza ingustarea lumenului vascular si reducerea fluxului sanguin

Structura peretelui arterial

Tunica adventitia Tunica media Tunica intima Endoteliu Tesut conjunctiv subendotelial

Celule musculare netede Fibre elastice/de colagen Membrana elastica externa

Aterogeneza

Aterogeneza Proces initiat de LDL

LDL = Low Density Lipoproteins oxLDL = oxidized LDL

Fragmentarea ApoB-100

Oxidarea fosfolipidelor Formarea de legaturi covalente intre aminoacizi (lisina si histidina) si aldehide libere (MDA and 4-HNE) oxLDL devine non-self

Aterogeneza Activarea endoteliului

Selectins ICAM - 1 VCAM - 1

Hansson et al. Ann Rev Path 2006

Aterogeneza Recrutarea monocitelor

Hansson et al. Ann Rev Path 2006

Aterogeneza Formarea celulelor spumoase

1 2 3 4

ScR = Scavenger receptors; M-CSF = Macrophage Colony Stimulating Factor TLR = Toll Like Receptors; IL-1 = Interleukin 1; TNF = Tumor Necrosis Factor IFN = Interferon gamma; Hansson et al. Ann Rev Path 2006

Aterogeneza Recrutarea si activarea limfocitelor T

Hansson et al. Ann Rev Path 2006

Aterogeneza Rolul limfocitelor NKT

NKT = Natural Killer T lymphocytes

Hansson et al. Ann Rev Path 2006

Aterogeneza Rolul celulelor musculare netede

SMC = Smooth Muscle Cells

Hansson et al. JAMA 2005

Aterogeneza Rolul celulelor musculare netede

Celula musculara contractila in tunica media

Celula musculara migratoare

Celula musculara sintetizanta in tunica intima

Aterogeneza Placa de aterom stadiu avansat

Invelis fibros Fibrous cap Centru necrotic necrotic core

SMC Fibre de colagen Celule spumoase Foam cells Lipide extracelulare Celule apoptotice si necrotice Resturi celulare

Stadiile placii de aterom

1. Leziunea initiala 2. Fatty streak - Acumulare subendoteliala de celule spumoase

3. Leziune intermediara Acumularea de lipide extracelulare

4. Ateroma Necrotic core + Fibrous cap + Microvascularizatie 5. Fibro-ateroma acumulare de tesut fibros si calciu 6. Leziune complicata Eroziuni Hemoragie in placa Rupturi Trombi

Aterogeneza

Aterogeneza

Aterogeneza

Aterogeneza

Aterogeneza

Aterogeneza

Remodelarea arteriala compensatorie (Ipoteza Glagov)

Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows

Normal vessel

Minimal CAD

Moderate CAD

Severe CAD

Regression
Adaptata dupa Glagov et al. N Engl J Med. 1987;316:1371-1375.

Imagine MRI a unei placi aterosclerotice in artera carotida

Remodelare compensatorie
PD

T1

T2

Goncalves et al, rezultate nepublicate

Clasificarea patogenetica a placilor de aterom

Placa vulnerabila - instabila Invelis fibros subtire
Infiltrat inflamator activitate proteolitica crescuta Bogata in lipide

Lumen Fibrous Cap

Lipid Core

Placa stabila Invelis fibros gros

Lumen Fibrous Cap

Lipid Core

Bogat in SMC cantitate crescuta de fibre de colagen Saraca in lipide

Libby P. Circulation. 1995;91:2844-2850.

Clasificarea patogenetica a placilor de aterom

Lumen Fibrous Cap

Lipid Core

Lumen Fibrous Cap

Lipid Core

Braunwald E - J Am Coll Cardiol 2000

Mechanismele care contribuie la destabilizarea placilor de aterom

Acumularea de lipide extracelulare Inflamatia locala Degradarea matricei extracelulare Moartea celulara Hemoragia in placa Stresul mecanic

Macrofagele secreta enzime care degradeaza matricea extracelulara

Enzime proteolitice MMP Matrix metalloproteinases Cysteine proteases

Macrofagele secreta enzime care degradeaza matricea extracelulara

Macrofage Colagen

Moartea celulara

Frecvent intalnita in placi Acumularea de lipide indica moarte celulara Afecteaza in primul rand macrofagele si SMC Capacitate redusa de reparare

Hemoragie in placa

Effectul stresului longitudinal

Cheng et al, Circulation 2006

Efectul pravastatinei asupra continutului lipidic in placa de aterom

Placebo Pravastatin

Continutul in lipide redus cu 63% in groupul tratat cu pravastatina

Continutul in oxLDL redus cu 40% in groupul tratat cu pravastatina

Lipids

OxLDL

Crisby et al, Circulation 2001

Efectul pravastatinei asupra continutului celular si mortalitatii celulare in placa de aterom

P<0.05
35

P<0.05
30 25

P<0.05

% of all cells

20 15 10 5 0 Macrophages T cells TUNEL Control Pravastatin

Crisby et al, Circulation 2001

Complicatiile aterosclerozei
Evenimente tromboembolice

2/3 datorate rupturii placilor vulnerabile 1/3 datorate eroziunilor endoteliale

Majoritatea infarctelor miocardice sunt cauzate de tromboze in regiuni ale circulatiei coronariene cu grad redus de stenoza
Severity of Coronary Artery Stenosis Before Acute MI (n=195) Culprit lesion

80 70 60 50 40 30 20 10 0

% Patients

<50

50-70 % Diameter Stenosis

>70

Data from 4 studies - Smith. Circulation. 1996.

Ruptura de placa si tromboza arteriala

Factori trombogenici
TF Tissue Factor Colagen

Complicatiile aterosclerozei
Stable Plaque Unstable Plaque Disrupted Plaque

Braunwald E et al. J Am Coll Cardiol 2000

Complicatiile aterosclerozei

Infarct miocardic

Stroke

Ischemie periferica

Effect of oxidized LDL peptide vaccines on atherosclerosis in mice

0.3
% atherosclerosis

0.25 0.2 0.15 0.1 0.05 0

Control Peptide 45 Peptide 210 Peptide 240

P<0.01

P<0.005

Nordin Fredrikson et al

Effect of passive immunization with recombinant human IgG against peptide 45 in LDLr KO mice overexpressing human apo B 100

Control IgG1

Anti-peptide 45 IgG1
Strm et al, Atherosclerosis 2007

Atherosclerotic plaques
Stable Plaque Unstable Plaque Disrupted Plaque

Braunwald E et al. J Am Coll Cardiol 2000;36:9701062.

Why does oxidized LDL become immunogenic?

Oxidation of phospholipids Fragmentation of apo B-100 Formation of covalent aldehyde (MDA and 4-HNE) and amino acid (lysine and histidine) adducts

The early atherosclerotic plaque

ICAM-1 VCAM-1 E-selectin

LDL

LDL oxidation and aggregation

The early atherosclerotic plaque the inflammatory reponse

T cell

LDL

Oxidized LDL Macrophage

The early atherosclerotic plaque removal of oxidized LDL by macrophages

T cell
LDL

Oxidized LDL Macrophage

The atherosclerotic plaque immune responses against oxidized LDL

LDL

T cell T cell receptor Oxidized LDL HLA-DR peptide receptor

Oxidized LDL Macrophage

Lipids and inflammation

The fibromuscular plaque

The fibromuscular plaque

The fibromuscular plaque

Plaque

The vulnerable plaque

Lipids and inflammation

A
Atheroma Lumen

Rupture Site

Lipid Core Images supplied by Steven E. Nissen, MD, Cleveland Clinic.

Adaptive immune responses to oxidized LDL