Aterogenesis Dr Fleming

clases del dr fleming

1. Aterogénesis y Enfermedad Aterogénesis y Enfermedad
CoronariaCoronaria

DR ALEJANDRO FLEMING MEZADR ALEJANDRO FLEMING MEZA
CARDIOLOGO HCVBCARDIOLOGO HCVB
VALPARAISOVALPARAISO

2. Lípidos
Hipertensión
Edad
Enfermedad
Vascular
Tabaquismo
Obesidad
Diabetes
Dieta
Historia familiarSedentarismo
A
M
B
I
E
N
T
A
L
G
E
N
E
T
I
C
A
Sexo
Factores
Trombogénicos

5. Chronology of the
interface between the
patient and the
clinician through the
progression of plaque
formation and the
onset of complications
of STEMI.
Management
Before STEMI
4
1234 5 6
Onset of STEMI
- Prehospital issues
- Initial recognition and management
in the Emergency Department (ED)
- Reperfusion
Hospital Management
- Medications
- Arrhythmias
- Complications
- Preparation for discharge
Secondary Prevention/
Long-Term Management
Presentation
Working Dx
ECG
Cardiac
Biomarker
Final Dx
UA
NQMI QwMI
No ST Elevation
NSTEMI
Ischemic Discomfort
Acute Coronary Syndrome
Unstable
Angina
Myocardial Infarction
ST Elevation
Modified from Libby. Circulation 2001;104:365,
Hamm et al. The Lancet 2001;358:1533 and
Davies. Heart 2000;83:361.

6. Aterotrombosis: un Proceso Aterotrombosis: un Proceso
Generalizado y ProgresivoGeneralizado y Progresivo
NormalNormal
EstríaEstría
lipídicalipídica
PlacaPlaca
fibrosafibrosa
PlacaPlaca
ateros-ateros-
cleróticaclerótica
Ruptura/fisura/Ruptura/fisura/
de la placa &de la placa &
trombosistrombosis IMIM
Isquemia Isquemia
crítica crítica
m.inferiorm.inferior
Clínicamente silenteClínicamente silente
MuerteMuerte
cardiovascularcardiovascular
Aumento de la edadAumento de la edad
Angina estableAngina estable
Claudicación intermitenteClaudicación intermitente
AnginaAngina
inestableinestable
SCASCA
SCA, síndrome coronario agudo; TIA, “transient ischemic
attack” isquemia cerebral transitoria
ACVACV
isquémico/isquémico/
TIA TIA

10. ‘Significant’ (> 70%)
stenosis
‘Insignificant’ (< 70%)
stenosis
CORONARY ANGIOGRAPHY

11. Nissen et al. In: Topol (ed.) Interventional Cardiology Update 14;1995.
Ultrasound reveals a large
crescent-shaped atheroma (arrow) that
narrows the lumen by about 50%
Arrow indicates a site in the left
main coronary artery where the
intravascular ultrasound catheter
was positioned
Angiographically unrecognised coronary
artery disease

12. Angiografía de la Angina InestableAngiografía de la Angina Inestable

13. Different Types of Vulnerable PlaqueDifferent Types of Vulnerable Plaque
CP1130695-18
A B C D E F G
Rupture-
prone
vulnerable
plaque
Ruptured/
healing
vulnerable
plaque
Erosion-
prone
vulnerable
plaque
Eroded
vulnerable
plaque
Vulnerable
plaque with
intra-plaque
hemorrhage
Vulnerable
plaque with
calcified
nodule
Critically
stenotic
vulnerable
plaque
Normal
Macrophage
Thin cap
Large lipid
core
Collagen
Ruptured
cap
Non-occlusive clot
Smooth
muscle cells
Dysfunctional
endothelium
Platelets
Proteoglycans
Non-occlusive
mural thrombus/
fibrin
Intact cap
Leaking vasa vasorum/
angiogenesis
Calcium
node
Extensive
calcification
Old
thrombus
Circ 108:1666, 2003

14. Ruptura de placaRuptura de placa

15. Characteristics of Unstable and Characteristics of Unstable and
Stable PlaquesStable Plaques
Thin Thin
Fibrous CapFibrous Cap
Inflammatory Inflammatory
CellsCells
FewFew
SMCsSMCs
UnstableUnstable
ErodedEroded
EndotheliumEndothelium
ActivatedActivated
MacrophagesMacrophages
ThickThick
Fibrous CapFibrous Cap
Lack ofLack of
Inflammatory Inflammatory
CellsCells
Foam CellsFoam Cells
IntactIntact
Endothelium Endothelium
MoreMore
SMCsSMCs
StableStable
Libby et al. Circulation 1995; 91:2844-50

16. CP1130695-22Circ 108:1667, 2003

17. NEJM 2000;343:915-22

18. CP1157202-12
Method of Intravascular Ultrasound InterrogationMethod of Intravascular Ultrasound Interrogation
JAMA 290(17):2292, 2003

19. FISIOPATOLOGIA DE PLACA VULNERABLEFISIOPATOLOGIA DE PLACA VULNERABLE
Lumen
EROSION O FISURA DE CAPSULA FIBROSA
GRAN NUCLEO LIPIDICO
PRESENCIA
CELS.INFLAMATORIAS
REMODELACION ARTERIAL
EXCENTRICA MAS CALCIFICACION
ALTO STRESS DE
PARED
INCREMENTO DE NEOVASCULARIZACION

20. Biochemical Profile:
Foam cell to Plaque Rupture
1° & Messenger
Inflamm Chemokines
• IL-1
• TNF-
• IL-6
• IL-18
• MCP-1
Cellular Adhesion
Molecules
• sICAM
• sVCAM
• sSelectins
Acute Phase Reactants
hs-CRP, SAA, Fibrinogen, WBC
Plaque
Destabilization
• MMPs
• IL-18
• MPO
• PAPP-A
• PGIF
Plaque
Rupture
• CD40L

21. Fernández-Real and Ricart: Endocrine Reviews 24:278, 2003
Possible Pathways Leading to Chronic Possible Pathways Leading to Chronic
Inflammation, Resulting in AtherosclerosisInflammation, Resulting in Atherosclerosis
AterosclerosisAterosclerosis
Inflamacion intrarterialInflamacion intrarterial
VejezVejez
Estimulo extravascularEstimulo extravascular
Inflamacion cronica subclinicaInflamacion cronica subclinica
TabacoTabacoObesidadObesidad
 Citoquinas proinflamatorias Citoquinas proinflamatorias
Sd. Resistencia InsulinaSd. Resistencia Insulina
HTA Hiperinsulinemia DislipidemiaHTA Hiperinsulinemia Dislipidemia
Intolerancia Glucosa Obesidad abdominalIntolerancia Glucosa Obesidad abdominal
infecciones mucosa oralinfecciones mucosa oral
CP1158202-69

22. adventitia
lipid corelipid core
Site of previous
plaque rupture
Resolving
thrombus
Recruitment of
new smooth
muscle cells
PLAQUE GROWTH
Weissberg PL Eur Heart J. 1999
Courtesy of P Weissberg

23. Plaque RupturePlaque Rupture
•Type 1 – Lipid Rich plaque
•Type 2 – Lipid Poor Plaque
•Younger victims
•Women
•Smokers
JACC 2003;41:15s-22s

24. Lipid Rich Plaque RuptureLipid Rich Plaque Rupture
Theory 1Theory 1
Fibrillar Collagen
Collagen Synthesis
Collagen Breakdown
“thinning of cap”
Prote
o
lys
i
s
+
MMP3
MMP-9
i-MMP3
i-MMP-9
ox-LDL
IL-1b
IL-6
O2-
CD-40L
sheer stress
+
Smc’s
-
Interferon gamma
Tissue macrophages
JACC 2003;41:15s-22s

25. Lipid Rich Plaque RuptureLipid Rich Plaque Rupture
Theory 2Theory 2
1. Exposure or secretion of pro-thrombotic substances
Lumen
2. Alteration of rheology
By SMC’s
3. Sheer-induced
Platelet Aggregation
4. Changes in thrombogenecity
and fibrinolytic activity
JACC 2003;41:15s-22s
Tissue macrophages
Lipid
Core
Lipid
Core
Lipid
Core

26. CP1158202-24
Kereiakes: Circ 107:2076, 2003
Vulnerable
plaque
Unstable
plaque
High-risk
blood
High-risk
plaque

27. CD40 Ligand: An important playerCD40 Ligand: An important player
Smitko P et al. Circulation 2003; 108: 1917-1923

28. Placa Alto riesgo
•Inflamacion en
curso
•Placa/radio lumen
•Grado remodelacion
excentrica
•Ubicacion
Plasma Alto riesgo
•Sheer Stress
•Infeccion
•Diabetes/ Insulina
• Fibrinogen
• PAI-1
•Interleukina
•PCR
•Celulas activadas
Paciente Alto riesgo
•Mal control HTA
•Mal control DM
•Dislipiodemia
•Obesidad
•Insuficiencia Renal
Lumen
Estrategias
Terapia
integrada

29. CP1158202-24
Kereiakes: Circ 107:2076, 2003
Vulnerable
plaque
Unfavorable
Plasma
Acute
Coronary
Syndrome
High-risk
patient

30. Inhibit Platelet
Aggregation
Stabilize the Plaque
Passivate the Plaque LDL-C
HDL-C
TG
Reduce Sheer
Stress
Endothelial function
Suppress
Inflammation
Stent the Vessel
Strategies to TreatStrategies to Treat PlaquePlaque

31. 4. Plaque rupture,
Cholesterol content,
inflammation (hs-CRP)
infection
(statins, antibiotics)
3. Platelet adhesion/
activation/aggregation
(ASA,clopidogrel,
GPIIb/IIIa inhibitors)
2. Activation of clotting
cascade – thrombin
(heparin/LMWH)
1. Downstream from thrombus
myocardial ischaemia/necrosis
(-blockers, Nitrates etc)
Platelet
GPIIb/IIIa
Receptor
FibrinogenFibrinogen
ThrombinThrombin
Fibrin Fibrin
clotclot
Pathophysiology of Acute Coronary Syndromes
and Potential Pharmacologic Interventions

32. Lumen
Statins
LDL-C reduction
Reduction in chylomicron and
VLDL-C remnants, IDL-C, LDL-C
Lipid
Core
Macrophages
SMCs
Restore endothelial function
Anti-inflammatory effects
Maintain SMC function
Decreased thrombosis
Potential Mechanisms of Benefit of
Statins in Acute Coronary Syndromes

33. lipid core
adventitia
adventitia
lipid core
STATIN THERAPY
STATINS
STABILIZE
PLAQUES