aterogenesis dr fleming
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clases del dr flemingTRANSCRIPT
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Aterogénesis y Enfermedad Aterogénesis y Enfermedad CoronariaCoronaria
DR ALEJANDRO FLEMING MEZADR ALEJANDRO FLEMING MEZA
CARDIOLOGO HCVBCARDIOLOGO HCVB
VALPARAISOVALPARAISO
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LípidosHipertensión
Edad
EnfermedadVascular
Tabaquismo
Obesidad
DiabetesDieta
Historia familiarSedentarismo
AMBIENTAL
GENETICA
Sexo
Factores Trombogénicos
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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
41 2 3 4 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 DiscomfortAcute Coronary Syndrome
UnstableAngina
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.
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Aterotrombosis: un Proceso Aterotrombosis: un Proceso Generalizado y ProgresivoGeneralizado y Progresivo
NormalNormalEstríaEstría
lipídicalipídicaPlacaPlaca
fibrosafibrosa
PlacaPlacaateros-ateros-
cleróticaclerótica
Ruptura/fisura/Ruptura/fisura/de la placa &de la placa &
trombosistrombosis IMIM
Isquemia Isquemia crítica crítica
m.inferiorm.inferiorClínicamente silenteClínicamente silente
MuerteMuertecardiovascularcardiovascular
Aumento de la edadAumento de la edad
Angina estableAngina estableClaudicación intermitenteClaudicación intermitente
AnginaAnginainestableinestable
SCASCA
SCA, síndrome coronario agudo; TIA, “transient ischemic attack” isquemia cerebral transitoria
ACVACVisquémico/isquémico/
TIA TIA
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‘Significant’ (> 70%)stenosis
‘Significant’ (> 70%)stenosis
‘Insignificant’ (< 70%) stenosis
‘Insignificant’ (< 70%) stenosis
CORONARY ANGIOGRAPHY
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Nissen et al. In: Topol (ed.) Interventional Cardiology Update 14;1995.
Ultrasound reveals a largecrescent-shaped atheroma (arrow) that narrows the lumen by about 50%
Arrow indicates a site in the leftmain coronary artery where theintravascular ultrasound catheterwas positioned
Angiographically unrecognised coronary artery disease
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Angiografía de la Angina InestableAngiografía de la Angina Inestable
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Different Types of Vulnerable PlaqueDifferent Types of Vulnerable Plaque
CP1130695-18
A B C D E F G
Rupture-prone
vulnerableplaque
Ruptured/healing
vulnerableplaque
Erosion-prone
vulnerableplaque
Erodedvulnerable
plaque
Vulnerableplaque withintra-plaquehemorrhage
Vulnerableplaque with
calcifiednodule
Criticallystenotic
vulnerableplaque
Normal
Macrophage
Thin cap
Large lipidcore
CollagenRuptured
cap
Non-occlusive clot
Smoothmuscle cells
Dysfunctionalendothelium
Platelets
Proteoglycans
Non-occlusivemural thrombus/
fibrin
Intact cap
Leaking vasa vasorum/angiogenesis
Calciumnode
Extensivecalcification
Oldthrombus
Circ 108:1666, 2003Circ 108:1666, 2003
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Ruptura de placaRuptura de placa
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Characteristics of Unstable and Characteristics of Unstable and Stable PlaquesStable Plaques
Thin Thin Fibrous CapFibrous Cap
Inflammatory Inflammatory CellsCells
FewFewSMCsSMCs
UnstableUnstable
ErodedErodedEndotheliumEndothelium
ActivatedActivatedMacrophagesMacrophages
ThickThickFibrous CapFibrous Cap
Lack ofLack ofInflammatory Inflammatory CellsCells
Foam CellsFoam Cells
IntactIntactEndothelium Endothelium
MoreMoreSMCsSMCs
StableStable
Libby et al. Circulation 1995; 91:2844-50
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CP1130695-22Circ 108:1667, 2003Circ 108:1667, 2003
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NEJM 2000;343:915-22
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CP1157202-12
Method of Intravascular Ultrasound InterrogationMethod of Intravascular Ultrasound InterrogationMethod of Intravascular Ultrasound InterrogationMethod of Intravascular Ultrasound Interrogation
JAMA 290(17):2292, 2003JAMA 290(17):2292, 2003
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FISIOPATOLOGIA DE PLACA VULNERABLEFISIOPATOLOGIA DE PLACA VULNERABLE
Lumen
EROSION O FISURA DE CAPSULA FIBROSA
GRAN NUCLEO LIPIDICO
PRESENCIA CELS.INFLAMATORIAS
REMODELACION ARTERIALEXCENTRICA MAS CALCIFICACION
ALTO STRESS DE PARED
INCREMENTO DE NEOVASCULARIZACION
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Biochemical Profile: Foam cell to Plaque Rupture
1° & Messenger Inflamm Chemokines
• IL-1• TNF-• IL-6• IL-18• MCP-1
Cellular AdhesionMolecules
• sICAM• sVCAM• sSelectins
Acute Phase Reactants
hs-CRP, SAA, Fibrinogen, WBC
Plaque Destabilization
• MMPs• IL-18• MPO• PAPP-A• PGIF
Plaque Rupture
• CD40L
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Fernández-Real and Ricart: Endocrine Reviews 24:278, 2003Fernández-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
Possible Pathways Leading to Chronic Possible Pathways Leading to Chronic Inflammation, Resulting in AtherosclerosisInflammation, Resulting in Atherosclerosis
AterosclerosisAterosclerosisAterosclerosisAterosclerosis
Inflamacion intrarterialInflamacion intrarterialInflamacion intrarterialInflamacion intrarterial
VejezVejezVejezVejez
Estimulo extravascularEstimulo extravascularEstimulo extravascularEstimulo extravascular
Inflamacion cronica subclinicaInflamacion cronica subclinica Inflamacion cronica subclinicaInflamacion cronica subclinica
TabacoTabacoTabacoTabaco ObesidadObesidadObesidadObesidad
Citoquinas proinflamatorias Citoquinas proinflamatorias Citoquinas proinflamatorias Citoquinas proinflamatorias
Sd. Resistencia InsulinaSd. Resistencia InsulinaSd. Resistencia InsulinaSd. Resistencia Insulina
HTA Hiperinsulinemia DislipidemiaHTA Hiperinsulinemia Dislipidemia Intolerancia Glucosa Obesidad abdominalIntolerancia Glucosa Obesidad abdominal
HTA Hiperinsulinemia DislipidemiaHTA Hiperinsulinemia Dislipidemia Intolerancia Glucosa Obesidad abdominalIntolerancia Glucosa Obesidad abdominal
infecciones mucosa oralinfecciones mucosa oralinfecciones mucosa oralinfecciones mucosa oral
CP1158202-69
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adventitia
lipid corelipid core
Site of previous plaque ruptureSite of previous plaque rupture
Resolving thrombus
Resolving thrombus
Recruitment of new smooth muscle cells
Recruitment of new smooth muscle cells
PLAQUE GROWTH
Weissberg PL Eur Heart J. 1999Courtesy of P Weissberg
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Plaque RupturePlaque Rupture
•Type 1 – Lipid Rich plaque
•Type 2 – Lipid Poor Plaque•Younger victims•Women•Smokers
JACC 2003;41:15s-22s
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Lipid Rich Plaque RuptureLipid Rich Plaque RuptureTheory 1Theory 1
Fibrillar Collagen
Collagen Synthesis
Collagen Breakdown“thinning of cap”
Proteolysis
+MMP3MMP-9
i-MMP3i-MMP-9
ox-LDLIL-1bIL-6O2-CD-40L sheer stress
+Smc’s
-Interferon gamma
Tissue macrophages JACC 2003;41:15s-22s
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Lipid Rich Plaque RuptureLipid Rich Plaque RuptureTheory 2Theory 2
1. Exposure or secretion of pro-thrombotic substances
Lumen
2. Alteration of rheologyBy SMC’s
3. Sheer-inducedPlatelet Aggregation
4. Changes in thrombogenecity and fibrinolytic activity
JACC 2003;41:15s-22s
Tissue macrophages
LipidCore
LipidCore
LipidCore
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CP1158202-24
Kereiakes: Circ 107:2076, 2003Kereiakes: Circ 107:2076, 2003
Vulnerableplaque
Vulnerableplaque
Unstableplaque
Unstableplaque
High-riskblood
High-riskblood
High-riskplaque
High-riskplaque
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CD40 Ligand: An important playerCD40 Ligand: An important player
Smitko P et al. Circulation 2003; 108: 1917-1923
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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
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CP1158202-24
Kereiakes: Circ 107:2076, 2003Kereiakes: Circ 107:2076, 2003
Vulnerableplaque
Vulnerableplaque
UnfavorablePlasma
UnfavorablePlasma
AcuteCoronarySyndrome
AcuteCoronarySyndrome
High-riskpatient
High-riskpatient
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Inhibit Platelet Aggregation
Stabilize the Plaque
Passivate the Plaque LDL-C HDL-CTG
Reduce Sheer Stress
Endothelial function
Suppress Inflammation
Stent the Vessel
Strategies to TreatStrategies to Treat PlaquePlaque
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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/IIIaReceptor
FibrinogenFibrinogenThrombinThrombin
Fibrin Fibrin clotclot
Pathophysiology of Acute Coronary SyndromesPathophysiology of Acute Coronary Syndromesand Potential Pharmacologic Interventionsand Potential Pharmacologic Interventions
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Lumen
StatinsLDL-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 Potential Mechanisms of Benefit of Statins in Acute Coronary SyndromesStatins in Acute Coronary Syndromes
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lipid core
adventitia
adventitia
lipid core
STATIN THERAPYSTATINS STABILIZE PLAQUES