Aterogénesis y Enfermedad Aterogénesis y Enfermedad CoronariaCoronaria

DR ALEJANDRO FLEMING MEZADR ALEJANDRO FLEMING MEZA

CARDIOLOGO HCVBCARDIOLOGO HCVB

VALPARAISOVALPARAISO

LípidosHipertensión

Edad

EnfermedadVascular

Tabaquismo

Obesidad

DiabetesDieta

Historia familiarSedentarismo

AMBIENTAL

GENETICA

Sexo

Factores Trombogénicos

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.

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

‘Significant’ (> 70%)stenosis

‘Significant’ (> 70%)stenosis

‘Insignificant’ (< 70%) stenosis

‘Insignificant’ (< 70%) stenosis

CORONARY ANGIOGRAPHY

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

Angiografía de la Angina InestableAngiografía de la Angina Inestable

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

Ruptura de placaRuptura de placa

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

CP1130695-22Circ 108:1667, 2003Circ 108:1667, 2003

NEJM 2000;343:915-22

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

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

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

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

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

Plaque RupturePlaque Rupture

•Type 1 – Lipid Rich plaque

•Type 2 – Lipid Poor Plaque•Younger victims•Women•Smokers

JACC 2003;41:15s-22s

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

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

CP1158202-24

Kereiakes: Circ 107:2076, 2003Kereiakes: Circ 107:2076, 2003

Vulnerableplaque

Vulnerableplaque

Unstableplaque

Unstableplaque

High-riskblood

High-riskblood

High-riskplaque

High-riskplaque

CD40 Ligand: An important playerCD40 Ligand: An important player

Smitko P et al. Circulation 2003; 108: 1917-1923

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

CP1158202-24

Kereiakes: Circ 107:2076, 2003Kereiakes: Circ 107:2076, 2003

Vulnerableplaque

Vulnerableplaque

UnfavorablePlasma

UnfavorablePlasma

AcuteCoronarySyndrome

AcuteCoronarySyndrome

High-riskpatient

High-riskpatient

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

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

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

lipid core

adventitia

adventitia

lipid core

STATIN THERAPYSTATINS STABILIZE PLAQUES