clases del dr fleming

2. Lípidos Hipertensión Edad Enfermedad Vascular Tabaquismo Obesidad Diabetes Dieta Historia familiar Sedentarismo AMBIENTAL GENETIC 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 1 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 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 Generalizado y Progresivo Normal Estría lipídica Placa fibrosa Placa ateros- clerótica Ruptura/fisura/ de la placa & trombosis IM Isquemia crítica m.inferior Clínicamente silente Muerte cardiovascular Aumento de la edad Angina estable Claudicación intermitente Angina inestable SCA SCA, síndrome coronario agudo; TIA, “transient ischemic attack” isquemia cerebral transitoria ACV isquémico/ TIA

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

11. Angiographically unrecognised coronary artery disease 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

12. Angiografía de la Angina Inestable

13. Different Types of Vulnerable Plaque CP1130695-18 Circ 108:1666, 2003 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

14. Ruptura de placa

15. Characteristics of Unstable and Stable Plaques Thin Fibrous Cap Inflammatory Cells Few SMCs Unstable Eroded Endothelium Activated Macrophages Thick Fibrous Cap Lack of Inflammatory Cells Foam Cells Intact Endothelium More SMCs Stable Libby et al. Circulation 1995; 91:2844-50

16. CP1130695-22 Circ 108:1667, 2003

17. NEJM 2000;343:915-22

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

19. FISIOPATOLOGIA 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

21. Fern á ndez-Real and Ricart: Endocrine Reviews 24:278, 2003 Possible Pathways Leading to Chronic Inflammation, Resulting in Atherosclerosis Aterosclerosis Inflamacion intrarterial Vejez Estimulo extravascular Inflamacion cronica subclinica Tabaco Obesidad  Citoquinas proinflamatorias infecciones mucosa oral CP1158202-69 Sd. Resistencia Insulina HTA Hiperinsulinemia Dislipidemia Intolerancia Glucosa Obesidad abdominal

22. adventitia lipid core lipid 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

24. Lipid Rich Plaque Rupture Theory 1 Fibrillar Collagen Collagen Synthesis Collagen Breakdown “ thinning of cap” Proteolysis + 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 Rupture Theory 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 player Smitko P et al. Circulation 2003; 108: 1917-1923

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

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

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 Fibrinogen Thrombin Fibrin clot 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. STATINS STABILIZE PLAQUES lipid core adventitia adventitia lipid core STATIN THERAPY