1. Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Saint-Joseph University School of Medicine Director of Cardiovascular Research Division of Cardiology Hotel Dieu de France Hospital

2. Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Chronic inflammation long time before ACSChronic inflammation long time before ACS ACS an acute inflammatory stateACS an acute inflammatory state -Evidence of inflammation inside the plaque -Evidence of inflammation in the circulation -Consequences of acute inflammation Widespread inflammation in ACSWidespread inflammation in ACS Anti-inflammatory therapy in ACSAnti-inflammatory therapy in ACS

3. Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Chronic inflammation long time before ACSChronic inflammation long time before ACS ACS an acute inflammatory stateACS an acute inflammatory state -Evidence of inflammation inside the plaque -Evidence of inflammation in the circulation -Consequences of acute inflammation Widespread inflammation in ACSWidespread inflammation in ACS Anti-inflammatory therapy in ACSAnti-inflammatory therapy in ACS

9. Value of Myeloperoxidase in Predicting MACE at 6 Months Odds Ratio P < 0.001 for trends Brennan et al. N Engl J Med 2003;349:1595-604

11. Sources of Inflammatory Markers

12. Risk of MI According to CRP Levels

13. CRP and Cholesterol in the Prediction of Cardiovascular Events

14. Markers of inflammation are associated with rapid CAD progression in patients with stable angina Zouridakis. Circulation 2004;110:1747-1753 Study performed in England Study performed in England 124 patients with stable angina 124 patients with stable angina Waiting for PCI Waiting for PCI Mean waiting time: 4.8 + 2.4 months Mean waiting time: 4.8 + 2.4 months CAD progression occurred in 28% of patients CAD progression occurred in 28% of patients Neopterin, hs-CRP, MMP-9, sICAMM-1 were independent predictors of rapid CAD progression Neopterin, hs-CRP, MMP-9, sICAMM-1 were independent predictors of rapid CAD progression

15. Atherosclerotic plaques can be classified according to their degree of stenosis tight Moderate

17. Characteristics of Unstable and Stable Plaques Platelets Lumen Thrombus Lipid rich core Smooth muscle cell Endothelium Thick fibrous cap Macrophage Large lipid core with thin fibrous cap, macrophages interacting with thrombus Reduced lipid core with thick fibrous cap reinforced with increased smooth muscle cells Thinfibrouscap Unstable Plaque Stable Plaque

18. Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Chronic inflammation long time before ACSChronic inflammation long time before ACS ACS an acute inflammatory stateACS an acute inflammatory state -Evidence of inflammation inside the plaque -Evidence of inflammation in the circulation -Consequences of acute inflammation Widespread inflammation in ACSWidespread inflammation in ACS Anti-inflammatory therapy in ACSAnti-inflammatory therapy in ACS

19. Unstable Plaques are Hot Difference of temp from background temp Stefanadis. Circ 99;99:1965

21. Macrophage Infiltration in ACS Results from Atherectomy Specimens Stable angina Unstable angina Non-Q wave MI P value Total plaque area 417 + 87 601 + 157 499 + 87 NS Macrophage- rich area 14 + 5 61 + 18 87 + 32 0.024 % of plaque area occupied by macrophages 3.14 + 1 13.3 + 5.6 14.6 + 4.6 0.018 Moreno et al. Circulation 1994;90:775-778

22. Macrophages and Tissue Factor in Unstable Angina Results from atherectomy specimens Linear stepwise regression analysis coronary tissue factor content correlates significantly with macrophages only in tissue from patients with UA r = 0.83; p < 0.001 p = 0.0001 p = 0.002 Moreno. Circulation 1996;94:3090-3097

23. Activation of Monocytes Through the Coronary Circulation in Patients with Unstable Angina Mean channel value for MAC-1 on monocytes P < 0.01

26. The shedding of sCD40L during platelets stimulation

31. Metalloproteinases Are Elevated in ACS Kai et al. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998;32:368-72Kai et al. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998;32:368-72 Uzui et al. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque. Role of activated macrophages and inflammatory cytokines. Circulation 2002:106:3024- 3030Uzui et al. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque. Role of activated macrophages and inflammatory cytokines. Circulation 2002:106:3024- 3030 Rajavashisth et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques. Evidence for activation by proinflammatory mediators. Circulation 1999;99:3103-3109Rajavashisth et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques. Evidence for activation by proinflammatory mediators. Circulation 1999;99:3103-3109 Blankenberg et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579-1585Blankenberg et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579-1585

32. Number of Thin Cap Atheromas in Patients with High and Low hs-CRP Burke; Circulation 2002;105:2019

33. Plaque Rupture Correlates with Elevated CRP P Odds Ratio 95% CI Age0.370.10.97-1.08 Male gender 0.670.380.3-6.1 Hypertension0.310.580.2-1.66 Diabetes0.082.70.88-8.2 High LDL 0.092.410.86-6.7 Obesity0.321.80.55-6 Plaque rupture 0.023.351.2-9.1 Deep calcium 0.230.540.2-1.46 (+) remodeling 0.182.330.68-7.9 Lesion EEM-CSA 0.621.030.9-1.07 Sano et al. Circulation 2003;108:282-285

34. Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Chronic inflammation long time before ACSChronic inflammation long time before ACS ACS an acute inflammatory stateACS an acute inflammatory state -Evidence of inflammation inside the plaque -Evidence of inflammation in the circulation -Consequences of acute inflammation Widespread inflammation in ACSWidespread inflammation in ACS Anti-inflammatory therapy in ACSAnti-inflammatory therapy in ACS

35. Widespread Coronary Inflammation in ACS A post-mortem study Widespread Coronary Inflammation in ACS A post-mortem study Flow cytometry on cell suspensions of enzymatically digested coronary arteries Acute MI Old MI No CAD % T- lymphocytes 11.675.671.71 Site of inflammation Infarct artery + Non infarct artery Infarct artery only None Spagnoli et al. JACC 2002;40:1579-88

36. Widespread Coronary Inflammation in Unstable Angina Buffon et al. N Engl J Med 2002;347:5-12 UA-LAD UA-RCA Stable Controls p < 0.001 p = 0.003 p = ns p = ns Myeloperoxidase index The Great cardiac vein does not drain the RCA

37. Multiple Atherosclerotic Plaque Ruptures in ACS Angiographic and IVUS images Rioufol. Circulation 2002; 106:804-808

38. Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Chronic inflammation long time before ACSChronic inflammation long time before ACS ACS an acute inflammatory stateACS an acute inflammatory state -Evidence of inflammation inside the plaque -Evidence of inflammation in the circulation -Consequences of acute inflammation Widespread inflammation in ACSWidespread inflammation in ACS Anti-inflammatory therapy in ACSAnti-inflammatory therapy in ACS

39. Relative risk of first MI according to CRP quartile in patients on placebo or aspirin Relative risk Quartiles CRP NEJM 97;336:973

40. Does Aspirin Therapy Lower hs-CRP? The HDF-Aspirin-Inflammation Study Aspirin n=18 Aspirin n=18 No drugs n=17 8 WEEKS 8 WEEKS 8 WEEKS Aspirin n=17 No drugs n=18 Azar et al. Am J Cardiol 2003;92:236-239

41. Aspirin Does Not Lower Levels of hs-CRP Mean hs-CRP mg/L Azar et al. Am J Cardiol 2003;92:236-239 p=ns

42. Benefit of Pravastatin is Most Prominent in Patients with Inflammation Ridker et al. Circulation 98;98:839

45. Measurement of hs-CRP for the Targeting of Statin Therapy in Primary Prevention. Data from AFCAPS/TexCAPS LDLhs-CRPRiskBenefit > 149 mg/dL--------HIGHYES (RR=0.53) < 149 mg/dL< 1.6 mg/dLLOWNO 1.6 mg/dLHIGHYES (RR=0.58) 1.6 mg/dLHIGHYES (RR=0.58) Ridker; NEJM 2001;344:1959

48. Anti-inflammatory therapy with methylprednisolone is not beneficial in unstable angina Azar et al. Eur Heart J 2000;21:2026-2032

49. The Inflammation Theory: Fact or Fiction? Conclusions Chronic inflammation is a FACT in stable coronary artery disease and leads to progression of the diseaseChronic inflammation is a FACT in stable coronary artery disease and leads to progression of the disease Acute inflammation is a FACT in acute coronary syndromes. It is incriminated in plaque rupture and in thrombosis and is a marker of adverse outcomeAcute inflammation is a FACT in acute coronary syndromes. It is incriminated in plaque rupture and in thrombosis and is a marker of adverse outcome Many drugs that improves the outcome of ACS exhibit anti-inflammatory activity. However, the role of direct anti-inflammatory drugs has not yet been establishedMany drugs that improves the outcome of ACS exhibit anti-inflammatory activity. However, the role of direct anti-inflammatory drugs has not yet been established

50. For more reading: American Heart Journal 1996;132:1101-6

51. CRP Does Not Predict the Severity or Extent of CAD Azar et al. Am J Cardiol 2000;86:205

53. Neutrophil Infiltration of Culprit Lesions in ACS Atherectomy specimen from 35 patient with stable angina (SA) and 32 patients with unstable angina (UA)Atherectomy specimen from 35 patient with stable angina (SA) and 32 patients with unstable angina (UA) UA: 14/32 (44%) of specimen contained neutrophilsUA: 14/32 (44%) of specimen contained neutrophils SA: 2/35 (6%) contained neutrophils (p < 0.01)SA: 2/35 (6%) contained neutrophils (p < 0.01) Circulation 2002;106:2894-2900