1. Inflammation Following Percutaneous Coronary Interventions Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital

2. Inflammation Following Percutaneous Coronary Interventions Inflammation in coronary artery disease Inflammation in coronary artery disease PCI induce systemic inflammation PCI induce systemic inflammation Relation between PCI, inflammation and restenosis Relation between PCI, inflammation and restenosis Determinant of the inflammatory response following PCI Determinant of the inflammatory response following PCI Anti-inflammatory therapy in the setting of PCI Anti-inflammatory therapy in the setting of PCI

3. Unstable Plaques are Hot. CRP probably identifies vulnerable plaques Difference of temp from background temp Stefanadis. Circ 99;99:1965

4. CRP Is a Risk Factor in Unstable Angina Liuzzo et al. N Engl J Med. 1994;331:417. CRP <0.3 mg/dL (n=11) CRP ≥0.3 mg/dL (n=20) p-value Ischemic episodes1.8±2.44.8±2.50.004 In-hospital events: Death02 MI05 Revascularization212 Total2 (18%)18 (90%)<0.001

5. Inflammation Following Percutaneous Coronary Interventions Inflammation in coronary artery disease Inflammation in coronary artery disease PCI induce systemic inflammation PCI induce systemic inflammation Relation between PCI, inflammation and restenosis Relation between PCI, inflammation and restenosis Determinant of the inflammatory response following PCI Determinant of the inflammatory response following PCI Anti-inflammatory therapy in the setting of PCI Anti-inflammatory therapy in the setting of PCI

6. Coronary Angioplasty Induces a Systemic Inflammatory Response Mean CRP mg/L P < 0.001 P = NS Azar et al. Am J Cardiol 1997;80:1476-8

7. Median plasma levels of CRP before and following PCI Gaspardone et al. AJC 1998;82:515

8. Event-free survival in patients with normal or high CRP 72 hours following PCI Gaspardone et al. AJC 1998;82:515

9. Relationship between circulating monocytes and in- stent neointima proliferation following coronary stenting Coronary stent implantation of 107 patients Coronary stent implantation of 107 patients Blood collected prior to PCI and each of the 7 days following PCI Blood collected prior to PCI and each of the 7 days following PCI Moncotye count increased and reached its peak 48 hours after stent implantation Moncotye count increased and reached its peak 48 hours after stent implantation At 6-month follow-up, all patients received angiographic and volumetric intravascular ultrasound analysis At 6-month follow-up, all patients received angiographic and volumetric intravascular ultrasound analysis Fukuda et al. JACC 2004;43:18-23

10. Relationship between maximum monocyte count and in- stent neointimal volume after 6-month follow-up Fukuda et al. JACC 2004;43:18-23

11. Monocyte Activation and Binding to Endothelial Cells (CD11b-VICAM)

12. Leukocyte activation, adhesion and migration

13. Serial changes in CD11b and 8B2 on the surface of PMNs from the coronary sinus samples following PCI Inoue et al. Circ 2003;107:1757

14. PTCA results in platelets activation Serrano et al. J Am Coll Cardiol 1997;29:1276-83

16. The shedding of sCD40L during platelets stimulation

18. Effects of sCD40L Initiation of the inflammatory response – Expression of ICAM, VICAM, E-selectin – Expression of chemokines (IL-6, IL-6, MCP-1) Prothrombotic effect – Expression of tissue factor – Interaction with the GP IIb/IIIa receptor Progression of atherosclerosis

19. Soluble CD40 Ligand is a predictor of restenosis following PCI Cipollone et al. J Am Coll Cardiol 2003;108:2776-2782

20. Inflammation Following Percutaneous Coronary Interventions Inflammation in coronary artery disease Inflammation in coronary artery disease PCI induce systemic inflammation PCI induce systemic inflammation Relation between PCI, inflammation and restenosis Relation between PCI, inflammation and restenosis Determinant of the inflammatory response following PCI Determinant of the inflammatory response following PCI Anti-inflammatory therapy in the setting of PCI Anti-inflammatory therapy in the setting of PCI

21. Severity of stent inflammation from pathology studies according to damage of the arterial wall by stent struts Farb et al. Circulation 1999;99:44-52

22. Clinical and procedural correlates with the inflammatory response following PCI ConditionCorrelation Vessel treatedNO Stent vs. balloonNO Maximal pressureNO No stentsNO AgeNO SexNO Baseline CRPYES Azar et al. Am J Cardiol 1997;80:1476-8 Liuzzo et al. Circulation 1998;98:2370

23. Inflammation Following Percutaneous Coronary Interventions Inflammation in coronary artery disease Inflammation in coronary artery disease PCI induce systemic inflammation PCI induce systemic inflammation Relation between PCI, inflammation and restenosis Relation between PCI, inflammation and restenosis Determinant of the inflammatory response following PCI Determinant of the inflammatory response following PCI Anti-inflammatory therapy in the setting of PCI Anti-inflammatory therapy in the setting of PCI

24. IMPRESS: Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Stent Implantation Inclusion: – Single vessel stenting – CRP 0.5 mg/dL 72 hours after stenting Treatment: – Randomly assigned, double blinded – Prednisone: 1 mg/kg for the first 10 days, 0.5 mg/kg day 11- 30, 0.25 mg/kg day 31-45 End-Points: – 12-month event free survival (death, MI, repeat revascularization) Versaci et al. J Am Coll Cardiol 2002;40:1935

25. Event-free survival according to treatment in patients with CRP > 5 mg/dL 72 hours after PCI Versaci et al. J Am Coll Cardiol 2002;40:1935

26. Abiciximab improves the outcome of PCI: 3-year event-free survival from EPIC JAMA 1997;278:478

27. Effect of abciximab use on inflammatory markers’ rise following PCI P=0.025 P<0.001 P=0.12 Median change at 48-hour Lincoff et al. Circ 2001;104:163-167

28. Abciximab decreases detectable CD11b on neutrophils from patients undergoing PCI Mickelson et al. J Am Coll Cardiol 1999;33:97-106

29. Mean elevations of CRP and IL-6 elevation following PCI in controls and in tirofiban users Azar et al. J Am Coll Cardiol 2003;supl A:1174-189 Azar et al. Am Journal Cardiol; January 15, 2005

30. Effect of tirofiban on sCD40L rise (patients in the upper quartile of sCD40L at baseline excluded) Azar et al. Am Journal Cardiol; January 15, 2005 41% inhibition

31. Statin therapy at the time of PCI confers an early and sustained survival benefit Chan et al. Circulation 2002;105:691-696

32. Mortality according to baseline CRP and statins use following PCI 1-year mortality (%) P = NS P < 0.009 Preprocedural CRP Chen et al. Circulation 2003;107:1750-1756

33. Effects of Statin Therapy on the Rise of Markers of Inflammation and on Platelets Activation Following Angioplasty -64% P = 0.008 Azar et al. Circulation, supplement, October 2004 Azar et al. Am Journal Cardiol; January 15, 2005 -32% P = NS

34. Statins suppress elevation of hs-CRP following angioplasty in patients with high levels of hs-CRP at baseline Azar et al. Circulation, supplement, October 2004 Azar et al. Am Journal Cardiol; January 15, 2005

35. Statins decrease CD11b expression and CD11b dependent adhesion of monocytes to endothelium in patients with hypercholesterolemia Weber et al. J Am Coll Cardiol 1997;30:1212

36. Conclusions PCI induce a systemic inflammatory response PCI induce a systemic inflammatory response The amplitude of this response correlates significantly with adverse events following PCI, especially restenosis The amplitude of this response correlates significantly with adverse events following PCI, especially restenosis This response depends mainly on the degree of damage inflicted to the arterial wall (media) and on the degree of plaque inflammation present before PCI This response depends mainly on the degree of damage inflicted to the arterial wall (media) and on the degree of plaque inflammation present before PCI Anti-inflammatory therapy may be beneficial in patients with high CRP following PCI Anti-inflammatory therapy may be beneficial in patients with high CRP following PCI Many drugs proven to be beneficial during PCI exhibit anti- inflammatory activity which probably contributes to their effectiveness Many drugs proven to be beneficial during PCI exhibit anti- inflammatory activity which probably contributes to their effectiveness

37. Non-fatal MI according to baseline CRP and statins use following PCI Pre-procedural CRP 1-year non-fatal MI (%) P = NS P = 0.09 P = 0.167

38. Revascularisation within 1 year according to baseline CRP and statins use following PCI Pre-procedural CRP 1-year revascularization rate (%) P = NS for all

39. Effects of tirofiban on CRP and IL-6 elevation following PCI Mean CRP change p = NS for all Mean IL-6 change p = NS for all placebo placebo tirofiban tirofiban Bonz et al. Am Heart J 2003;145:693-9

40. Maximum monocyte count following PCI is an independent predictor of in-stent neointimal volume at 6-month follow-up Regressionp value coefficient Age0.0520.572 Male sex- 0.0030.977 HTN0.0090.919 Diabetes0.0740.41 Hyperlipidemia0.1220.171 Stent volume immediately after implantation0.423<0.0001 Maximum monocyte count0.3240.0007 Fukuda et al. JACC 2004;43:18-23

41. The increase in CD11b at 48-hour is positively correlated with late lumen loss at 6-month follow up Inoue et al. Circ 2003;107:1757

42. Leukocyte-platelet complexes increase following PCI % of leukocytes highly bound to platelets P<0.05 P<0.05 Mickelson et al. J Am Coll Cardiol 1996;28:345-353

43. Leukocyte-platelet aggregates are associated with increased adverse event rate following PCI Mickelson et al. J Am Coll Cardiol 1996;28:345-353

44. SMC Proliferation Migration Matrix secretion SMC receptors Mechanism of Neointimal Formation Arterial injury Growth Factors & cytokines ThrombusInflammation G0G0 G1G1 G2G2 S M Smooth muscle cell (SMC) Signal transduction Cell cycle

45. Response of CRP and SAA to PTCA according to clinical status and baseline markers levels Liuzzo et al. Circulation 1998;98:2370

46. Inflammatory markers measured 24 hours after PCI are predictor of restenosis Cipollone et al. J Am Coll Cardiol 2003;108:2776-2782

47. Sources of Inflammatory Markers

48. Risk of MI According to CRP Levels

49. IMPRESS Study: Clinical Outcome Prednisone therapy mainly reduces the incidence of TVR Event rate (%) Versaci et al. J Am Coll Cardiol 2002;40:1935

50. Effect of tirofiban on sCD40L rise following PCI Azar et al. Am Journal Cardiol; January 15, 2005