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Inflammation Following Percutaneous Coronary Interventions

Inflammation Following Percutaneous Coronary Interventions. Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital. Inflammation Following Percutaneous Coronary Interventions. Inflammation in coronary artery disease PCI induce systemic inflammation

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Inflammation Following Percutaneous Coronary Interventions

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  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 • PCI induce systemic inflammation • Relation between PCI, inflammation and restenosis • Determinant of the inflammatory response following 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 CRP <0.3 mg/dL (n=11) CRP ≥0.3 mg/dL (n=20) p-value Ischemic episodes 1.8±2.4 4.8±2.5 0.004 In-hospital events: Death 0 2 MI 0 5 Revascularization 2 12 Total 2 (18%) 18 (90%) <0.001 Liuzzo et al. N Engl J Med. 1994;331:417.

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

  15. The shedding of sCD40L during platelets stimulation

  16. 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

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

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

  19. 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

  20. Clinical and procedural correlates with the inflammatory response following PCI Condition Correlation • Vessel treated NO • Stent vs. balloon NO • Maximal pressure NO • No stents NO • Age NO • Sex NO • Baseline CRP YES Azar et al. Am J Cardiol 1997;80:1476-8 Liuzzo et al. Circulation 1998;98:2370

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

  22. IMPRESS: Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Stent Implantation • Inclusion: • Single vessel stenting • CRP < 0.5mg/dL before stenting and > 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

  23. 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

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

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

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

  27. 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

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

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

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

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

  32. 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

  33. 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

  34. Conclusions • PCI induce a systemic inflammatory response • 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 • 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

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

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

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

  38. Maximum monocyte count following PCI is an independent predictor of in-stent neointimal volume at 6-month follow-up Regression p value coefficient Age 0.052 0.572 Male sex - 0.003 0.977 HTN 0.009 0.919 Diabetes 0.074 0.41 Hyperlipidemia 0.122 0.171 Stent volume immediately after implantation 0.423 <0.0001 Maximum monocyte count 0.324 0.0007 Fukuda et al. JACC 2004;43:18-23

  39. 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

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

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

  42. Mechanism of Neointimal Formation Arterial injury Thrombus Inflammation Growth Factors & cytokines Smooth muscle cell (SMC) SMC receptors Signal transduction S Cell cycle G0 G1 G2 M SMC Proliferation Migration Matrix secretion

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

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

  45. Sources of Inflammatory Markers

  46. Risk of MI According to CRP Levels

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

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

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