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Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction

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.

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Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction

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  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 ACS • ACS an acute inflammatory state • Evidence of inflammation inside the plaque • Evidence of inflammation in the circulation • Consequences of acute inflammation • Widespread inflammation in ACS • Anti-inflammatory therapy in ACS

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

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

  5. Risk of MI According to CRP Levels

  6. CRP and Cholesterol in the Prediction of Cardiovascular Events

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

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

  9. T h i n f i b r o u s c a p Characteristics of Unstable and Stable Plaques • Large lipid core with thin fibrous cap, macrophages interacting with thrombus • Reduced lipid core with thick fibrous cap reinforced with increased smooth muscle cells Thrombus Lumen Endothelium Thickfibrous cap Smoothmuscle cell Lipid rich core P l a t e l e t s Macrophage Stable Plaque Unstable Plaque

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

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

  12. Macrophage Infiltration in ACSResults from Atherectomy Specimens Moreno et al. Circulation 1994;90:775-778

  13. Macrophages and Tissue Factor in Unstable AnginaResults from atherectomy specimens p = 0.0001 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 = 0.002 Moreno. Circulation 1996;94:3090-3097

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

  15. The shedding of sCD40L during platelets stimulation

  16. 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;32:368-72 • Uzui et al. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque. Role of activated macrophages and inflammatory cytokines. Circulation 2002:106:3024-3030 • Rajavashisth 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;107:1579-1585

  17. Plaque Rupture Correlates with Elevated CRP Sano et al. Circulation 2003;108:282-285

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

  19. Widespread Coronary Inflammation in ACSA post-mortem studyFlow cytometry on cell suspensions of enzymatically digested coronary arteries Spagnoli et al. JACC 2002;40:1579-88

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

  21. Multiple Atherosclerotic Plaque Ruptures in ACSAngiographic and IVUS images Rioufol. Circulation 2002; 106:804-808

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

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

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

  25. The Inflammation Theory: Fact or Fiction?Conclusions • Chronic 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 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 established

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

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