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Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Saint-Joseph University.

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Presentation on theme: "Acute Coronary Syndromes and The Inflammation Theory: Fact or Fiction Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Saint-Joseph University."— Presentation transcript:

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

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

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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: 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: months Mean waiting time: 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

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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

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21 Macrophage Infiltration in ACS Results from Atherectomy Specimens Stable angina Unstable angina Non-Q wave MI P value Total plaque area NS Macrophage- rich area % of plaque area occupied by macrophages Moreno et al. Circulation 1994;90:

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 < p = p = Moreno. Circulation 1996;94:

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

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26 The shedding of sCD40L during platelets stimulation

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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: 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: 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: Rajavashisth et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques. Evidence for activation by proinflammatory mediators. Circulation 1999;99: Rajavashisth et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques. Evidence for activation by proinflammatory mediators. Circulation 1999;99: Blankenberg et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107: Blankenberg et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:

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 Age Male gender Hypertension Diabetes High LDL Obesity Plaque rupture Deep calcium (+) remodeling Lesion EEM-CSA Sano et al. Circulation 2003;108:

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 Site of inflammation Infarct artery + Non infarct artery Infarct artery only None Spagnoli et al. JACC 2002;40:

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 < p = 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:

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:

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

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

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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

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

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

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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:


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