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Arterial remodeling in stable versus unstable coronary syndromes

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Arterial remodeling in stable versus unstable coronary syndromes

  1. 1. Arterial Remodeling In Stable VersusArterial Remodeling In Stable Versus Unstable Coronary Syndromes:Unstable Coronary Syndromes: An Intravascular Ultrasound StudyAn Intravascular Ultrasound Study Arterial Remodeling In Stable VersusArterial Remodeling In Stable Versus Unstable Coronary Syndromes:Unstable Coronary Syndromes: An Intravascular Ultrasound StudyAn Intravascular Ultrasound Study Paul Schoenhagen, MD,FAHAPaul Schoenhagen, MD,FAHA Steven E Nissen, MD,FACCSteven E Nissen, MD,FACC E Murat Tuzcu, MD,FACCE Murat Tuzcu, MD,FACC The Cleveland Clinic FoundationThe Cleveland Clinic Foundation Paul Schoenhagen, MD,FAHAPaul Schoenhagen, MD,FAHA Steven E Nissen, MD,FACCSteven E Nissen, MD,FACC E Murat Tuzcu, MD,FACCE Murat Tuzcu, MD,FACC The Cleveland Clinic FoundationThe Cleveland Clinic Foundation
  2. 2. BackgroundBackground • Originally, Glagov described arterial remodeling as anOriginally, Glagov described arterial remodeling as an increase in external elastic membrane area withinincrease in external elastic membrane area within atherosclerotic lesions.atherosclerotic lesions. • In early CAD, remodeling maintains lumen area despiteIn early CAD, remodeling maintains lumen area despite increasing plaque burden.increasing plaque burden. • Although first observed in necropsyAlthough first observed in necropsy studiesstudies, remodeling, remodeling has been confirmedhas been confirmed in vivoin vivo by intravascular ultrasound.by intravascular ultrasound. • The relationship between remodeling and various clinicalThe relationship between remodeling and various clinical ischemic syndromes remains uncertain.ischemic syndromes remains uncertain.
  3. 3. Intravascular UltrasoundIntravascular Ultrasound vessel wall/ plaquelumen IVUS Catheter
  4. 4. Objectives and Study DesignObjectives and Study Design •• Retrospectively analyze intravascular ultrasoundRetrospectively analyze intravascular ultrasound images in a series of patients with either stable anginaimages in a series of patients with either stable angina or recent onset of unstable symptomatology.or recent onset of unstable symptomatology. •• Examine the relationship between clinical presentationExamine the relationship between clinical presentation and plaque features at the culprit lesion, including:and plaque features at the culprit lesion, including: • Presence, direction and extent of arterial remodelingPresence, direction and extent of arterial remodeling • Plaque morphology (echogenicity)Plaque morphology (echogenicity) • Plaque eccentricityPlaque eccentricity
  5. 5. Methods: PatientsMethods: Patients Patients with pre-interventionalPatients with pre-interventional ultrasound of native coronary arteriesultrasound of native coronary arteries (n=216)(n=216) Excluded (n=85) Study Patients (n=131)Study Patients (n=131) Stable (n=46)Stable (n=46) Stable Angina (n=37)Stable Angina (n=37) (+) ETT (n=9)(+) ETT (n=9) Unstable (n=85)Unstable (n=85) Unstable Angina (n=76)Unstable Angina (n=76) Acute MI (n=9)Acute MI (n=9) Ostial or bifurcation lesions,Ostial or bifurcation lesions, heavy calcium, image qualityheavy calcium, image quality
  6. 6. Methods: Image AnalysisMethods: Image Analysis • Intravascular ultrasound images obtained from aIntravascular ultrasound images obtained from a proximal reference site and culprit lesion site.proximal reference site and culprit lesion site. • Quantitative variables:Quantitative variables: – EEM area, lumen area, and plaque areaEEM area, lumen area, and plaque area • Plaque morphology:Plaque morphology: – Echolucent, echodense, mixed, calcifiedEcholucent, echodense, mixed, calcified • Eccentricity Index:Eccentricity Index: MaximumMaximum -- Minimum Plaque ThicknessMinimum Plaque Thickness Maximum Plaque ThicknessMaximum Plaque Thickness xx 100100
  7. 7. Positive Remodeling Culprit Lesion EEM Contour Proximal Reference Proximal Reference Direction of Arterial RemodelingDirection of Arterial Remodeling Schoenhagen et al. Circulation 2000; 101:598-603 Negative Remodelin g Culprit Lesion EEM Contour Remodeling Ratio (RR) = EEM area lesion / EEM area proximal reference Negative Remodeling RR < 0.95 Positive Remodeling RR > 1.05
  8. 8. Example: Positive RemodelingExample: Positive Remodeling RemodelingRemodelingIndexIndex == 18.918.9 mmmm22 14.914.9 mmmm22 == 1.271.27 Proximal Reference Lesion EEM = 14.9 mm2 EEM = 18.9 mm2
  9. 9. Example: Negative RemodelingExample: Negative Remodeling Proximal ReferenceProximal Reference LesionLesion EEMEEM = 16.0 mm= 16.0 mm22 EEMEEM = 11.5 mm= 11.5 mm22 RemodelingRemodelingIndexIndex == 11.511.5 mmmm22 16.016.0 mmmm22 == 0.720.72
  10. 10. Clinical and Demographic FeaturesClinical and Demographic Features Stable (n = 46)Stable (n = 46) Unstable (n = 85)Unstable (n = 85) p = NS for all characteristics AgeAge 62.6 years62.6 years 59.5 Years59.5 Years MaleMale 71.7 %71.7 % 64.7 %64.7 % FemaleFemale 28.3%28.3% 35.3 %35.3 % LADLAD 56.6%56.6% 51.8%51.8% LCxLCx 21.7%21.7% 17.6%17.6% RCARCA 21.7%21.7% 30.6%30.6%
  11. 11. Clinical and Demographic CharacteristicsClinical and Demographic Characteristics SSttaabblle (e (nn=4=466)) UUnsnsttaabblle (e (nn==885)5) DiDiaabbeteteess 226.6.11%% 119.9.77%% HHypypeerrtteennsisioonn 447.7.88%% 663.3.22%% HHypypeerrlilippidideemimiaa 446.6.77%% 550.0.00%% SSmomokikinngg 552.2.22%% 660.0.55%% CCAAD FaD Fammililyy HHisisttoorryy 226.6.11%% 228.8.99%% Risk Factors for Coronary Artery Disease p = NS for all characteristics
  12. 12. Reference and Lesion MeasurementsReference and Lesion Measurements Stable Unstable p value Proximal Reference Plaque Area 6.20 mm2 6.10 mm2 NS EEM Area 14.1 mm2 15.2 mm2 NS % Area Reduction 42.3 40.3 NS Target Lesion Plaque Area 11.1±4.8 mm2 13.9±5.5 mm2 0.005 EEM Area 13.0±4.8 mm2 16.1±6.2 mm2 .04 % Area Reduction 83.1±6.7 85.0+6.4 NS Remodeling Index 0.94 1.06 0.008
  13. 13. Results: Extent of RemodelingResults: Extent of Remodeling 00 2020 4040 6060 Percent of Cohort Positive Remodeling Absence of Remodeling Negative Remodeling Unstable Stable *p=0.0003 *p=0.3 *p=0.006 Schoenhagen et al. Circulation 2000; 101:598-603
  14. 14. Results: Plaque MorphologyResults: Plaque Morphology 0 10 20 30 40 Percent of Cohort Echolucent Echodense Mixed Calcified Unstable Stable p=0.02 p=0.4 p=1.0 p=0.3 Schoenhagen et al. Circulation 2000; 101:598-603
  15. 15. Stable Presentation and Negative RemodelingStable Presentation and Negative Remodeling Proximal ReferenceProximal Reference LesionLesion EEMEEM = 10.5 mm= 10.5 mm22 EEMEEM = 7.5 mm= 7.5 mm22 Mixed Morphology with Remodeling Index = 0.71 Schoenhagen et al. Circulation 2000; 101:598-603
  16. 16. Unstable Presentation: Positive RemodelingUnstable Presentation: Positive Remodeling Echolucent Plaque with Remodeling Index = 1.42 Proximal ReferenceProximal Reference EEMEEM = 14.3 mm= 14.3 mm22 EEMEEM = 20.3 mm= 20.3 mm22 Culprit LesionCulprit Lesion Schoenhagen et al. Circulation 2000; 101:598-603
  17. 17. LimitationsLimitations • Selection bias:Selection bias: – The cohort included only relatively severe lesionsThe cohort included only relatively severe lesions selected for pre-interventional ultrasound imaging.selected for pre-interventional ultrasound imaging. • Presence of ultrasound catheter within severePresence of ultrasound catheter within severe lesions may alter vessel geometry.lesions may alter vessel geometry. • Classification of plaque morphology based uponClassification of plaque morphology based upon subjective visual criteria.subjective visual criteria.
  18. 18. ConclusionConclusion • Significant differences in ultrasound characteristicsSignificant differences in ultrasound characteristics between unstable and stable lesions:between unstable and stable lesions: – Greater plaque burden despite similar luminal narrowingGreater plaque burden despite similar luminal narrowing – Greater extent of positive remodelingGreater extent of positive remodeling • A prospective study of the relationship between clinicalA prospective study of the relationship between clinical presentation and plaque morphology is warranted:presentation and plaque morphology is warranted: – Hypothesis: Bulky remodeled plaques may be moreHypothesis: Bulky remodeled plaques may be more vulnerable to mechanical forces, thus leading to plaquevulnerable to mechanical forces, thus leading to plaque rupture and acute coronary syndromes.rupture and acute coronary syndromes.
  19. 19. Remodeling and Clinical PresentationRemodeling and Clinical Presentation Stable and Unstable Syndromes and Remodeling: IVUS Pathology Smits et al. Schoenhagen et al. Nakamura et al. Filardo et al. Nishioka et al. Alibelli-Chemarin et al. Burke et al. Varnava et al. Cardiovas. Res.’99;41:458-464 Circulation ‘00;101:598-603 J Am Coll Cardiol ‘01;37:63-9 Am J Cardiol ‘00;85:760-762 JACC ‘97;29:125A, abstract JACC ‘98;31:276A, abstract Circulation ’02;105:297-303 Circulation ’02;105:939-943
  20. 20. Coronary RemodelingCoronary Remodeling ProgressioProgressio nn EEM shrinkageEEM shrinkage NormalNormal vesselvessel MinimalMinimal CADCAD EEM expansionEEM expansion Lumen shrinkageLumen shrinkage SevereSevere CADCAD ModerateModerate CADCAD SevereSevere CADCAD Period of Instability?Period of Instability? Regression?Regression? Schoenhagen et al. JACC 2001;38:297-306
  21. 21. Arterial Remodeling In Stable VersusArterial Remodeling In Stable Versus Unstable Coronary Syndromes:Unstable Coronary Syndromes: An Intravascular Ultrasound StudyAn Intravascular Ultrasound Study Arterial Remodeling In Stable VersusArterial Remodeling In Stable Versus Unstable Coronary Syndromes:Unstable Coronary Syndromes: An Intravascular Ultrasound StudyAn Intravascular Ultrasound Study Paul Schoenhagen, MD,FAHAPaul Schoenhagen, MD,FAHA Steven E Nissen, MD,FACCSteven E Nissen, MD,FACC E Murat Tuzcu, MD,FACCE Murat Tuzcu, MD,FACC The Cleveland Clinic FoundationThe Cleveland Clinic Foundation Paul Schoenhagen, MD,FAHAPaul Schoenhagen, MD,FAHA Steven E Nissen, MD,FACCSteven E Nissen, MD,FACC E Murat Tuzcu, MD,FACCE Murat Tuzcu, MD,FACC The Cleveland Clinic FoundationThe Cleveland Clinic Foundation
  22. 22. BackgroundBackground • Originally, Glagov described arterial remodeling as anOriginally, Glagov described arterial remodeling as an increase in external elastic membrane area withinincrease in external elastic membrane area within atherosclerotic lesions.atherosclerotic lesions. • In early CAD, remodeling maintains lumen area despiteIn early CAD, remodeling maintains lumen area despite increasing plaque burden.increasing plaque burden. • Although first observed in necropsyAlthough first observed in necropsy studiesstudies, remodeling, remodeling has been confirmedhas been confirmed in vivoin vivo by intravascular ultrasound.by intravascular ultrasound. • The relationship between remodeling and various clinicalThe relationship between remodeling and various clinical ischemic syndromes remains uncertain.ischemic syndromes remains uncertain.
  23. 23. Intravascular UltrasoundIntravascular Ultrasound vessel wall/ plaquelumen IVUS Catheter
  24. 24. Objectives and Study DesignObjectives and Study Design •• Retrospectively analyze intravascular ultrasoundRetrospectively analyze intravascular ultrasound images in a series of patients with either stable anginaimages in a series of patients with either stable angina or recent onset of unstable symptomatology.or recent onset of unstable symptomatology. •• Examine the relationship between clinical presentationExamine the relationship between clinical presentation and plaque features at the culprit lesion, including:and plaque features at the culprit lesion, including: • Presence, direction and extent of arterial remodelingPresence, direction and extent of arterial remodeling • Plaque morphology (echogenicity)Plaque morphology (echogenicity) • Plaque eccentricityPlaque eccentricity
  25. 25. Methods: PatientsMethods: Patients Patients with pre-interventionalPatients with pre-interventional ultrasound of native coronary arteriesultrasound of native coronary arteries (n=216)(n=216) Excluded (n=85) Study Patients (n=131)Study Patients (n=131) Stable (n=46)Stable (n=46) Stable Angina (n=37)Stable Angina (n=37) (+) ETT (n=9)(+) ETT (n=9) Unstable (n=85)Unstable (n=85) Unstable Angina (n=76)Unstable Angina (n=76) Acute MI (n=9)Acute MI (n=9) Ostial or bifurcation lesions,Ostial or bifurcation lesions, heavy calcium, image qualityheavy calcium, image quality
  26. 26. Methods: Image AnalysisMethods: Image Analysis • Intravascular ultrasound images obtained from aIntravascular ultrasound images obtained from a proximal reference site and culprit lesion site.proximal reference site and culprit lesion site. • Quantitative variables:Quantitative variables: – EEM area, lumen area, and plaque areaEEM area, lumen area, and plaque area • Plaque morphology:Plaque morphology: – Echolucent, echodense, mixed, calcifiedEcholucent, echodense, mixed, calcified • Eccentricity Index:Eccentricity Index: MaximumMaximum -- Minimum Plaque ThicknessMinimum Plaque Thickness Maximum Plaque ThicknessMaximum Plaque Thickness xx 100100
  27. 27. Positive Remodeling Culprit Lesion EEM Contour Proximal Reference Proximal Reference Direction of Arterial RemodelingDirection of Arterial Remodeling Schoenhagen et al. Circulation 2000; 101:598-603 Negative Remodelin g Culprit Lesion EEM Contour Remodeling Ratio (RR) = EEM area lesion / EEM area proximal reference Negative Remodeling RR < 0.95 Positive Remodeling RR > 1.05
  28. 28. Example: Positive RemodelingExample: Positive Remodeling RemodelingRemodelingIndexIndex == 18.918.9 mmmm22 14.914.9 mmmm22 == 1.271.27 Proximal Reference Lesion EEM = 14.9 mm2 EEM = 18.9 mm2
  29. 29. Example: Negative RemodelingExample: Negative Remodeling Proximal ReferenceProximal Reference LesionLesion EEMEEM = 16.0 mm= 16.0 mm22 EEMEEM = 11.5 mm= 11.5 mm22 RemodelingRemodelingIndexIndex == 11.511.5 mmmm22 16.016.0 mmmm22 == 0.720.72
  30. 30. Clinical and Demographic FeaturesClinical and Demographic Features Stable (n = 46)Stable (n = 46) Unstable (n = 85)Unstable (n = 85) p = NS for all characteristics AgeAge 62.6 years62.6 years 59.5 Years59.5 Years MaleMale 71.7 %71.7 % 64.7 %64.7 % FemaleFemale 28.3%28.3% 35.3 %35.3 % LADLAD 56.6%56.6% 51.8%51.8% LCxLCx 21.7%21.7% 17.6%17.6% RCARCA 21.7%21.7% 30.6%30.6%
  31. 31. Clinical and Demographic CharacteristicsClinical and Demographic Characteristics SSttaabblle (e (nn=4=466)) UUnsnsttaabblle (e (nn==885)5) DiDiaabbeteteess 226.6.11%% 119.9.77%% HHypypeerrtteennsisioonn 447.7.88%% 663.3.22%% HHypypeerrlilippidideemimiaa 446.6.77%% 550.0.00%% SSmomokikinngg 552.2.22%% 660.0.55%% CCAAD FaD Fammililyy HHisisttoorryy 226.6.11%% 228.8.99%% Risk Factors for Coronary Artery Disease p = NS for all characteristics
  32. 32. Reference and Lesion MeasurementsReference and Lesion Measurements Stable Unstable p value Proximal Reference Plaque Area 6.20 mm2 6.10 mm2 NS EEM Area 14.1 mm2 15.2 mm2 NS % Area Reduction 42.3 40.3 NS Target Lesion Plaque Area 11.1±4.8 mm2 13.9±5.5 mm2 0.005 EEM Area 13.0±4.8 mm2 16.1±6.2 mm2 .04 % Area Reduction 83.1±6.7 85.0+6.4 NS Remodeling Index 0.94 1.06 0.008
  33. 33. Results: Extent of RemodelingResults: Extent of Remodeling 00 2020 4040 6060 Percent of Cohort Positive Remodeling Absence of Remodeling Negative Remodeling Unstable Stable *p=0.0003 *p=0.3 *p=0.006 Schoenhagen et al. Circulation 2000; 101:598-603
  34. 34. Results: Plaque MorphologyResults: Plaque Morphology 0 10 20 30 40 Percent of Cohort Echolucent Echodense Mixed Calcified Unstable Stable p=0.02 p=0.4 p=1.0 p=0.3 Schoenhagen et al. Circulation 2000; 101:598-603
  35. 35. Stable Presentation and Negative RemodelingStable Presentation and Negative Remodeling Proximal ReferenceProximal Reference LesionLesion EEMEEM = 10.5 mm= 10.5 mm22 EEMEEM = 7.5 mm= 7.5 mm22 Mixed Morphology with Remodeling Index = 0.71 Schoenhagen et al. Circulation 2000; 101:598-603
  36. 36. Unstable Presentation: Positive RemodelingUnstable Presentation: Positive Remodeling Echolucent Plaque with Remodeling Index = 1.42 Proximal ReferenceProximal Reference EEMEEM = 14.3 mm= 14.3 mm22 EEMEEM = 20.3 mm= 20.3 mm22 Culprit LesionCulprit Lesion Schoenhagen et al. Circulation 2000; 101:598-603
  37. 37. LimitationsLimitations • Selection bias:Selection bias: – The cohort included only relatively severe lesionsThe cohort included only relatively severe lesions selected for pre-interventional ultrasound imaging.selected for pre-interventional ultrasound imaging. • Presence of ultrasound catheter within severePresence of ultrasound catheter within severe lesions may alter vessel geometry.lesions may alter vessel geometry. • Classification of plaque morphology based uponClassification of plaque morphology based upon subjective visual criteria.subjective visual criteria.
  38. 38. ConclusionConclusion • Significant differences in ultrasound characteristicsSignificant differences in ultrasound characteristics between unstable and stable lesions:between unstable and stable lesions: – Greater plaque burden despite similar luminal narrowingGreater plaque burden despite similar luminal narrowing – Greater extent of positive remodelingGreater extent of positive remodeling • A prospective study of the relationship between clinicalA prospective study of the relationship between clinical presentation and plaque morphology is warranted:presentation and plaque morphology is warranted: – Hypothesis: Bulky remodeled plaques may be moreHypothesis: Bulky remodeled plaques may be more vulnerable to mechanical forces, thus leading to plaquevulnerable to mechanical forces, thus leading to plaque rupture and acute coronary syndromes.rupture and acute coronary syndromes.
  39. 39. Remodeling and Clinical PresentationRemodeling and Clinical Presentation Stable and Unstable Syndromes and Remodeling: IVUS Pathology Smits et al. Schoenhagen et al. Nakamura et al. Filardo et al. Nishioka et al. Alibelli-Chemarin et al. Burke et al. Varnava et al. Cardiovas. Res.’99;41:458-464 Circulation ‘00;101:598-603 J Am Coll Cardiol ‘01;37:63-9 Am J Cardiol ‘00;85:760-762 JACC ‘97;29:125A, abstract JACC ‘98;31:276A, abstract Circulation ’02;105:297-303 Circulation ’02;105:939-943
  40. 40. Coronary RemodelingCoronary Remodeling ProgressioProgressio nn EEM shrinkageEEM shrinkage NormalNormal vesselvessel MinimalMinimal CADCAD EEM expansionEEM expansion Lumen shrinkageLumen shrinkage SevereSevere CADCAD ModerateModerate CADCAD SevereSevere CADCAD Period of Instability?Period of Instability? Regression?Regression? Schoenhagen et al. JACC 2001;38:297-306
  41. 41. The prevalence of inflammatory cells in non ruptured atherosclerotic plaques G. Pasterkamp Experimental Cardiology, UMC and Interuniversity cardiology Institute of the Netherlands, Utrecht, The Netherlands Published in part in : Arterioscl Thromb and Vasc Biol 1999;19:54-58.
  42. 42. Background Plaque rupture and subsequent plaque thrombosis is found to be associated with the presence of inflammatory cells. Davies et al. Br Heart J 1985;53:363-373 Van der Wal et al. Circulation 1994;89:36-44 Moreno et al. Circulation 1994;90:775-778
  43. 43. Plaque rupture
  44. 44. Question Is the presence of inflammatory cells A- specific for plaque rupture or B- a commonly observed phenomenon in atherosclerotic lesions? What is the prevalence of moderate/heavy local inflammation in non ruptured atherosclerotic lesions?
  45. 45. Post mortem study: • Atherosclerotic femoral (n=50) and coronary arteries (n=74) from patients that did not die of cardiovascular disease. • In each artery, 4-6 non ruptured cross-sections revealing atherosclerosis were studied for the presence of macrophages (CD 68) and T- lymphocytes (CD45RO).
  46. 46. positive negative
  47. 47. positive negative
  48. 48. Femoral artery 45% of all cross-sections revealed moderate or heavy staining for macrophages in the cap or shoulder of non ruptured plaques.
  49. 49. Question If one would randomly stain 5-6 cross-sections obtained from an atherosclerotic artery for inflammatory cells, how often would at least one cross-section reveal moderate to heavy staining for inflammatory cells?
  50. 50. positive negative
  51. 51. positive negative
  52. 52. Femoral arteries In 84% of all femoral arteries at least one cross-section revealed moderate or haevy staining for macrophages or T-lymphocytes in cap or shoulder of the non ruptured athertosclerotic plaque.
  53. 53. Question If one would find many cross-sections with inflammation in one coronary artery: would that be predictive for the occurrence of plaque inflammation in another coronary artery? Right and left coronary arteries were compared within the individual (next slide)
  54. 54. -= no staining, + = moderate staining, ++ = heavy staining, No relation was observed between the degree of staining for inflammatory cells between the left and right coronary artery. Left coronary artery Right coronary artery - + ++ - 3 4 0 + 2 11 2 ++ 0 3 0
  55. 55. Conclusion • The presence of inflammatory cells is a common phenomenon in non ruptured atherosclerotic lesions. • The degree of local inflammation is locally determined and has no/low predictive value for the presence of inflammation in other arteries. (Pasterkamp et al. ATVB 1999, Vink et al JACC 2001)
  56. 56. Discussion • Considering these results: what is the predictive value of local inflammation for the occurrence of plaque rupture? • Visualization of the vulnerable plaque when inflammation is used as marker: – Specificity for local plaque rupture or predictive value for plaque rupture may be disappointing.
  57. 57. Definitions of arterial remodeling in post mortem and Intravascular ultrasound research G. Pasterkamp Experimental Cardiology, UMC and Interuniversity cardiology Institute of the Netherlands, Utrecht, The Netherlands
  58. 58. Arterial remodeling Gradual Luminal narrowing Expansive remodeling Constrictive remodeling Glagov et al. New Engl J Med 1987;316:1371-1375 Pasterkamp et al. Circulation 1995;91:1444-1449
  59. 59. Background In international literature, the modes of arterial geometrical remodeling are differentially defined resulting in different prevalence numbers. The current presentation will show and discuss the most widely used definitions
  60. 60. L = Lesion R1 = most proximal site R2 = proximal reference with normal lumen and least amount of plaque R3 = distal reference with normal lumen and least amount of plaque lumen plaque LR2 R3R1
  61. 61. Definition 1 Remodeling Index (RI)= VA L / ( (VA R2 + VA R3)/2) lumen plaque LR2 R3R1 Expansive remodeling when RI >1.05 Intermediate remodeling when RI >0.95 or < 1.05 Constrictive remodeling when RI <0.95 Smits et al. Heart 1999;82:461-464 von Birgelen et al. J Am Coll Cardiol 2001;37:1864-1870. Schoenhagen et al. Circulation 1999;101:598-603
  62. 62. Definition 2 RI= VA L / ( (VA R2 + VA R3)/2) lumen plaque LR2 R3R1 Expansive remodeling when RI >1.0 Constrictive remodeling when RI <1.0 Dangas et al. Circulation 1999;99:3149-3154. Nakamura et al. J Am Coll Cardiol. 2001 Jan;37(1):63-9 Okura et al. J Am Coll Cardiol 2001;37:1031-1035.
  63. 63. Definition 3 lumen plaque LR2 R3R1 Expansive remodeling when VA L > VA R2 and VA L > VA R3 Constrictive remodeling when VA L < VA R2 and VA L < VA R3 Other values: intermediate remodeling Nishioka et al. J Am Coll Cardiol 1996;27:1571-1576 Wexberg et al. J Am Coll Cardiol 2000;36:1860-1869.
  64. 64. Definition 4 lumen plaque Expansive/no remodeling when VA L / VA R2 > 0.78 Constrictive remodeling when VA L / VA R2 < 0. 78 Mintz et al Circulation 1997;95:1791-1798. Upper limit of normal tapering over 10 mm never exceeds 21% of vessel area reference limit at 0.78 LR2 R3R1
  65. 65. Definition 5 RI= VA L / ( VA R1) lumen plaque LR2 R3R1 Expansive remodeling when RI >1.0 Constrictive remodeling when RI <1.0 Taylor et al. J Am Coll Cardiol 1999 Sep;34(3):760-7
  66. 66. Definition 6 RI = VA L / VA R2 (site with least amount of plaque lumen plaque LR2 R3R1 Expansive remodeling when RI > 1.05 Constrictive remodeling when RI < 0.95 Other values: intermediate remodeling Pasterkamp et al. J Am Coll Cardiol 1995;26:422-428. (Only applied peripheral arteries)
  67. 67. Remodeling definitions lead to large variations in prevalence numbers. expansive remodeling intermediate remodeling constrictive remodeling definition remodeling Mintz et al 512 (85%) 91 (15%) 4 Nishioka et al 19 (53%) 7 (20%) 9 (27%) 3 Smits et al 24 (35%) 16 (23%) 29 (42%) 1 Wexberg et al 70 (29%) 110 (45%) 64 (26%) 3 Dangas et al. 269 (42%) 377 (58%) 2 Nakamura et al. 68 (54%) 57 (46%) 2 Okura et al. 59 (55%) 49 (45%) 2 Von Birgelen et al. 38 (48%) 22 (28%) 19 (24%) 1 Pasterkamp et al. 226 (37%) 383 (63%) 2 Schoenhagen et al. 70 (53%) 26 (20%) 35 (27%) 1
  68. 68. Which definition is best? All studies are cross-sectional The reference is not free of atherosclerotic disease The reference may have been remodeled in either direction We do not know which definition gives us the best estimate of the prevalence of the different remodeling modes.
  69. 69. Which definitions make sense? • Definitions 1-4 share the same receipt, only the tresholds differ. • Definition 5 may be used in casuistic studies, but in larger studies on prevalence this definition should not be used (it will, by definition, approximate the 50% for each remodeling mode) • Definition 6 can only be used in non tapering vessels.
  70. 70. Conclusion • The prevalence of constrictive and expansive remodeling differs widely in literature due to the application of different definitions. • Without serial studies, there is no gold standard for the reference site. • The definition of the remodeling modes merit careful consideration when prevalences are mentioned.
  71. 71. Plaque Thermography:Plaque Thermography: Some Like it Hot.Some Like it Hot. Hippokration Hospital, Dept. of Cardiology, Athens Medical School
  72. 72. Thermography CatheterThermography Catheter
  73. 73. Thermography CatheterThermography Catheter One thermistor Sizes: 3 – 4.5 F Limitations -‘Flail’ phenomenon in large vessels or stenoses < 50% - One thermistor
  74. 74. New Thermography Catheters Balloon-Occluded Thermography Catheter Low pressure balloon Thermistor
  75. 75. New Thermography Catheters Balloon-Occluded Multisensor Thermography Catheter Low pressure balloon Thermistors
  76. 76. Thermal Heterogeneity – Clinical SyndromeThermal Heterogeneity – Clinical Syndrome Stefanadis et al, Circulation April 1999
  77. 77. Statins and TemperatureStatins and Temperature Stefanadis et al. Eur Heart J (in press) StatinsNo statins Temperaturedifference 2.5 2.0 1.5 1.0 .5 0.0 -.5 P<0,001
  78. 78. Statins and TemperatureStatins and Temperature Stefanadis et al. Eur Heart J (in press) StatinsNo statins Temperaturedifferences(o C) 2.5 2.0 1.5 1.0 .5 0.0 -.5 SYNDROME SA UA AMI P<0,001
  79. 79. ΔΤ - Percutanenous Coronary InterventionsΔΤ - Percutanenous Coronary Interventions FV EventNo Event 2.0 1.5 1.0 0.5 0 -0.5 P < 0.01 Stefanadis C et al, J Am Col Cardiol 2001 April
  80. 80. AMIUAEA 2.0 1.5 1.0 0.5 0 -0.5 P < 0.10 P < 0.01 P < 0.001 ΔΤ - Percutanenous Coronary InterventionsΔΤ - Percutanenous Coronary Interventions Stefanadis C et al, J Am Col Cardiol 2001 April
  81. 81. Stefanadis C et al, J Am Col Cardiol 2001 April ΔΤ - Percutanenous Coronary InterventionsΔΤ - Percutanenous Coronary Interventions
  82. 82. Coronary Thermography • Thermal heterogeneity exists in vivo in atherosclerotic plaque • Statins decrease thermal heterogeneity possibly by anti-inflammatory mechanism • Thermal heterogeneity in the culprit lesion is a prognostic factor for adverse cardiac events after percutaneous interventions • Is thermal heterogeneity a sensitive marker for future cardiac events?
  83. 83. Primary end point: Death, MI, TLR in 12 months Secondary end points: -Procedural complications -Cost effectiveness over 12 months Stenting of culprit lesion only Stenting of culprit + non-culprit lesions Randomization Non-culprit lesion(s) with > 0.10O C ∆T Patients with ACS and multivessel disease THERMO ACS: Culprit or Multivessel Revascularization based on Thermography in patients with ACS
  84. 84. …… Thermography Beyond Coronary ArteriesThermography Beyond Coronary Arteries
  85. 85. Aortic Thermography CatheterAortic Thermography Catheter Thermistor Dept. of Cardiology, Athens Medical School 2001
  86. 86. Study PopulationStudy Population •18 patients with angiographically documented CAD •12 patients angiographically normal coronary arteries
  87. 87. Aortic Thermography Ongoing ProtocolsAortic Thermography Ongoing Protocols Dept. of Cardiology, Athens Medical School 2001 • Measurement of atherosclerotic lesions in the aorta • Measurement of the stenotic aortic valves
  88. 88. Vulnerable Lesion or Vulnerable Patient?
  89. 89. Coronary Sinus ThermographyCoronary Sinus Thermography Increased Coronary Sinus Temperature inIncreased Coronary Sinus Temperature in Patients With Coronary Artery Disease asPatients With Coronary Artery Disease as Determined by Coronary SinusDetermined by Coronary Sinus ThermographyThermography
  90. 90. To investigate whether there is temperature difference of blood between the coronary sinus and the right atrium in patients with significant lesions in left coronary artery vs patients without lesions evaluated by angiography by a new coronary sinus thermography catheter. PurposePurpose
  91. 91. Study PopulationStudy Population •18 patients with angiographically documented CAD •12 patients angiographically normal coronary arteries
  92. 92. Temperature MeasurementsTemperature Measurements
  93. 93. Thermography SystemThermography System
  94. 94. CS Th In Vivo Coronary Sinus ThermographyIn Vivo Coronary Sinus Thermography
  95. 95. 37,8 37,85 37,9 37,95 38 38,05 38,1 38,15 38,2 38,25 0 100 200 300 400 500 600 700 800 Coronary Sinus Right Atrium Coronary Sinus Right Atrium DΤ(o C) In Vivo Coronary Sinus ThermographyIn Vivo Coronary Sinus Thermography
  96. 96. ResultsResults CADControl Temperaturedifference(o C) .4 .3 .2 .1 0.0 P=0.02
  97. 97. Ongoing ProtocolsOngoing Protocols Temperature MeasurementTemperature Measurement Tachycardia Arrhythmias (Atrial Fibrillation) Medication Heart Failure Transplantation Organ Function Brain Liver Kidneys
  98. 98. ConclusionsConclusions • New catheters for coronary thermography are being developed to increase the sensitivity of the current systems. • Thermography is currently being used in the whole cardiovascular system (peripheral arteries, valves) • Coronary sinus temperature measurements may provide in the future important information for the patient; not only for the plaque
  99. 99. Revisiting the Basics, Culprit vs. Non-Culprit: Luminal Narrowing, Plaque Volume, Cap thickness and plaque inflammation It is now widely accepted that the main determinant(s) of acute clinical events in coronary heart disease is the composition of the atherosclerotic lesion. In this review, we will discuss several plaque characteristics that are considered to be factors in the plaque vulnerability. Abstract
  100. 100. Abstract (con’t) Luminal narrowing. In a classic paper, Ambrose et al, reported that acute myocardial infarctions frequently developed in lesions that were not considered stenotic a few months before the ischemic event. Shortly afterwards, Little et al confirmed these findings. Moreover, in their series, 19 out of 29 patients had an occluded vessel responsible for their new myocardial infarction that was less than 50% stenotic in their previous angiogram, and 28 out of 29 patients had less than 70% narrowing in their culprit vessel on the first angiogram. In some biomechanical models, increase of stenosis leads to decrease of peak stress in the plaque, especially in lipid-rich plaques. It should be remembered, however, that plaque burden is a strong predictor of vascular events as demonstrated by a high EBCT score. The plaque burden, however, is predictive of the patient’s prognosis, not of a particular lesion progression. Also, a prospective five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study showed that initial lesion severity was predictive of late segment occlusion.
  101. 101. Plaques containing a highly thrombogenic lipid-rich core are more at risk for rupture if the size of the lipid core is large. In studies on aortae of individuals who died suddenly of coronary artery disease, Davis et al estimated that when lipid accounted for >40% of the plaques, there is high risk for plaque rupture. It is also possible that the chemical components of the atheroma are major determinants of plaque consistency and therefore, of plaque vulnerability. Specifically, liquid cholesterol esters are softer than crystalline cholesterol. Likewise, higher core temperature induces core softness, making it less likely for the fibrous cap to bear the circumferential stress and predisposing it for rupture. . Abstract (con’t) Plaque volume and composition
  102. 102. Abstract (con’t) Fibrous cap thickness. • Extracellular collagen-rich matrix produced by smooth muscle cells underlie the cap thickness and strength. The peak circumferential stress is inversely related to the cap thickness. An important determinant of cap thickness and composition is the presence or absence of inflammatory cells, mainly macrophages.
  103. 103. Abstract (con’t) Plaque inflammation (mainly cap and vicinity). Disruption of the fibrous cap is usually associated with heavy infiltration by macrophages and not uncommonly, T-lymphocytes as well. Macrophages especially may release several matrix-degrading proteases (MMPs): MMP-1 (collagenases), MMP-2 and 9 (gelatinases) and MMP-3 (stromelysin). Their main role is to degrade the fibrillar collagen that underlies the skeleton of the fibrous cap. A word of caution is well advised since Pasterkamp et al showed significant inflammation of the caps and shoulders of plaques in the femoral and coronary arteries. Clearly, inflammation is only one of many parameters, many yet to be reported, that determine plaque vulnerability.
  104. 104. Abstract (con’t) Summary In summary, size and composition of the lipid core, thickness and composition of the fibrous cap, and inflammation within or in the vicinity of the fibrous cap are well-established predictors of plaque rupture. Predictors of other forms of lesions underlying luminal thrombosis (e.g. erosion) are not yet well characterized.
  105. 105. Myocardial infarction frequently develops from previously non-severe lesions • Initial percent stenosis of infarct-related artery at restudy of 23 patients with myocardial infarction (Group I), or new occlusions in 18 patients without myocardial infarctions (Group II). The degree of stenosis was lower in the infarct group. From Ambrose et al, JACC 1988;12:56-62
  106. 106. Relation between severity of the stenosis at the future infarct site and time from initial angiography • There is no relation between severity of the stenosis at the future infarct site and the time from initial angiography until the development of the acute myocardial infarction. In addition, severe stenoses were infrequent in the infarct-related artery on the initial angiogram. From Little at al. Circulation 1988;78:1157-66
  107. 107. Review of studies that examined the severity of coronary stenosis lesions before the myocardial infarction • From Fishbein & Siegel. Circulation 1996;94:2662-6
  108. 108. Is the size of the lipid core related to the degree of vessel stenosis? The size of the lipid core has no correlation with the severity of the arterial stenosis. From Davies MJ et al. Br Heart J 1993;69:377-81
  109. 109. Plaque lipid content is a marker of vulnerability Unstable plaques have a higher lipid content than stable plaques. From Davies MJ et al. Basic Res Cardiol 1994;89:I:33-9
  110. 110. Lipid contents in stable (group A), combined stable and unstable plaques (B) and unstable plaques (C). Although there was considerable overlap between the groups the mean values were very different. Only one plaque in group A had a value over 40% while 41 of the 45 plaques in group C exceeded the value of 40%. From Davies MJ et al. Br Heart J 1993;69:377-81
  111. 111. Macrophage and smooth muscle cell contents of the fibrous cap in stable and unstable plaques Lipid-filled macrophages occupy a larger portion of the cap tissue in unstable plaques. Conversely, the volume of cap tissue occupied by smooth muscle cells is much smaller in unstable plaques. From Davies MJ et al. Basic Res Cardiol 1994;89:I;33- 9
  112. 112. Is cap thickness inversely related to the maximum circumferential stress? In arterial models, decreasing cap thickness dramatically increases the maximum circumferential stress, thus predisposing to plaque rupture. From Loree et al. Circ Res 1992;71:850-8
  113. 113. Is stenosis inversely related to the maximum circumferential stress? When a lipid core is present, increasing stenosis severity markedly decreases the maximum circumferential stress. In the absence of lipid core, this relationship is not as steep. From Loree et al. Circ Res 1992;71:850-8
  114. 114. Why is peak circumferential stress important? The peak circumferential stress was compared in 12 ruptured and 12 stable coronary lesions. Peak stresses are significantly increased in ruptured plaques and are considered an important factor in the genesis of the rupture. From Cheng et al. Circulation 1993;87:1179-87
  115. 115. Is the plaque rupture site related to the stress concentration? There is a very good correlation between the rupture site and the regions of peak stress concentration. From Cheng et al. Circulation 1993;87:1179-87
  116. 116. Ratio of smooth muscle cells and macrophages in cap tissue in different plaques settings Stable plaques are characterized by an excess of smooth muscle cells. In unstable plaques the ratio reaches unity or less. From Davies MJ et al. Basic Res Cardiol 1994;89:I-33-9
  117. 117. Fibrous cap extracellular matrix and cellularity in vulnerable plaques Arterial segment with atheromatous core with heavy staining of picro Sirius red within the cap confirmed with polarized light microscopy (A and C), and absent staining for CD68 in the cap and moderate CD68 staining in the shoulder and heavy CD68 staining at the base of the plaque (E) (asterick). Arterial segment with atheromatous core and thin/local absent picro Sirius red staining of the cap confirmed by polarized light microscopy (B and D). CD68 staining was heavily positive for cap and shoulder (F).
  118. 118. Thermal heterogeneity in the coronary atherosclerotic plaque Based on earlier studies by Casscells et al showing termal heterogeneity in ex-vivo atherosclerotic plaques, Stefanadis et al showed that temperature heterogeneity increases progressively from stable angina to acute myocardial infarction patients. From Stefanadis et al. Circulation 1999;99:1965-71
  119. 119. CONCLUSIONS • Size and composition of lipid core, thickness and composition of fibrous cap, and inflammation within or in the vicinity of the fibrous cap are well-established predictors of plaque rupture. • Predictors of other forms of lesions underlying luminal thrombosis (e.g. erosion) are not as well characterized.
  120. 120. Out of Hospital Sudden CardiacOut of Hospital Sudden Cardiac Death (SCD): Declining orDeath (SCD): Declining or Escalating?Escalating? Alireza Zarrabi, M.D.Alireza Zarrabi, M.D. Center for Vulnerable Plaque ResearchCenter for Vulnerable Plaque Research The University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at Houston and, Texas Heart Institute, U.S.A.and, Texas Heart Institute, U.S.A. March 2002March 2002
  121. 121.  Every 29 seconds, one American suffers from anEvery 29 seconds, one American suffers from an unexpected heart attack. Sadly, one will dieunexpected heart attack. Sadly, one will die nearly every minute.nearly every minute.  Every year 225,000 people die of heart attackEvery year 225,000 people die of heart attack before reaching the hospital.before reaching the hospital.
  122. 122.  The single most important cause of death in the adultThe single most important cause of death in the adult population of the industialized world is sudden cardiacpopulation of the industialized world is sudden cardiac death (SCD) due to coronary disease.death (SCD) due to coronary disease. 11  SCD is defined as follows: " Natural death due to cardiacSCD is defined as follows: " Natural death due to cardiac causes, heralded by abrupt loss of consciousness withincauses, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms; preexistingone hour of the onset of acute symptoms; preexisting heart disease may have been known to be present, butheart disease may have been known to be present, but the time and mode of death are unexpected.the time and mode of death are unexpected. 22
  123. 123.  50% of victims of sudden out-of-hospital cardiac50% of victims of sudden out-of-hospital cardiac death have no prior diagnosis of heart diseasedeath have no prior diagnosis of heart disease (asymptomatic).(asymptomatic). 33  More than 60% of cardiac death continues toMore than 60% of cardiac death continues to remain sudden. In 1998, there were 719 456remain sudden. In 1998, there were 719 456 cardiac disease deaths among US residentscardiac disease deaths among US residents aged >=35 years, of which 456,076 (63.3%)aged >=35 years, of which 456,076 (63.3%) were defined as SCD.were defined as SCD. 44
  124. 124.  The number of adolescents and young adultsThe number of adolescents and young adults dying each year from sudden cardiac arrest rosedying each year from sudden cardiac arrest rose by about 10% between 1989 and 1996, the firstby about 10% between 1989 and 1996, the first study of nationwide trends in the United Statesstudy of nationwide trends in the United States has shown.has shown. 77  The number of sudden cardiac deaths in the 15-The number of sudden cardiac deaths in the 15- 34 age group went up from 2,724 in 1989 to34 age group went up from 2,724 in 1989 to 3,000 in 1996, an increase of 10%. Of all the3,000 in 1996, an increase of 10%. Of all the young people who died over the eight yearyoung people who died over the eight year period, 71% were men and 29% women.period, 71% were men and 29% women. 77
  125. 125. Age-adjusted death rates (per 100 000 US population) for sudden cardiac death among men aged 35 years and older by race in the US from 1989 to 1990. Adapted from:Adapted from: Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989 to 1998 .Circulation. 2001;104:2158to 1998 .Circulation. 2001;104:2158
  126. 126. Age-adjusted death rates (per 100 000 US population) for sudden cardiac death among women aged 35 years and older by race in the US from 1989 to 1990. Adapted from:Adapted from: Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989 to 1998 .Circulation. 2001;104:2158to 1998 .Circulation. 2001;104:2158
  127. 127.  400,000 to 450,000 SCD per year from 1989400,000 to 450,000 SCD per year from 1989 to 1998 occurred out of hospital, in theto 1998 occurred out of hospital, in the emergency room, or as "dead on arrival."emergency room, or as "dead on arrival." 66  The automated external defibrillators (AEDs)The automated external defibrillators (AEDs) represents an efficient method of deliveringrepresents an efficient method of delivering defibrillation to persons experiencing out-of-defibrillation to persons experiencing out-of- hospital cardiac arrest and its use appears to behospital cardiac arrest and its use appears to be safe and effective.safe and effective. 88
  128. 128. Survival to 1 month relative to delay time from cardiac arrest to firstSurvival to 1 month relative to delay time from cardiac arrest to first defibrillation for bystander-witnessed patients with ventriculardefibrillation for bystander-witnessed patients with ventricular tachycardia/ventricular fibrillation on first electrocardiogram (n =tachycardia/ventricular fibrillation on first electrocardiogram (n = 2,748).2,748). ArrowArrow indicates median delay time (13 minutes).indicates median delay time (13 minutes). Adapted from: Holmberg M, Holmberg S, Herlitz J.; The problem of out-of-hospital cardiac-arrest prevalence of sudden death in Europe today. Am J Cardiol. 1999 Mar 11;83(5B):88D-90D. (Minutes)
  129. 129.  There is evidence of a slight decline in averageThere is evidence of a slight decline in average delay times in patients hospitalized in 1997 (5.5delay times in patients hospitalized in 1997 (5.5 hours) compared with those hospitalized in 1994hours) compared with those hospitalized in 1994 (5.7 hours).(5.7 hours).  Approximately 20% of patients presented to theApproximately 20% of patients presented to the hospital within 1 hour of acute symptom onset,hospital within 1 hour of acute symptom onset, and slightly more than two thirds presentedand slightly more than two thirds presented within 4 hours.within 4 hours.
  130. 130.  Delay times are shorter in patients withDelay times are shorter in patients with cardiogenic shock than less severely ill patients.cardiogenic shock than less severely ill patients.  Patients with previous acute MI or those withPatients with previous acute MI or those with history of coronary angioplasty presented tohistory of coronary angioplasty presented to hospital with shorter delay times.hospital with shorter delay times.
  131. 131.  Poor knowledge of warning symptoms of heartPoor knowledge of warning symptoms of heart attack and lack of a convenient method for out-attack and lack of a convenient method for out- of-hospital screening of patients with chestof-hospital screening of patients with chest discomfort are among major factors contributingdiscomfort are among major factors contributing to the overwhelming burden of out-of-hospitalto the overwhelming burden of out-of-hospital SCD.SCD.
  132. 132. ConclusionConclusion “Epidemiology”“Epidemiology” I.I. Women increasingly die with SCD out-of-Women increasingly die with SCD out-of- hospital.hospital. II.II. The increased death rates for SCD amongThe increased death rates for SCD among younger women warrants additionalyounger women warrants additional investigation of their potential risk factors.investigation of their potential risk factors.
  133. 133. ConclusionConclusion “Pathology”“Pathology” I.I. Coronary thrombosisCoronary thrombosis (a product of vulnerable(a product of vulnerable plaque and vulnerable blood)plaque and vulnerable blood) does not exist indoes not exist in 43-51% of SCD cases. In other words, about43-51% of SCD cases. In other words, about half of SCDs are not caused by plaque rupturehalf of SCDs are not caused by plaque rupture or coronary thrombosis.or coronary thrombosis. II.II. This reiterates the fact that SCD is a productThis reiterates the fact that SCD is a product ofof vulnerable plaque + vulnerable blood +vulnerable plaque + vulnerable blood + vulnerable myocardiumvulnerable myocardium..
  134. 134. ConclusionConclusion “Public Health”“Public Health” I.I. Pre-hospital delay in the US has not declinedPre-hospital delay in the US has not declined in the past few decades and holds as a majorin the past few decades and holds as a major bottle neck in our challenge against SCD.bottle neck in our challenge against SCD.
  135. 135. ConclusionConclusion “Public Health”“Public Health” II.II. The encouraging declines in the proportion ofThe encouraging declines in the proportion of cardiac deaths occurring in the hospital or thecardiac deaths occurring in the hospital or the emergency room may reflect the improvements inemergency room may reflect the improvements in emergency services and more timely andemergency services and more timely and appropriate treatment in hospital.appropriate treatment in hospital. However, the increased trend in SCD outside ofHowever, the increased trend in SCD outside of the hospital reiterates the need for public healththe hospital reiterates the need for public health initiatives to improve the early recognition of heartinitiatives to improve the early recognition of heart attack symptoms and signs with rapidattack symptoms and signs with rapid intervention.intervention.
  136. 136.  For saving more lives from SCD which one ofFor saving more lives from SCD which one of the following should be our first impression:the following should be our first impression: A.A. Detection and treatment of vulnerableDetection and treatment of vulnerable plaque?plaque? B. Detection and treatment of vulnerable heart?B. Detection and treatment of vulnerable heart? C. Rapid out-of-hospital screening, detection,C. Rapid out-of-hospital screening, detection, and treatment of patients with cardiac chestand treatment of patients with cardiac chest discomfort?discomfort?
  137. 137. ReferencesReferences 1- Priori SG, Wellens JJ, Zipes DP, et al.; Task Force on Sudden Cardiac Death of the1- Priori SG, Wellens JJ, Zipes DP, et al.; Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J. 2001 Aug;22(16):1374-450.European Society of Cardiology. Eur Heart J. 2001 Aug;22(16):1374-450. 2- Braunwald E, Heart disease: a tetbook of cardiovascular medicine. WB Saunders2- Braunwald E, Heart disease: a tetbook of cardiovascular medicine. WB Saunders Publishing Co., 1997:742-79.Publishing Co., 1997:742-79. 3- Wellens JJ; JACC 1997; 30:1500.3- Wellens JJ; JACC 1997; 30:1500. 4- Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States,4- Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989 to 1998 .Circulation. 2001;104:2158.1989 to 1998 .Circulation. 2001;104:2158. 5- Farb A, Virmani R, et al. Sudden coronary death.frequency of active coronary lesions,5- Farb A, Virmani R, et al. Sudden coronary death.frequency of active coronary lesions, and MI. Circulation 1995; 92:1701.and MI. Circulation 1995; 92:1701. 6- Goff DC Jr, Sellers DE, McGovern PG, et al. Knowledge of heart attack symptoms in a6- Goff DC Jr, Sellers DE, McGovern PG, et al. Knowledge of heart attack symptoms in a population survey in the United States: the REACT Trial. Rapid Early Action forpopulation survey in the United States: the REACT Trial. Rapid Early Action for Coronary Treatment. Arch Intern Med. 1998; 158: 2329–2338.Coronary Treatment. Arch Intern Med. 1998; 158: 2329–2338. 7-7- 2002 Heart and Stroke Statistical Update; American Heart Association. 8- Marenco JP, Wang PJ, Link MS, Homoud MK, Estes NA 3rd. ; Improving survival from sudden cardiac arrest: the role of the automated external defibrillator. JAMA. 2001 Mar 7;285(9):1193-200. 9- Goldberg RJ, Gurwitz JH, Gore JM.; Duration of, and temporal trends (1994-1997) in, prehospital delay in patients with acute myocardial infarction: the second National Registry of Myocardial Infarction. Arch Intern Med 1999 Oct 11;159(18):2141-7.
  138. 138. Abstract Macrophage apoptosis: a double edge sword? Apoptosis, a form of genetically programmed cell death, plays an essential role in different physiologic and pathologic processes including atherosclerosis, in which it affects all cell types including endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages. Over the course of the plaque progression, pro- and anti-apoptotic signals abound. In other organ systems, apoptosis limits the number of a particular cell type that accumulates in the lesion. The issue in atherosclerosis, however, is clearly more complex. The loss of VSMCs can be detrimental for plaque stability since most of the fibrous cap collagen required for the tensile strength of the cap is produced by VSMCs. Apoptosis of macrophages, on the other hand, could be beneficial for plaque stability if apoptotic bodies were removed. Several investigators have reported, however, that apoptotic bodies in the advanced atherosclerotic plaque are often not scavenged, can activate the coagulation cascade, potentially leading to plaque rupture and luminal thrombosis. Many of the apoptotic bodies are of macrophage origin. Moreover, interventions like statin therapy have shown that beneficial effects on the plaque, namely shrinkage of the lipid core, decrease of the inflammatory burden and thickening of the fibrous cap, are accompanied by a decrease in apoptotic activity. It is therefore not surprising that most investigators believe that apoptosis is detrimental to plaque stability.
  139. 139. Abstract (con’t) Macrophage apoptosis: a double edge sword? Our group has long been interested in the thermal heterogeneity of the atherosclerotic plaque and on the effect of plaque heating on the processes of inflammation and apoptosis. In a recent study by Dr. Birendra Lal in Dr. Yong-Jian Geng’s laboratory at the University of Texas Houston, eleven freshly living human carotid endarterectomy specimens were heated in DMEM medium at 42°C for 15 minutes followed by incubation at 37°C for 6 hours. In unheated controls, 4% of the VSMCs and 8% of macrophages were TUNEL positive. In the specimens with the short term heating, 46% of the macrophages and 10% of the SMCs were TUNEL positive. Immunostaining for tumor necrosis factor-α (TNF-α) and interleukin-6 (IL- 6) demonstrated lower levels of both cytokines in the heated group. Moreover, thermal stimulation also inactivated NF-κB (a transcription factor involved in cytokine expression, cell proliferation, etc) in macrophages derived from THP-1 cells by phorbol esters as demonstrated by gel shift assays.
  140. 140. Abstract (con’t) Macrophage apoptosis: a double edge sword? In another set of experiments performed by Dr. Mitra Rajabi in Dr. Yong-Jian Geng’s laboratory at the University of Texas Houston, mouse VSMCs were divided in two groups, half heated at 42°C for 15 minutes before returning to 37°C. Two hours after heating, both heated and non-heated dishes were divided in 3 groups: a) TNF-α 10ng/ml, b) TNF-α 10ng/ml and IFN-γ 10ng/ml, and c) no cytokines. After 12, 36 and 48 hours, the nitrite production, a marker of iNOS expression, was statistically significant lower in the heated as compared to the non-heated groups.
  141. 141. Abstract (con’t) Macrophage apoptosis: a double edge sword? We therefore believe that specific therapies like local gentle heating have a potential therapeutic effect by decreasing markers of inflammation coupled to their pro-apoptotic effects on macrophages. In addition, the operator in the catheterization laboratory could add adjuvant therapy like balloon dilation, stenting and anticoagulation, thereby preventing the potential complications of plaque rupture and thrombosis from happening in vivo. In summary, although large body of evidence considers apoptosis in the plaque to be risky and detrimental, we believe that under certain controlled conditions, gentle heating could decrease the plaque vulnerability.
  142. 142. APOPTOSIS & ATHEROSCLEROSIS ∀• While apoptosis is a key negative regulator of the cell density in oncogenesis, organ development, and immune response, the role of apoptosis in atherosclerosis is more complex. • Variation in the rate of apoptosis of different cell types promotes differences in growth rates, structure and stability of the plaques. • Several cytokines known to be pro-apoptotic, such as tumor necrosis-α (TNF-α), interleukin-1β, and interferon γ (IFN- γ) and products of genes involved in the cell cycle regulation (Fas/Fas ligand, caspase, p53 and c-Myc) have been found in vascular cells and atherosclerotic plaques. • Apoptotic rate is higher in advanced plaques
  143. 143. APOPTOSIS OF DIFFERENT CELL TYPES IN PLAQUE TISSUE ENDOTHELIAL CELLS ∀ • Lesion-prone regions show increased endothelial cell (EC) turnover ratio. ∀ • ECs undergo apoptosis when coming in contact with circulating or local factors like angiotensin II, oxidized LDL, reactive oxygen species (ROS) and inflammatory cytokines. • Apoptotic ECs assume pro-coagulant characteristics due to increased exposure to phosphatidylserine and loss of normal anticoagulant membrane properties. • Apoptotic ECs increase migration of monocytes and T-lymphocytes.
  144. 144. APOPTOSIS OF DIFFERENT CELL TYPES IN PLAQUE TISSUE VASCULAR SMOOTH MUSCLE CELLS  Apoptosis of vascular smooth muscle cells (VSMC) reduces the rate of plaque growth. At the same time, since VSMCs are the source of interstitial collagen fibers type I, plaque stability might be affected.  Migration of macrophages to areas of VSMC apoptosis has been described.  Overall effects of VSMCs apoptosis are complex and difficult to predict but generally felt to be deleterious for plaque stability.
  145. 145. APOPTOSIS OF DIFFERENT CELL TYPES IN PLAQUE TISSUE MACROPHAGES •• Macrophages may activate several matrix metalloproteinases which degrade interstitial collagen, thus weakening the fibrous cap. • Macrophages produce cytokines that may induce VSMCs apoptosis. • Loss of macrophages results in decreased scavenging products of cell degradation, leading to accumulation of necrotic debris and coagulation activation. • Therefore, apoptosis of macrophages, may have both pro- and anti-destabilizing effects.
  146. 146. APOPTOSIS OF DIFFERENT CELL TYPES IN PLAQUE TISSUE T-LYMPHOCYTES ∀• Lymphocytes produce molecules with important regulatory functions on the plaque cell death (cytokines, perforin, Fas). ∀• Apoptosis of lymphocytes is not well understood in the context of atherosclerosis.
  147. 147. Effect of heat on apoptosis of macrophages and smooth muscle cells At 37 °C, the proportion of apoptotic SMC and macrophage were 4% and 8% respectively. At 42 °C, these proportions increased to 10% and 46% respectively.
  148. 148. Effect of heat on macrophage apoptosis ∀ TUNEL and HAM-56 double staining. There is significant increase in the number of TUNEL positive macrophages after heating (8% to 46%)
  149. 149. Effect of heat on SMC apoptosis ∀ TUNEL and α actin double staining. There is insignificant increase in the number of TUNEL positive SMCs after heating (4% to 10%).
  150. 150. Effect of heat on macrophage ultrastructure ∀ Human carotid atherectomy specimen. A: Normal macrophage in unheated plaque. B: Two apoptotic macrophages inheated plaque condensed chromatin is same in both cells.
  151. 151. Effect of heat on macrophage ultrastructure (con’t) ∀ C: Enlarged view of B. D: Foam cell at the end stage of apoptotic process. Extra cellular debris is also present.
  152. 152. Effect of heat on TNF -α immunoreactivity ∀ TNF- α immunoreactivity decreases markedly with heating
  153. 153. Conclusion ∀  Gentle short-term thermal treatment induces apoptosis in human atherosclerotic lesions, reduces expression of pro-inflammatory cytokines TNFα and IL-6, and inactivates NFκB (as demonstrated by electrophoretic mobility shift assay, data not shown).  These data suggest that thermal treatment may have potential for treating advanced atherosclerotic lesions by reducing inflammation and triggering apoptosis in macrophages.
  154. 154. Contrast Enhanced MRI of the Vulnerable Plaque, Black or White? Maziar Azadpour, MD Morteza Naghavi, MD Center for Vulnerable Plaque Research
  155. 155. One can divide intravascular MRI contrast media into three different phases: • Arterial • Blood pool • Extracellular
  156. 156. Arterial Phase is the most suitable one for angiography and needs rapid sequences with minimum TR to optimize the enhancement. Blood Pool Phase is significant for highly vascular organs such as liver, which benefits the most from enhancement in this phase. Extracellular Phase in which certain tissues such as fibrous tissue and inflammatory processes could be detected. Different MRI contrasts agents have their own unique property to affect each of the above mentioned phases.
  157. 157. Yuan et al. demonstrated that multi-spectral MRI Without contrast media can produce high- resolution Images of carotid plaques and can discriminate between clinically relevant structural components Of atherosclerotic vessel wall.
  158. 158. Weiss, Cannon et al used positive enhancement Contrast media, Gadolinium-DTPA (Whitening) to Obtain double inversion recovery, fast spin echo images of the common carotid arteries and infrarenal aorta at 1.5 T both before and after injection in 52 subjects which 17 of whom had no risk factors for atherosclerosis and thus served as controls.
  159. 159. They hypothesized that arterial inflammation would cause increases in wall thickness, T2- weighted signal intensity, and/or arterial Wall gadolinium contrast enhancement Because Of enhanced endothelial permeability with Increased tissue water, cellular infiltration and Vasa vasorum dilation or neovascularization.
  160. 160. Levels of serum markers of inflammation in subjects with abnormal MRI compared to groups with normal MRI Bar graphs show levels of serum markers of inflammation in 22 Subjects With abnormal MRI compared with 30 subjects with normal MRI vascular studies. Weiss CR, Arai AE, Bui MN, Agyeman KO, Waclawiw MA, Balaban RS, Cannon RO 3rd. Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans. : J Magn Reson Imaging 2001 Dec
  161. 161. Levels of serum markers of inflammation in subjects with increased Wall thickness, normal wall thickness but increased postcontrast Signal intensity and/or T2-weighted and with normal MRI studies. Weiss CR, Arai AE, Bui MN, Agyeman KO, Waclawiw MA, Balaban RS, Cannon RO 3rd. Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans. : J Magn Reson Imaging 2001 Dec Bar graphs show levels of serum markers of inflammation in 14 subjects With increased wall thickness but increased postcontrast signal intensity And/or T2-weighted (Gd/T2), and 30 subjects with normal MRI studies.
  162. 162. • Weiss and colleagues suggested that MRI with gadolinium may permit the identification Of inflammation, even in the absence of increased Wall thickness. • They determined that T2-weighted and gadolinium contrast-enhanced properties Of MRI may identify arterial inflammation at an earlier Stage than is manifested by increased thickness of the arterial wall.
  163. 163. • Also confirming the findings of Weiss et al, Wasserman and Colleagues recently presented That gadolinium enhancement of carotid arteries By MRI was associated with fibrocellular tissue In atherosclerotic plaque during subsequent Microscopic analysis following endarterectomy. • Preliminary work indicates gadolinium accumulates In the arterial wall of patients with elevated serum Markers of inflammation and in more advanced Atheroma. Wasserman et al. determined that contrast Administration (gadolinium) increased the MRI signal of atherosclerotic plaques in rabbits.
  164. 164. Recently Yuan et al also showed that the use of gadolinium improve the ability of MRI to detect Neovascularization in the carotid atherosclerotic Plaque and improve the differentiation of necrotic Core from fibrous tissue in the plaque. : Yuan C, Kerwin WS, Ferguson MS, Polissar N, Zhang S, Cai J, Hatsukami TS Contrast-enhanced high resolution MRI for atherosclerotic carotid artery tissue characterization. Magn Reson Imaging. 2002 Jan
  165. 165. Ruehm,Schmitz and Naghavi independently reported a new method for MR imaging of inflammation in atherosclerotic Plaque using SPIO (super paramagnetic iron Oxide). SPIO nanoparticles are FDA approved Negative (blackening) contrast media for cancer detection and lymphography. They are avidly taken up by circulating monocytes and tissue macrophages Thereby creating irregular dark spot on the inflamed Atherosclerotic plaques.
  166. 166. Schmitz et al J. Inv. Radiol. 2000 Control SPIO Injected
  167. 167. Schmitz et al J. Inv. Radiol. 2000
  168. 168. Conclusion: 1. Gadolinium accumulates in the inflamed region of arterial wall because of enhanced endothelial Permeability with increased tissue water, cellular Infiltration and vasa vasorum dilatation or Neovascularization. 2. This technique may provide additional Information related to activity of plaque, besides structural imaging.
  169. 169. Conclusion: 3. SPIO has shown promising pre-clinical results As an MRI contrast medium for the detection of Atherosclerotic plaques, by providing negative Enhancement (darkening) of the affected area. 4. Further clinical studies for both group of agents Are required in order to confirm the hypothesis And apply this methods in the clinical settings.
  170. 170. References: 1. Lauenstein T, Holtmann G, Schoenfelder D, Bosk S, Ruehm SG, Debatin JF MR colonography without colonic cleansing: a new strategy to improve patient acceptance.AJR Am J Roentgenol. 2001 Oct;177(4):823-7. 2. Schmitz SA, Taupitz M, Wagner S, Wolf KJ, Beyersdorff D, Hamm B. Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles.J Magn Reson Imaging. 2001 Oct; 3. Morteza Naghavi, Mitra Rajabi, Mohammad Asif, Michael Quast, Jingna Wei, Daniel Chan, Mohammad Madjid, Khawar Gul, Samuel Ward Casscells III, James T. Willerson. Detection of Macrophage infiltration and intraplaque hemorrhage in Vulnerable atherosclerotic plaque using Magnetic Resonance Imaging contrast media, Super paramagnetic iron oxide (SPIO). Proc Intl Soc. Mag Reson Med 9 (2001) 640. 4. Yuan C, Hatsukami TS, Obrien KD High-Resolution magnetic resonance imaging of normal and atherosclerotic human coronary arteries ex vivo: discrimination of plaque tissue components. J Investig Med. 2001 Nov
  171. 171. References: 5. Yuan C, Mitsumori LM, Ferguson MS, Polissar NL, Echelard D, Ortiz G, Small R, Davies JW, Kerwi In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid- rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques, Circulation. 2001 Oct 23 6. Weiss CR, Arai AE, Bui MN, Agyeman KO, Waclawiw MA, Balaban RS, Cannon RO 3rd. Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans. J Magn Reson Imaging. 2001 Dec 7. Wasserman BA, Haacke EM, Li D. Carotid plaque formation and its evaluation with angiography, ultrasound, and MR angiography.J Magn Reson Imaging. 1994 Jul-Aug
  172. 172. Atherosclerosis, an Autoimmune Disease? What could be the culprit antigen(s)? A brief appraisal of the role of heat shock proteins. Mohammad Madjid, MD Center for Vulnerable Plaque Research University of Texas-Houston Health Science Center and Texas Heart Institute
  173. 173.  In1856 Virchow described atherosclerosis as “endarteritis”. A century later Russel Ross named atherosclerosis “an inflammatory disease”. Ross likened atherosclerosis to other chronic inflammatory diseases such as rheumatoid arthritis and glomerulonephritis. 1  The central role of immune system in atherosclerosis and its clinical complications is now widely accepted. Many investigators are searching to find out what antigens attract immune cells into the arterial wall and possibly later on into atherosclerotic plaques. 2,3,4  Autoantibodies against oxidized low-density lipoprotein (oxLDL), cardiolipin, beta2-glycoprotein-I and heat-shock protein 60/65 have been suggested. 2
  174. 174.  Georg Wick, Qingbo Xu, and colleagues have hypothesized that an autoimmune reaction against heat shock protein 60s, expressed by endothelial cells in areas that are subject to increased hemodynamic stress, is the initiating event in atherogenesis. 5,6  The hypothesis indicates that because a high degree of antigenic homology exists between microbial (bacterial and parasitic) and human HSP60, the 'cost' of immunity to microbes might be the danger of cross- reactivity with human HSP60 expressed by the endothelial cells of stressed arteries subjected to classical risk factors.7
  175. 175.  Two major families of HSPs (60s and 70s) have been related to atherosclerosis. Unlike HSP60s, HSP70s are not reported as strong triggers of autoimmune reactions, however, Bond, Johnson and colleagues have suggested certain role for HSP70s in atherosclerosis. 8,9  Chen et al described autologous hsp60 as a danger signal to the innate immune system.10  Xu et al. showed induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. 5  George, Afek, and colleagues reported induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. 11,12
  176. 176.  A number of other experimental and observational studies have shown a significant relationship between heat shock proteins and atherosclerosis. 9,11,13,14  In humans, expression of HSP60 is correlated positively with atherosclerotic severity, with the highest levels of expression seen in the shoulder regions and around the necrotic core of atherosclerotic plaques. 15
  177. 177.  In addition to its antigenic properties, bacterial HSP60 product may stimulate macrophages by production of cytokines such as TNF-α and also MMPs. It may as well interfere with innate immunity by binding to CD14 and activating monocytes and/or macrophages and endothelial cells. 8, 21, 22  Bocharov et al reported that HSP60 is a high-affinity high- density lipoprotein binding protein suggesting a potential mechanism to explain the known association between immunity developed against HSP60 and the development of atherosclerosis. 16
  178. 178.  Comparing the similarities between atherosclerosis and other autoimmune disorders such as rheumatoid arthritis (as indicated by Ross in the following slide) can also give some hints about the potential role of autoimmune mechanisms in atherosclerosis and it’s complications. 1  Interestingly, recent studies have uncovered an important role for heat shock proteins in pathogenesis of rheumatoid arthritis. 17,18  Like in rheumatoid arthritis, the suggested role of HSPs in atherosclerosis may also in part explain the missing link between infectious agents and atherosclerosis where a high degree of antigenic homology between human and microbial HSPs can cause cross-reaction. 17,7
  179. 179. DiseaseDisease Monocytes &Monocytes & MacrophageMacrophage LymphocyteLymphocyte GranulocyteGranulocyte Connective-Connective- Tissue CellsTissue Cells ExtracellularExtracellular MatrixMatrix Pathogenetic MechanismsPathogenetic Mechanisms AtherosclerosisAtherosclerosis ++ ++ -- SMCsSMCs Collagen type I,Collagen type I, III, IV, elastin,III, IV, elastin, fibronectin,fibronectin, proteoglycanproteoglycan Endothelial-cell injury andEndothelial-cell injury and dysfunction; fibrous cap; newdysfunction; fibrous cap; new matrix formation &matrix formation & degeneration; necrotic coredegeneration; necrotic core CirrhosisCirrhosis ++ ++ -- FibroblastsFibroblasts Collagen type I,Collagen type I, IIIIII Parenchymal cell injury, newParenchymal cell injury, new matrix and scarring replacingmatrix and scarring replacing necrotic parenchymanecrotic parenchyma RheumatoidRheumatoid arthritisarthritis ++ ++ +/-+/- SynovialSynovial fibroblastsfibroblasts Collagen type I,Collagen type I, III, fibronectin,III, fibronectin, proteoglycanproteoglycan Synovial-cell injury; erosion ofSynovial-cell injury; erosion of cartilage; new matrix scarringcartilage; new matrix scarring (pannus)(pannus) Glomeruloscle-Glomeruloscle- rosisrosis ++ ++ -- Mesangial cellsMesangial cells Collagen type I,Collagen type I, IV, fibronectinIV, fibronectin Epithelial- and endothelial-cellEpithelial- and endothelial-cell injury and dysfunction; decreaseinjury and dysfunction; decrease in glomerular filtration; newin glomerular filtration; new matrix formation;matrix formation; Pulmonary fibrosisPulmonary fibrosis ++ ++ +/-+/- SMCs,SMCs, FibroblastsFibroblasts Collagen typeCollagen type III, IV,III, IV, fibronectinfibronectin Inflammatory exudate in alveoliInflammatory exudate in alveoli & bronchi; organized by& bronchi; organized by extensive matrix deposition andextensive matrix deposition and scarringscarring ChronicChronic pancreatitispancreatitis ++ ++ -- FibroblastsFibroblasts Collagen,Collagen, fibronectin,fibronectin, proteoglycanproteoglycan Epithelial injury; periductalEpithelial injury; periductal inflammation; interstitial fatinflammation; interstitial fat necrosis; new matrix formationnecrosis; new matrix formation Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26
  180. 180.  Kanwar, Krissansen, et al. found that expression of HSP60 and HSP70 was strongly upregulated very early at lesion-prone sites in the aortas of young apoE-/- knockout mice and then dramatically down- regulated in the chronic lesions of aged mice. 20  They showed that HSP60 and HSP70 were detectable in the aortas of 3-week-old apoE-/- mice and were highly expressed in the aortas of 8-week-old mice. 20
  181. 181.  Kanwar et al. indicated that in 8-week-old apoE-/- mice, HSP60 and 70 were strongly expressed at valve commissures of the aortic sinus, extending to the free aortic wall and including expression by endothelial and intimal cells. 20  They concluded that HSP60 and HSP70 were heterogeneously expressed in lesions of 20-week-old mice. HSP60 and HSP70 were strongly expressed in advanced plaques of the abdominal aorta of 20-week- old mice, whereas medial layers lack expression. 20
  182. 182.  In 69-week-old mice, there was complete loss of HSP60 and HSP70 in advanced complicated collagen-rich plaques of the aortic sinus. (down- regulated in aged mice) 20  As a result of this study, lesion-prone sites displayed strong endothelial HSP60 expression, whereas non–lesion-prone sites of the distal abdominal aorta lacked hsp expression. 20  Monocytes/macrophages expressing HSP70 and hsp60 (data not shown) were the most prominent cell type in lesions. 20
  183. 183. Summary:Summary: 1- Autoimmune reactions (cellular and humoral) against HSPs particularly HSP60s may play an important role in early stage development of atherosclerosis. 2- HSP60s and HSP70s released from necrotic cells in the core area of advanced plaques may stimulate the innate immune response to promote inflammation and attract new inflammatory cells thereby may link to complications of plaque such as rupture and or thrombosis. 3- Humoral and cellular reactions against HSP60 work in conjunction with classical proven CVD risk factors.
  184. 184. Debates:Debates: I. According to our current body of knowledge, the development of atherosclerosis seems to have two major preceding components, metabolic disorder (lipid abnormality etc.) and inflammatory disorder (enhanced immune or autoimmune response). The question is which one comes first? II. Since the complication of atherosclerosis (vulnerable plaque) is more important than it’s development (stable plaque), the question is which one of the two (1-metabolic, 2- Immune) components of atherosclerosis plays a more important role?
  185. 185. Debates:Debates: III. How feasible is the idea of vaccination against HSPs or oxidized-LDL or other suggested antigens? Can we induce tolerance against HSPs without damaging the innate immune system? IV. Which one is more feasible? Eradication of atherosclerosis by vaccination against triggers of plaque development, or, eradication of vulnerable plaque by vaccination against triggers of plaque vulnerability?
  186. 186. 1. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26. Review 2. Shoenfeld Y, Sherer Y, George J, Harats D. ;Autoantibodies associated with atherosclerosis. Ann Med. 2000 Dec;32 Suppl 1:37-40. Review. 3. Hansson, G.; Immunological markers of atherosclerosis. Lancet. 1993 Jan 30;341(8840):278. 4. Witztum JL, Palinski W. ; Are immunological mechanisms relevant for the development of atherosclerosis? Clin Immunol. 1999 Feb;90(2):153-6. Review. 5. Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G. ; Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb. 1992 Jul;12(7):789-99. 6. Wick G, Schett G, Amberger A, Kleindienst R, Xu Q.; Is atherosclerosis an immunologically mediated disease?; Immunol Today. 1995 Jan;16(1):27-33. Review. References
  187. 187. 7. Wick G, Perschinka H, Millonig G. ; Atherosclerosis as an autoimmune disease: an update.; Trends Immunol. 2001 Dec 1;22(12):665-669. 8. Johnson AD, Berberian PA, Tytell M, Bond MG. ; Differential distribution of 70-kD heat shock protein in atherosclerosis. Its potential role in arterial SMC survival.; Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):27-36. 9. Berberian PA, Myers W, Tytell M, Challa V, Bond MG.; Immunohistochemical localization of heat shock protein-70 in normal-appearing and atherosclerotic specimens of human arteries.; Am J Pathol. 1990 Jan;136(1):71-80. 10. Chen W, Syldath U, Bellmann K, Burkart V, Kolb H.; Human 60-kDa heat-shock protein: a danger signal to the innate immune system.; J Immunol. 1999 Mar 15;162(6):3212-9. 11. George J, Shoenfeld Y, Afek A, Gilburd B, Keren P, Shaish A, Kopolovic J, Wick G, Harats D.; Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock protein-65. Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):505-10. References
  188. 188. 12. Afek A, George J, Gilburd B, Rauova L, Goldberg I, Kopolovic J, Harats D, Shoenfeld Y.; Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis.; J Autoimmun. 2000 Mar;14(2):115-21. 13. Hansen PR, Chew M, Zhou J, Daugherty A, Heegaard N, Jensen P, Mouritsen S, Falk E.; Freunds adjuvant alone is antiatherogenic in apoE-deficient mice and specific immunization against TNFalpha confers no additional benefit. Atherosclerosis. 2001 Sep;158(1):87-94. 14. George J, Afek A, Gilburd B, Shoenfeld Y, Harats D.; Cellular and humoral immune responses to heat shock protein 65 are both involved in promoting fatty-streak formation in LDL-receptor deficient mice. J Am Coll Cardiol. 2001 Sep;38(3):900-5. 15. Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G. Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions.; Am J Pathol. 1993 Jun;142(6):1927-37. References
  189. 189. 16. Bocharov AV, Vishnyakova TG, Baranova IN, Remaley AT, Patterson AP, Eggerman TL.; Heat shock protein 60 is a high-affinity high-density lipoprotein binding protein.; Biochem Biophys Res Commun. 2000 Oct 14;277(1):228-35. 17. Gaston, JS.; Heat shock proteins and arthritis--new readers start here. Autoimmunity. 1997;26(1):33-42. Review. 18. Schett G, Tohidast-Akrad M, Steiner G, Smolen J.; The stressed synovium.; Arthritis Res. 2001;3(2):80-6. Review. 19. Gaston, JS. ; Heat shock proteins and arthritis--new readers start here.; Autoimmunity. 1997;26(1):33-42. Review. 20. Rupinder K. Kanwar, Jagat R. Kanwar, Dongmao Wang, Douglas J. Ormrod, and Geoffrey W. Krissansen Temporal Expression of Heat Shock Proteins 60 and 70 at Lesion-Prone Sites During Atherogenesis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol 2001 21: 1991-1997. References
  190. 190. 21.21. Kol A, Sukhova GK, Lichtman AH, Libby P.Kol A, Sukhova GK, Lichtman AH, Libby P. Chlamydial heat shock protein 60 localizes inChlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrixhuman atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation. 1998 Jul 28;98(4):300-7.metalloproteinase expression. Circulation. 1998 Jul 28;98(4):300-7. 22.22. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA.Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA. Cutting edge: heat shock proteinCutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60(HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol. 2000 Jan 1;164(1):13-7.activation of mononuclear cells. J Immunol. 2000 Jan 1;164(1):13-7. References
  191. 191. Embolic Protection Devices Jay S. Yadav M.D. Director, Vascular Intervention Department of Cardiovascular Medicine The Cleveland Clinic Foundation
  192. 192. Everyone Embolizes ejt 048–114 Pettelot, et al. Circ 97:1522, 1998Pettelot, et al. Circ 97:1522, 1998
  193. 193. Embolization Common and under recognized CABG 6% stroke CEA 3-10% SVG PTCA 4-18% NQMI Coronary Intervention 9%? Arterial Thrombolysis 6-20% foot ischemia Venous Thrombolysis 5-20% pulm embol Mitral Valvuloplasty 1-28% AAA stent grafting 5-11% foot ischemia
  194. 194. Acute Coronary Syndromes ejt 029–144 The “Hot” VesselThe “Hot” Vessel MicrovascularMicrovascular ObstructionObstruction 1000x1000x 5x5x
  195. 195. BasalBasal PeakPeak 00 55 1010 1515 2020 2525 Heparin Alone, N=98 Abciximab, N=102 ² * Coronary Flow Velocity (cm/s)² * Coronary Flow Velocity (cm/s) IIb/IIIa ↓ in Acute MI ejt 106– 2110 ↑↑ Microvascular PerfusionMicrovascular Perfusion p = 0.15 * From baseline to day 14* From baseline to day 14 p = 0.024 Neumann, et al. Circ 98:2695–2701, 1998Neumann, et al. Circ 98:2695–2701, 1998
  196. 196. Transcranial Doppler (TCD) MIDDLE CEREBRAL ARTERY VELOCITY CM/SEC EMBOLI BALLOON INFLATED DEFLATED
  197. 197. Ex-Vivo Carotid Plaque Embolization Model - Ohki
  198. 198. Embolic Particles were generated from each plaque Ex-Vivo Carotid Plaque Embolization Model Ohki T et al. J Vasc Surg 1998; 27:463-71 YADAV
  199. 199. Ex-Vivo Carotid Plaque Embolization Model Ohki T et al. J Vasc Surg 1998; 27:463-71 Number of emboli and lesion characteristics Echolucent 0 25 50 75 100 125 Echogenic Numberofparticles p=0.012 Numberofparticles 0 25 50 75 100 125 50 60 70 80 90 100 % Stenosis
  200. 200. Why Are There Not More Strokes With Carotid Stenting? Rapp et al J Vasc Surgery 2000;32:68-76 Ex vivo carotid plaque PTA Particles injected into Rat ICA Grp A: <200 u 100 particles Grp B: 200 to 500 u 100 particles 50 atheroemboli / gram of brain Human brain 1300 g, rat brain 2 g
  201. 201. Rapp et al J Vasc Surgery 2000;32:68-76 Most particles released during PTA/Stenting <200 u 200-500 u Day 1 & 3 nl neuronal isch Day 7 neuronal ischemia
  202. 202. Anti-Embolization Devices Occlusive: – Distal Flow Arrest » Theron - Balloon Occlusion Catheter » PercuSurge - Balloon Occlusion Guidewire – Proximal Flow Arrest » Arteria- Balloon Occlusion Guide Catheter
  203. 203. Anti-Embolization Devices Non-Occlusive: – Supported Filters: » AngioGuard - Guidewire Filter » MedNova - Guidewire Filter » Trap- Nitinol Filter – Unsupported Filters: » EPI- Guidewire Filter » Etrap - Guidewire Filter
  204. 204. PercuSurge Guard Wire
  205. 205. AngioGuard XP
  206. 206. ArteriA PAEC
  207. 207. Arteria Proximal Flow Arrest - Parodi
  208. 208. External to internal carotid flow during common carotid Occlusion: Baseline External Occlusion: 1 pt ICA to ECA flow: 10 pts / 7.3 % ECA to ICA flow: 62 pts / 84.9 % Results:
  209. 209. 1st Generation 3.9F sheath - 0.014” Wire Capture Efficiency Particle Retention Trackability & Flexibility One to One Torquability Radiopacity Withdraws into 0.035” angioplasty balloon Universal Application Uninterrupted blood flow ( 80µm pores ) EPI
  210. 210. E-TRAP® FILTER (MSD)
  211. 211. DeviceWire • Offered in 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, and 7.0 mm basket diameters*. 7.0mm 4.0mm 2.5mm *Sizes Nominal Microvena Trap
  212. 212. PercuSurge Guard Wire SAFER trial SVG’s randomized to regular wires vs Percusurge 750 pts 60 centers
  213. 213. PercuSurge Guard Wire Age 68 DM 35% Class III/IV angina 75% Lesion length 15 mm Thrombus 38%
  214. 214. PercuSurge Guard Wire PS No PS TIMI III 98 % 94 % No Reflow 3.4 % 8 % Q MI 1.1 % 2.2 % NQ MI 7.3 % 14.4 % MACE 8.4 % 17.3 % p=.001
  215. 215. Acute MI Belli, AJC,2000, TCT abstracts 20 pts AMI Percusurge 17 primary PTCA, 3 rescue All received Abciximab Procedural success: 18/20 TIMI III: 14/20
  216. 216. Renal Artery Intervention Henry, AJC, Oct 2000, TCT abstracts 30 renal arteries - 27 ostial Percusurge Technical Success: 30/30 Renal art occl time: 418 secs (149 - 797) No renal fx deterioration at 6 months
  217. 217. Percusurge Renal Stent
  218. 218. Percusurge Renal Stent
  219. 219. Reduced Delivery Profile New 4 mm @ 3.2 F profile Current 4 mm @ 4.6 F profile Crossing Profiles 4 mm 3.2 F 5 mm 3.3 F 6 mm 3.5 F 7 mm 3.7 F 8 mm 3.9 F Lubricious coating on delivery sheath
  220. 220. AngioGuard XP
  221. 221. German Experience Eberhard Grube, Siegburg, GR 21 patients : –9 native coronary –4 carotid bifurcation –6 SVG
  222. 222. Cordis AngioGuard Clinical Data Vessel diam 3.3 + 0.35 mm (2.8-5.8) Stenosis 89% + 8.5% (70% - 95%) Procedural Success 100%
  223. 223. Cordis AngioGuard Pathologic Data U of Minnesota Particles recovered from all patients Number 147 + 111 (20 - 361) Size (Area) 0.10 mm2 + 0.5 mm2 (0.015-20) Embolic Burden per pt: 37 mm2 + 36 mm2 (0.6 mm2 - 110 mm2 )
  224. 224. Filter Surface Coverage 31 32 36 0 5 10 15 20 25 30 35 40 % Filter Surface Coverage SVG Carotid Native Coronary Average % of filter surface covered with embolic particles Range 0-80Range 0-60Range 5-50
  225. 225. Embolic Particle Size 0 100000 200000 300000 400000 X-sectionalareaum^2 Largest SVG Carotid Native Coronary Maximum particle size recovered
  226. 226. Embolic Particle Size 0 10000 20000 30000 40000 X-sectionalareaum^2 Average SVG Carotid Native Coronary Average particle size recovered
  227. 227. Coronary SVG Carotid E. Grube Siegburg, GR
  228. 228. Material Recovered during PTCA
  229. 229. SAPPHIRE RCT + Registry – 30 Centers – 600 - 900 RCT – 400 Registry – 30 patients per center
  230. 230. SAPPHIRE – Asymptomatic >80% – Symptomatic >70% – RCT – High risk
  231. 231. SAPPHIRE: Profile of high risk patients in trial CHF class III/IV and / or LVEF <30% Open heart surgery W/I 6 weeks Recent MI (>24hrs <4weeks) Unstable angina (CCS class III/IV) Synchronous severe CAD and carotid disease Severe pulmonary disease (FEV<1.0)
  232. 232. SAPPHIRE: Profile of high risk patients in trial Contralateral carotid occlusion Contra. laryn palsy; post-rad Rx, prev. CEA CCA lesions below clavicle High cervicl ICA Severe tandem lesions
  233. 233. Sapphire Status of Patient Entry Total enrollment – 715 pts - Randomized – 312 pts Stent registry – 400 pts (closed) Surgical registry – 3
  234. 234. CREST - RCT Symptomatic Patients (NASCET) Enrolling 2500 – CEA vs. CS – 60 Centers – Enrollment - 40+ pts/center - 3 yrs
  235. 235. REGISTRIES – ARCHER 300 pts – EndoTex 300 pts – Shelter 630 pts – CARESS 2000 pts – Maverick 400 pts
  236. 236. Guidant ACCUNET™ Embolic Protection System Filter Basket Specifications Polyurethane filter over Nitinol basket Diameters: 4-8 mm Filter pore size ≤ 120 microns Designed to maintain perfusion Caution: Investigational device. Limited by Federal (U.S.) Law to investigational use.
  237. 237. CAROTID Trials Trials Device D.P.D. Sapphire 5F Precise Angioguard-ex Crest 6F Acculink Accunet Shelter 5.5 F Wallstent Percusurge Caress 5.5 F Wallstent Percusurge EndoTex 5F Nexstent TBA Archer 6F Acculink Accunet Maverick Medtronic-AVE Percusurge Bard 7F Memotherm Trial Stopped EPI
  238. 238. Conclusions Definite Role for Emboli Prevention Devices in Coronary and Peripheral Intervention Selective and Data Driven Most Compelling for Carotids, SVGs, MI, Renals
  239. 239. GPIIb/IIIa Inhibition and EmboliGPIIb/IIIa Inhibition and Emboli Prevention Devices?Prevention Devices?
  240. 240. Editorial Slides VP Watch, January 16, 2002, Volume 2, Issue 2 Part II - Animal Models of Heart Attack?A Review
  241. 241. Part - I  Cell culture is a convenient way to ask mechanistic questions, but it lacks complexity of a real disease thus limiting the scope of testable hypotheses. Human observations provide rich soil for making hypotheses, but for obvious ethical reasons our ability to test these hypotheses in men is very limited. Animal models are essential for testing mechanistic hypotheses in a controlled manner.1  Ideal animal model is situated in the middle of this range. 1
  242. 242. 1- Japanese quail 2- Pigeon 3- Chicken Reported Animal Models for Atherosclerosis 4- Dog 5- Monkey 6- Pig 7- Rat 8- Rabbit 9- Mouse
  243. 243.  Quail: - Studies on Japanese quail have shown that the RES birds were resistant to the disease and developed little atherosclerosis on a diet containing 1% cholesterol. The SUS birds were sensitive and developed severe atherosclerosis in 8-9 wks on a diet containing only 0.5% cholesterol. 14,15,16
  244. 244.  Pigeon: - Tesar and Kottke showed that two distinct types of fatty streaks can be identified in white Carneau pigeon and their biologic features can be defined and related to their propensity for atherogenesis.6
  245. 245.  Chicken: - Wong discussed that chicken is a good animal model for the study of atherosclerosis research because it is able to develop spontaneous atherosclerosis and capable of producing atherosclerosis after cholesterol feeding with elevated hypercholesterolemia. There is no essential difference between vascular lesions seen in chickens as a result of cholesterol diet and that of atherosclerosis observed in man.2,3
  246. 246.  Dog: - Reducing platelet accumulation at sites of balloon angioplasty may attenuate restenosis. Willerson, et al. tested this hypothesis by inducing repetitive platelet aggregation at coronary angioplasty sites in cholesterol sensitive dogs and measured subsequent neointima formation. 4,5
  247. 247.  Monkey: - Blaton and Peeters discussed that the chimpanzee lipoproteins are useful models for understanding the relationship between function and structure of the plasma lipoproteins in health and disease. Baboon and rhesus monkeys show similar results, but more differences to the human lipoproteins in health and disease were observed.8,9
  248. 248.  Swine: - Massmann, and others showed relations between spontaneous and induced arterial lesions in swine and arteriosclerosis in humans. 7,21
  249. 249.  Rat: - Bennani-Kabchi et al. showed the potential of the sand rat to develop atherosclerotic lesions at different stages which opens the field to therapeutic tests of new anti- atherogenic agents. - More recently Herrera et al. demonstrated that cholesteryl ester transfer protein can be proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in the pathogenesis of atherosclerosis in Tg [hCETP] DS rats substantiates epidemiological observations in humans.10,11
  250. 250.  Rabbit: - Hereditary Watanabe rabbit - Clubb et al. evaluated temporal distribution of leukocytes, macrophages, foam cells, vascular smooth muscle cells, and subendothelial lipid in Watanabe heritable hyperlipedimic (WHHL) rabbit aortas.19 - Cholesterol fed New Zealand rabbit - Atherosclerotic plaques were produced in New Zealand White rabbits by intermittent cholesterol feeding.20
  251. 251.  Rekhter, et al. have developed a rabbit model in which an atherosclerotic plaque can be ruptured at will after an inflatable balloon becomes embedded into the plaque. This model as well can be used for induction of thrombi associated with plaque rupture. 17
  252. 252.  Mouse: - The apoE-deficient mouse contains the entire spectrum of lesions observed during atherogenesis and is the first mouse model to develop lesions similar to those in humans. 12,13
  253. 253. Part - II  The process of atherosclerotic plaque disruption has been difficult to monitor because of the lack of an animal model of plaque rupture. 23  More than 30 years ago, Constantinides and Chakravarti triggered plaque rupture and thrombosis in aorta of chlolesterol fed rabbits by intraperitoneal injection of Russell's viper venom (RVV, a potent procoagulant and endothelial toxin) followed by the intravenous injection of histamine, a vasopressor. 25  The aortas of the rabbits were then accordingly found to have disrupted atherosclerotic plaques with overlying platelet-rich thrombi. 25
  254. 254.  The advantage of Constantinides model is use of a biological intervention for triggering localized plaque thrombosis. However the non-physiological use of a toxic and potent thrombogenic substance (snake toxin) to induce plaque thrombosis can be considered a major drawback. 24  Other disadvantages of the Constantinides model are the low yield of triggering (only about one third of the rabbits developed thrombosis) and the long (8-month) preparatory period. 24
  255. 255.  Abela, Muller and colleagues challenged the limitations of Constantinides model by having the rabbits undergo aortic balloon injury followed by 8 weeks of 1% cholesterol diet. 24  In addition, they wanted to determine whether mechanical injury to the aorta early in the preparatory phase could enhance the development of vulnerable plaques, thereby increasing the yield of disrupted plaques and shortening the preparatory period. the rate of plaque disruption after pharmacological triggering increased to 71%. 24  They found that the rate of plaque disruption after pharmacological triggering increased up to 71%.24
  256. 256.  Johnstone, Manning, and colleagues used the modified Constantinides model and documented plaque disruption by MRI that resemble those found in human coronary arteries. 23  A major advantage of the use of a rabbit over other animals is that the rabbit’s aorta is approximately the same anatomic size as the human coronary artery. 23
  257. 257.  As highlighted in this week of VP Watch, Braun, Krieger, et al. showed that mice with homozygous null mutations in the genes for both the LDL and apoE receptors (SR-BI/apoE double knockout mice) exhibit morphological and functional defects with similarities to those seen in human coronary heart disease.22  The SR-BI/apoE dKO mice are distinct because they have extensive coronary artery lesions with fibrin deposition and spontaneously develop extensive MIs on a standard chow diet at a very young age (5 weeks).22
  258. 258.  The authors indicated that severe occlusive, fibrin-containing coronary arterial lesions, probable ischemia, multiple MIs, enlarged hearts, and cardiac dysfunction in very young ('5 weeks old), low-fat/ low-cholesterol fed SR-BI/apoE dKO mice provide a novel model of CHD.22  Fibrin deposits were found in the core regions of 8 of 10 lesions in 3 of 3 dKO mice.22  However, clear evidence for plaque rupture was not found in these animals neither was thin fibrous cap.22

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