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Existing intravascular imaging technology for plaque characterization

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Existing intravascular imaging technology for plaque characterization

  1. 1. The Ultimate Existing IntravascularThe Ultimate Existing Intravascular Imaging Technology for PlaqueImaging Technology for Plaque CharacterizationCharacterization Patrick W. Serruys, MD, PhDPatrick W. Serruys, MD, PhD Professor of Interventional CardiologyProfessor of Interventional Cardiology Thoraxcenter, Erasmus MC, RotterdamThoraxcenter, Erasmus MC, Rotterdam 1212stst Nov 2005, 14:30-14:45,Nov 2005, 14:30-14:45, Hyatt Regency HotelHyatt Regency Hotel AEHA VP summit Luminology, Virtual Histology, Palpography, Shear Stress Mapping and Vasa vasorum Imaging All in One!
  2. 2. C h e s t- P a in a tta c k N o n - In v a s iv e Im a g in g B io m a r k e r s E n tr ie s in t h e D ia g n o s tic p r o c e s s µ The “new diagnostic world“ of the vulnerable plaque Chest pain MSCT Biomarkers QCA <50%DS QIVUS >50% EEM obstruction VH Necrotic core rich lesion Palpography High-Strain iv MRI OCT Thin cap Invasive assessment of non-flow limiting lesion Chest pain High Risk Vasa vasorum Necrotic core
  3. 3. Mean PB (%) Mean MLD (mm) Proximal Distal 0 10 20 30 40 50 60 0 1 2 3 4 5 6 90 patients 121 vessels 4840 CSAs Percentage mm Sub-segments 1 2 3 4 Luminology Conclusions At the startof the stenosis, ICUS demonstrated a mean 50±11% totalvessel area stenosis, with a characteristic loss of disease-free arcs of arterial wall Escaned J and Serruys PW. Circulation. 1996 Sep 1;94(5):966-72.
  4. 4. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) (Vasa vasorum) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  5. 5. A B D a b c d Distal TOMTEC Surgical view® ECG gated acquisition C remodeling Non-ECG gated acquisition First step identify regions with 40 - 50 % EEM Obstruction
  6. 6. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) (Vasa vasorum) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  7. 7. Nair A et al. Circulation. 2002;106:2200-2206 FIBROUS FIBROFATT Y CALCIUM LIPID CORE MEDIA VH Legend Virtual Histology or… How to convert an ex Vivo IVUS image into a color coded histological cross section… by correlating backscattered radiofrequency signals with human ex vivo coronary histology
  8. 8. Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Coronary artery remodeling and plaque composition Plaque Composition and Shear Stress Change in plaque composition along coronary artery Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press. GA Rodriguez-Granillo et al and Serruys. Submitted Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related to clinical presentation.analysis is related to clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries. Rodriguez Granillo GA, Serruys PW et al. JACC. In press  Rodriguez Granillo GA, Serruys PW et al. JACC. In press   Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision. In-vivo relationship between compositional and mechanica imaging of coronary arteries In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press. #1 #2 #3 #4 #5 #6
  9. 9. Definition of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) 1. Focal (adjacent to non-TCFA) 2. Lipid core ≥10% 3. In direct contact with the lumen 4. Percent area obstruction ≥40% CALCIFIED PLAQUE MACROPHAGE FOAM CELLS NECROTIC CORE COLLAGEN FIBROUS FIBROFATT Y CALCIUM LIPID CORE MEDIA VH Legend Histology legend •Per 3 consecutive frames with all characteristics Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press.
  10. 10. IDTCFAIDTCFA IDTCFA/cmIDTCFA/cm Stable (N=Stable (N= 3232)) ACSACS (N=(N=2323)) p valuep value 1.0 (0.0,2.8)1.0 (0.0,2.8) 0.2 (0.0,0.7)0.2 (0.0,0.7) 3.0 (0.0, 5.0)3.0 (0.0, 5.0) 0.7 (0.0,1.3)0.7 (0.0,1.3) 0.0310.0310.0180.018 Incidence of IDTCFA lesions in non-culprit coronary vessels (n= 55) Continuous variables are presented as medians (25th , 75th percentile) or means ± SD when indicated. Rodriguez-Granillo GA et al. J Am Coll Cardiol. In press. #1
  11. 11. Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Coronary artery remodeling and plaque composition Plaque Composition and Shear Stress Change in plaque composition along coronary artery Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press. GA Rodriguez-Granillo et al and Serruys. Submitted Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related to clinical presentation.analysis is related to clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries. Rodriguez Granillo GA, Serruys PW et al. JACC. In press  Rodriguez Granillo GA, Serruys PW et al. JACC. In press   Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision. In-vivo relationship between compositional and mechanica imaging of coronary arteries In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press. #1 #2 #3 #4 #5 #6
  12. 12. Baseline characteristics (n: 40) 20 patients with one or more plaque ruptures 20 patients without plaque rupture n (%) Age (years±SD) 55.7±11.0 Male sex 29 (72.0) Diabetes 4 (10.0) Hypertension 17 (42.5) Current smoking 15 (37.5) Previous smoking 6 (15.0) Hypercholesterolemia 20 (50.0) Family history of coronary disease 19 (47.5) Body mass index (kg/m2 ±SD) 27.1±3.4 LDL (mmol/L±SD) 2.70±0.7 HDL (mmol/L±SD) 1.20±0.5 Clinical Presentation Stable angina 13 (32.5) Unstable angina 12 (30.0) Acute myocardial infarction 15 (37.5) #1
  13. 13. Three-vessel imaging using IVUS-VH in a 57 year-old male presenting with unstable angina. Plaque rupture in the ostial LAD (LAD a). The underlying substrate of the cavity is rich in necrotic- core (red) and calcium (white), whereas the thrombus has migrated distally (LAD c, *). Patient 051229 #2
  14. 14. Differences between the coronaries (n= 101)   LAD (n= 37) LCx (n= 32) RCA (n=32) p value     Analyzed length (mm±SD) 42.37±17.7 48.85±20.9 51.76±16.6 0.06 Geometrical parameters Lumen CSA (mm2 ) 8.53±2.6 9.26±3.2 11.07±4.6 0.01 Vessel CSA (mm2 ) 14.94±4.6 14.18±5.6 16.81±6.8 0.17 Plaque CSA (mm2 ) 6.43±2.8 4.92±3.3 5.74±3.0 0.13 Plaque max. thickness (mm) 1.05±0.3 0.84±0.3 0.85±0.3 0.002 Plaque burden (%) 42.2±9.9 33.17±9.2 33.96±10.3 <0.001   Compositional parameters Calcium (%) 3.81±3.2 2.94±2.9 1.78±1.7 0.01 Fibrous (%) 59.52±13.1 53.44±14.3 57.39±14.9 0.20 Fibrolipidic (%) 18.46±8.3 17.07±7.7 19.45±9.8 0.54 Necrotic core (%) 11.48±6.8 8.88±6.1 8.78±5.2 0.12 Values are expressed in means ±SD. ANOVA was used to compare groups except from * where Kruskal-Wallis was applied. LAD, LCx and RCA refer to left anterior descending, left circumflex and right coronary arteries, respectively. CSA refers to cross-sectional area. #2 < < > > > > The LAD presented more severe plaques, more calcified plaques and showed a trend towards larger necrotic core content of plaques compared to the LCx and the RCA respectively
  15. 15. Focal characteristics of ruptured plaques (20) and minimal lumen area (MLA) controls (n= 28)   Rupture site MLA site p value   Geometrical parameters Lumen CSA (mm2 ) 9.47±6.3 6.76±4.2 <0.001 Vessel CSA (mm2 ) 19.09±9.3 19.15±9.8 0.95 Plaque CSA (mm2 ) 9.63±4.2 12.38±6.9 0.01 Plaque max. thickness (mm) 1.38±0.3 1.71±0.5 0.002 Plaque burden (%) 51.32±10.6 64.06±10.1 <0.001   Compositional parameters Calcium (%) 6.07±6.3 4.60±4.6 0.10 Fibrous (%) 59.46±11.8 60.22±9.6 0.60 Fibrolipidic (%) 16.99±9.4 22.08±9.8 0.01 Necrotic core (%) 17.48±10.8 13.10±6.5 0.03 Values are expressed in means ±SD. CSA refers to cross-sectional area. #2 Plaque rupture sites showed a higher relative content of necrotic core compared to MLA sites (17.48±10.8 % vs. 13.10±6.5 %, p= 0.03) and a trend towards higher calcified component. < > < < >
  16. 16. IVUS-derived of patients with and without the presence of plaque rupture   Rupture (n=20) No rupture (n=20) p value   Geometrical parameters Lumen CSA (mm2 ) 9.6±3.3 9.2±2.3 0.60 Vessel CSA (mm2 ) 16.5±6.0 13.8±2.7 0.08 Plaque CSA (mm2 ) 6.9±3.3 4.6±1.4 0.01 Plaque max. thickness (mm) 1.0±0.2 0.8±0.2 0.02 Plaque burden (%) 40.7±7.6 33.7±8.4 0.01   Compositional parameters Calcium CSA (mm2 ) 0.15±0.16 0.07±0.08 0.05 Fibrous CSA (mm2 ) 2.48±1.7 1.24±0.7 0.01 Fibrolipidic CSA (mm2 ) 0.82±0.8 0.44±0.3 0.06 Necrotic core CSA (mm2 ) 0.44±0.3 0.22±0.2 0.01 Values are expressed in means ±SD. CSA refers to cross-sectional area. #2 Conclusions: In this study, patients with at least one PR in their coronary tree had in average more severe IVUS-derived characteristics compared to patients without evidence of PR. > > > > > > >
  17. 17. Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Coronary artery remodeling and plaque composition Plaque Composition and Shear Stress Change in plaque composition along coronary artery Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press. GA Rodriguez-Granillo et al and Serruys. Submitted Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related to clinical presentation.analysis is related to clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries. Rodriguez Granillo GA, Serruys PW et al. JACC. In press  Rodriguez Granillo GA, Serruys PW et al. JACC. In press   Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision. In-vivo relationship between compositional and mechanica imaging of coronary arteries In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press. #1 #2 #3 #4 #5 #6
  18. 18. Positive remodeled sections have been associated with: 1. Worse clinical presentation 2. Higher macrophage counts 3. Larger lipid cores 4. Pronounced medial thinning Vulnerable plaque phenotype Smits PC, et al. Heart. 1999;82:461-4. Schoenhagen P, et al. Circulation. 2000;101:598-603. Nakamura M, et al. J Am Coll Cardiol. 2001;37:63-9. Vascular remodeling Burke AP, et al. Circulation. 2002;105:297-303. Varnava AM, et al. Circulation. 2002;105:939-43. Schaar JA, et al. Eur Heart J. 2004;25:1077-82. Positive remodeling Negative remodeling RI = EEM CSA (MLA site) / EEM CSA (reference site) = RI= RI ≥ 1.05≥ 1.05 = RI ≤ 0.95= RI ≤ 0.95 Remodeling index (RI) #3
  19. 19. y: 47,197x - 32,165 r: 0,83 p: <0,0001 0 5 10 15 20 25 30 35 0,5 0,6 0,7 0,8 0,9 1 1,1 1,2 1,3 1,4 Remodeling index Lipidcore%CSA Coronary Artery Remodeling is related to plaque composition determined by IVUS- VH n= 41 r:0.83, p<0.0001 #3 0.95 1.05 Remodeling LipidScore%CSA Positive remodeling Negative remodeling
  20. 20. Geometrical and compositional data at the site of the minimal lumen area Remodeling index: ≤0.95 0.96-1.04 ≥1.05 n= 29 (70.7)3 (7.3) 9 (22) EEM area obstruction (MLA) 63.1±7.5 69.1±8.6 59.9±9.9 Calcium CSA (%) 1.38±2.7 2.07±3.2 1.67±1.6 Fibrous CSA (%) 68.6±13.7 62.9±9.5 58.1±12.9 Fibrolipidic CSA (%) 23.5±9.9 19.9±6.9 18.1±12.6 Lipid core CSA (%) 6.66.6±6.9±6.9 15.1±7.6 22.1±6.3*15.1±7.6 22.1±6.3* * p<0.0001 #3
  21. 21. Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Coronary artery remodeling and plaque composition Plaque Composition and Shear Stress Change in plaque composition along coronary artery Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press. GA Rodriguez-Granillo et al and Serruys. Submitted Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related to clinical presentation.analysis is related to clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries. Rodriguez Granillo GA, Serruys PW et al. JACC. In press  Rodriguez Granillo GA, Serruys PW et al. JACC. In press   Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision. In-vivo relationship between compositional and mechanica imaging of coronary arteries In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press. #1 #2 #3 #4 #5 #6
  22. 22. Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries Atherosclerosis has a tendency to arise more frequently in low-oscillatory shear stress (LOSS) regions such as in inner curvature of non-branching segments and opposite to the flow-divider (FD) at bifurcations. Jeremias et al. Atherosclerosis 2000;152:209-15. Kimura et al. J Am Coll Cardiol 1996;27:825-31 Kornet L et al. Arterioscler Thromb Vasc Biol 1999;19:2933-9. In-vivo data regarding tissue composition of the flow divider remains unknown. Furthermore, to date, no study has explored the characteristics of plaques located in the proximal LAD compared to the left main coronary artery (LMCA). In the present study, we sought to explore the morphological and compositional characteristics of plaque located at an acknowledged LOSS area (outer wall of the ostial LAD, OLAD) and compare them to the characteristics of plaque located at an average shear stress region (distal LMCA, DLMCA). Rodriguez-Granillo GA, García-García HM, Wentzel J et al. J Am Coll Cardiol. In press. #4
  23. 23. Shear stress in a bifurcation Steinman et al. 1999 # 4
  24. 24. The carina was identified as the frame immediately distal to the take-off of the circumflex. The maximal plaque thickness (MPT) was calculated at this level and spatially located according to a circumference ranging from 0 to 360º, being the inner and opposite part of the carina at 0 and 180º respectively. hemisphere of the carina. LCx (0º) Mean angle MPT (171º) Carina Distal left main METHODS Rodriguez-Granillo GA, García-García HM, Wentzel J et al. J Am Coll Cardiol. In press. #4
  25. 25. OLAD DLMCA p value Plaque burden (%) 45±10.2 36.4±10.8 <0.0001 Plaque eccentricity 14.5±11.6 10.4±7.6 0.05 Max. plaque thickness (mm) 1.24±0.4 1.04±0.3 0.002 Necrotic core (%) 12.4±9.2 7.9±8.6 <0.0001 Calcium (%) 4.1±5.1 1.3±2.0 <0.0001 Fibrous (%) 64.5±13.6 64.9±13.3 0.82 Fibrolipidic (%) 18.4±11.8 24.9±12.8 0.005 Geometrical and compositional comparative results between the ostial left anterior descending coronary artery (OLAD) and the distal left main coronary artery (DLMCA) (n= 44). Rodriguez-Granillo GA, García-García HM, Wentzel J et al. J Am Coll Cardiol. In press. RESULTS Values are presented as means ± standard deviation. Plaque eccentricity was defined as the ratio of maximal to minimal plaque thickness. Plaque burden was defined as {[(EEMarea -Lumenarea )/EEMarea ] X 100} < > > > > > Atherosclerosis has a tendency to arise more frequently in low-oscillatory shear stress (LOSS) regions such as in segments opposite to the flow-divider (FD) at bifurcations. #4
  26. 26. Necrotic core content distribution along left coronary artery 0 10 20 30 40 50 * * LMCA Carina 1° 2° 3° 4° 5° 6° Long LMCA ( n= 2 4 )Short LMCA ( n= 2 4 )NecroticCore(%) Length of LMCA was stratified according to median value (6 mm) *: p<0.05 vs. short LMCA Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo #4
  27. 27. Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Coronary artery remodeling and plaque composition Plaque Composition and Shear Stress Change in plaque composition along coronary artery Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press. GA Rodriguez-Granillo et al and Serruys. Submitted Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related to clinical presentation.analysis is related to clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries. Rodriguez Granillo GA, Serruys PW et al. JACC. In press  Rodriguez Granillo GA, Serruys PW et al. JACC. In press   Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In VivoDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision. In-vivo relationship between compositional and mechanica imaging of coronary arteries In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press. #1 #2 #3 #4 #5 #6
  28. 28. IVUS-VH cross sectional areas along a coronary vessel Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo #5
  29. 29. 0 -10mm 11 -20 mm 21 -30 mm 31-40 mm Lipidcore% SA group (n=28) UA group (n=15) Whole population (n=43) 10 20 30 40 0 Per-segment distribution of relative lipid content in the study population #5 Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo
  30. 30. 0 5 10 15 20 25 30 35 40 0-10 11-20 21-30 ≥31 IDTCFA Distance from the ostium (mm) Percent Total lesions = 99 p=0.008 35.4 % 31.3 % 19.2 % 14.1 % Clustering of IDTCFA along the coronaries (In-Vivo data) Rodriguez-Granillo GA et al. J Am Coll Cardiol. In press. #5
  31. 31. Kolodgie F, Virmani R. Curr Op in Cardiol. 2001;16:285- Clustering of vulnerable plaque (Ex-vivo data) #5
  32. 32. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) (Vasa vasorum) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  33. 33. Palpography… How to convert an ex vivo IVUS image into a color coded high strain/low strain tomogram… by correlating backscattered radiofrequency signals with human ex vivo coronary histology Sensitivity (88%) and Specificity(89%) to detect vulnerable plaque defined as : Fibrous cap ≤250 um, moderate to heavy macrophage infiltration, and ≥ 40% atheroma Schaar JA, et al.Serruys Circulation 2003; 108: 2636
  34. 34. ROtterdam Classification (ROC) 0-0.60-0.6II 0.6-0.90.6-0.9IIII 0.9-1.20.9-1.2IIIIII >1.2>1.2IVIV Strain (%)Strain (%)Grades (ROC)Grades (ROC)
  35. 35. Baseline Follow Up IBIS # 62
  36. 36. Palpography at follow-up, paired data (n=51) BLBL FUPFUP P-valueP-value Stable/silent (N=23)Stable/silent (N=23) ROC III/IV per cmROC III/IV per cm Unstable (N=16)Unstable (N=16) ROC III/IV per cmROC III/IV per cm STEMI (N=12)STEMI (N=12) ROC III/IV per cmROC III/IV per cm IBIS StudyIBIS Study 0.290.29 1.211.21 1.171.17 0.560.56 1.781.78 1.411.41 2.302.30 1.151.15 0.0030.003 0.02 C . Van Mieghem et al,Serruys JACC, in press In contrast to conventional imaging modalities that frequently reveal static luminal and plaque dimensions, novel IVUS-based plaque -palpography -can detect significant alterations in coronary plaque characteristics over a relatively short time interval. This study highlights the dynamic changes in the strain of coronary plaques that are remote from the culprit lesions in patients with myocardial infarction. Whether the persistence of a high-strain pattern is a harbinger of cardiovascular events remains to be determined in future much larger studies.
  37. 37. Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Coronary artery remodeling and plaque composition Plaque Composition and Shear Stress Change in plaque composition along coronary artery Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press. GA Rodriguez-Granillo et al and Serruys. Submitted Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related to clinical presentation.analysis is related to clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries. Rodriguez Granillo GA, Serruys PW et al. JACC. In press  Rodriguez Granillo GA, Serruys PW et al. JACC. In press   Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision. In-vivo relationship between compositional and mechanical imaging of coronary arteries In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press. #1 #2 #3 #4 #5 #6
  38. 38. LCx LCx LMCA Distal LAD * * 040471 What is the agreement between strain (palpography) and compositional (IVUS-VH) imaging? # 6
  39. 39. In-vivo relationship between compositional and mechanical imaging of coronary arteries Insights From Intravascular Ultrasound Radiofrequency Data Analysis 123 palpography previously analyzed spots (27 patients) were randomly selected by an independent observer ROC III-IV, n= 60 (high strain, labelled red and yellow respectively) ROC I-II, n= 63 (low strain, labelled blue) Co-localization of the same spots in the IVUS-VH software with side-by-side view Two IVUS pullbacks: PalpographyPalpography: 20 MHz Avanar IVUS-VHIVUS-VH: 30 MHz Ultracross # 6
  40. 40. What is the agreement between strain (palpography) and compositional (IVUS-VH) imaging? After adjusting for all IVUS-VH derided variablesAfter adjusting for all IVUS-VH derided variables (calcified(calcified content, fibrous content, fibrolipidic content, necrotic corecontent, fibrous content, fibrolipidic content, necrotic core content, eccentricity index, percent atheroma volume andcontent, eccentricity index, percent atheroma volume and contact of necrotic core with the lumen)contact of necrotic core with the lumen) ,, the only independent predictor of high strain was thethe only independent predictor of high strain was the contact of NC with the lumen [OR 5.0 (CI 95% 1.7-contact of NC with the lumen [OR 5.0 (CI 95% 1.7- 14.1), p= 0.003].14.1), p= 0.003]. # 6
  41. 41. 7 # Distribution of necrotic core in human7 # Distribution of necrotic core in human coronary plaques is related to the bloodcoronary plaques is related to the blood flow direction: An in vivo assessmentflow direction: An in vivo assessment using intravascular ultrasoundusing intravascular ultrasound radiofrequency data analysisradiofrequency data analysis 8 # Shear stress imaging and palpography8 # Shear stress imaging and palpography Frank Gijsen et al and Serruys, work in progress Garcia Garcia et al and Serruys, work in progress
  42. 42. Biological observations related to flow direction Dirksen et al., Circ. 1998 Flow High density Low density High densityLow density Tricot et al., Circ. 2000 Macrophages Flow Smooth muscle cells Hemodynamics Laboratory Thoraxcenter Rotterdam
  43. 43. Most diseased part Sub-segment 2 Sub-segment 1 Sub-segment 3 Sub-segment 2 UPSTREAM DOWNSTREAM Flow direction
  44. 44. Total no. of CSA with NC >10% Mean PB (%) Mean MLD (mm) p=0.014 Proximal Distal 0 100 200 300 400 500 600 0 10 20 30 40 50 60 0 1 2 3 4 5 6 90 patients 121 vessels 4840 CSAs NumberofCSA Percentage mm Sub-segments 1 2 3 4 MLA
  45. 45. # Distribution of necrotic core in human# Distribution of necrotic core in human coronary plaques is related to the bloodcoronary plaques is related to the blood flow direction: An in vivo assessmentflow direction: An in vivo assessment using intravascular ultrasoundusing intravascular ultrasound radiofrequency data analysisradiofrequency data analysis # Shear stress imaging and palpography# Shear stress imaging and palpography Frank Gijsen et al and Serruys, work in progress Garcia Garcia et al and Serruys, work in progress
  46. 46. MethodsMethods Shear stress: 3D lumen and wall info from ANGUS (biplane ANGiography and IVUS) combined with Computational Fluid Dynamics. Strain data: IVUS based data palpography data render radial strain map at lumen wall. Challenge: match ANGUS (CVIS) with palpography data (Volcano) using anatomical landmarks. Wentzel JJ, Serruys PW et al. Circ 2003;Jul 8;108(1):17-23. Slager CJ, Serruys PW et al. Circ 2000; Aug 1;102(5):511-6.
  47. 47. High SS High SS
  48. 48. Shear stress distribution over advanced plaque High shear stress Cap Blood flow Lipid core Low shear stress Hemodynamics Laboratory Thoraxcenter Rotterdam Patient population: 10 patients 21 segments 22 plaques
  49. 49. midcap upstream shoulder shoulder downstream flow Scoring system for shear stress and strain: 1: high 0: average -1: low Patient population: 10 patients 21 segments 22 plaques MethodsMethods
  50. 50. Results: shear stressResults: shear stress 1 0 -1 downstream 15 1 0 -1 shoulders 14 8 1 0 -1 midcap 11 5 1 1 0 -1 upstream 1 87 u s m d 0.38 0.64 0.59 -1.00
  51. 51. Results:Results: strainstrain 0.31 0.55 0.12 -0.47 u s m d 1 0 -1 downstream 9 42 1 0 -1 shoulders 12 10 1 0 -1 upstream 8 5 3 1 0 -1 midcap 4 11 2
  52. 52. ResultsResults u s m d meanstrain p < 0.01 p < 0.01 meanshearstress 0.38 0.64 0.59 -1.00 p = 0.07 0.31 0.55 0.12 -0.47
  53. 53. Slager et al, Serruys. Nature Clinical Practice, Nature 2005; 2:401-7
  54. 54. When non-flow limiting lesion < 50% stenosis When TCFA focal (3 slices), proximal < 30mm When ROC 3/4 When positive remodeling index > 1.05 When EEM obstruction>40% When large lipid core (> 10%) in direct contact with lumen Thin Cap Fibro Atheroma ? Vulnerable Plaque?
  55. 55. Prone to erosion No necrotic lipid pool No thin fibrous cap No inflammation Calcified Nodule (eruptive) lesion with fibrous cap disruption Intra-plaque Hemorrhage Leaking from vasa vasorum or extensive angiogenesis Micro CT imagingMicro CT imaging No specific diagnostic tool ?No specific diagnostic tool ? Micro CT imagingMicro CT imaging High cholesterol diet (12 weeks) Imaging techniques targeting Vulnerable Plaque other than TCFA
  56. 56. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) (Vasa vasorum) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  57. 57.  Main design specifications efficient at transmit (fc = 20 MHz) sensitive at receive (fc = 40 MHz) small size (< 1 mm) by Rik Vos, Erik Droog and Gerrit van Dijk TU Delft & TNO-TPD New IVUS catheter for detection of vasa vasorum
  58. 58. In vivo Experiments: Example 1 20 MHz Fundamental 40 MHz Harmonic - Bolus Injection of Dec. Sonovue - Rabbit 6 wks atherosclerosis Scale = 10 mm across
  59. 59. Conclusions •The development of an accurate diagnostic tool with the capability of simultaneously assessing more than one of the different acknowledged features of “high-risk” plaques could potentially enhance the prognostic value of the invasive detection of vulnerable plaque. •A high prevalence of “high-risk” lesions has been found throughout the coronary tree by means of palpography and IVUS- VH. •The distribution of the high risk plaques along the coronaries is clearly clustered from the ostium, compromising mainly the proximal segment. •Prospective studies are needed in order to evaluate the prognostic value and natural history of the allegedly high-risk lesions. •The multifocal aspect of the instability process added to the unpredictability of the natural history of these lesions and the uncertainty about whether vulnerable plaque characteristics might subsequently lead to fatal or non-fatal ischemic events –are suggesting that potential local preventive strategies could not be cost-effective.
  60. 60. Conclusions •A high prevalence of “high-risk” lesions has been found throughout the coronary tree by means of palpography and IVUS-VH. •The multifocal aspect of the instability process added to the unpredictability of the natural history of these lesions and the uncertainty about whether vulnerable plaque characteristics might subsequently lead to fatal or non-fatal ischemic events –are suggesting that potential local preventive strategies could not be cost-effective.
  61. 61. When non-flow limiting lesion < 50% stenosis When TCFA focal (3 slices), proximal < 30mm When positive remodeling index > 1.05 When EEM obstruction>40% When large lipid core (> 10%) in direct contact with lumen Vulnerable Plaque?
  62. 62. Virtual histology RF Signal Post Processing SignalsInvestigational Use Only Nair A, et al. Circulation; 106: 2200
  63. 63. 5 2 6 1 3 4 Frequency (MHz) dB Spectral Parameters Database of Parameters Classification Tree Minimum,maximum power ,slope,frequency band etc… Nair A, et al. Circulation; 106: 2200
  64. 64. ROI 111 roof ROI 54 mid-band fit >-11.4 ROI 57ROI 57 mid-bandmid-band fit <-11.4fit <-11.4 ROI 22 minimum power >-8.6 type= C ROI 32ROI 32 minimumminimum power <-8.6power <-8.6 ROI 23ROI 23 slope>-0.05slope>-0.05 ROI 12 slopeROI 12 slope >.0305>.0305 ROI 45 slopeROI 45 slope <.0305<.0305 ROI 9 slope<-0.05 type= F ROI 5 maximum power >-12.65 type=FL ROI 7 maximum power <-12.65 type=FL ROI 17 mid-ROI 17 mid- band fit >-16band fit >-16 ROI 28 mid-ROI 28 mid- band fit <-16band fit <-16 ROI 17ROI 17 frequency atfrequency at maxmax power>23.34power>23.34 ROI 6ROI 6 frequency atfrequency at maxmax power<23.34power<23.34 type = Ctype = C ROI 7ROI 7 slope>0.23slope>0.23 type=type= CNCN ROI 10ROI 10 slope<0.23slope<0.23 ROI 5 slope>0.08 type= CN ROI 5 slope<0.08 type= F ROI 12ROI 12 frequency atfrequency at max power>29.9max power>29.9 type = Ftype = F ROI 5ROI 5 frequency atfrequency at max power<29.9max power<29.9 type = Ftype = F ROI 17 Y-int>-26.8ROI 17 Y-int>-26.8 ROI 11 Y-int<-26.8 type= F ROI 11ROI 11 minimumminimum power >-24.8power >-24.8 ROI 6 minimum power <-24.8 type=FL ROI 5ROI 5 maximummaximum power >-13.3power >-13.3 type=FLtype=FL ROI 6ROI 6 maximummaximum power <-13.3power <-13.3 type=Ftype=F Statistical classification + calcium - calcium + fibrous - fibrous + lipid -lipid + NECROTIC -NECROTIC
  65. 65. FIBROUS FIBROFATTY CALCIUM LIPID CORE MEDIA VH LegendClassification Tree Ma xP < -25.05 Type: Colla gen #of RO Is : 5 Ma xP > -25.05 Type: Colla gen # of RO Is : 26 Int < -28.65 # of RO Is : 3 1 Int < -14.8 Type: Colla ge n #of RO Is: 5 Int > -14.8 Type: Colla ge n #of RO Is: 5 F at MaxP < 21 .045 #of RO Is: 10 F at MaxP > 21 .045 Typ e: Collage n #of RO Is: 17 MB F < -65.0 9 #of RO Is : 27 Int < -4.195 Type: Calcium # of RO Is : 6 Int > -4.195 Typ e: Collage n # of RO Is : 5 MB F > -65.0 9 #of RO Is : 11 F at Ma xP < 30.03 # of RO Is : 38 MaxP < -16.09 5 Type: Colla gen #of RO Is : 6 F at MaxP < 34.275 Typ e: N ecr otic #of RO Is : 6 MB F < -6 6.66 Typ e: Fib roLipidic # of RO Is : 5 MB F > -6 6.65 Type: Collagen # of RO Is : 5 Ma xP < -1 2.145 #of RO Is : 10 Ma xP > -1 2.145 Typ e: Fibro-Lipidic # of RO Is : 5 F at MaxP > 34.275 # of RO Is : 15 MaxP < -9.915 #of RO Is : 21 F at Ma xP < 35.5 Type: Colla ge n #of RO Is : 8 F at Ma xP > 35.5 Type: Colla ge n #of RO Is : 9 MaxP > -9.915 #of RO Is : 17 MaxP > -16.09 5 #of RO Is : 38 F at Ma xP > 30.03 #of RO Is : 44 Int > -28.65 # of RO Is : 8 2 MBF < -55.6 95 #of RO Is : 1 13 MinP <-17 .9 15 Typ e: Collagen #of RO Is : 5 MB F < -53.15 Type: Calcium #of RO Is : 8 MB F > -53.15 Type: Calcium # of RO Is : 20 MinP > -17.9 15 # of RO Is : 2 8 MB F >-5 5.695 #of RO Is : 33 146 # of RO Is :   TREE ROOT              IVUS virtual histology
  66. 66. efinition of rget segment IVUS OCT Off-Line Data Synchronization
  67. 67. Interm * distalproximal LCX D1 D2 Palpography 4-D IVUS Interm Second step identify regions with 40 - 50 % EEM Obstruction which contains at least one high strain spot ROC III /IV
  68. 68. • Large necrotic lipid core • Thin fibrous cap • Paucity of SMCs • Dense Macrophage infiltration (metalloproteinases) • Progressive matrix degeneration •Angiographically non-significant • Positive remodelling Rupture Prone Plaque Specific diagnostic tool ?Specific diagnostic tool ?
  69. 69. Imaging techniques targeting the TCFA Modality Resolution Penetration Fibrous cap Lipid core Angioscopy NA Poor + ++ OCT 10 um Poor ++++++ ++ Thermography NA Poor - - Spectroscopy NA Poor + ++ IVMRI 160 um Good + ++++++ IVUSIVUS 100 um Good + ++ PalpographyPalpography NA NA ++ + VHVH 100 um Good ++ ++++++ Modality Inflammation Calcium Thrombus Remodeling Angioscopy - - ++++++ - OCTOCT ++ ++++++ + - Thermography ++++++ - - - Spectroscopy ++ ++ - - IVMRI - + - - IVUSIVUS - ++++++ + ++++++ PalpographyPalpography ++ - + - VHVH - ++++++ - ++++++ NC
  70. 70. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  71. 71. Should we pursue a combined approach using different catheter- based techniques to potentially enhance the prognostic value for the detection of vulnerable plaque? While exciting and promising, there is still no gold-standard and all current techniques have different pitfalls…
  72. 72. ynchronization IVUS OCT Off-Line Data Synchronization
  73. 73. IVUS OCT Off-Line Data Synchronization
  74. 74. OCT ROC III Dense calcium 10% Fibrous 67% Fibro-fatty 8% Necrotic core 15% Lumen: 8.00 mm2 Vessel: 15.92 mm2 Plaque burden: 50% Synchronized IVUS and OCT PB 2
  75. 75. IVUS OCT 2 % 0 %ROC III Dense calcium 10% Fibrous 67% Fibro-fatty 8% Necrotic core 15% direct lumen contact Lumen: 8.00 mm2 Vessel: 15.92 mm2 Plaque burden: 50% Vulnerable Plaque ? Thin fibrous cap 0.12mm Synchronized IVUS and OCT PB 2
  76. 76. MSCT Left coronary artery LAD LCx1st Marginal Left main LAD Ca++ 3D rendered
  77. 77. P MSCT Left main IVUS VH HU MSCT Mean HU: 588 Distal
  78. 78. P MSCT Left main IVUS VH HU MSCT Mean HU: 231 Mid
  79. 79. P MSCT Left main IVUS VH HU MSCT Mean HU: 76 Proximal
  80. 80. Low Shear Stress Slager et al, Serruys. Nature Clinical Practice, in press.
  81. 81. Spatially restricted endothelial anti-inflammatory signaling Slager et al and Serruys, Nat Clin Pract Card 2005 Hemodynamics Laboratory Thoraxcenter Rotterdam
  82. 82. Mean PB (%) Mean MLD (mm) p=0.014 Proximal Distal 0 10 20 30 40 50 60 0 1 2 3 4 5 6 90 patients 121 vessels 4840 CSAs Percentage mm Sub-segments 1 2 3 4 Luminology
  83. 83. Intravascular ultrasound findings at the site proximal to the stenosis (A), at the start of the stenosis as defined by automated stenosis analysis (B), and at the site of maximal luminal obstruction (C), defined also by automated stenosis analysis. Note the marked change in distribution of atheroma around the lumen (center of the crosshair) at the three levels.
  84. 84. Downstream Upstream ROI Vessel Lumen Geometrical analysis Composition analysis MDP
  85. 85. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) (Vasa vasorum) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  86. 86. BACKUP SLIDES
  87. 87. The “new diagnostic world“ of the vulnerable plaque Non-invasive assessment µ QCA <50%DS QIVUS >50% EEM obstruction VH Necrotic core rich lesion Palpography High-Strain iv MRI OCT Thin cap Vasa vasorum Necrotic core
  88. 88. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) (Vasa vasorum) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  89. 89. Intravascular Imaging Modalities IVUS (gray scale) (plaque size) (echogenicity) IVUS Palpography (mechanical properties) Optical Coherence Tomography Intravascular MRI Virtual Histology (plaque composition) Acquired with single pull back IVUS catheter
  90. 90. Restricted diffusion → slow decay of MR signal → Low ADC Restricted diffusion → slow decay of MR signal → Low ADC Non- restricted diffusion → Fast decay of MR signal → High apparent diffusion coefficient (ADC) Non- restricted diffusion → Fast decay of MR signal → High apparent diffusion coefficient (ADC) Diffusion Weighted MR – Concept
  91. 91. Intravascular MRI CatheterIntravascular MRI Catheter NC NCMagnet Coil Luminal Zone Mural Zone Schneiderman J. J Am Coll Cardiol. 2005;45(12):1961-
  92. 92. Ex-Vivo AortasEx-Vivo Aortas (single sector; n=16(single sector; n=16(( Fibrous cap atheroma Ulcerated plaque Healthy tissue Vulnerable plaque 250µ 100µ 100µ 100µ 100µ Schneiderman J. J Am Coll Cardiol. 2005;45(12):1961-
  93. 93. 29 Lesions Device Success28 6 Guide wire artifact 3 Extensive calcium/Extensive calcium/ Incomplete appositionIncomplete apposition to vessel wallto vessel wallImaging Success19 Top Image I Coronary Study Results
  94. 94. IVMRI Lipid Fraction in Ex-vivo Coronaries and In-vivo FIM Patients #11
  95. 95. P Aorta Left main LAD IVUS VH Left main Prox > distal
  96. 96. P Distal cross-section Mid cross-section Prox cross-section LAD LCx DMP P M D MSCT Left main
  97. 97. Number of patients Proof of concept registries Cross correlation studies Natural history trials Randomized therapy studies Diagnosis*Diagnosis* ** 1. Biomarkers1. Biomarkers 2. Plaque physiology2. Plaque physiology 3. Plaque morphology3. Plaque morphology 5-105-10 yearsyears TherapyTherapy Clinical Trial ParadigmClinical Trial Paradigm
  98. 98. Case 605 LCx IVUS probe position MRI probe position IVUS IVUS - VH MRI IV-MRI – Rotterdam patients
  99. 99. Conclusions •In this in vivo study, IVUS-VH identified IVUS-derived thin-cap fibroatheroma as a more prevalent finding in ACS than in stable angina patients. •The significantly higher prevalence of IDTCFA in non-culprit coronaries of patients presenting with an ACS supports the theory that holds ACS as multifocal processes. •The distribution of the IDTCFA in the coronaries was in line with previous ex vivo and clinical studies, with a clear clustering pattern from the ostium, thus supporting the non-uniform distribution of vulnerable plaques along the coronary tree. •We found no significant correlation between the presence of conventional risk factors and the occurrence of IDTCFA . •Prospective studies are needed in order to evaluate the prognostic value and natural history of such finding.
  100. 100. A high prevalence of “high-risk” lesions has been found throughout the coronary tree by means of angiography 33 , angioscopy 11 , IVUS 32 and palpography 15 . Furthermore, the unpredictability of the natural history of such lesions and the uncertainty about if vulnerable plaque characteristics might subsequently lead to fatal or non-fatal ischemic events suggests that potential local preventive strategies could not be cost-effective. Nevertheless, the development of an accurate diagnostic tool with the capability of simultaneously assessing more than one of the different acknowledged features of “high-risk” plaques could potentially enhance the prognostic value of the invasive detection of vulnerable plaque. Since IVUS-VH and palpography utilize the same source data (radiofrequency data analysis), information regarding both techniques might be obtained using the same pullback; potentially increasing the prognostic value of certain seemingly pejorative plaque characteristics assessed in prospective natural history studies.
  101. 101. Co-localization 1) Localize selected palpo frame in colour blinded view 2) Localize matching frame in IVUS VH using: Longitudinal and cross-sectional views Landmarks (side-branches, veins, pericardium) Calcified spots and morpholohy of the plaque 3) Reconstruct the IVUS-VH image4) Contruct IVUS-VH database with all IVUS- VH variables of the matched frame (Calcium %, fibrous %, fibrolipidic %, necrotic core %, vessel area obtruction %, eccentricity index, necrotic core contact with the lumen) 5) Unblind (Process the Palpography results and match them with the IVUS-VH’s)
  102. 102. TCFA detection “We clearly can’t apply all these techniques due to practical issues, therefore we should focus on a single state-of-the-art tool” IVUS + VH + Palpography? (1 pullback provides information about lipid core, inflammation, remodeling and cap thickness)
  103. 103. Accordingly, the combined approach using different catheter- based techniques might potentially enhance the prognostic value for the detection of vulnerable plaque While exciting and promising, there is still no gold-standard and all techniques have different pitfalls…
  104. 104.  What is the prognostic value of allWhat is the prognostic value of all these diagnostic tools?these diagnostic tools?  The prognostic value needs to beThe prognostic value needs to be established in longitudinal follow-upestablished in longitudinal follow-up studies!studies!
  105. 105. C h e s t- P a in a tta c k N o n - In v a s iv e Im a g in g B io m a r k e r s E n tr ie s in t h e D ia g n o s tic p r o c e s s Q C A < 5 0 % D S Q IV U S > 5 0 % E E M r e d u c tio n V H L ip id - n e c r o tic le s io n P a lp o g r a p h y H ig h - S tra in T h e r m o g r a p h y > 0 .0 8 C e lc iu s O C T < 1 6 0 In v a s iv e a s s e s s m e n t o f n o n - flo w lim itin g le s io n µ The “new diagnostic world “ of the vulnerable plaque Chest pain MSCT Biomarkers Vulnerable plaque triage Identify high risk patients (Framingham score) Cholesterol levels + CRP Non-invasive imaging + novel biomarkers In case of invasive assessment If non-flow limiting lesion < 50% stenosis If TCFA focal (3 slices), proximal < 30mm DES If ROC 3/4 If positive remodeling index > 1.05 Cost Benefit??? If EEM obstruction>40% Systemi c therapy If large lipid core (> 10%) in direct contact with lumen
  106. 106. Vulnerable Coronary Tree
  107. 107. MS-CT Plaque Burden
  108. 108. RCA 51 9372 70 55 25 LCA 55 90 42 51 71 48 48 30 53 16 MSCT Coronary Plaque Burden Distribution (%) (41 patients: stable / unstable 59.5 ± 10 yrs)
  109. 109. Necrotic core relation with the lumen No contact Contact p value Calcium (%) 0.25± 0.7 1.6± 2.5 0.001 + Fibrous (%) 76± 13.7 64± 12 <0.001 - Fibrolipidic (%) 21± 14 19± 9 0.21 = Necrotic core (%) 3± 4 16± 11 <0.001 + PAV (%) 49± 9 51± 11 0.38 = Eccentricity index 0.15± 0.1 0.23± 0.1 0.01 + Percent atheroma volume (PAV) was defined as EEMarea -Lumenarea /EEMarea X 100, where EEM refers to external elastic membrane. EI refers to plaque eccentricity index, defined as minimum plaque thickness divided by maximum plaque thickness. Plaque composition and conventional intravascular ultrasound output in cross-sections with and without necrotic core contact with the lumen
  110. 110. 38% 62% P(-) P(+) Noncalc MX Calc 32% 43% 25% 53% > 50%<50% Plaque Extent Plaque Type Plaque Size 47% MSCT Coronary Plaque Burden 41 patients (473 segments)
  111. 111. Clinical presentation Acute coronary syndrome Younger < 60 yrs Diabetes Troponin positive Biological marker hsCRP Non-invasive MSCT Calcific plaque Non-calcific plaque Total coronary plaque burden Invasive techniques ICUS Palpography Thermography OCT High-risk patient Presence of plaque High-risk plaque Algorithm to detect high-risk plaque in a high-risk patient
  112. 112. Disrupted Coronary Plaque Unstable patient with ST-segment depression
  113. 113. Vulnerable Coronary Plaque ?
  114. 114. Major criteria Yes? Lipid core size No Thin Cap No Inflammation MSCT Vulnerable Plaque: Limitations Naghavi Circulation 2003;108:1664 Lipid plaque Thrombotic plaque 35 HU 10 HU Yes Coronary stenosis No Fissured plaque No Endoth. denudation
  115. 115. 64-MSCT coronary plaque imaging Mixed plaqueNon-calcific plaque Calcific plaque
  116. 116. Major criteria Yes? Lipid core size No Thin Cap No Inflammation Yes Coronary stenosis No Fissured plaque No Endoth. denudation MSCT Vulnerable Plaque: Limitations Minor criteria Yes Remodeling No Endothelial dysf. No Intraplaque hemorrh. No Glistening yellow No Superf. Calc. nodule Naghavi Circulation 2003;108:1664 Lipid plaque Thrombotic plaque 35 HU 10 HU
  117. 117. Trophy Images or Reality ?Trophy Images or Reality ? Sens.: 77% (38 – 94) Spec. :71% (42 – 97) Budoff JACC 2003;42:1867 Third generation Bornert et al. Magn. Reson. Med 2001;46:789-794
  118. 118. 16 slice MSCT Ruptured Plaque “ Indirect evidence “
  119. 119. Imaging techniques targeting the TCFA Modality Resolution Penetration Fibrous cap Lipid core Angioscopy NA Poor + ++ OCT 10 um Poor +++ ++ Thermography NA Poor - - Spectroscopy NA Poor + ++ IVMRI 160 um Good + +++ IVUSIVUS 100 um Good + ++ PalpographyPalpography NA NA ++ + VHVH 100 um Good ++ +++ Modality Inflammation Calcium Thrombus Remodeling Angioscopy - - +++ - OCT ++ +++ + - Thermography +++ - - - Spectroscopy ++ ++ - - IVMRI - + - - IVUSIVUS - +++ + +++ PalpographyPalpography ++ - + - VHVH - +++ - +++ NC
  120. 120. RCA: prox and distal lesion
  121. 121. RCA: prox and distal lesion
  122. 122. Major criteria Yes? Lipid core size No Thin Cap No Inflammation Yes Coronary stenosis No Fissured plaque No Endoth. denudation MSCT Vulnerable Plaque: Limitations Minor criteria Yes Remodeling No Endothelial dysf. No Intraplaque hemorrh. No Glistening yellow No Superf. Calc. nodule Naghavi Circulation 2003;108:1664 Lipid plaque Thrombotic plaque 35 HU 10 HU
  123. 123. • Male, 56 years, stable angina,Male, 56 years, stable angina, history of non-Q-wave MIhistory of non-Q-wave MI • Risk factors: Smoking,Risk factors: Smoking, NIDDM, hypertension,NIDDM, hypertension, hypercholesterolemia, familyhypercholesterolemia, family historyhistory • Proximal LAD 36% stenosisProximal LAD 36% stenosis Fibrous Lesion Lipid-Rich LesionLipid-Rich Lesion • Male, 77 years, unstable anginaMale, 77 years, unstable angina • Risk factors: HypertensionRisk factors: Hypertension • Proximal LAD 21% stenosisProximal LAD 21% stenosis Coronary Study Typical Cases
  124. 124. How to integrate information from different intravascular tools?
  125. 125. IVUS probe position MRI probe position IVUS IVUS - VH MRI Matching by Angiography
  126. 126. 2.9F 20 MHz Solid state transducer (64 elements)  Gray scale  VH IVUS  Palpography Simultaneous Data Acquisition Volcano Eagle Eye Catheter
  127. 127. LADLAD IVUS and OCT EvaluationIVUS and OCT Evaluation IVUS PB OCT PB Off-Line Data Synchronization
  128. 128. IVUS OCT 2 % 0 %ROC III Dense calcium 10% Fibrous 67% Fibro-fatty 8% Necrotic core 15% direct lumen contact Lumen: 8.00 mm2 Vessel: 15.92 mm2 Plaque burden: 50% Vulnerable Plaque ? Thin fibrous cap 0.12mm Synchronized IVUS and OCT PB 2
  129. 129. • High incidence of yellow non-disrupted plaques in by angioscopy (3.4±1.8, n=21). • Yellow plaques were equally prevalent in the infarct-related and non–infarct-related coronary arteries ACS as a multifocal instability process Asakura M. J Am Coll Cardiol. 2001 Apr;37(5):1284-8 Culprit lesion
  130. 130. Multiple plaque rupture: 3-vessel IVUS assessment in 24 first ACS patients 0 10 20 30 40 50 60 70 80 90 100 Patients(%) In culprit lesion Outside culprit lesion In other vessel In both other vessels Rioufol G et al. Circulation.2002;106:804
  131. 131. One-year outcome of single vs multiple complex coronary plaques after MI 0 5 10 15 20 25 30 35Patients(%) Recurrent AC S Repeat PTCA PTCA non-culprit CA BG Single Multiple Goldstein JA. NEJM. 2000;343:527-8 p≤ 0.001 p≤ 0.001 p≤ 0.001 p≤ 0.001
  132. 132. Editorial: “The coronary tree may veritably teem with plaques at high risk of rupture and thrombosis” “For every culprit lesion, other potentially troublesome plques may lurk undetected” Libby P. J Am Coll Cardiol 2005; 45(10):1585-1594. “Clearly, early invasive management, including local intervention on the culprit lesion in conjunction with contemporary pharmacologic “adjuvants,” can improve outcomes of many with acute coronary syndromes. Still, recurrent cardiovascular events in this population remain unacceptably high. We must think not only locally, fixed by our traditional focus on the culprit lesion, but also consider globally the other vulnerable plaques in the coronary and other arteries of patients with acute coronary syndromes.”
  133. 133. Angiographically complex lesions were present in 40% of patients with ACS Goldstein JA. NEJM. 2000;343:527-8
  134. 134. “Because the vulnerable plaques are not abundant and are often located proximally in major arteries, an effort to detect vulnerable plaques is justified”. Narula J, Finn AV and DeMaria AN. J Am Coll Cardiol. 2005;45(12):1970-1973
  135. 135. Imaging techniques targeting the TCFA Modality Resolution Penetration Fibrous cap Lipid core Angioscopy NA Poor + ++ OCT 10 um Poor +++ ++ Thermography NA Poor - - Spectroscopy NA Poor + ++ IVMRI 160 um Good + +++ IVUSIVUS 100 um Good + ++ PalpographyPalpography NA NA ++ + VHVH 100 um Good ++ +++ Modality Inflammation Calcium Thrombus Remodeling Angioscopy - - +++ - OCT ++ +++ + - Thermography +++ - - - Spectroscopy ++ ++ - - IVMRI - + - - IVUSIVUS - +++ + +++ PalpographyPalpography ++ - + - VHVH - +++ - +++
  136. 136. In Vitro Predictive Accuracy of IVUS based Tissue Characterization from Results, 61LADs, 104 sections Tissue Type Predictive Accuracies Train – 75% Test – 25% Fibrous (n = 115) 90 80 Fibro-Lipid (n = 63) 93 81 Lipid-Core (n = 88) 89 85 Calcium (n = 56) 91 93
  137. 137. In Vitro Experience 91 88 93 87 85 83 Calcified, lipid necrotic core Fibrotic cap about 400 µm
  138. 138. Should we pursue a combined approach using different catheter- based techniques to potentially enhance the prognostic value for the detection of vulnerable plaque? While exciting and promising, there is still no gold-standard and all techniques have different pitfalls…
  139. 139. In-vivo relationship between compositional and mechanical imaging of coronary arteries Insights From Intravascular Ultrasound Radiofrequency Data Analysis Objective: To explore in vivo the hypothesis that high strain regions have necrotic core-rich plaques as sub-intimal substrate. Definition of high strain A region was defined as a high-strain spot when it had high strain [>1.2% at 4 mm Hg pressure difference (ROC III-IV)] that spanned an arc of at least 12° at the surface of a plaque (identified on the IVUS recording) adjacent to low-strain regions (<0.5% at 4 mm Hg pressure difference). The highest value of strain was taken as the strain level of the spot. Such characteristics should be present for at least 1 whole cardiac cycle.
  140. 140. 123 palpography previously analyzed spots (27 patients) were randomly selected by an independent observer ROC III-IV, n= 60 (high strain, labelled red and yellow respectively) ROC I-II, n= 63 (low strain, labelled blue) Co-localization of the same spots in the IVUS-VH software with side-by-side view Two IVUS pullbacks: Palpography: 20 MHz Avanar IVUS-VH: 30 MHz Ultracross
  141. 141. LCx LCx LMCA Distal LAD * * 040471
  142. 142. Necrotic core relation with the lumen No contact Contact p value Calcium (%) 0.25± 0.7 1.6± 2.5 0.001 + Fibrous (%) 76± 13.7 64± 12 <0.001 - Fibrolipidic (%) 21± 14 19± 9 0.21 = Necrotic core (%) 3± 4 16± 11 <0.001 + PAV (%) 49± 9 51± 11 0.38 = Eccentricity index 0.15± 0.1 0.23± 0.1 0.01 + Percent atheroma volume (PAV) was defined as EEMarea -Lumenarea /EEMarea X 100, where EEM refers to external elastic membrane. EI refers to plaque eccentricity index, defined as minimum plaque thickness divided by maximum plaque thickness. Plaque composition and conventional intravascular ultrasound output in cross-sections with and without necrotic core contact with the lumen
  143. 143. What is the relation between strain (palpography) and compositional (IVUS-VH) imaging? After adjusting for all IVUS-VH derided variablesAfter adjusting for all IVUS-VH derided variables (calcified(calcified content, fibrous content, fibrolipidic content, necrotic corecontent, fibrous content, fibrolipidic content, necrotic core content, eccentricity index, percent atheroma volume andcontent, eccentricity index, percent atheroma volume and contact of necrotic core with the lumen)contact of necrotic core with the lumen) ,, the only independent predictor of high strain was thethe only independent predictor of high strain was the contact of NC with the lumen [OR 5.0 (CI 95% 1.7-contact of NC with the lumen [OR 5.0 (CI 95% 1.7- 14.1), p= 0.003].14.1), p= 0.003].
  144. 144. ““The coronary tree may veritably teem with plaques atThe coronary tree may veritably teem with plaques at high risk of rupture and thrombosis”high risk of rupture and thrombosis” ““For every culprit lesion, other potentially troublesomeFor every culprit lesion, other potentially troublesome plaques may lurk undetected”plaques may lurk undetected” Libby P. J Am Coll Cardiol 2005; 45(10):1585-1594. Editorial comment: ““Because the vulnerable plaques are not abundant andBecause the vulnerable plaques are not abundant and are often located proximally in major arteries, an effort toare often located proximally in major arteries, an effort to detect vulnerable plaques is justified”.detect vulnerable plaques is justified”. Narula J, Finn AV and DeMaria AN. J Am Coll Cardiol. 2005;45(12):1970-1973
  145. 145. One-year outcome of single vs multiple complex coronary plaques after MI Goldstein JA. NEJM. 2000;343:527-8 0 5 10 15 20 25 30 35 Patients(%) Recurrent ACS Repeat PTCA PTCA non-culprit CABG Single Multiple p≤ 0.001p≤ 0.001 p≤ 0.001 p≤ 0.001 Angiographically complex lesions were present in 40% of patients with ACS
  146. 146. Multiple plaque rupture: 3-vessel IVUS assessment in 24 first ACS patients 0 10 20 30 40 50 60 70 80 90 100 Patients(%) In culprit lesion Outside culprit lesion In other vessel In both other vessels Rioufol G et al. Circulation.2002;106:804
  147. 147. • High incidence of yellow non-disrupted plaques in by angioscopy (3.4±1.8, n=21). • Yellow plaques were equally prevalent in the infarct-related and non–infarct-related coronary arteries ACS as a multifocal instability process Asakura M. J Am Coll Cardiol. 2001 Apr;37(5):1284-8 Culprit lesion
  148. 148. Non-invasive assessment (MSCT)
  149. 149. RCA 51 9372 70 55 25 LCA 55 90 42 51 71 48 48 30 53 16 MSCT Coronary Plaque Burden Distribution (%) (41 patients: stable / unstable 59.5 ± 10 yrs)
  150. 150. 38% 62% P(-) P(+) Noncalc MX Calc 32% 43% 25% 53% > 50%<50% Plaque Extent Plaque Type Plaque Size 47% MSCT Coronary Plaque Burden 41 patients (473 segments)
  151. 151. Major criteria Yes? Lipid core size No Thin Cap No Inflammation MSCT Vulnerable Plaque: Limitations Naghavi Circulation 2003;108:1664 Lipid plaque Thrombotic plaque 35 HU 10 HU Yes Coronary stenosis No Fissured plaque No Endoth. denudation
  152. 152. 64-MSCT coronary plaque imaging Mixed plaqueNon-calcific plaque Calcific plaque
  153. 153. Major criteria Yes? Lipid core size No Thin Cap No Inflammation Yes Coronary stenosis No Fissured plaque No Endoth. denudation MSCT Vulnerable Plaque: Limitations Minor criteria Yes Remodeling No Endothelial dysf. No Intraplaque hemorrh. No Glistening yellow No Superf. Calc. nodule Naghavi Circulation 2003;108:1664 Lipid plaque Thrombotic plaque 35 HU 10 HU
  154. 154. 16 – slice MSCT ( prototype Straton 370ms ) Selected patients (61) with atypical chest pain or stable angina HR < 70 bpm (spontaneous / drugs) No or mild presence of calcium Coronary tree (> 2 mm) Sensitivity 95 % Specificity 98 % Mollet JACC 2005;45:128
  155. 155. -200 -100 0 100 200 300 400 500 600 700 Sal Low Mid High CM Pla Ca Surr Impact of lumen attenuation on plaque measurementsImpact of lumen attenuation on plaque measurements HU Calcium andCalcium and peri-vascularperi-vascular fat are notfat are not influenced byinfluenced by intra-luminalintra-luminal attenuation.attenuation. PlaquePlaque attenuationattenuation increases asincreases as the intra-the intra- vascularvascular attenuationattenuation increases.increases.
  156. 156. Method • High quality digital imagesHigh quality digital images of histology were printed.of histology were printed. • Transparent film was tapedTransparent film was taped over page.over page. • Borders drawn with blackBorders drawn with black permanent markerpermanent marker • Dr Virmani asked to reviewDr Virmani asked to review corresponding slide andcorresponding slide and draw her version of VH ondraw her version of VH on the transparent film usingthe transparent film using coloured markers.coloured markers. • Green – fibrous; LimeGreen – fibrous; Lime green – fibrofatty; Red –green – fibrofatty; Red – necrotic core; purple –necrotic core; purple – calciumcalcium • Dr Virmani was not shownDr Virmani was not shown the Grayscale or VHthe Grayscale or VH
  157. 157. CCF 04106 B2 Color Scheme – Same as VH Except, Calcium = Purple • Notes:Notes:  FibroatheromaFibroatheroma  Blue = vesselsBlue = vessels  Necrotic core with speckledNecrotic core with speckled microcalficationmicrocalfication Grey-Scale VH Virmani-VH
  158. 158. Intracoronary OCT Calcified Nodule Thickness of fibrous cap: 0.17mm Calcified nodule: 0.43mm2 Plaque With a disruptive calcified nodule
  159. 159. Why do we need to detect the TCFA? In a series of 200 sudden death cases, 60% of acute thrombi resulted from disruption of TCFA Virmani R. Arterioscler Thromb Vasc Biol. 2000;5:1262-75
  160. 160. 64-slice MSCT : Higher resolution, faster ! Assessment of entire coronary tree Isotropic imaging: 0.4 x 0.4 x 0.4mm tube rotation time: 330 msec Scan time: ∼12 seconds 51 patients; 61 yrs Sensitivity :95% Specificity :96% Mollet ACC 2005, abst.
  161. 161. Definition of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA) 1. Focal (adjacent to non-TCFA) 2. Lipid core ≥10% 3. In direct contact with the lumen 4. Vessel area obstruction ≥40% FIBROU S FIBROFAT Y CALCIU M LIPID CORE MEDIA VH Legend •Per 3 consecutive frames with all characteristics Rodriguez-Granillo GA, García- García HM, McFadden E et al. J Am Coll Cardiol. In press.
  162. 162. Does spatialDoes spatial heterogeneity ofheterogeneity of (experimental) plaques(experimental) plaques contain informationcontain information
  163. 163. • Plaque rupture occurs predominantelyPlaque rupture occurs predominantely upstream of plaques in carotid arteryupstream of plaques in carotid artery • Vulnerable plaque occurs at first 30 cmVulnerable plaque occurs at first 30 cm of coronary arteriesof coronary arteries • This heterogeneity may help to identifyThis heterogeneity may help to identify us with regional mechanismus with regional mechanism independent of classical risk factorsindependent of classical risk factors Introduction
  164. 164. • Introduce a new 3D histology techniqueIntroduce a new 3D histology technique • Provide evidence for the mechanismProvide evidence for the mechanism that local accumulation of lipidsthat local accumulation of lipids activates inflammatory cells to produceactivates inflammatory cells to produce plaque weakoning factorsplaque weakoning factors Introduction
  165. 165. oxLDL Macrophages MMPs SMC
  166. 166. 50403020100 x106 Distance from Renal Artery (mm) 0 1 2 3 PlaqueArea(µm2 ) Plaque Area Distance from Renal Artery (mm) 5 1 0 1 5 0 50403020100 Density(%) Macrophages 60 50403020100 40 20 Density(%) Distance from Renal Artery (mm) Lipids 0 60 50 40 30 20 10 0 50403 0 2 0 100 Density(%) Distance from Renal Artery (mm) Smooth Muscle Cells
  167. 167. 0 5 10 15 20 25 50403020100 Distance from Renal Artery (mm) VI-index Plaque area VI-index VI= SMC MO + Lipids
  168. 168. A C D B
  169. 169. oxLDL distibutionMMP activity smcsmc mac mac MMP-activity Ox-LDL accumulation unknown unknown
  170. 170. A B
  171. 171. Plaque rupture proximal of minimal lumen • Coronary arteryCoronary artery Fujii, et al. Circulation 2003Fujii, et al. Circulation 2003 • Carotid arteryCarotid artery Lovett and Rothwell,Lovett and Rothwell, Cerebrovasc Dis 2003Cerebrovasc Dis 2003 Dirksen et al., CirculationDirksen et al., Circulation 19981998 Masawa, PathologyMasawa, Pathology International 1994International 1994  Reason(s)?  Direct mechanical effect of shear stress Gertz and Roberts, Editorial Am J Card, 1990  Biological effect of shear stress on cap stability Hemodynamics Laboratory Thoraxcenter Rotterdam Slager et al., Nat Clin Pract Card 2005
  172. 172. Cap weakening due to High Shear Stress
  173. 173. 0 100 200 300 400 500 600 No. of CSA with NC >10% Mean PB * 10 Mean MLD *100 p=0.014 Proxima l Distal
  174. 174. -4 -2 0 2 4 Log Calcium -4 -2 0 2 4 LogNecroticCore Pearson Correlation Coefficient 0,74**, p=0.000 **Correlation is significant at the 0.01 level (2-tailed).
  175. 175. 1 2 3 4 NC>20% NC>15% NC>10% NC>5% 0 100 200 300 400 500 600 700 800 900 Distribution of the number of CSAs according to the mean percentage of necrotic core along the atherosclerotic plaque
  176. 176. 1 2 3 4 NC>20% NC>15% NC>10% NC>5% 0 100 200 300 400 500 600 700 800 900
  177. 177. Directed Flush Catheter (Lightlab OPTICAL COHERENCE TOMOGRAPHY (OCT) 140140 1–151–15 Thin fibrous cap Resolution Probe Size (μm) (μm)
  178. 178.  Detection of lipid-rich plaque Yabushita, Circulation 2002.  Spectroscopy: chemical composition Schmitt, IEEE, 2002.  Vizualization of thin fibrous cap Jang, 4th VP Symposium, Chicago 2002  Detection of macrophages OCT – Potential for VP DetectionOCT – Potential for VP Detection MacNeill, JACC 2004 I. K. Jang, presented in Chicago 2002
  179. 179. dist prox Plaque rupture? Thrombus OCT Imaging: Culprit lesion
  180. 180. dist prox a a a b b b TCFA OCT Imaging: Culprit lesion
  181. 181. Can OCT help us in predicting intraplaque hemorrage? Intracoronary OCT Side Branch or Vasa Vasorum?
  182. 182. 020854 LAD 62 year, male, CCS III hypertension, smoking, hypercholesterolemia Intracoronary OCT Thick Fibrous Cap Atheroma Plaque Prone to Erosion Lipid Necrotic Core Lipid
  183. 183. calcium thrombus E. Regar, P.W. Serruys Plaque With a disruptive calcified nodule
  184. 184. MSCT Pim de Feyter Carlos van Mieghem Nico Mollet Thoraxcenter’s “vulnerable plaque detection”group: IVUS-VH Gastón Rodriguez-Granillo Héctor M. García-García Marco Valgimigli Palpography Anton van der Steen Johannes Schaar OCT / IVMRI Evelyn Regar
  185. 185. METHODOLOGY Geometrical validation of intravascular ultrasound radiofrequency data analysisGeometrical validation of intravascular ultrasound radiofrequency data analysis (Virtual Histology(Virtual HistologyTMTM ) acquired with a 30 MHz Boston Scientific Corporation imaging) acquired with a 30 MHz Boston Scientific Corporation imaging catheter.catheter. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Catheter Cardiovasc Interv.Catheter Cardiovasc Interv. In press.In press. Reproducibility of Intravascular Ultrasound Radiofrequency Data Analysis:Reproducibility of Intravascular Ultrasound Radiofrequency Data Analysis: Implications for the Design and Conduction of Longitudinal Studies. RodriguezImplications for the Design and Conduction of Longitudinal Studies. Rodriguez Granillo GA, Serruys PW et al. In process.Granillo GA, Serruys PW et al. In process. Methodological Considerations and Approach to Cross-Technique Comparisons usingMethodological Considerations and Approach to Cross-Technique Comparisons using In Vivo Coronary Plaque Characterization Based on Intravascular UltrasoundIn Vivo Coronary Plaque Characterization Based on Intravascular Ultrasound Radiofrequency Data Analysis: Insights From the Integrated Biomarker and ImagingRadiofrequency Data Analysis: Insights From the Integrated Biomarker and Imaging Study (IBIS).Study (IBIS). Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. International Journal of CardiovascularInternational Journal of Cardiovascular Interventions.Interventions. 2005;7(1):52-8.2005;7(1):52-8. Rationale and methods of the integrated biomarker and imaging study (IBIS):Rationale and methods of the integrated biomarker and imaging study (IBIS): combining invasive and non-invasive imaging with biomarkers to detectcombining invasive and non-invasive imaging with biomarkers to detect subclinical atherosclerosis and assess coronary lesion biologysubclinical atherosclerosis and assess coronary lesion biology Van Mieghem CAG,Van Mieghem CAG, Serruys PW et al.Serruys PW et al. Int J Cardiovasc Imaging. 2005 Aug;21(4):425-Int J Cardiovasc Imaging. 2005 Aug;21(4):425- 41.41.
  186. 186. PLAQUE COMPOSITION OF NON-CULPRIT ARTERIES Coronary plaque composition of non-culprit lesions by in vivoCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data analysis is related tointravascular ultrasound radiofrequency data analysis is related to clinical presentation.clinical presentation. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press Global characterization of coronary plaque rupture phenotype using 3-Global characterization of coronary plaque rupture phenotype using 3- vessel intravascular ultrasound radiofrequency data analysis.vessel intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al.
  187. 187. HISTOLOGICAL SURROGATES In vivo intravascular ultrasound derived thin-cap fibroatheromaIn vivo intravascular ultrasound derived thin-cap fibroatheroma detection using utrasound radiofrequency data analysis.detection using utrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. J Am Coll Cardiol.J Am Coll Cardiol. InIn presspress
  188. 188. CORONARY REMODELLING Coronary artery remodelling is related to plaqueCoronary artery remodelling is related to plaque composition.composition. Rodriguez Granillo GA, Serruys PW, García-Rodriguez Granillo GA, Serruys PW, García- García HM, et al. Heart. Jun 17; [Epub aheadGarcía HM, et al. Heart. Jun 17; [Epub ahead of print].of print].
  189. 189. NON-UNIFORM DISTRIBUTION OF PLAQUE COMPOSITION ALONG CORONARY VESSELS Distance from the Ostium as an Independent Determinant ofDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An IntravascularCoronary Plaque Composition In Vivo An Intravascular Ultrasound Study Based Radiofrequency Data Analysis InUltrasound Study Based Radiofrequency Data Analysis In Humans.Humans. Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Submitted.Submitted. Plaque composition in the left main Stem mimics the distal butPlaque composition in the left main Stem mimics the distal but not the proximal tract of left coronary artery. Influence ofnot the proximal tract of left coronary artery. Influence of clinical presentation, length of the left main trunk, lipid profileclinical presentation, length of the left main trunk, lipid profile and systemic inflammatory status.and systemic inflammatory status. SubmitedSubmited Valgimigli M, Serruys PW et al.Valgimigli M, Serruys PW et al.
  190. 190. COMBINED IMAGING APPROACH Detection of a lipid-rich, highly deformable plaque in an angiographically non-diseasedDetection of a lipid-rich, highly deformable plaque in an angiographically non-diseased proximal LAD.proximal LAD. Rodriguez Granillo GA, Serruys PW et al. Eurointervention. In press.Rodriguez Granillo GA, Serruys PW et al. Eurointervention. In press. In vivo relationship between compositional and mechanical imaging of coronaryIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights from intravascular ultrasound radiofrequency data analysis.arteries: insights from intravascular ultrasound radiofrequency data analysis. Rodriguez Granillo GA, Serruys PW et al. Am Heart J. Submitted.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. Submitted. In vivo, cardiac-cycle related intimal displacement of coronary plaques assessed by 3-In vivo, cardiac-cycle related intimal displacement of coronary plaques assessed by 3- D ECG-gated intravascular ultrasound: exploring its correlate with tissueD ECG-gated intravascular ultrasound: exploring its correlate with tissue deformability identified by palpography.deformability identified by palpography. Rodriguez Granillo GA, Serruys PW et al. International Journal of CardiovascularRodriguez Granillo GA, Serruys PW et al. International Journal of Cardiovascular Imaging. In press.Imaging. In press. Non-invasive Detection of Subclinical Coronary Atherosclerosis Coupled WithNon-invasive Detection of Subclinical Coronary Atherosclerosis Coupled With Assessment, Using Novel Invasive Imaging Modalities, of Changes in PlaqueAssessment, Using Novel Invasive Imaging Modalities, of Changes in Plaque Characteristics: The IBIS Study (Characteristics: The IBIS Study (IIntegratedntegrated BBiomarker andiomarker and IImagingmaging SStudy).tudy). Van Mieghem, Serruys PW et al. J Am Cardiol C. In press.Van Mieghem, Serruys PW et al. J Am Cardiol C. In press.
  191. 191. PLAQUE PROGRESSION In vivo variability in quantitative coronary ultrasound and tissueIn vivo variability in quantitative coronary ultrasound and tissue characterization with mechanical and phased-array catheters.characterization with mechanical and phased-array catheters. Rodriguez Granillo GA, Serruys PW et al. International Journal ofRodriguez Granillo GA, Serruys PW et al. International Journal of Cardiovascular Imaging. In press.Cardiovascular Imaging. In press. Statin therapy promotes plaque regression: a meta-analysis of theStatin therapy promotes plaque regression: a meta-analysis of the studies assessing temporal changes in coronary plaque volumestudies assessing temporal changes in coronary plaque volume using intravascular ultrasound.using intravascular ultrasound. Rodriguez Granillo GA, Serruys PW et al. Submitted.Rodriguez Granillo GA, Serruys PW et al. Submitted.
  192. 192. Shear Stress • Plaque Composition and its Relationship withPlaque Composition and its Relationship with Acknowledged Shear Stress Patterns inAcknowledged Shear Stress Patterns in Coronary Arteries.Coronary Arteries. • Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. JACC. In pressJACC. In press
  193. 193. C h e s t- P a in a tta c k N o n - In v a s iv e Im a g in g B io m a r k e r s E n tr ie s in t h e D ia g n o s tic p r o c e s s The “new diagnostic world“ of the vulnerable plaque Chest pain MSCT Biomarkers High Risk
  194. 194. Focal characteristics of ruptured plaques (20) and minimal lumen area (MLA) controls (n= 28)   Rupture site MLA site p value   Geometrical parameters Lumen CSA (mm2 ) 9.47±6.3 6.76±4.2 <0.001 Vessel CSA (mm2 ) 19.09±9.3 19.15±9.8 0.95 Plaque CSA (mm2 ) 9.63±4.2 12.38±6.9 0.01 Plaque max. thickness (mm) 1.38±0.3 1.71±0.5 0.002 Plaque burden (%) 51.32±10.6 64.06±10.1 <0.001   Compositional parameters Calcium CSA (mm2 ) 0.33±0.3 0.35±0.3 0.62 Calcium (%) 6.07±6.3 4.60±4.6 0.10 Fibrous CSA (mm2 ) 3.76±2.2 5.48±3.8 0.01 Fibrous (%) 59.46±11.8 60.22±9.6 0.60 Fibrolipidic CSA (mm2 ) 1.27±1.3 2.19±2.0 0.02 Fibrolipidic (%) 16.99±9.4 22.08±9.8 0.01 Necrotic core CSA (mm2 ) 0.98±0.7 1.10±0.7 0.34 Necrotic core (%) 17.48±10.8 13.10±6.5 0.03 Values are expressed in means ±SD. CSA refers to cross-sectional area. #1
  195. 195. GA Rodriguez-Granillo, HM Garcia-Garcia, M Valgimigli, et al. Submitted Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam Global characterization of coronary plaque rupture phenotype using 3-vessel intravascular ultrasound radiofrequency data analysis Disclosure: GA Rodriguez-Granillo has received a research grant from Volcano Therapeutics. #1
  196. 196. 1 2 3 4 Subsegments 0 10 20 30 40 50 60 70 % CALCIFIED LIPIDCORE FIBROLIPID FIBROUS Upstream Downstream
  197. 197. 37 37 36 36 35 35 34 34 34 33 33 32 32 31 31 30 30 29 29 28 28 28 27 27 26 26 25 Frames 0 20 40 60 80 100Relativecomposition CALCIFIED LIPIDCORE FIBROLIPID FIBROUS pat 40122 MDP DownstreamUpstream

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