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Vulnerable Plaque

Vulnerable Plaque. Simon Redwood St Thomas’ Hospital, London. Definitions of Vulnerable Plaque. Functional Definition A plaque, often non-stenotic , that has a high likelihood of becoming disrupted and forming a thrombogenic factor after exposure to an acute risk factor

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Vulnerable Plaque

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  1. Vulnerable Plaque Simon Redwood St Thomas’ Hospital, London

  2. Definitions of Vulnerable Plaque • FunctionalDefinition • A plaque, often non-stenotic, that has a high likelihood of becoming disrupted and forming a thrombogenic factor after exposure to an acute risk factor • Histological Definition • Plaque containing a thin fibrous cap, lipid pools and macrophages • Prospective Definition • A signature that has been proven in a prospective study to identify a plaque that is prone to disrupt and can be recognised and measured in the cath lab James Muller

  3. Causes of Coronary Thrombosis Erosion Rupture Calcified nodule Rupture Site Calcified Nodule NC Th Th Th Th NC FC Th Th Th Th Virmani R, et al. Arterioscler Thromb Vasc Biol 2000;20:1262

  4. The impact of early “vulnerable” plaque detection and therapy would be a major breakthrough in the management of patients with coronary, peripheral and neurovascular disease!!! Vulnerable Plaque Thin fibrous cap + lipid core + dense macrophages Plaque rupture

  5. Thermography, Spectroscopy, MRI with targeted CM Activity Inactive and non-inflamed plaque Active and inflamed plaque Morphology IVUS MRI w/o CM OCT Morphology vs. Activity Imaging

  6. up to +2.2°C Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis 50 Carotid endarterectomy samples Casscells et al. Lancet 1996;25:1447-1451

  7. up to +2.6°C Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter 45 controls 15 stable angina 15 unstable angina unresponsive to Rx 15 AMI within 6 hrs Stefanadis et al. Circulation 1999;20:1965-1971

  8. up to +1.5°C Increased local temperature in human coronary atherosclerotic plaques: an independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention Stefanadis et al. JACC 2001;37:1277-1283

  9. up to +1.2°C Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques Stefanadis et al. EHJ 2002;23:1664-1669

  10. Figure 1. Severe stenosis in the mid left anterior descending artery Figure 2. The VolcanoThermography Catheter Basket with five peripheral thermistors and one central sensor. Figure 3 An example of temperature measurements at the site of a left anterior descending artery plaque. The mid vessel temperature, and the variations from this at the sites of apposition of the peripheral sensors, are displayed

  11. IVUS at 90mmHg (t1, P1) Processing (t2,P2) IVUS elastogram IVUS at 85mmHg Intravascular Elastography/ Palpography The response of tissue to compression is a function of its mechanical properties and composition In vitro – related to composition Thoraxcentre, Rotterdam

  12. VH Legend MEDIA FIBROUS M-OA FIBROLIPIDIC CALCIUM LIPID CORE Virtual Histology

  13. Controversies • Vulnerable Plaque • Is it an outdated concept? • Which plaques cause events?

  14. Vulnerable Plaque An Outdated Concept?? More important to identify patients in whom disruption of a vulnerable plaque is likely to result in a clinical event: ‘The Vulnerable Patient’

  15. Diffuse Vulnerability:Vulnerable Arterial Bed 24 patients with ACS, 72 arteries explored with IVUS 80% of ACS patients have > 1 ruptured plaque Patients (%) Number of ruptured plaques in addition to culprit lesion Rioufol et al. , Circulation 2002; 106:804-808

  16. Clinical Outcomes After PCI One-year FU for Adverse Clinical Events Percent of Events ACS (N=2,971) P=0.0007 Non-ACS (N=5,051) P=0.0008 19.0% 13.2% 15.9% P=0.0013 P=NS 10.6% 4.2% 4.7% 4.6% 2.8% Death MI Non-TVR Death/MI/Non-TVR

  17. Widespread coronary inflammation in unstable angina • Neutrophil myeloperoxidase measured in 5 groups of patients • LAD (n=24) and RCA (n=9) unstable angina • Stable angina (n=13) • Variant angina with recurrent ischaemia (n=13) • Controls (n=6) • Aorta and great cardiac vein sampling • Drains LAD territory Buffon et al. (Maseri) New Engl J Med 2002; 347: 5-12

  18. Vulnerable Coronary Arterial Bed • Sampling in the coronary sinus • A-V difference in Myeloperoxidase index Buffon et al. New Engl J Med 2002; 347: 5-12

  19. Transcardiac Cytokine Gradient 16 ** **P<0.01 • 38 pts with Braunwald IIIb UA • Time from symptom onset 8.6 + 5.7 hrs • Simultaneous aorta and coronary sinus sampling • Divided according to troponin status ** 12 P=ns 8 IL-6(ng/mL) 4 0 All Patients TnT +ve TnT -ve Cusack & Redwood JACC 2002;39:1917-23

  20. Stefanadis et al. Circulation 1999;20:1965-1971

  21. 54 year old male • Admitted with 6 hours intermittent pain • Troponin-T positive • Dynamic inferior ST/T changes

  22. Aalst Stefanadis

  23. Serological Markers of VulnerabilityReflecting Metabolic and Immune Disorders • Lipoprotein profile • High LDL, low HDL, Lp-A, lipid peroxidation (ox-LDL, ox-HDL), etc • Markers of inflammation • hsCRP, IL-6, CD40L, ICAM-1, VCAM-1, P-selectin, leucocytosis, anti-LDL Ab, anti-HSP Ab, etc • Markers of metabolic syndrome • eg diabetes, hypertriglyceridaemia • Others • Homocysteine, PAPP-A, ADMA, DDAH, NEFA

  24. Serological Markers of VulnerabilityReflecting Hypercoagulability • Blood Hypercoagulability • Fibrinogen, d-dimer, factor V leiden, factors V, VII, VIII, XIII, von Willebrand factor, protein S and C, thrombomodulin, antithrombin III • Transient factors: smoking, dehydration, infection, cocaine, postprandial, etc • Platelet activation/ aggregation • Gene polymorphisms of IIb/IIIa, Ia/IIa, Ib/IX • Other • Anticardiolipin Abs, thrombocytosis, sickle, polycythaemia, diabetes, hypercholesterolaemia, hyperhomocysteinaemia, etc

  25. Which Plaques Cause ACS? Falk, Shah and Fuster, Circulation 1995 “Acute Coronary Syndromes most often occur at the site of mild stenoses”

  26. Which Plaques Cause ACS? • A few small studies • Retrospective • Selection bias • No QCA or IVUS • Visual estimation • Variable follow-up • Likely that many ‘mild’ stenoses progressed prior to occlusion

  27. % Occlusion at 5 Year Coronary Segments (n) 25 2161 Occlusion at FU 500 20 400 15 300 10 200 5 100 1% 2% 10% 24% 0 0 None 5-49% 50-80% 81-95% None 0-49% 50-80% 81-95% Stenosis Severity at Baseline Stenosis Severity at Baseline Coronary Occlusion at 5 Years as a Function of Initial Stenosis Severity Alderman et al, JACC 93

  28. MACE (%) > 5 (n=193) 4.0 - 4.9 (n =55) 3.0 - 3.9 (n=36) 2.0 - 2.9 (n=17) Minimum Luminal CSA (mm²) Long-term Follow-up After PTCA was Deferred Based on IVUS Findings • 357 lesions • 13 month follow-up • Independent predictors of MACE: • IVUS MLA • IVUS AS Abizaid, Circ 99

  29. % of Total Number (n=182) of Stenoses Mean = 91 % Area Stenosis  68 % Diameter Stenosis Area Stenosis (%) Severity of Atherosclerosis at Sites of Plaque Rupture with Occlusive Thrombus • Autopsy data • 182 patients who died from AMI • Plaque rupture with occlusive thrombus occurs at the site of tight stenoses Qiao, JACC 91

  30. Angio Autopsy IVUS % of Total Number of Stenoses Any Cardiac Event (%) % Occlusion at 5 Years 70 25 60 20 50 15 40 30 10 20 5 10 0 0 > 5 (n=193) 4.0 - 4.9 (n =55) 3.0 - 3.9 (n=36) 2.0 - 2.9 (n=17) None5-49% 50-80% 81-95% 67-75% 76-80% 81-90% >90% Area Stenosis (%) Stenosis Severity at Baseline Minimum Luminal CSA (mm²) Risk of Coronary Events Increases with the Severity of Luminal Narrowing

  31. FFR for Risk Stratification of Patients with an Intermediate Stenosis • 107 patients • SA or UA (I or II) • 40-70% stenosis on angio (in addition to treated lesion) • No perfusion defect on SPECT • 1 year follow-up • Divided according to FFR > or < 0.75 Chamuleau et al, AJC 2002; 89: 377-380

  32. Conclusions • Imaging ‘vulnerable’ plaques is a fascinating research tool providing useful insights into the pathophysiology of ACS • At present, it has little clinical use • ‘Local’ therapy, in the absence of documented ischaemia, is unproven

  33. Conclusions • Risk stratification should be based on ischaemia detection, markers of necrosis, inflammation and thrombogenicity • All patients should have ‘systemic’ therapy aimed at ‘stabilising’ plaques • Aspirin/ clopidogrel/ IIbIIIa antagonists • B blockers and ACE inhibitors • High dose statins

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