Biological Markers & Diagnosis of Unstable Plaques

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1 Identification of vulnerable atherosclerotic plaques and impact on treatment decision Chairmen : A. K. Banerjee, C. Erol Stocholm, August 30 th, 2010 Biological Markers & Diagnosis of Unstable Plaques C.D. Liapis MD, FACS, FRCS, Professor and Chairman Department of Vascular Surgery Attikon University Hospital Athens University Medical School

2 Atherosclerosis αθήρι (athere=gruel) and σκληρός (skleros=hard) Atherosclerosis develops over the course of the years, beginning in the early teens. Progressive lumen stenosis of cardiac or extracardiac arteries triggers ischemia However abrupt plaque rupture or erosion and consequent thrombosis leads to acute cardiovascular events C.Liapis. Atherosclerotic Risk Factors. Ruterfords 7 th Edition 2010

3 Vulnerable plaque The Challenge of Terminology Vulnerable : susceptible to injury or susceptible to attack, as in we are vulnerable both by water and land, without either fleet or army (Alexander Hamilton). Vulnerable Plaque: thrombosis-prone plaques with a high probability of undergoing rapid progression, thus becoming culprit plaques Vulnerable Plaque: A Prospective Term Culprit Plaque: A Retrospective Term Vulnerable Plaque = Future Culprit Plaque

4 The Vulnerable Patient Consensus Statement Lessons Learned by Coronary Plaques Naghavi et al. Circulation. 2003;108:1664

5 Vulnerable plaque Vulnerable plaque: Thin fibrous cap, large necrotic lipid core, inflammation, less calcium deposition, surface irregularities Vulnerable plaque prone to rupture, erosion and/or thrombosis leads to: 1. Acute coronary syndromes 2. Ischemic strokes and transient ischemic attacks (TIAs)

6 Markers for Defining Vulnerable Plaque Major criteria Active inflammation (monocyte/macrophage -T-cells) Thin cap with large lipid core Endothelial denudation & platelet aggregation Fissured plaque Critical Stenosis Minor criteria Superficial calcified nodule Glistening yellow Intraplaque hemorrhage Endothelial dysfunction Outward (positive) remodeling

7 Carotid vs Coronary Vulnerable Plaque Carotid Artery Disease STROKE ~ Coronary Artery Disease AMI y) Virmani R et al. Neurosurgery 2006

8 Why is it important to detect the Vulnerable Plaque? RISK OF STROKE,MI,CARDIO VASCULAR DEATH Patient Selection & Treatment Planning

9 Markers of Vulnerability Imaging Biological Markers

10 Current diagnostic modalities are insufficient to detect vulnerable carotid lesions DSA CTA MRA Adequate for anatomy and degree of stenosis but... No accurate info on plaque activity and composition

11 Imaging of The Vulnerable Plaque Ultrasound Plaque Classification based on ultrasonic appearance Type I (uniformly echolucent) Type II (predominately echolucent) Type III (predominately echogenic) Type IV (uniformly echogenic) Type V (heavy calcification) Lack of uniformity on reporting, operator dependency and the settings used on the equipment limited its widespread use for clinical management of patients.

12 Imaging of The Vulnerable Plaque Ultrasound Gray Scale Median (Computer analyzed global echogenicity of the plaque) Low GSM (<25), echolucent/high risk plaques High GSM (>25), echogenic/low risk plaques

13 Imaging of The Vulnerable Plaque Ultrasound Gray Scale Median... - is a predictor of stroke in natural history studies - is a predictor of stroke during CAS - does not modify the risk of stroke during CEA Biasi, G. M. et al. Circulation 2004

14 Ultrasonographic Risk Score of Carotid Plaques

15 Imaging of The Vulnerable Plaque Intravascular ultrasound (IVUS) Provides real-time, cross-sectional and high-resolution images with 3-D reconstruction capabilities - Advantages - Shows morphology of plaque - Differs between stable and unstable plaques - Disadvantages - Doesn t give information about inflammation - Low spatial resolution ( ~ 200 µm ) - Deeper plaque is not imaged

16 Imaging of The Vulnerable Plaque IVUS Virtual Histology Compared with histology, IVUS-VH correctly identified the presence of fibrous, fibro-fatty, and necrotic tissue in 58.33%, 38.33%, and 38.33% of lesions, respectively. IVUS-VH was not accurate in detecting the relative amount of specific plaque components Granada JF, et al, Arterioscler Thromb Vasc Biol 2007

17 Imaging of The Vulnerable Plaque Optical Coherence Tomography Measures the intensity of reflected near-infrared light from tissue - Advantages - Very high resolution ( ~ 10 µm ) - Near video rate ( 8 frames/sec. ) - Catheters are small ( inch ) - Disadvantages - Long image acquisition time - Cost - Limited penetration - Lack of physiologic data

18 Imaging of The Vulnerable Plaque High resolution MRI

19 Imaging of The Vulnerable Plaque Molecular MRI

20 Imaging of The Vulnerable Plaque High resolution MRI & PET High-resolution MRI and 18F-FDG PET in a patient with recent stroke, demonstrating increased metabolic activity in a plaque causing severe stenosis of the left internal carotid artery Muir KW. Inflammation and ischemic stroke. Curr Opin Neur 2007

21 Imaging of The Vulnerable Plaque High resolution PET & PET/CT Tahara, N. et al. J Am Coll Cardiol 2006;48 Tahara, N. et al. J Am Coll Cardiol 2007;49:1533

22 Imaging of The Vulnerable Plaque Emerging imaging technology Predicts the Vulnerable Plaque Adequate for plaque activity and composition but High operator dependence Poor diagnostic accuracy Invasive EXPENSIVE

23 Biomarkers, if applicable: Non operator dependent Non invasive Cost effective High sensitivity specificity (?)

24 Evolving Biomarkers in Carotid Vulnerability: Inflammatory markers CRP Fibrinogen Cytokines (TNF-a, IFN-g, IL-1b, IL-6, IL-8, IL-4, IL-10) MMPs (MMP-7, MMP-8, MMP-9, MMP-12) Infectious markers Chlamydia pneumoniae Helicobacter Cytomegalovirus Haemostatic markers Fibrinogen D-dimers Plasminogen activator inhibitor (PAI) Procoagulant factor VII Vascular calcification markers Osteopontin Osteoprotegerin Genomics & Proteomics (New Biomarker Targets)

25 Current Evidence for Biomarkers as predictors of vulnerable carotid plaques They predict the natural history of carotid and cerebrovascular disease They predict perioperative risk They may guide medical treatment They may guide carotid intervention (technique, timing etc)

26 Biomarkers as early predictors of cerebrovascular events 26 Follow up studies stratified by biomarker category and number of patients recruited. 19 demonstrate a positive prediction

27 Biomarkers as early predictors of cerebrovascular events 26 Follow up studies stratified by biomarker category and number of patients recruited. 19 demonstrate a positive prediction

28 Biomarkers as diagnostic tools of cerebrovascular events 20 Studies comparing symptomatic (stroke) and asymptomatic patients. 16 demonstrate a positive correlation

29 Biomarkers as diagnostic tools of cerebrovascular events 20 Studies comparing symptomatic (stroke) and asymptomatic patients. 16 demonstrate a positive correlation

30 Biomarkers predict the natural history of carotid and cerebrovascular disease Prospective studies relating baseline plasma CRP levels to the risk of first cerebrovascular event Di Napoli, M. et al. Stroke 2005

31 Biomarkers predict the natural history of carotid and cerebrovascular disease HRs of Ischemic stroke associated to baseline concentrations of CRP and Fibrinogen Patients with high levels of both CRP & Fibrinogen exhibit additive risk Tanne D. et al. Stroke 2006;37:

32 Biomarkers predict the natural history of carotid and cerebrovascular disease Patients indicated for CEA depict significantly higher blood cytokine levels Profumo et al. Clin Exp Immunol 2008

33 Biomarkers predict the natural history of carotid and cerebrovascular disease Elevated levels of MMP-9 in patients with >50% carotid stenosis are associated with a 2-fold risk of ipsilateral stroke or cardiovascular death. Eldrup N et al. Circulation 2006

34 Biomarkers predict the natural history of carotid and cerebrovascular disease Patients with CAD (76 asymptomatic & 69 symptomatic) MMP-7, -8, -9 and TIMP-1 are significantly enhanced in symptomatic patients. Combination of more than one biomarker enhances significantly the positive predictive value (PPV) for neurological symptoms compared to single MMP Single MMP: PPV 62.5% MMP-7MMP-9: PPV 73.1% MMP-7MMP-8MMP-9: PPV 73.8% Heider P, Pelisek J, Poppert H, Eckstein HH. Vasc Endovasc Surg 2009

35 Biomarkers predict the natural history of carotid and cerebrovascular disease Anti Cp IgA seropositivity in symptomatic and asymptomatic patients 78 patients indicated for CEA. Serum levels of Cp IgA are significantly correlated with CAD symptomatology asympt pts 30 p=< anti-cp IgA (-) 0 asymptom atic pts sym ptomati c pts () Kaperonis EA, Liapis CD, et al, JVS 2006

36 Biomarkers predict the natural history of carotid and cerebrovascular disease The Caerphilly study followed for 4 years suggests that fibrinogen, d-dimer, plasminogen activator inhibitor (PAI) activity, and procoagulant factor VII are independent risk factors that increase the prediction of stroke in middle aged men. Smith A et al. Circulation 2005

37 Biomarkers predict the natural history of carotid and cerebrovascular disease Vascular calcification markers predict carotid symptomatology 114 patients with CAD >50% ICA stenosis VARIABLES\ GROUPS Osteopontin (ng/ml) Osteoprotegerin (pmol/l) Symptomatic (60 pts) Asymptomatic (54 pts) Controls (50 pts) 79.72±51.1 a,b 54.58±27.91 c 41.84± P values p< ±4.02 a,b 6.78±2.05 c 5.74±2.39 p<0.05 hscrp (mg/l) 4.49±2.09 a,b 2.93±1.95 c 1.68±0.93 p<0.05 GSM 57.41±38.19 a 76.32±36.72 (a) p<0.05 group A vs B, (b) p<0.01 group A vs C, (c) p<0.05 group B vs C Kadoglou N, Liapis C, et al. J Vasc Surg 2008

38 Athero-Express Biobank Study - The study has succeeded to identify plaque characteristics that are predictive of restenosis and cardiovascular events after CEA - Combination of the prospective study design with a proteomics approach has enabled identification of several potential biomarkers to predict risk of future cardiovascular events - The validation process of these markers is ongoing and is expected to yield additional predictive markers in the near future Project Leaders: Prof G Pasterkamp, Prof F. Moll

39 Biomarkers related to carotid intervention outcome n Intervention Prognostic Value Comment CRP or hscrp Heider P, et al CEA Independent hscrp (but not CRP) RF for new periprocedural DWI cerebral lesions Groschel K, et al CAS Independent CRP RF of post-cas 30d stroke and death Fibrinogen Heider P, et al CEA Independent RF for new periprocedural DWI cerebral lesions WBC Aronow HD, et al CAS Independent Increased preprocedural WBC count is a RF for microembolic signals in TCD IL-6 Abe Y, et al CAS Independent Higher IL-6 levels were associated with new ischemic lesions All studies showed a positive prediction but the numbers of patients were small..

40 Biomarkers predict perioperative risk Preoperative levels of hscrp & Fibrinogen predict microembolization during CEA 183 patients with high grade ICA stenosis. The higher preop hscrp or Fibrinogen predicted higher rates of new cerebral lesions in postoperative diffusion weighted imaging Heider P, Eckstein HH, et al. JVS 2007;46

41 Biomarkers predict perioperative risk Preoperative levels of WBC predict microembolization during CAS Greater pre-procedure WBC is associated with more frequent TCD-detected distal embolisation during CAS. Aronow HD, et al Stroke 2005

42 Biomarkers predict perioperative risk Elevated CRP predicts perioperative stroke and death following CAS Groeschel K, et al. AJNR 2007

43 Biomarkers and Vulnerable Plaque Predict the natural history of carotid disease Predict perioperative risk of embolization Biomarkers are a useful adjunct to detect the vulnerable carotid plaque

44 Guidelines Recommendation 6. Treatment options according to carotid plaque morphology Plaque morphology should be assessed in all cases before invasive treatment. The plaque at risk of peri-procedural embolisation should be identified by validated imaging (GSM, etc.) or other diagnostic techniques such as biological markers [C]. Liapis CD, Bell PR, Mikhailidis D, Sivenius J, Nicolaides A, Fernandes e Fernandes J, Biasi G, Norgren L; ESVS Guidelines Collaborators. ESVS guidelines. Eur J Vasc Endovasc Surg. April 2009

45 Vulnerable Carotid Plaque and Treatment Planning RISK OF STROKE

46 ICSS Results 1,713 patients All Symptomatics (120 days) Lancet Feb 2010 The incidence of stroke, death, or procedural MI was 8,5% in the CAS group compared with 5,2% in the CEA group. Completion of long-term follow-up is needed to establish the efficacy of CAS compared with CEA.

47 % CREST Results N Engl J Med 2010 CREST ,1 C E 2 2,3 2,3 1 0 STROKE MI 1, patients 47% Asymptomatics On the composite primary endpoint of any stroke, myocardial infarction (MI) or death during the periprocedural period or ipsilateral stroke on follow-up, no significant difference

48 The Key for Carotid Intervention CAS Vulnerable Plaque??? CEA

49 Vulnerable Plaque oriented Stent and EPD Selection Vulnerable Plaques have a greater tendency to embolize Embolic protection devices prevent stroke during the procedure, whereas stents provide postprocedural stroke prevention.

50 Vulnerable Plaque oriented Stent and EPD Selection Proximal occlusion EPD (MOMA-INVATEC, PARODI -GORE) Embologenic lesions should preferably be managed with proximal EPD

51 Vulnerable Plaque oriented Stent and EPD Selection The broader the stent free cell area the higher the embolic event rate Bosiers et al. EJVES 2007

52 Biomarkers may also guide medical treatment Aggressive lipid lowering is more effective than moderate lipid lowering, in carotid plaque stabilization 1-year follow up study of 140pts with CAD not indicated for intervention Target LDL-C<100mg/dl Target LDL-C<70mg/dl Target LDL-C<100mg/dl Target LDL-C<70mg/dl Target LDL-C<100mg/dl Target LDL-C<70mg/dl Target LDL-C<100mg/dl Target LDL-C<70mg/dl Kadoglou N., Liapis C., et al. J Vasc Surg 2010

53 Conclusions Emerging imaging modalities & Biological markers Identify the vulnerable carotid plaque Choose the best interventional strategy NEED FOR INCLUSION IN RANDOMIZED STUDIES

54 Christos Liapis, MD, FACS, FRCS Professor of Vascular Surgery Director Department of Vascular Surgery National Kapodistrian University of Athens

55 You are cordially invited to attend..