Tasneem Z Naqvi, MD, FRCP (UK), RVT, MMM Director Non-invasive Cardiology and Echocardiography

1. Latest developments in non-invasive imaging of atherosclerosis using carotid ultrasound (CIMT and Plaque) In the New Era of PCI Preventive Cardiovascular Imaging Tasneem Z Naqvi, MD, FRCP (UK), RVT, MMM Director Non-invasive Cardiology and Echocardiography Professor of Medicine and Clinical Scholar Keck School of Medicine University of Southern California, Los Angeles

2. Disclosure I personally perform carotid IMT and plaque assessment for CV risk assessment in my patients (often free of charge!)

3. PCI (IMT) is In the Guidelines! For CAD risk assessment in asymptomatic adults at intermediate risk (Level of Evidence B) “a Reasonable Test” Benefit >> Risk IIa • 2010 ACCF/AHA Guidelines

4. Carotid Artery Wall Layers Noninvasive, no radiation External carotid artery Transducer Near wall Tip of the flow divider CCA ECA Far wall (10 mm) (10 mm) bulb bulb (10 mm) Internal carotid artery Carotid bifurcation Common carotid artery CCA ICA • IMT is a normal structure, made up of about 80% media and 20% intima • Atherosclerosis is largely an intimal process

5. Carotid Artery Intima Media Thickness Assessment, Measurement & Reporting • Varying comprehensivenss– single vs. multiple segments, single vs. multiple angles, far wall only, far and near wall, plaque inclusive vs. plaque exclusive • Phase of cardiac cycle, single vs. multiple frames • IMT measure - average mean, mean max, max, caliper vs. automated

6. Carotid Artery Intima Media Thickness Assessment, Measurement & Reporting • 75th percentile, standard deviation, upper and lower quartile or tertile, >0.9 mm • ASE and ACC/AHA recommend 75th percentile • Differences in Pixel resolution among US systems and transducers

7. Plaque Definition and Assessment in Clinical Studies Focal thickening of the carotid wall that is at least 0.5 mm or 50% of surrounding IMT value Focal region with CIMT 1.5 mm that is distinct from adjacent boundary and protrudes into the lumen QuantitativeAssessment Categorical: Yes and No Quantitative Plaque Burden Number of plaques, Plaque thickness, Area, Plaque volume, Vessel volume Qualitative Assessment • Plaque heterogeneity, irregularity, plaque vascularity, plaque calcification

8. Plaque Morphology

9. Predictive Value of IMT vs. Plaque in Population Based Studies - Future MI Meta-analysis,11studies, 54,336 patients Sensitivity SROC Curve 1-specificity Inaba Y et al Atherosclerosis Volume 220,2012 128 - 133

10. Prediction of Clinical Cardiovascular Events with Carotid Intima-media Thickness N=37,197 FU 5.5 yrs RR MI & stroke 1.26 & 1.32 per 1 SD CCA IMT difference 1.15 & 1.18 per 0.10-mm CCA IMT difference *Adjusted for age, sex, body mass index, systolic and diastolic blood pressure, LDL cholesterol, smoking and diabetes. †Adjusted for age, sex, systolic and diastolic blood pressure, smoking, and diabetes. ‡Adjusted for age, sex, BMI, systolic and diastolic blood pressure, total and HDL cholesterol, smoking, and diabetes. §Adjusted for age, sex, systolic and diastolic blood pressure, total and HDL cholesterol, smoking, diabetes, and cardiovascular disease. Lorenz M W et al. Circulation 2007;115:459-467

11. Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction:  A Meta-analysis N=45,828, FU 11 yrs FRS C statistic 0.757 FRS and CIMT 0.759 NRI with common CIMT was 0.8% In Intermediate risk, NRI improvement 3.6% Ruizter H et al. JAMA. 2012;308(8):796-803

12. ARIC Study - Evaluation of Predictive Role of IMT and Plaque n=13145 (5682 men, 7463 women) n=13145 (5682 men, 7463 women At each category of CIMT the presence of plaque is associated with higher incidence of CHD Nambi V, et al. JACC 2010;55:1600-1607

13. ARIC Study Net Reclassification Index Using Various Models Nambi V, et al. JACC 2010;55:1600-1607

14. Predictive Role of Carotid Plaque and IMT in Older Adults 5895 CHD-free adults aged 65–85years, FU 5.4 yrs No Plaque Plaques at 1 site Plaques at 2 sites or more p= <.001 HR plaques: 1 site = 1.5 plaques at ≥2 sites = 2.2 ROC curve - 0.728 to 0.745 NRI =13.7% Non adjusted probability of first coronary event Follow- up (Months) <0.61mm 0.61-0.67mm 0.67-0.73mm 0.73-0.81mm >0.81mm p= 0.30 Non adjusted probability of first coronary event HR IMT: 0.8 Follow- up (Months) Celermajerc D et al Atherosclerosis Volume 219, 2011 917 - 924

15. Proportion of MI According to Total Plaque Area Men N=6226, FU 6 yrs, age 25-84 HR 1.56 Cumulative probability of myocardial infarction Women Follow-up time, years No Plaque 1. tertile 2. tertile 3. tertile No Plaque 1. tertile 2. tertile 3. tertile Adj. RR highest plaque tertile vs. no plaque HR 3.95 Cumulative probability of myocardial infarction Follow-up time, years Johnsen S H et al. Stroke 2007;38:2873-2880

16. Proportion of MI According to IMT Men HR 1.73 1. quartile 2. quartile 3. quartile 4. quartile 1. quartile 2. quartile 3. quartile 4. quartile Cumulative probability of myocardial infarction 0 1 2 3 4 5 6 Follow-up time, years Women Adj. RR highest vs. lowest IMT quartile No predictive value if bulb IMT excluded Cumulative probability of myocardial infarction HR 2.86 0 1 2 3 4 5 6 Follow-up time, years Johnsen S H et al. Stroke 2007;38:2873-2880

17. Proportion of Ischemic Stroke According to Total Plaque Area Hazard Ratio highest quartile vs. no plaque 1.73, p, 0.04 1.62, p, 0.03 Mathiesen E B et al. Stroke 2011;42:972-978

18. Proportion of Ischemic Stroke According to IMT No diff in stroke risk across quartiles of IMT HR 1 SD IMT 8% HR 1 SD IMT 24% Mathiesen E B et al. Stroke 2011;42:972-978

19. Internal Carotid Artery IMT and Plaque and not CCA IMT Predicts Probability of New Onset CVD 2965 Framingham Offspring Study FU 7.2 yrs HR 1SD IMT MnCCA IMT 1.13 Max ICA IMT 1.21 NRI max , mean CCA IMT 0%, Max ICA IMT 7.6%, plaque presence 7.3% Polak et al N Engl J Med 2011; 365:213-221

20. Effect of Plaque Thickness on Vascular Events N=2189 FU 6.9 yrs HR: 2.8 44% of low FRS Had 18% risk if plaque present Rundek T et al. Neurology 2008 ;70(14):1200-7

21. Carotid intima-media Thickness Progression to Predict Cardiovascular Events in the General Population 16 studies, 36 984 participants, FU 7 yrs Lorenz M et al The Lancet Volume 379, Issue 9831 2012 2053 - 2062

22. Carotid Plaque Morphology Improves Stroke Risk Prediction N=1,348 FU 12 yr • TPRS • Stenosis degree • Plaque surface irregularity • Echolucency • Texture Prati P et al Cerebrovasc Dis 2011;31(3):300-

23. Carotid Plaque Burden as a Measure of Subclinical Atherosclerosis : Comparison With Other Tests for Subclinical Arterial Disease Chi Square: 450 Chi Square: 24 ... Sillesen H et al. JACC Imag 2012;;5, 681 - 689

24. High Prevalence of Carotid Atherosclerosis in Subjects with Low FRS Chi square=15.12, Pr=0.001 Chi square=9.1, Pr=0.01 Percent Patients without or with IMT >75th Centile on Ultrasound Percent Patients without or with Carotid Artery Plaque on Ultrasound Naqvi TZ et al. J Am Soc Echocardiogr. 2010;23:809-15

25. Prospective epidemiologic study • Study population: White (38%), African American (28%), Hispanic (22%), Chinese(12%) • N=6698 (47.2% M), age 45-84 • Median follow up: 3.9 years • HR for highest vs. lowest quartile: -HR: 3.3 for maximal internal carotid IMT -HR: 2.3 for maximal common carotid IMT The Multi-Ethnic Study of Atherosclerosis (MESA) Folsom, A. R. et al. Arch Intern Med 2008;168:1333-1339

26. 5 yr risk 5.6% vs. 19.5% Baseline Plaque Area & Plaque Progression Predicts CV Events N=1686 N=1085 5 yr risk 9.4% vs. 15.7% Spence JD. Et al Stroke 2002 Dec;33(12):2916-22

27. 3D Plaque Volume and Vessel Volume Ainsworth C D et al. Stroke 2005;36:1904-1909 Shai I et al. Circulation 2010;121:1200-1208

28. Summary • Lack of uniform definition of IMT and of plaque • CCA IMT alone without plaque assessment does not appear to be clinically useful over and above FRS compared to IMT inclusive of bulb and ICA • Plaque predicts CV events better than IMT • Plaque burden assessment and assessment of plaque charateristics are better measures of atherosclerosis and CV risk than presence or absence of plaque • Plaque progression and regression may be a powerful tool to evaluate effect of therapy

29. Plaque vs. IMT • The dynamic range of measurements varies by ∼100-fold for TPV compared to ∼2-fold for the IMT • The resolution of carotid ultrasound is ∼0.2 mm, whereas the annual change of IMT is ∼0.15 mm, so change cannot be measured within individuals in clinically meaningful time frames • Carotid TPA changes on average by ∼10 mm2allowing measurement of progression or regression within months

30. Plaque is a Great Equalizer • 12, 576 individuals • 15.2 yr mean follow up • CHD end points, no stroke • Mean IMT of CCA IMT vs All segment IMT mean C statistic • ACRS 0.741 • All IMT and plaque 0.754 • CCA mean and plaque 0.753 Nambi V et al. Eureart H2012;33:183-90

31. Presence of Calcified Carotid Plaque Predicts Vascular Events: The Northern Manhattan Study Prabhakaran S et al Atherosclerosis 2007;195”e197 - e201

32. Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction:  A Meta-analysis Ruizter H et al. JAMA. 2012;308(8):796-803

33. HRP - BioImage Study - 63% > 2 Risk Factors No CVD or Significant Others Control No Imaging Control Phone 6104 4 Baseline Imag. 1085 3 Advanced Imag. Am Heart J. 2010 Jul;160(1):49-57.e1.

34. Predictive Value of IMT vs. Plaque Diagnostic Cohort Studies - CAD Metanalysis, 27 diagnostic cohort studies, 4,878 patients Diagnostic accuracy of carotid ultrasound for the detection of CAD SROC Curve Sensitivity 1-specificity Inaba Y et al Atherosclerosis Volume 220, Issue 1 2012 128 - 133

35. Definitions of the Carotid Segments Lorenz M W et al. Circulation 2007;115:459-467