1. 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 LATEST DEVELOPMENTS IN NON-INVASIVE IMAGING OF ATHEROSCLEROSIS USING CAROTID ULTRASOUND (CIMT AND PLAQUE) IN THE NEW ERA OF PCI Preventive Cardiovascular Imaging

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) 2010 ACCF/AHA Guidelines IIa “a Reasonable Test” Benefit >> Risk

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

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 75 th percentile, standard deviation, upper and lower quartile or tertile, >0.9 mm ASE and ACC/AHA recommend 75 th percentile Differences in Pixel resolution among US systems and transducers

7. PLAQUE DEFINITION AND ASSESSMENT IN CLINICAL STUDIES Foca l 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 Quantitative Assessment 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 Inaba Y et al Atherosclerosis Volume 220,2012 128 - 133 SROC Curve Meta-analysis,11studies, 54,336 patients Sensitivity 1-specificity

10. Prediction of Clinical Cardiovascular Events with Carotid Intima-media Thickness Lorenz M W et al. Circulation 2007;115:459-467 *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. 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

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

12. ARIC STUDY - EVALUATION OF PREDICTIVE ROLE OF IMT AND PLAQUE Nambi V, et al. JACC 2010;55:1600-1607 At each category of CIMT the presence of plaque is associated with higher incidence of CHD n=13145 (5682 men, 7463 women n=13145 (5682 men, 7463 women)

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

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

16. Proportion of MI According to IMT Johnsen S H et al. Stroke 2007;38:2873-2880 Cumulative probability of myocardial infarction Follow-up time, years 1. quartile 2. quartile 3. quartile 4. quartile 1. quartile 2. quartile 3. quartile 4. quartile 01 2 3 4 5 6 Men Women Adj. RR highest vs. lowest IMT quartile No predictive value if bulb IMT excluded HR 1.73 HR 2.86

17. Mathiesen E B et al. Stroke 2011;42:972-978 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

18. Mathiesen E B et al. Stroke 2011;42:972-978 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%

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

20. EFFECT OF PLAQUE THICKNESS ON VASCULAR EVENTS Rundek T et al. Neurology 2008 ;70(14):1200-7 N=2189 FU 6.9 yrs HR: 2.8 44% of low FRS Had 18% risk if plaque present

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

22. CAROTID PLAQUE MORPHOLOGY IMPROVES STROKE RISK PREDICTION Prati P et al Cerebrovasc Dis 2011;31(3):300- TPRS Stenosis degree Plaque surface irregularity Echolucency Texture N=1,348 FU 12 yr

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

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

25. The Multi-Ethnic Study of Atherosclerosis (MESA) 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 Folsom, A. R. et al. Arch Intern Med 2008;168:1333-1339

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

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

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 mm 2 allowing 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. Eur eart 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 Am Heart J. 2010 Jul;160(1):49-57.e1. No CVD or Significant Others Control Phone Control No Imaging 6104 4 Baseline Imag. 1085 3 Advanced Imag.

34. PREDICTIVE VALUE OF IMT VS. PLAQUE DIAGNOSTIC COHORT STUDIES - CAD Metanalysis, 27 diagnostic cohort studies, 4,878 patients SROC Curve Sensitivity 1-specificity Diagnostic accuracy of carotid ultrasound for the detection of CAD 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