1. Atherosclerosis quantification by ultrasound Henrik Sillesen MD, DMSc Chairman & professor Dept. Vascular Surgery, Rigshospitalet Univ. of Copenhagen, Denmark Henrik Sillesen MD, DMSc Chairman & professor Dept. Vascular Surgery, Rigshospitalet Univ. of Copenhagen, Denmark

2. What should we look at? Intima-media thickness Plaque

3. CAPS-study 10-year results

4. Conclusion: Despite cIMT being predictive for cardiovascular endpoints, it did not consistently improve the risk classification of individuals Lorenz et al, Eur Heart J 2010

5. Transducer

7. Why IMT is irrelevant for the individual person

9. Plaque imaging IS relevant Small plaque Larger plaque

10. Assessment of plaque Plaque Presence Plaque Presence Plaque quantification Plaque quantification Plaque area Plaque area Degree of stenosis Degree of stenosis Plaque burden Plaque burden Plaque volume Plaque volume Plaque Presence Plaque Presence Plaque quantification Plaque quantification Plaque area Plaque area Degree of stenosis Degree of stenosis Plaque burden Plaque burden Plaque volume Plaque volume

11. PLAQUE PRESENCE

12. Plaque definition Well defined (consensus) in Europe and US: Well defined (consensus) in Europe and US: Localized thickening of 50% or greater compared to surrounding vessel wall Localized thickening of 50% or greater compared to surrounding vessel wall Protrusion into lumen 0.5 mm or greater Protrusion into lumen 0.5 mm or greater IMT > 1,5 mm IMT > 1,5 mm Consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. J Am Soc Echocardiogr 2008; 21:93–111 Toubul PJ, Hennerici MG, Meairs S. Mannheim carotid intima media thickness consensus 2004-6. Cerebrovasc Dis 2007;23:75– 80. Well defined (consensus) in Europe and US: Well defined (consensus) in Europe and US: Localized thickening of 50% or greater compared to surrounding vessel wall Localized thickening of 50% or greater compared to surrounding vessel wall Protrusion into lumen 0.5 mm or greater Protrusion into lumen 0.5 mm or greater IMT > 1,5 mm IMT > 1,5 mm Consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. J Am Soc Echocardiogr 2008; 21:93–111 Toubul PJ, Hennerici MG, Meairs S. Mannheim carotid intima media thickness consensus 2004-6. Cerebrovasc Dis 2007;23:75– 80.

13. Polak et al, NEJM 2011 Framingham Off-Spring

14. Polak et al: JAHE 2013 MESA study Any plaque

15. Plaque area

16. Spence et al, stroke 2002

17. Tromsø Study Johnsen et al. Stroke 2007 Plaque area and risk of MI – men and women

18. Plaque Burden

19. BioImage Study Muntendam et al: Am Heart J 2010;160:49-57

20. HRP introduced the ”cross sectional sweep”

21. “Manual 3D” Cross-sectional Carotid Sweep Sillesen et al., JACC Img 2012 Area of all carotid plaques was summed yielding a continuous metric of total carotid atherosclerosis: carotid plaque burden (cPB)

22. CAC groups vs ”plaque burden” and IMT Spearman: 0.194Spearman: 0.441 P < 0.01 IMT Plaque ”burden”

23. Analysis time, Days Cumulative MACE by Carotid Plaque Burden No PlaqueTertile 1 Tertile 2Tertile 3 150413671236433cPB Tertile 3 150413431230413cPB Tertile 2 150413311204415cPB Tertile 1 131911811080433cPB= 0 Number at risk 0.0 5.0 10.0 05001000 Cumulative Incidence, % p-value<.0001

24. Adjusted Hazard ratios for MACE (all-cause mortality) Conventional vascular risk factors Unadjusted Categories of CAC score Age and sex adjusted >400 1-99 100-399 5.12 (3.39, 7.72) 1.86 (1.17, 2.95) 1.58 (0.91, 2.73) 1.79 (1.13, 2.85) 1.53 (0.97, 2.43) 2.28 (1.37, 3.81) 3.55 (2.28, 5.54) 1.40 (0.88, 2.22) 2.98 (1.81, 4.93) 2.21 (1.41, 3.47) 3.28 (2.00, 5.38) 2.23 (1.33, 3.73) 2.61 (1.57, 4.34) 1.65 (0.96, 2.85) ratio (95% CI) 1.36 (0.86, 2.17) 4.21 (2.60, 6.82) 3.89 (2.50, 6.06) 1.59 (0.92, 2.75) Hazard <0.0001 P for trend <0.0001 2.23 (1.33, 3.73) 1.5124810 Hazard ratio vs. no detectable plaque / CAC Top third Bottom third Middle third Top third Bottom third Middle third Top third Bottom third Middle third >400 1-99 100-399 >400 1-99 100-399 Conventional vascular risk factors Unadjusted Age and sex adjusted Unadjusted and adjusted hazard ratios for MACE (all-cause death, myocardial infarction, ischemic stroke, unstable angina or coronary revascularization) associated with CAC (top panel) and cPB (bottom panel) Thirds of detectable Carotid Plaque Burden

25. Net Reclassification Index for MACE Proportion Correctly Reclassified, % (n=3899) (n=1613) (n=296)

26. Plaque Volume by 3D US Now possible – great potential However, no trials done yet so the true value is unknown.

27. Combined carotid plaque and CAC JACC 2015:1065-74

28. Atherosclerosis 2001

29. Value of ultrasound in risk prediction for the individual IMT: DOES NOT WORK IMT: DOES NOT WORK Plaque presence: doubles risk Plaque presence: doubles risk Plaque area, degree of stenosis, plaque thickness and 2D plaque burden all discriminate better – plaque burden best Plaque area, degree of stenosis, plaque thickness and 2D plaque burden all discriminate better – plaque burden best Power of ”zero plaque” seems equal to that of CACS = 0 Power of ”zero plaque” seems equal to that of CACS = 0 Maybe better to evaluate more than 1 location Maybe better to evaluate more than 1 location IMT: DOES NOT WORK IMT: DOES NOT WORK Plaque presence: doubles risk Plaque presence: doubles risk Plaque area, degree of stenosis, plaque thickness and 2D plaque burden all discriminate better – plaque burden best Plaque area, degree of stenosis, plaque thickness and 2D plaque burden all discriminate better – plaque burden best Power of ”zero plaque” seems equal to that of CACS = 0 Power of ”zero plaque” seems equal to that of CACS = 0 Maybe better to evaluate more than 1 location Maybe better to evaluate more than 1 location