Is carotid intima media thickness a clinical marker of evolutive atherosclerotic disease?

1. ESC CONGRESS 2003 VIENNA,30 August - 3 September Is carotid intima media thickness a clinical marker of evolutive atherosclerotic disease? Damiano Baldassarre E. Grossi Paoletti Center and Cardiologico Monzino Center, Department of Pharmacological Sciences, University of Milan

2. The asymptomatic coronary disease is prevalent in the general population   • Individuals with asymptomatic coronary disease have a higher risk than healthy subjects to progress to an overt coronary disease and to a myocardial infarction   • Early identification and preventative treatment of this kind of patients could potentially lower the risk of the consequent overt coronary disease development

3. ANGIOGRAPHIC TECHNIQUES ALLOW TO MONITOR PROGRESSION AND REGRESSION OF ATHEROSLEROTIC LESIONS

4. Angiography Advantages Limitations • ideal method to visualise severe atherosclerotic lesions in deep vessels (coronary arteries) • Inappropriate to investigate early vascular lesions in asymptomatic subjects • Invasive • Not applicable in primary prevention trials • No information about arterial wall characteristics

5. Angiography vs intravascular ultrasound (IVUS)

6. B-mode ultrasound image of a carotid bifurcation ECA ICA BULB CC

7. B-mode ultrasound image of a carotid bifurcation ECA ICA Complicated Atherosclerotic plaque Size and characteristics of the arterial wall BULB CC

8. Blood intima interface media-adventitia interface Intima Media thickness (IMT) ICA BULB COMMON CAROTID IMT ECA

9. Intimal plus media thickness of the arterial wall: a direct measurement with ultrasound imaging Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Circulation1986;74:1399-1406

10. Blood intima interface Media Adventitia interface Lumen { Echogenic lines Ultrasound Adventitia { Histology Intima Media thickness (IMT)

11. High resolution Ultrasonography Intimal medial thickness of superficial arteries: marker of atherosclerosis in clinical and epidemiological studies to evaluate: • the natural evolution of atherosclerotic disease in the superficial arteries • the influence of atherosclerosis risk factors on the arterial walls • the arterial wall changes induced by diet or pharmacological treatments

12. epidemiological and clinical evidences that allow to answer the question: Is carotid intima media thickness a clinical marker of evolutive atherosclerotic disease ?

13. IMT is related with the same vascular risk factors known to affect atherosclerosis in other vascular districts Age and Gender Baldassarre et al., Stroke 2000 Smoking habits Haapanen et al., Circulation 1989 Diabetes Kawamori et al., Diabetes Care 1992; Niskanen et al., Stroke 1996 Hyperomocysteinemia Malinow et al. Circulation 1993; Demuth et al. ATVB 1998 Hypertension Suurkula et al., Arterioscler Thromb 1994; Lemne et al., Stroke 1995 Hypercholesterolemia Poli et al., Atherosclerosis 1988; Wendelhag et al., Arterioscler Thromb 1992 Hypoalphalipoproteinemia Baldassarre et al ATVB 2002 High levels of Lp(a) Baldassarre et al., Stroke 96; Tatò et al., Atherosclerosis. 1993 High levels of triglycerides and post prandial lipemia Gronholdt et al., Stroke 1996; Karpe et al., Atherosclerosis 1998 Many others..

14. An increased IMT is associated with the coronary disease assessed from a clinical point of view Crouse et al. Stroke 1986 Craven et al. Circulation 1990 Chambless et al. Am J Epidemiol 1997 Vrtovec et al. Coronary Artery Dis 1999 Nowak et al. Stroke 1998

15. Association of Coronary Heart Disease incidence with CC-IMT The Atherosclerosis Risk In Communities (ARIC Study) 1.1 Bifurcation Women Men 1.01 1 0.97 Internal 0.89 0.9 Basale IMT (mm) Common 0.82 0.8 0.78 0.8 0.74 0.71 0.69 0.7 0.66 0.66 0.6 0.6 0.5 No CHD event n=7193 CHD event n=96 No CHD event n=5358 CHD event n=194 The risk of myocardial infarction comparing patients with an IMT < 1 vs >1 was 5.07 for women and 1.85 for men Chambless et al. Am J Epidemiol 1997

16. An increased IMT is associated with the occurrence and severity of coronary disease assessed by angiography Wofford et al. Arterioscl Thromb 1991 Geroulakos et al. Eur Heart J 1994 Kallikazaros et al. Stroke 1999

17. Relation of extent of extracranial carotid artery atherosclerosis as measured by B-mode ultrasound to the extent of coronary atherosclerosis 12 10 8 Women B-mode score (mm) 6 Men 4 2 0 0 1 2 3 4 Number of coronary vessels with an obstruction of 50% or greater Wofford et al. Arterioscl Thromb 1991

18. POST HOC ANALYSIS OF THE CLAS STUDY Carotid artery IMT progression, recorded in 2 years of follow up by B-mode ultrasound, is related to the atherosclerotic change occurring at coronary levels as measured by quantitative angiography in the same period of time. Mack et al., Atherosclerosis 2000

19. An increased IMT value is associated with abnormal ECG Bruckert et al. Atherosclerosis 1992 Okin et al. Hypertension 1997 Nagai et al. Circulation 1998

20. Carotid stenosis is a powerful predictor of a positive exercise electrocardiogram in a large hyperlipidemic population s Exercise ECG Total Negative Borderline Positive n=778 (%) (%) (%) Normal Artery 418 89.7 6.5 3.8 (IMT < 1 mm) IMT 129 81.4 10.9 7.8 (> 1 mm) Plaque 196 86.7 7.7 5.6 ( < 30% of stenosis) Stenosis 35 65.7 8.6 25.7 (> 30% of stenosis) Bruckert et al. Atherosclerosis 1992

21. An increased IMT is a good predictor of future vascular events Salonen et al. Arterioscler Thromb 1991 Bots et al. J Int Med 1995 Hodis et al. Ann Int Med 1998 Bots et al. Circulation 1999 O’Leary et al. New Eng J Med 1999

22. Ultrasonographically assessed carotid morphology and the risk of Coronary Heart Disease Relative hazard of a coronary event Salonen et al. Arterioscler Thromb 1991

23. Absolute 10-year risk of stroke, 10-year of Coronary Heart Disease and 11.5-year risk of death by common carotid Intima-Media Thickness 50 45 Death 40 CHD 35 Stroke 30 Absolute risk (%) 25 20 15 10 5 0 1 2 3 4 5 Intima-Media Thickness (quintiles) Bots et al., J Int Med, 1995

24. CC-IMT and Risk of Stroke and Myocardial Infarction: the Rotterdam Study Baseline characteristics 1 0.909 0.9 0.858 0.795 0.8 CC-IMT (mm) 0.7 n=1373 n=98 n=96 0.6 0.5 Control subjects Myocardial Infarction Stroke Per SD increase in CC-IMT: the risk of myocardial infarction increased 43% the risk of stroke increased 41% Bots et al. Circulation 1999

25. Carotid artery intima and media thickness as a risk factor for Myocardial infarction and stroke in older adults 40.9 Maximal CCA IMT 40 Maximal ICA IMT 36.5 36.1 Maximal CCA and ICA IMT 30 23.8 Rate of myocardial infarction or stroke per 1000 person-years 22.3 21.4 22.2 18.4 20 16.4 16 13.7 13.6 9.2 8.6 10 7.8 0 1 2 3 4 5 Quintiles of IMT O’Leary et al. New Eng J Med 1999

26. Cumulative Event-free Rates for the Combined End Point of Myocardial Infarction or Stroke, According to Quintile of Combined Intima-Media Thickness O’Leary et al. New Eng J Med 1999

27. LIMITATIONS OF INTIMA MEDIA THICKNESS I Before routine measurement of IMT can be proposed in clinical practice as a diagnostic tool for stratifying cardiovascular risk in primary prevention and for aggressive treatment decision • the methods of measurement, including the site and the analysis of it, have to be standardized • a threshold of IMT above which the risk of cardiovascular event can be considered to be substantially increased in one person have to be clearly and precisely defined • inter-reader variability is fairly high and have to be improved

28. The atherosclerotic nature of ultrasound-detected IMT have to be unequivocally proved. The fact that IMT may be considered as a marker of atherosclerosis, also depends on whether the plaques are incorporated into the IMT measurements or not

29. B-MODE ULTRASOUND PROTOCOL ICA 1 cm BULB CC CC 1 cm 1 cm Multiple carotid site Common carotid

30. ? Ultrasonography cannot distinguish Intima } Arterial wall Media Adventitia INTIMA THICKENING MEDIA THICKENING { } CC-IMT ATHEROSCLEROSIS ? MEDIAL HYPERTROPHY ?

31. LIMITATIONS OF INTIMA MEDIA THICKNESS II The ability of IMT to predict an event may be limited by: the presence of coronary artery remodelling process (arterial dilatation which occurs in the presence of atherosclerotic plaque which tends to maintain the arterial lumens until late in the atherosclerotic process) conditions associated with medial thickening (Glycation of extracellular matrix in diabetic patients), in which changes in IMT may be less representative of changes in cardiovascular risk. In addition: The occurrence of an acute event, such as myocardial infarction, depends not only on the condition of the arterial walls but also on the existence of precipitating factors for which the IMT may not be a good indicator.

32. CONCLUSIONS IMT gives a comprehensive picture of the alterations caused by multiple risk factors over time on arterial walls. Prospective primary and secondary prevention studies demonstrated that an increased IMT is associated to coronary artery disease and that it is a powerful predictor of coronary and cerebrovascular complications. Thus, on the basis of the studies I have presented we can conclude that, at least from a research point of view, carotid intima media thickness may be effectively considered as a good clinical marker of evolutive atherosclerotic disease. Several evidences also suggest that, once that the methodological limitation will be overcome, IMT measurement might participate in the stratification risk of asymptomatic patients in primary prevention and for the decision to treat or not the patient with an aggressive therapeutic intervention.