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Natural History of Atherosclerosis in The Diabetic patients Arturo FERNÁNDEZ-CRUZ

Natural History of Atherosclerosis in The Diabetic patients Arturo FERNÁNDEZ-CRUZ Professor and Director Cardiovascular Preventive Area Hospital Clínico MADRID. Nice 2005. The challenge of atherosclerosis cardiovascular disease. Leading causes of death – United States 2001.

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Natural History of Atherosclerosis in The Diabetic patients Arturo FERNÁNDEZ-CRUZ

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  1. Natural History of Atherosclerosis in The Diabetic patients Arturo FERNÁNDEZ-CRUZ Professor and Director Cardiovascular Preventive Area Hospital Clínico MADRID Nice 2005

  2. The challenge of atherosclerosiscardiovascular disease Leading causes of death – United States 2001 AHA Heart Disease and Stroke Statistics – 2004 Update

  3. Loss of life expectancy due to diabetes Years of life lost Females 8 Males 7 6 5 4 3 2 1 0 <25 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90+ Age at diagnosis Hopkinson et al (1999)

  4. Diabetes is a state of premature death associated with hyperglycaemia Miles Fisher, 1998 Having Diabetes is as serious as having cancer Ian Campbell, 2000 Diabetes is NOT a mild Disease

  5. Clinical Manifestations of Atherosclerosis • Coronary heart disease • Angina pectoris, myocardial infarction, sudden cardiac death • Cerebrovascular disease • Transient ischaemic attacks, stroke • Peripheral vascular disease • Intermittent claudication, gangrene

  6. Myocardial Infarction and Microvascular Disease Microvasculardisease Incidence per1000 patient-years Myocardialinfarction Updated mean HbA1c (%) UKPDS 35. BMJ 2000; 321: 405-12

  7. CAUSES OF MORTALITY IN UKPDS PATIENTS 15% patients median age 53 years at diagnosis, died (702/3867) 59% Diabetes Related 49% Cardiac 8% Stroke 2% Other 41% Non Diabetes related 24% Cancer 17% Other UKPDS 33, Lancet 1998

  8. ¿Cuál es el volumen de ateromaTotal (VAT)?

  9. Preclinical atherosclerosis in men with newly diagnosed diabetes and established diabetes Moderate to large plaques Carotid arteries 60 * 1,05 * 50 1 * 40 * 0,95 Percentage 30 Intima/Media (mm) 0,9 20 0,85 10 0,8 0,75 0 Healthy Newly diagnosed Established Healthy Newly diagnosed Established diabetes diabetes diabetes diabetes N=197 N=24 N=50 Sigurdardottir et al. Diabetes Care 2004;27:880-4

  10. The role of Lp-PLA2 in CHD LUMEN Oxidized LDL INTIMA MEDIA

  11. The role of Lp-PLA2 in CHD LUMEN Adhesion molecules Oxidized LDL Lp-PLA2 INTIMA Lyso-PC OxFA MEDIA

  12. The role of Lp-PLA2 in CHD LUMEN Monocytes Plaque formation Cytokines Adhesion molecules Oxidized LDL Lp-PLA2 Macrophage Foam cell INTIMA Lyso-PC OxFA MEDIA

  13. B-MODE CAROTID ULTRASOUND- TSA- Grosor de la media e intima de la Carótida • ARICstudy Am J Epidemiol 1997 • Cardiovascular Health Study (CHS) • O´leary NEJM 1999 añade información • adicional al riesgo global en los de • riesgo intermedio. • CLAS Ann Int Med 1998 • ASAP Lancet 2001 PCR • ARBITER study Circulation 2002 regresión • a 1 año terapia intensiva vs moderada. PCR

  14. Kaplan-Meier survival curves:Lp-PLA2 in ARIC cohort Patients categorized in tertiles (n=1350; 609 cases) 1 Probability of event-free survival 2 Lp-PLA2 Tertile 1 <311ng/mL 2 311-422ng/mL 3 >422ng/mL p=0.5639 3 p=0.0170 Time to CHD (years) Data on file, diaDexus, Inc.

  15. Inflammation, a key element of the atherosclerotic plaques in diabetics Diabetics Non-diabetics p<0.05 26 24 22 20 % positive staining/mm2 Macro phages 18 16 14 12 10 Non-diabetics (n=17) Diabetics (n= 15) p<0.05 7 6 T-cells 5 % positive staining/mm2 4 3 2 1 0 Non-diabetics (n=17) Diabetics (n= 15) Martin-Ventura JL et al. (unpublished data)

  16. CRP PREDICTOR OF RISK IN ATHEROSCLEROSIS • < 0.1 low risk • > 0.1 < 0.2 moderate • > 0.2 < 0.3 moderate-high • > 0.3 high CRP Polymorphism and incidence of angioplasty restenosis A Fernandez-Cruz et al Atherosclerois 2004; 176:393-96

  17. C-reactive protein and diabetes CRP and cardiovascular events survival in diabetics (n=746) 5 years follow-up Women´s Health Study (n=27628) 4 years follow-up p<0.05 0,8 0,7 0,6 0,5 CRP<1 mg/L C-reactive Protein (mg/dL) 0,4 0,3 CRP=1-3 mg/L CRP>3 mg/L 0,2 0,1 0 Diabetics (n=168) Controls (n=362) Schulze et al. Diabetes Care 2004;27:889-94 Pradhan et al. JAMA 2001;286:327-34

  18. Endothelial dysfunction: the impact of AGE Wautier et al. Circ Res 2004;95:233-238

  19. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus p<0.05 p<0.05 300 80 ICAM-1 E-selectin 250 60 (ng/mL) (ng/mL) 200 40 20 150 0 100 Controls (n=785) Cases (n=737) Controls (n=785) Cases (n=737) 600 p<0.05 550 VCAM-1 (ng/mL) 500 450 Controls (n=785) Cases (n=737) Meigs et al .JAMA 2004;291:1978-86

  20. Fas Ligand, a novel marker of endothelial dysfunction ? Fas Fas Ligand Normal Endothelium Leucocyte Apoptosis Dysfunctional Endothelium Rolling Adhesion Endothelium Adhesion molecules and chemoattractant proteins Transendothelitation

  21. Circulating Fas ligand is decreased in diabetic patients p<0.0001 140 123 111 120 100 69 80 sFasL (pg/mL) 49 60 44 40 20 0 Carotid atherosclerosis (n=16) Diabetes (n=17) + Atorvastatin (n=58) Healthy (n=15) Familial hyperlipidemia (n=58) Blanco-Colio et al. J Am Coll Cardiol. 2004;43:1188-94 Blanco-Colio et al. (unpublished data)

  22. HOSPITAL CLÍNICO SAN CARLOS (MADRID) • Instituto Cardiovascular • A. Calle A. Fernández-Cruz • D. Vincent D. Gomez Garre • BRIGHAM AND WOMEN’S HOSPITAL (BOSTON) • N. Varo P. Libby • U. Shonbeck • P. Nuzzo • Veves • P. Jarolim • Goldfine • E. Horton

  23. A 12 10 8 6 4 2 Controls Type 1 DM B 12 10 8 sCD40L (ng/ml) 7.36(3) 6.5(3.3) 6 4 2 1.43(2.32 1.38(1.8) Controls Type 2 DM Fdez-Cruz, Calle, Schonbeck, Libby et al Circulation 2003

  24. 10 n=7 n=16 n=5 0 -10 n=3 compared to baseline n=22 -20 n=10 n=9 -30 TZDs ( -40 Placebo change -50 n=4 -60 % All type 2 DM Type 2 DM Type 2 DM Type 2 DM patients recent onset no comp. Complic. Fdez-Cruz, Calle, Shonbeck, Libby et al Circulation 2003

  25. The Metabolic Syndrome andAssociated CVD Risk Factors Hypertension Abdominal obesity Atherosclerosis Hyperinsulinaemia Insulin Resistance Diabetes Hypercoagulability EndothelialDysfunction Dyslipidaemia • high TGs • small dense LDL • low HDL-C

  26. Plasma sCD40L in insulin resistant (IR) and non-insulin resistant (non-IR) patients 691.1±199.1* *Mean ± S.E.M. p<0.05 Pg//ml 420.1± 89.2* 302.7±58.4* IRnon-IRcontrolgroup

  27. Correlation between plasma levels of sCD40L and fasting insulin concentrations r=0.32, p=0.015 Pg/ml uU/ml

  28. Correlation between plasma sCD40L concentrations and waist girth r= 0.33, p=0.01 Pg/ml cm

  29. Plasma sCD40L in insulin resistant (IR) patientswith and without statin therapy 1038.9±401.6* *Mean ± S.E.M. p<0.05 pg//ml 471.3±183.3* 420.1±89.2* IR patients IR patients control group without statins with statins

  30. HOSPITAL CLÍNICO SAN CARLOS (MADRID) • Instituto Cardiovascular • A. Calle A. Fernández-Cruz • C. Filozof D. Gómez Garre • ML González-Rubio • FUNDACIÓN JIMÉNEZ DÍAZ (MADRID) • L. Blanco-Colio J. Egido • JL. Martín-Ventura F. Vivanco • MC. Durán

  31. HSP27 SECRETION: FROM ARTERIAL WALL TO PLASMA Two-dimensional gels of secretomes from control endartery (A) and complicated plaque (B). Circles show spots corresponding to HSP27 in two different phosphorylation states. Martín-Ventura et al, Circulation 2004;110:***-***

  32. * * * ELISA HSP27 SECRETION: FROM ARTERIAL WALL TO PLASMA CONDITIONED MEDIA Western blot Martín-Ventura et al, Circulation 2004;110:***-***

  33. PLASMA HSP27 SECRETION: FROM ARTERIAL WALL TO PLASMA Martín-Ventura et al, Circulation 2004;110:***-***

  34. PLASMA LEVELS OF HSP27 IN DIABETIC PATIENTS A. Fernández-Cruz et al (unpublished data)

  35. AGE –HSP27 in diabetic rat kidneys Padival et al FEBS letters 2003;551:113

  36. We can help Just do it

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