2. Modification de la réponse thérapeutique à visée cardiovasculaire chez l’insuffisant rénal chronique du fait de l’inflammation Dr Gérard London Centre hospitalier F.H. Manhes Service de Néphrologie-Hémodialyse Fleury-Mérogis

3. Arteriosclerosis versus atherosclerosis (atheromatosis) Arteriosclerosis (sclerosis=hardening) Generalized involvement of arterial tree, principally the elastic arteries, associated with aging Intimal and medial thickening with enlargement and increased length of arteries thinning, fragmentation, disorganization of elastin fibers, increased in collagen and calcium content alteration of dampening function - increased stiffness Atherosclerosis (atheros=gruel) Inflammatory response to oxidized LDLand others Limited and patchy distribution starting in the intima with presence of plaques Evolution from foam cells - fatty streak- preatheroma-atheroma- fibroatheroma alteration of conduit function- stenosis and occlusions

4. Arteriosclerosis vs Atherosclerosis in CRF altered tensile stress (hypertension) age homocysteine antiatherogenic factors AGE AOPPLp(a) gender altered shear stress (change in blood flow) local growth factors / inhibitors Ca, P, Vit D, PTH lipoprotein changes

5. Prevalence of discrete plaques on common carotid artery in control subjects and ESRD patients ControlsESRD Age (years) 48.5 ± 16 51 ± 16 NS Plaques (%)17.8%56.3%< 0.01 Type of plaques Calcified23.1%91.5%<0.01 Soft/mixed77%9%<0.01 London et al Sem Dial 1999

6. Common carotid artery (CCA) geometry in controls and ESRD patients on hemodialysis CCA diameter (mm)5.75+0.826.45+0.88*** CCA intima-media thickness (µm)713+96797+110*** CCA wall-to-lumen ratio0.25+0.030.25+0.03 *** p < 0.001 ControlsHD London et al Kidney Int 1996

7. Functional characteristics of arterial system in control subjects and ESRD patients Controls ESRD Common carotid artery distensibility (kPa -1.10 -3 )19.3 ± 7.115.8 ± 8.8** Common carotid artery elastic modulus (kPa.10 3 ) + 0.50 ± 0.220.74 ± 0.46*** Aortic pulse wave velocity (cm/s)1020 ± 1801115 ± 309** Radial artery elastic modulus (kPa.10 3 )3.3 ± 2.45.53 ± 4* Brachial pulse wave velocity (cm/s)1117 ± 1701167 ± 170* Mean ± SD; *p<0.05; **p<0.01; ***p<0.001 / + (controls n=20; ESRD n=20) London et al OUP 2001

8. Arterial structural and functional parameters according to the calcification score (0 to 4) in hemodialysis patients Parameter01234ANOVA CCA diameter (mm)6 ± 0.826.3 ± 0.896.3 ± 0.706.67 ± 0.976.73 ± 0.800.001 CCA IMT (  m)700 ± 95784 ± 156800 ± 102849 ± 80830 ± 810.001 Aortic root (mm)26.4 ± 426.3 ± 427.8 ± 3.927.5 ± 4.129.7 ± 4.50.01 Aortic bifurc. (mm)16 ± 2.416.7 ± 4.416.7 ± 1.517.8 ± 3.318.1 ± 2.60.01 CCA Einc (kPa. 10 - 3 )0.47 ± 0.240.61 ± 0.310.62 ± 0.480.76 ± 0.371.01 ± 0.600.001 Aortic PWV (cm/s)940 ± 180946 ± 1411040 ± 2681270 ± 3841302 ± 3170.001 Guérin et al. NDT 2000 Values are means ± SD. Abbreviations used : CCA common carotid artery, IMT intima-media thickness; Einc-elastic incremental modulus, PWV pulse wave velocity

9. Multiple regression report for arterial calcifications score (0-4) in hemodialysis patients Independent  coefficientP valueSequentialPartial r 2 variable r 2 (adj. for rest ) Age (years) 0.050.000000.36380.3517 Pulse pressure (mm Hg)0.0120.002870.40850.0766 Smoking (packs/year)0.0170.001050.42530.0918 Phosphoremia (mmol/l)0.410.045980.45820.0351 CaCO 3 (g of Ca/day)0.230.012150.53030.0548 Duration of HD (months)0.0080.000000.63210.2855 Diabetes (0-no ; 1-yes)1.280.000080.68030.1308 Adjusted r 2 6603 ; F ratio 34.04 ; p< 0.00000 Guerin et al NDT 2000

10. 400 575 750 925 1100 15.040.065.090.0115.0140.0 CCA pulse pressure (mm Hg) CCA intima-media thickness (  m ) Correlation between common carotid artery (CCA)pulse pressure and CCA intima-media thickness in end-stage renal disease patients R=0.563 p<0.0001 London et al Kidney Int 1996

11. 400 575 750 925 1100 1.03.05.0 Correlation between serum CRP and Carotid Artery wall thickness in end-stage renal disease patients Serum CRP (Ln mg/l) Carotid wall thickness (mm) R=0.544 p<0.0001 London GM Personal data

12. 400 575 750 925 1100 15.035.055.075.095.0 Age (years) CCA intima-media thickness(  m) Correlation between Age and Common carotid artery intima-media thickness in ESRD patients R=0.566 p<0.0001 London et al Kidney Int 1996

13. 400 575 750 925 1100 57911 CCA diameter (mm) CCA intima-media thickness (  m ) Correlation between Common carotid artery (CCA) diameter and CCA intima-media thickness R=0.736 p<0.0001 London et al Kidney Int 1996

14. Correlation Between LV Outflow Velocity and CCA Diameter in ESRD Patients London GM et al. Kidney Int 1996;50:600-608 9 4 Diameter (mm) r = 0.50 P <0.0001 15 3045 LV outflow velocity integral (cm/beat) CCA = common carotid artery

15. 0 5 10 15 20 25 012345 Correlation between the CRP and aortic pulse wave velocity (PWV) measured at the end of follow-up R=0.617 p<0.001 Serum CRP (Ln mg/L) Aortic PWV (m/s) London et al submitted

16. Determinants of aortic pulse wave velocity in ESRD (multiple regression) Independent bcoefficientP valueSequentialPartial r 2 variable r 2 (adj. for rest ) Age (years) 6.10.000030.41150.1729 Gender (0-M,1-F)-67.40.067000.44440.0300 Systolic BP (mm Hg)3.040.000000.57950.1884 Heart rate (b/m)3.330.021360.58980.0420 CRP (mg/l)5.150.013340.61860.0615 Duration of HD (months)-1.00.000230.63080.1254 Aortic calcification (0-no ; 1-yes)1930.000180.68690.1520 Adjusted sequential r 2 0.6652 ; F ratio 31.65 ; p< 0.00000

17. Probality of all-cause survival according to calcification score. Calcification score : 0 0.25 0.50 0.75 1 0 0 20406080 Calcification score : 1 Calcification score : 2 Calcification score : 3 Calcification score : 4 Duration of follow-up (months) Probality of survival Blacher et al Hypertension 2001

18. 0.00 0.25 0.50 0.75 1.00 0255075100 TIME (months) SURVIVORSHIP 0 MAC IAC Probability of all-cause survival in ESRD patients according to absence of arterial calcifications (0),medial calcifications (MAC) and intimal calcifications (IAC) P<0.0001 P<0.01  ²=59.2; p<0.0001 London et al submitted

19. Probability of overall survival in hemodialysis patients according to aortic PWV Duration of follow-up (months) 0 1 0 35 70105140 0.50 0.75 0.25 PWV < 9.4 m/s 9.4 < PWV < 12.0 m/s PWV > 12.0 m/s Blacher et al. Circulation. 1999 Probability of overall survival

20. measured pressure wave forward/incident pressure wave reflected pressure wave pulse wave velocity Pressure wave analysis

21. Reflected Wave SPTI DPTI SPTI DPTI

22. Superimposed simultaneous phasic recording of aortic (Ao) and left ventricular (LV) pressures and coronary blood flow (CBF) 100 0 LV Ao STTI DPTI LA or PA Wedge Ao sTTI DPTI BP (mmHg) CBF (ml/min) (Buckeberg et al. Circ Res 1972) 0

23. 200 100 Aortic pulse wave velocity (cm/sec) Left ventricular mass (g/m 2 ) 150 500100015002000 r = 0.52 p < 0.001 Correlation between morphologic and functional cardiovascular parameters in HD patients London et al Adv Nephrol 1998

24. Approach to reduction of aortic stiffness with antihypertensive treatment Control of overhydration perindoprilnitrendipine Perindopril + atenolol Nitrendipine + atenolol Perindopril-atenolol-nitrendipineNitrendipine-atenolol-perindopril BP>160/90 Guérin et al Circulation 2001

25. All cause survival according to changes in aortic pulse wave velocity (  PWV) in response to BP decrease  2 = 28.01 P<0.00001 Guérin et al. Circulation. 2001. Negative  PWV 0.25 0.50 0.75 1 0 0 35 70 105 140 Positive  PWV Duration of follow-up (months) Survival rate

26. Cox regression- cardiovascular mortality VARIABLE RR (95% CI ) P value CVD (yes-1/no-0)4.72 (1.91-11.6)0.00077 LV massix (+10g)1.11 (1.03-1.19)0.00844  PWV (+=1/ neg= 0) 2.35 (1.23-4.51)0.01004 ACE inhibitor (1yes/0 no)0.18 (0.06-0.55)0.00274  ²=59.54 ; p<0.00001 Guerin et al Circulation 2001

27. Characteristics of Responders and Nonresponders Parameters Responders (n = 72) Nonresponders (n = 81) Baseline (1)Follow-up (2)Baseline (3)Follow-up (4) Interdialytic weight gain (kg) 2.56 ± 0.742.55 ± 0.702.42 ± 0.622.45 ± 0.5 Serum albumin (g/L)40.5 ± 2.940.7 ± 2.839.8 ± 3.039.7 ± 3.2 CRP (mg/L)5.1 ± 3.05.3 ± 2.711.9 ± 12.0**12.2 ± 12.1*** Body weight (kg)63.1 ± 14.063.6 ± 1460.6 ± 11.759.7 ± 11.9 1 vs 2; 3 vs 4: ***P <0.001 1 vs 3: **P <0.01 London et al JASN 2001

28. LOGISTIC REGRESSION REPORT: VARIABLES RELATED TO  AORTIC PULSE WAVE VELOCITY (0-Responders;1-Nonresponders) Variable CRP(Ln mg/l) ACEi (yes;no)  MBP (mm Hg) Intercept  PTH (pg/ml) Regression coefficient Standard error  ²;  =0 Probability level -0.069 0.053 -1.722 0.632 0.016 0.503 0.014 0.488 0.228 0.009 0.02 0.0001 0.0004 0.0055 0.0645 0.8905 14.89 12.43 7.68 3.42 R-squared 0.2927 Model Summary  ²=51.31 Probability 0.00001 Abbreviations - MBP -mean blood pressure; ACEi -Perindopril; CRP - C-reactive protein, PTH -parathormone from Guérin et al. Circulation 2001

29. -8 -6 -4 -2 0 2 4 6 8 012345 Correlation between CRP and  aortic pulse wave velocity (PWV) during the follow-up r=0.431 p<0.001 Serum CRP (Ln mg/L)  Aortic PWV (m/s) London et al submitted

30. -80 -35 15 60 -8-338 Changes in aortic PWV (m/s) Changes in LV mass (% ) R=0.566 p<0.001 Correlation between changes of aortic pulse wave velocity (PWV) and changes in left ventricular (LV) mass London et al. JASN 2001 London et al JASN 2001

31. -200 -150 -100 -50 0 50 100 150 012345 Relationship between  Left ventricular (LV) mass index (g/m²) during the follow-up and the C-Reactive Protein (Ln CRP) r=0.408 p<0.001 Serum CRP (Ln mg/L)  LV mass index (g/m²) London et al submitted

32. LOGISTIC REGRESSION REPORT: VARIABLES RELATED TO  LEFT VENTRICULAR MASS INDEX (0-Responders;1-Nonresponders) Variable  Hgb(g/dl) ACEi (yes;no)  PWV (m/s) Intercept Regression coefficient Standard error  ²;  =0 Probability level 1.038 0.370 -0.856 -0.454 0.318 0.010 0.416 01458 10.68 0.0001 0.0387 0.0018 0.0011 14.76 4.43 9.74 R-squared 02404 Model Summary  ²=46.84 Probability 0.00001 Abbreviations -PWV-pulse wave velocity ; ACEi -perindopril;Hgb-hemoglobin, from Guérin et al. Circulation 2001

33. Without ACEiWith ACEi Serum CRP (LN mg/l) P=0.009 (11.8  11.1) (7.3  9.7) Serum CRP levels in ESRD patients with treatment including or not ACE inhibitor (Perindopril) London et al submitted

34. VARIABLES ASSOCIATED WITH CRP (LN mg/L) IN ESRD PATIENTS (Multivariate analysis) Variable Triglycerides (mMol/l) DHP (0 no;1 yes) ACEi (0 no;1 yes) Age (years) Gender (0 M;1-F) P value Increment sequent r² Cumul sequent r² Partial r - 0.0001 0.0027 0.0056 0.0401 0.0621 0.2447 0.0781 0.0609 0.0192 0.0170 -0.2795 0.2492 0.1853 -0.1695 0.5420 0.3228 0.3837 0.4029 0.4199 R-squared 0.2927 Model Summary  ²=51.31 Probability 0.00001 Abbreviations - MBP -mean blood pressure; ACEi -Perindopril; CRP - C-reactive protein, PTH -parathormone from Guérin et al. Circulation 2001 0.2447

35. CCA wall-to-lumen ratio AOPP (µmol/l) Correlation between advanced oxidation protein products (AOPP) and carotid artery (CCA) wall-to-lumen ratio in ESRD patients 0.14 0.18 0.22 0.26 50100150200250 r=0.56 P<0.0001 Drüeke et.al Circulation 2002

36. 0 2000 4000 6000 8000 10000 12000 14000 012345 Correlation between the CRP (Ln CRP) and the weekly dose of erythropoietin necessary to maintain hemoglobin level between 10-11 g/dl R=0.500 p<0.001 Dose of EPO (units/week) Serum CRP (Ln mg/l)

37. 0 1 2 3 4 5 020406080100 Age (years) CRP (Ln mg/L) Correlation between age and CRP (Ln CRP) in ESRD patients R=0.495 p<0.001

38. 0 350 700 1050 1400 01000200030004000 r=0.60 P<0.0001 Serum Ferritin (pg/ml) Dose of elemental iron (mg/year) Correlation between the dose of elemental iron and serum ferritin in ESRD patients Drüeke et.al. Circulation 2002

39. Ferritin (pg/ml) AOPP (µmol/l) Correlation between serum ferritin and advanced oxidation protein products (AOPP) in ESRD patients 50 100 150 200 250 035070010501400 r=0.42 P<0.0001 Drüeke et. Circulation 2002

40. 500 580 660 740 820 900 0.0 17503500 Correlation between yearly dose of elemental iron (mg) and carotid artery wall thickness Dose of elemental Iron (mg/year) Carotid wall thickness (mg) 875 2625 r=0.368 p=0.0153 Drüeke et al Circulation 2002