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

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

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

Prevalence of discrete plaques on common carotid artery in control subjects and ESRD patients ControlsESRD Age (years) 48.5 ± ± 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

Common carotid artery (CCA) geometry in controls and ESRD patients on hemodialysis CCA diameter (mm) *** CCA intima-media thickness (µm) *** CCA wall-to-lumen ratio *** p < ControlsHD London et al Kidney Int 1996

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

Arterial structural and functional parameters according to the calcification score (0 to 4) in hemodialysis patients Parameter01234ANOVA CCA diameter (mm)6 ± ± ± ± ± CCA IMT (  m)700 ± ± ± ± ± Aortic root (mm)26.4 ± ± ± ± ± Aortic bifurc. (mm)16 ± ± ± ± ± CCA Einc (kPa )0.47 ± ± ± ± ± Aortic PWV (cm/s)940 ± ± ± ± ± 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

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) Pulse pressure (mm Hg) Smoking (packs/year) Phosphoremia (mmol/l) CaCO 3 (g of Ca/day) Duration of HD (months) Diabetes (0-no ; 1-yes) Adjusted r ; F ratio ; p< Guerin et al NDT 2000

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< London et al Kidney Int 1996

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< London GM Personal data

Age (years) CCA intima-media thickness(  m) Correlation between Age and Common carotid artery intima-media thickness in ESRD patients R=0.566 p< London et al Kidney Int 1996

CCA diameter (mm) CCA intima-media thickness (  m ) Correlation between Common carotid artery (CCA) diameter and CCA intima-media thickness R=0.736 p< London et al Kidney Int 1996

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

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

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

Probality of all-cause survival according to calcification score. Calcification score : 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

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< P<0.01  ²=59.2; p< London et al submitted

Probability of overall survival in hemodialysis patients according to aortic PWV Duration of follow-up (months) PWV < 9.4 m/s 9.4 < PWV < 12.0 m/s PWV > 12.0 m/s Blacher et al. Circulation Probability of overall survival

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

Reflected Wave SPTI DPTI SPTI DPTI

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

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

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

All cause survival according to changes in aortic pulse wave velocity (  PWV) in response to BP decrease  2 = P< Guérin et al. Circulation Negative  PWV Positive  PWV Duration of follow-up (months) Survival rate

Cox regression- cardiovascular mortality VARIABLE RR (95% CI ) P value CVD (yes-1/no-0)4.72 ( ) LV massix (+10g)1.11 ( )  PWV (+=1/ neg= 0) 2.35 ( ) ACE inhibitor (1yes/0 no)0.18 ( )  ²=59.54 ; p< Guerin et al Circulation 2001

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 ± ± ± ± 0.5 Serum albumin (g/L)40.5 ± ± ± ± 3.2 CRP (mg/L)5.1 ± ± ± 12.0**12.2 ± 12.1*** Body weight (kg)63.1 ± ± ± ± vs 2; 3 vs 4: ***P < vs 3: **P <0.01 London et al JASN 2001

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 R-squared Model Summary  ²=51.31 Probability Abbreviations - MBP -mean blood pressure; ACEi -Perindopril; CRP - C-reactive protein, PTH -parathormone from Guérin et al. Circulation 2001

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

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

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

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 R-squared Model Summary  ²=46.84 Probability Abbreviations -PWV-pulse wave velocity ; ACEi -perindopril;Hgb-hemoglobin, from Guérin et al. Circulation 2001

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

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 R-squared Model Summary  ²=51.31 Probability Abbreviations - MBP -mean blood pressure; ACEi -Perindopril; CRP - C-reactive protein, PTH -parathormone from Guérin et al. Circulation

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 r=0.56 P< Drüeke et.al Circulation 2002

Correlation between the CRP (Ln CRP) and the weekly dose of erythropoietin necessary to maintain hemoglobin level between g/dl R=0.500 p<0.001 Dose of EPO (units/week) Serum CRP (Ln mg/l)

Age (years) CRP (Ln mg/L) Correlation between age and CRP (Ln CRP) in ESRD patients R=0.495 p<0.001

r=0.60 P< 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

Ferritin (pg/ml) AOPP (µmol/l) Correlation between serum ferritin and advanced oxidation protein products (AOPP) in ESRD patients r=0.42 P< Drüeke et. Circulation 2002

Correlation between yearly dose of elemental iron (mg) and carotid artery wall thickness Dose of elemental Iron (mg/year) Carotid wall thickness (mg) r=0.368 p= Drüeke et al Circulation 2002