Arterial Pressure in CKD5 - ESRD Population Gérard M. London INSERM U970 Paris

SBP & DBP by Age, Ethnicity &Gender (US Population Age 18 Years, NHANES III) 70 80 110 130 150 70 80 110 130 150 (mm Hg) DBP SBP (mm Hg) DBP SBP Non-Hispanic Black Non-Hispanic White Mexican American 70 80 110 130 150 70 80 110 130 150 (mm Hg) DBP SBP Pulse pressure Pulse pressure 18-29 30-39 40-49 50-59 60-69 70-79 80+ 18-29 30-39 40-49 50-59 60-69 70-79 80+ Men, Age (y) Women, Age (y) Burt VI, et al. Hypertension. 1995;25:305-313.

Evolution of Untreated Systolic and Diastolic BP: The Framingham Heart Study. Adapted from Franklin et al. Circulation 1997;96:308. 160 140-159 120-139 <120

Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by Age ISH (SBP ³140 mm Hg and DBP <90 mm Hg) SDH (SBP ³140 mm Hg and DBP ³90 mm Hg) IDH (SBP <140 mm Hg and DBP ³90 mm Hg) } Diastolic Hypertension 17% 16% 16% 20% 20% 11% 20 40 60 80 100 Frequency of hypertension subtypes in all untreated hypertensives (%) <40 40-49 50-59 60-69 70-79 80+ Age (y) Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874. 1

Difference Between SBP and DBP in CHD Prediction, as a Function of Age* *Ages 20 to 79 Adjusted for age, sex, & other risk factors 1.0 + 0.5 Favor SBP (SBP) - (DBP) 0.0 Favor DBP -0.5 - (SBP) - (DBP) = 1.49 + 0.029*age (P=0.008) -1.0 -1.5 25 35 45 55 65 75 Age (years) Franklin et al. Circulation 2001;103:1245-1249

Hypertension Control by Age Group 100 91 92 85 80 69 60 Age <=60 (n=295) 48 % Controlled Age 61-75 (n=533) 40 34 Age >75 (n=361) This slide shows the association of age with blood pressure control. Increasing age was associated with poorer rates of SBP control and overall control, whereas it was associated with improved rates of control to DBP goal. 20 DBP Goal SBP Goal Cross-sectional analysis among 1189 treated hypertensive subjects from Framingham Lloyd-Jones Hypertension 2000;36:594

Steep Rise in Pulse Pressure With Increasing Age Data From the Framingham Study Slide 8 160 140-159 120-139 120 Group Data Individual Data 78 68 58 48 38 135 115 95 75 55 35 Pulse Pressure (mm Hg) Pulse Pressure (mm Hg) Steep Rise in Pulse Pressure With Increasing Age: Data From the Framingham Study In an analysis of data from the Framingham Heart Study designed to evaluate age-related changes in BP in normotensive and untreated hypertensive subjects, 2,036 participants were divided into 4 groups based on level of SBP.1 As the graphs on the previous slide showed, SBP continues to rise with age while DBP levels off between the ages of 50 to 60 years and then declines. As a result of this divergence, pulse pressure rises dramatically with age, as the graphs on this slide show. The graph on the left shows pulse pressure, according to baseline level of SBP, rising with age. The graph on the right shows a group-averaged individual regression analysis (essentially demonstrating the same pattern). Reference 1. Franklin SS, Gustin IV W, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation. 1997;96:308-315. 60 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 30 35 40 45 50 55 65 70 75 80 85 Age (y) Age (y) n=2036 Franklin SS et al. Circulation 1997;96:308-315.

Relationship of SBP and DBP to risk for CHD in a dual component model: The Framingham Heart Study Adjusted for age, sex, and other risk factors P = probability for  coefficients 3 2.5 SBP 170 mm Hg (P = 0.01) CHD hazard ratio 2 1.5 SBP 150 mm Hg (P = 0.02) Slide 6 BP and coronary disease risk Franklin et al re-analyzed the Framingham 36-year data and the offspring study to identify the relative roles of SBP, DBP, and pulse pressure (PP) in predicting CHD. (Franklin, et al. 1999) For any level of DBP, those with higher SBP had a greater risk of CHD. (Franklin, et al. 1999) SBP appears to play a greater role in determining BP stage and eligibility for therapy than previously believed. (Lloyd-Jones, et al. 1999) Future guidelines might consider a greater role for SBP than for DBP in determining the presence of hypertension, risk of cardiovascular events, eligibility for therapy, and benefits of treatment. (Lloyd-Jones, et al. 1999) References Franklin SS, Khan SA, Wong ND, Larson, MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circ. 1999;100:354-360. Lloyd-Jones DM, Evans JC, Larson MG, O’Donnell CJ, Levy D. Differential impact of systolic and diastolic blood pressure level on JNC-VI staging. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertens. 1999;34:381-385. SBP 130 mm Hg (P = 0.06) 1 SBP 110 mm Hg (P = 0.03) 0.5 60 70 80 90 100 110 DBP (mm Hg) Franklin SS, et al. Circ. 1999;100:354. Mean age = 61 years (range: 50-79), n = 1924

Cardiovascular Risk Associated with Increasing SBP at Fixed Values of DBP 0.04 0.08 0.12 0.16 0.20 0.24 0.28 EWPHE (n = 840) SYST-EUR (n = 4695) SYST-CHINA (n = 2394) 75 80 85 90 95 DBP (mm Hg) 2-year risk of endpoint 240 220 200 180 160 140 120 SBP (mm Hg) Two-year risk adjusted for active treatment, sex, age, previous CV complications, and smoking by multiple Cox regression. Staessen, et al. Lancet. 2000;355:865–872.

Blood Pressure and CHD Risk Dual BP Component Models Chi Sq. Hazard Ratio P Value Model 1 SBP 35.6 1.22 (1.15-1.30) <0.001 DBP 5.2 0.86 (0.75-0.98) <0.05 Model 2 DBP 0.7 1.04 (0.94-1.16) NS PP 35.6 1.22 (1.15-1.30) <0.001 Hazards per 10 mm Hg increment Adjusted for age, sex, smoking, ECG-LVH, BMI, glucose intolerance, total/HDL cholesterol Franklin et al. Circulation 1999;100:354

Blood Pressure and Risk for CHD by Age Groups: Results of a Single BP Component† Model 2.0 SBP (10 mm Hg) DBP (10 mm Hg) PP (10 mm Hg) 1.6 *** *** * *** * *** 1.2 ** CHD Hazard Ratio/10 mm Hg (CI) 1.0 0.8 0.4 0.0 <50 50-59 60 Age (y) † Adjusted for age, sex, and other risk factors *P<0.1, **P<0.01, ***P<0.001 Franklin SS, et al. Circulation 2001;103:1245-1249.

Evolution of Systolic and Diastolic BP in CKD patients Rohrscheib MP et al CJASN 2008;3:1407

Rohrscheib MP et al CJASN 2008;3:1407

Klassen PS et a l. JAMA 2002;287:1548-55. n=37069

Liu M et al. NDT 2003; 18:563

Adjusted for level of systolic blood pressure One Year Mortality for Patients on Hemodialysis predicted by pulse pressure Adjusted for level of systolic blood pressure 20 18 16 14 n = 37,069 12 Predialysis PP Hazard Ratio for Death 10 Postdialysis PP 8 6 That question is addressed by adjusting for level of systolic blood pressure in the Cox proportional hazards model. When systolic pressure is adjusted for, there is a dramatic and consistent association between higher pulse pressure and greater risk of death. To give this a clinical face, this relationship suggests that when considering a group of patients with a systolic blood pressure of 180, those with a diastolic pressure of 90 (and a pulse pressure of 90) have a death risk that is four to six times higher than those with a diastolic pressure of 120 (and a pulse pressure of 60). CHANGED 4 2 Ref 20-30 30-40 40-50 50-60 60-70 70-80 80-90 90- 100- >110 100 110 Categories of Pulse Pressure (mmHg) Klassen et al. JAMA 2002;287:1548-1555

Brachial Pulse Pressure and Cardiovascular mortality in ESRD patients 1.000 PPbr≦55 mm Hg 0.750 P<0.001 PPbr ≦75 mm Hg Cardiovascular free events 0.500  NS PPbr≧75 mm Hg 0.250 Cox model: P=0.033 adjusted for age and mean BP 0.000 0.0 28.0 56.0 84.0 112.0 140.0 Follow-up (months) Safar ME et al Hypertension 2002

Common Carotid Pulse Pressure and Cardiovascular mortality in ESRD patients 1.00 PPcc <50 mm Hg 0.75 P<0.05 PPcc≦75 mm Hg Cardiovascular free events P<0.00001 0.50 P<0.001 PPcc≧70 mm Hg 0.25 Cox model: P=0.0049 adjusted for age and mean BP 0.00 0.0 28 56 84 112 140 Follow-up (months) Safar ME et al Hypertension 2002

1-year Mortality predicted by SBP Experience at 782 US dialysis facilities 2.5 n = 37,069 2 1.5 Predialysis SBP Hazard Ratio for Death Ref Postdialysis SBP 1 0.5 < 115 115 - 125 - 135 - 145 - 155 - 165 - > 175 125 135 145 155 165 175 Categories of SBP (mmHg) Klassen et al. JAMA 2002;287:1548-1555

1-year Mortality predicted by DBP Experience at 782 US dialysis facilities 6 Adjusted for level of systolic blood pressure 5 n = 37,069 4 Hazard Ratio For Death 3 2 Predialysis Postdialysis 1 30-40 40-50 50-60 60-70 70-80 80-90 90-100 100-110 > 110 DBP (mmHg) Klassen et al. JAMA 2002;287:1548-1555

Survival curves in hemodialysis patients for each baseline level of diastolic BP 1.0 0.8 0.6 0.4 Baseline d BP (mm Hg) 100+ 90-99 80-89 70-79 -69 Proportion surviving 0 12 24 36 48 60 Duration of observation, months ISEKI K. et al. Kidney Int 1997

Hypertension 2005;45:811

Adjusted Cox Z-value –2.23; p=0.02 All cause mortality according Systolic blood pressure (PAS) N = 5692 P<0.01 Adjusted Cox Z-value –2.23; p=0.02 0.992 (0.988-0.991) for 1 mmHg increase Fouque D et al Observatoire National

Adjusted Cox: Z-value = –6.73; p<0.001 All cause mortality according Diastolic blood pressure (PAd) N = 5692 P<0.01 Adjusted Cox: Z-value = –6.73; p<0.001 0.977 (0.971-0.984) for 1 mmHg increase Fouque D. et al Observatoire National

Systolic pressure 140 Pulse pressure mm Hg Mean BP 80 Diastolic pressure Systolic pressure: ventricular ejection (stroke volume and ejection time) arterial stiffness wave reflection Diastolic pressure: arterial resistance arterial Stiffness Diastolic decay time Mean BP: Cardiac output peripheral resistance

aortic pulse wave velocity and stroke volume (n=230) Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity and stroke volume (n=230) 160 160 R=0.47 p<0.0001 R=0.60 p<0.0001 132 132 104 104 Systolic Pressure (mm Hg) Systolice Pressure (mm Hg) 76 76 48 48 20 20 -40 -15 10 35 60 500 1000 1500 2000 2500 Augmentation Index (%) Aortic pulse wave velocity (cm/s) 160 R=0.17 P <0.05 132 104 Systolic Pressure (mm Hg) 76 48 20 London et al KI 1996 20 55 90 125 160 Stroke volume (ml)

Relationship of Resistance ®, Compliance (C) and Stiffness (S=1/C)with diastolic pressure decay 140  = R.C  =1/ = 1/R.C  =S/R Blood pressure . . . . . . . . . . . .  . . 80 . Blood pressure * 4.6 . . . . -time constant of diastolic decay . . * log scale . . .  . -slope of diastolic decay 4.38 Time (sec) Adapted from Simon et al. Am J Physiol 1979

Aortic pulse wave velocity-PWV (cm/s) 230 1800 200 1520 170 Aortic pulse wave velocity-PWV (cm/s) 1240 Systolic pressure (mm Hg) 140 960 r = 0517 P < 0.0001 Adjust for Systolic BP Age and SV r = 0.21 P = 0.015 NS-PWV and SV adjusted 110 680 80 400 0.5 1.1 1.7 2.3 2.8 3.4 4.0 0.5 1.1 1.7 2.3 2.8 3.4 4.0 Interdialysis body weight changes (kg) Interdialysis body weight changes (kg) 180 r = 0.284 P < 0.01 Adjust. For Systolic BP and PWV 156 132 Stroke volume - SV (mL) 108 84 60 0.5 1.1 1.7 2.3 2.8 3.4 4.0 Interdialysis body weight changes (kg) London et al Kidney Int 1989

Diagrammatic representation of pressure-volume relationships Einc=2 Einc=1 Pressure Mean BP dP/dV Volume

ROC Curves of CVdeath Sensitivity 1-Specificity Pulse Pressure AUC 72.7±3.2 1.0 Aortic PWV AUC 83.4±2.7 0.75 Brachial PWV AUC 58.9±3.9 Sensitivity 0.50 Femoral PWV AUC 56.2±4.0 0.25 0.00 0.00 0.25 0.50 0.75 1.0 1-Specificity Pannier B et al Hypertension 2005

Correlation between Age and Aortic Pulse Wave Velocity in General population ( ) and ESRD patients ( ) 25 600 500 r=0.525 P<0.00001 20 400 r=0.625 p<0.00001 Characteristic impedance (dynes.s.cm-5) 15 300 Aortic PWV (m/s) 200 r=0.340 P<0.01 10 100 r=0.719 p<0.00001 5 25 50 75 100 10 20 30 40 50 60 70 80 90 100 Age (years) Age (years) Pannier et al Artery 2007;1:78-89

Age related changes in arterial internal diameters 12 6.5 11 5.8 10 5.2 9 Carotid artery diameter (mm) Brachial artery diameter (mm) 4.5 8 3.8 7 3.2 6 5 2.5 20 30 40 50 60 70 80 90 20 30 40 50 60 70 80 Age (years) Age (years) Controls (r = 0.400; P < 0.01) Controls (r = 0.525;P < 0.01) ESRD (r = 0.438; P < 0.0001) ESRD (r = 0.277;P = 0.065) Controls ESRD patients

Age related changes in Carotid IMTh 1.10 1.00 0.90 0.80 Common carotid artery IMTh(mm) 0.70 0.60 0.50 0.40 10 20 30 40 50 60 70 80 90 Age (years) Controls ESRD patients Pannier et al Hypertension 2005

Probability of overall survival in hemodialysis patients according to aortic PWV 1 PWV < 9.4 m/s 0.75 9.4 < PWV < 12.0 m/s 0.50 Probability of overall survival 0.25 PWV > 12.0 m/s 35 70 105 140 Duration of follow-up (months) Blacher et al. Circulation. 1999

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

Changes of mean blood pressure and aortic PWV MBP (mmHg) PWV (m/s) MBP (mmHg) PWV (m/s) 120 14 120 14 13 13 12 12 110 110 11 11 10 10 100 9 100 9 Inclusion At target BP End of follow up Inclusion At target BP End of follow up Survivors Non Survivors Guérin and al. circulation 2001 ; 103 : 987 - 92

ROC Curve of CV mortality Criterions 1.00 Age; AUC 72±5% Pulse Pressure; AUC 72±5% 0.75 Sensitivity Carotid IMT;AUC 68±6% 0.50 LVmassix; AUC 72±5% Calcification score; AUC 82±4% 0.25 Aortic PWV; AUC 82±4% 0.00 0.00 0.25 0.50 0.75 1.00 1-Specificity PWV2 = Einc x arterial IMT/arterial radius wher Einc is incremental elastic modulus London et al. Cur Op hypertens Nephrol 2006

Schematic representation of reactive hyperemic response in the human forearm after five minutes of ischemia Peak flow 40 * Flow debt repayment=B/A 30 Forearm blood flow ml/100 ml/min B = Excess hyperemic flow ml/100ml 20 * Duration of hyperemia * 10 * * * * * * * * * * * * * * * * * * * * * * A = Flow debt mL/100 mL 1 2 3 4 5 6 7 8 9 10 11 baseline occlusion postocclusion Time,min

Flow debt repayment (%) Time to debt repayment (s) 250 400 188 300 Flow debt repayment (%) 125 200 Time to debt repayment (s) 63 100 Controls ESRD Controls ESRD Pannier B et al. Kidney Int 2001

Probability of survival in ESRD patients according to postischemic forearm flow debt repayement (FDR) 1.00 0.75 FDR>85% Survivorship 0.50 0.25 ²=17.9 P<0.001 FDR<85% 0.00 20 40 60 80 100 Follow-up (months) London GM et al. Kidney Int 2003

Methods of stimulating increased blood flow Mullen, M. J. et al. Circ Res 2001;88:145-151

Echotracking is 3 to 10 x more precise than image based techniques Signal averaging 10-10 000 RF lines IMT RF Signal 2 D TM Spatial resolution 200-400 µm 20-40 µm

Graphs show FMD, GTN-induced dilation, and RH in normotensive subjects (white circles and bars) and in patients with essential hypertension (black circles and bars) Ghiadoni, L. et al. Hypertension 2003;41:1281-1286

Endothelial cell biology and shear stress Traub, O. et al. Arterioscler Thromb Vasc Biol 1998;18:677-685 Endothelial cell biology and shear stress

Brachial artery characteristics Controls ESRD Baseline BA diameter (mm) 4.12 ± 0.13 4.56 ± 0.11 < 0.01 BA compliance (m 2 .kPa – 1 .10 – 7 ) 0.45 ± 0.02 0.37 ± 0.02 < 0.01 BA distensibility (kPa – 1 .10 – 3 ) 3.5 ± 0.22 2.6 ± 0.19 < 0.001 BA incremental elastic modulus (kPa.10 3 ) 3.0 ± 0.22 5.0 ± 0.42 < 0.001 BA circumferential wall stress (kPa) 60 ± 2.5 65 ± 1.9 NS Baseline mean flow velocity (cm/s) 4.6 ± 0.40 3.4 ± 0.30 < 0.01 Baseline mean flow (ml/min) 39 ± 4.6 33 ± 3.6 NS Baseline mean SR (s-1) – 53 ± 2.9 39 ± 3.5 < 0.01 Baseline peak SR (s-) 1 365 ± 23 324 ± 26 < 0.05 Whole blood viscosity (cPoise) 3.57 ± 0.07 2.79 ± 0.06 < 0.0001 Baseline mean SS (dynes/cm²) 19 ± 1.15 10.7 ± 1.0 < 0.001 Baseline peak SS (dynes/cm²) 129 ± 9 83 ± 5 < 0.001 Verbeke et al JASN 2007

Relationship in Controls and ESRD patients between brachial artery (BA) diameter and compliance and BA shear stress Verbeke et al JASN 2007

Verbeke et al . JASN 2007 P < 0.05 35 35.0 30.0 28 25.0 21 20.0 TNT- Brachial artery diameter (%) TNT-MD (% from baseline) 15.0 14 10.0 7 5.0 0.0 Controls ESRD 1 2 2 3 4 5 5 6 Brachial artery distensibility (kPa10-3) Verbeke et al . JASN 2007