Arterial Pressure in CKD5 - ESRD Population Gérard M. London INSERM U970 Paris
150 SBP & DBP by Age, Ethnicity &Gender (US Population Age 18 Years, NHANES III) 150 SBP (mm Hg) 130 110 80 Non-Hispanic Black Non-Hispanic White Mexican American SBP (mm Hg) 130 110 80 DBP (mm Hg) 70 DBP (mm Hg) 70 0 150 0 150 SBP (mm Hg) 130 SBP (mm Hg) 130 110 Pulse pressure 110 Pulse pressure 80 80 DBP (mm Hg) 70 DBP (mm Hg) 70 Burt VI, et al. Hypertension. 1995;25:305-313. 0 18-29 30-39 40-49 50-59 60-69 70-79 80+ Men, Age (y) 0 18-29 30-39 40-49 50-59 60-69 70-79 80+ Women, Age (y)
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) 100 } Diastolic Hypertension 17% 16% 16% 20% 20% 11% Frequency of hypertension subtypes in all untreated hypertensives (%) 80 60 40 20 0 <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.
Difference Between SBP and DBP in CHD Prediction, as a Function of Age* 1.0 *Ages 20 to 79 Adjusted for age, sex, & other risk factors + β(sbp) - β(dbp) 0.5 0.0-0.5-1.0 β(sbp) - β(dbp) = 1.49 + 0.029 * age (P=0.008) Favor SBP Favor DBP - -1.5 25 35 45 55 65 75 Age (years) Franklin et al. Circulation 2001;103:1245-1249
Hypertension Control by Age Group 100 85 91 92 % Controlled 80 60 40 69 48 34 Age <=60 (n=295) Age 61-75 (n=533) Age >75 (n=361) 20 0 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 Pulse Pressure (mm Hg) 78 68 58 48 38 Group Data Pulse Pressure (mm Hg) 135 115 95 75 55 35 Individual Data 160 140-159 120-139 <120 Age (y) Age (y) Franklin SS et al. Circulation 1997;96:308-315. n=2036
Relationship of SBP and DBP to risk for CHD in a dual component model: The Framingham Heart Study CHD hazard ratio 3 2.5 2 1.5 1 SBP 150 mm Hg (P = 0.02) SBP 130 mm Hg (P = 0.06) SBP 110 mm Hg (P = 0.03) Adjusted for age, sex, and other risk factors P = probability for β coefficients 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 2-year risk of endpoint 0.28 0.24 0.20 0.16 0.12 0.08 EWPHE (n = 840) SYST-EUR (n = 4695) SYST-CHINA (n = 2394) 75 80 85 90 95 DBP (mm Hg) 0.04 120 140 160 180 200 220 240 SBP (mm Hg) Two-year risk adjusted for active treatment, sex, age, previous CV complications, and smoking by multiple Staessen, et al. Lancet. 2000;355:865 872. Cox regression.
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 CHD Hazard Ratio/10 mm Hg (CI) 2.0 1.6 1.2 1.0 0.8 0.4 0.0 *** SBP (10 mm Hg) DBP (10 mm Hg) *** PP (10 mm Hg) * * *** ** <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
One Year Mortality for Patients on Hemodialysis predicted by pulse pressure 20 18 16 Adjusted for level of systolic blood pressure Hazard Ratio for Death 14 12 10 8 6 n = 37,069 Predialysis PP Postdialysis PP 4 2 Ref 0 20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100 100-110 >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 Cardiovascular free events 0.750 0.500 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) PPbr 55 mm Hg P<0.001 PPbr 75 mm Hg NS PPbr 75 mm Hg Safar ME et al Hypertension 2002
Common Carotid Pulse Pressure and Cardiovascular mortality in ESRD patients 1.00 Cardiovascular free events 0.75 0.50 0.25 PPcc <50 mm Hg PPcc 75 mm Hg PPcc 70 mm Hg Cox model: P=0.0049 adjusted for age and mean BP 0.00 0.0 28 56 84 112 140 P<0.05 P<0.001 P<0.00001 Follow-up (months) Safar ME et al Hypertension 2002
1-year Mortality predicted by SBP Experience at 782 US dialysis facilities 2.5 2 n = 37,069 Hazard Ratio for Death 1.5 1 Ref Predialysis SBP Postdialysis SBP 0.5 0 < 115 115-125 125-135 135-145 145-155 155-165 165-175 > 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 Hazard Ratio For Death 6 5 4 3 2 1 n = 37,069 Predialysis Postdialysis Adjusted for level of systolic blood pressure 0 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 Baseline d BP (mm Hg) 100+ Proportion surviving 0.8 0.6 90-99 80-89 70-79 -69 0.4 0 12 24 36 48 60 Duration of observation, months ISEKI K. et al. Kidney Int 1997
Hypertension 2005;45:811
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
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 mm Hg Mean BP Pulse pressure 80 Diastolic pressure Mean BP: Cardiac output peripheral resistance Systolic pressure: ventricular ejection (stroke volume and ejection time) arterial stiffness wave reflection Diastolic pressure: arterial resistance arterial Stiffness Diastolic decay time
Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity and stroke volume (n=230) 160 160 Systolic Pressure (mm Hg) 132 104 76 48 R=0.47 p<0.0001 Systolice Pressure (mm Hg) 132 104 76 48 R=0.60 p<0.0001 20-40 -15 10 35 60 Augmentation Index (%) 160 20 500 1000 1500 2000 2500 Aortic pulse wave velocity (cm/s) Systolic Pressure (mm Hg) 132 104 76 48 R=0.17 P <0.05 London et al KI 1996 20 20 55 90 125 160 Stroke volume (ml)
Relationship of Resistance, Compliance (C) and Stiffness (S=1/C)with diastolic pressure decay 140 80 τ-time constant of diastolic decay Blood pressure α-slope of diastolic decay 4.6 4.38 Adapted from Simon et al. Am J Physiol 1979 Blood pressure *....... τ......... α.. τ = R.C α =1/τ = 1/R.C α =S/R * log scale Time (sec)
Systolic pressure (mm Hg) 230 200 170 140 110 r = 0.21 P = 0.015 NS-PWV and SV adjusted 80 0.5 1.1 1.7 2.3 2.8 3.4 4.0 Interdialysis body weight changes (kg) Aortic pulse wave velocity-pwv (cm/s) 1800 1520 1240 960 680 400 r = 0517 P < 0.0001 Adjust for Systolic BP Age and SV 0.5 1.1 1.7 2.3 2.8 3.4 4.0 Interdialysis body weight changes (kg) Stroke volume - SV (ml) 180 156 132 108 84 r = 0.284 P < 0.01 Adjust. For Systolic BP and PWV 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 1.0 0.75 0.50 0.25 Pulse Pressure AUC 72.7±3.2 Aortic PWV AUC 83.4±2.7 Brachial PWV AUC 58.9±3.9 Femoral PWV AUC 56.2±4.0 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 Aortic PWV (m/s) 20 15 10 5 r=0.625 p<0.00001 25 50 75 100 Age (years) r=0.719 p<0.00001 Characteristic impedance (dynes.s.cm-5) 500 400 300 200 100 0 r=0.525 P<0.00001 r=0.340 P<0.01 10 20 30 40 50 60 70 80 90 100 Age (years) Pannier et al Artery 2007;1:78-89
Age related changes in arterial internal diameters Carotid artery diameter (mm) 12 11 10 9 8 7 6 5 2.5 20 30 40 50 60 70 80 90 Age (years) Brachial artery diameter (mm) 6.5 5.8 5.2 4.5 3.8 3.2 20 30 40 50 60 70 80 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 Common carotid artery IMTh(mm) 1.10 1.00 0.90 0.80 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 Probability of overall survival 1 0.75 0.50 0.25 0 0 35 70 105 140 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. 1999
All cause survival according to changes in aortic pulse wave velocity (Δ PWV) in response to BP decrease Survival rate 1 0.75 0.50 Decreased PWV χ 2 = 28.01 P<0.00001 0.25 0 Unchanged or PWV 0 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 13 110 12 11 110 12 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 Sensitivity 1.00 0.75 0.50 Criterions Age; AUC 72±5% Pulse Pressure; AUC 72±5% Carotid IMT;AUC 68±6% LVmassix; AUC 72±5% 0.25 Calcification score; AUC 82±4% Aortic PWV; AUC 82±4% 0.00 0.00 0.25 0.50 0.75 1.00 1-Specificity PWV 2 = 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 Forearm blood flow ml/100 ml/min 40 30 20 10 0 * * * * * * A = Flow debt ml/100 ml Peak flow * * * Flow debt repayment=b/a B = Excess hyperemic flow ml/100ml Duration of hyperemia * * * * * * * * * * * * * * * * 0 1 2 3 4 5 6 7 8 9 10 11 baseline occlusion postocclusion Time,min
P<0.0001 P<0.0001 250 400 Flow debt repayment (%) 188 125 63 0 Controls ESRD Time to debt repayment (s) 300 200 100 0 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 Survivorship 0.75 0.50 0.25 0.00 χ²=17.9 P<0.001 0 20 40 60 80 100 Follow-up (months) FDR>85% FDR<85% 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 Spatial resolution 2 D TM RF Signal 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
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 1.kPa.10 7 ) 0.45 ± 0.02 0.37 ± 0.02 < 0.01 1 BA distensibility (kpa.10 3 ) 3.5 ± 0.22 2.6 ± 0.19 < 0.001 3 BA incremental elastic modulus (kpa.10 ) 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 ) 1 Baseline peak SR (s-) 53 ± 2.9 39 ± 3.5 < 0.01 365 ± 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
TNT-Δ Brachial artery diameter (%) 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 Controls P < 0.05 ESRD TNT-MD (% from baseline) 35 28 21 14 7 0 0 1 2 2 3 4 5 5 6 Brachial artery distensibility (kpa10-3) Verbeke et al. JASN 2007