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

2. 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:

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

4. 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: 1

5. 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) = *age
(P=0.008)
-1.0
-1.5 25 35 45 55 65 75
Age (years)
Franklin et al. Circulation 2001;103:

6. Hypertension Control by Age Group
100 91 92 85 80 69 60
Age <=60 (n=295) 48
% Controlled
Age (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

7. Steep Rise in Pulse Pressure With Increasing Age Data From the Framingham Study
Slide 8
160
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: 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:

8. 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:
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:
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

9. 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.

10. Blood Pressure and CHD Risk Dual BP Component Models
Chi Sq.
Hazard Ratio
P Value
Model 1
SBP
35.6
1.22 ( )
<0.001
DBP
5.2
0.86 ( )
<0.05
Model 2
DBP
0.7
1.04 ( ) NS PP
35.6
1.22 ( )
<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

11. 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:

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

13. Rohrscheib MP et al CJASN 2008;3:1407

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

15. Liu M et al. NDT 2003; 18:563

16. 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:

17. 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

18. 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<
0.50
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

19. 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:

20. 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
> 110
DBP (mmHg)
Klassen et al. JAMA 2002;287:

21. 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
Duration of observation, months
ISEKI K. et al. Kidney Int 1997

22. Hypertension 2005;45:811

23. 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 ( ) for 1 mmHg increase
Fouque D et al Observatoire National

24. 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 ( ) for 1 mmHg increase
Fouque D. et al Observatoire National

25. 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

26. 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)

27. 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

28. 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 <
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

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

30. 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

31. Correlation between Age and Aortic Pulse Wave Velocity
in General population ( ) and ESRD patients ( ) 25
600
500
r=0.525
P< 20
400
r=0.625
p<
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< 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

32. Age related changes in arterial internal diameters12
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 < )
ESRD (r = 0.277;P = 0.065)
Controls
ESRD patients

33. 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

34. 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

35. 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<
0.25
Unchanged or  PWV 35 70
105
140
Duration of follow-up (months)
Guérin et al. Circulation

36. 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 :

37. 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

38. 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

39. 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

40. 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

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

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

43. 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:

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

45. 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
<
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

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

47. 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