Arterial Pressure in CKD5 - ESRD Population

Gérard M. London

INSERM U970

Paris

18-29 30-39 40-49 50-59 60-69 70-79 80+0

70

80

110

130

150

18-29 30-39 40-49 50-59 60-69 70-79 80+0

70

80

110

130

150

0

70

80

110

130

150

0

70

80

110

130

150

DB

P(m

m H

g)SB

P(m

m H

g)D

BP

(mm

Hg)

SBP

(mm

Hg)

DB

P(m

m H

g)SB

P(m

m H

g)D

BP

(mm

Hg)

SBP

(mm

Hg)

Men, Age (y) Women, Age (y)

Non-Hispanic BlackNon-Hispanic BlackNon-Hispanic WhiteNon-Hispanic WhiteMexican AmericanMexican American

Pulse pressurePulse pressure Pulse pressurePulse pressure

SBP & DBP by Age, Ethnicity &Gender (US Population Age 18 Years, NHANES III)

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.

160140-159120-139<120

<40 40-49 50-59 60-69 70-79 80+Age (y)

17% 16% 16% 20% 20% 11%

Distribution of Hypertension Subtype in the untreated Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by AgeHypertensive 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)

0

20

40

60

80

100

Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874.

Frequency of hypertension

subtypes in all untreated

hypertensives (%)

}Diastolic Hypertension

Difference Between SBP and DBP in CHD Prediction, as a Function of Age*

Franklin et al. Circulation 2001;103:1245-1249

Age (years)

1.0

25

(S

BP

) - (

DB

P)

0.5

0.0

-0.5

-1.0

-1.535 45 55 65 75

(SBP) - (DBP) = 1.49 + 0.029*age(P=0.008)

*Ages 20 to 79 Adjusted for age, sex, & other risk factors

Favor SBP

Favor DBP

+

-

85

69

91

48

92

34

0

20

40

60

80

100

DBP Goal SBP Goal

% C

ontr

olle

d

Age <=60 (n=295)

Age 61-75 (n=533)

Age >75 (n=361)

Hypertension Control by Age Group

Cross-sectional analysis among 1189 treated hypertensive subjects from FraminghamLloyd-Jones Hypertension 2000;36:594

78

68

58

48

38Pu

lse

Pre

ssu

re (

mm

Hg)

135

115

95

75

55

35P

uls

e P

ress

ure

(m

m H

g)

Age (y) Age (y)

30-3

435

-39

40-4

445

-49

50-5

455

-59

60-6

465

-69

70-7

475

-79

80-8

4

30 35 40 45 50 55 60 65 70 75 80

Steep Rise in Pulse Pressure With Increasing Age Data From the Framingham Study

160140-159120-139120

85

Franklin SS et al. Circulation 1997;96:308-315. n=2036

Group Data Individual Data

Franklin SS, et al. Circ. 1999;100:354.

60 70 80 90 100 110

DBP (mm Hg)

0.5

1

1.5

2

2.5

3

SBP 170 mm Hg (P = 0.01)SBP 150 mm Hg (P = 0.02)SBP 130 mm Hg (P = 0.06)

SBP 110 mm Hg (P = 0.03)

CH

D h

azar

d r

atio

Relationship of SBP and DBP to risk for CHD in a dual component model: The Framingham Heart

Study

Mean age = 61 years (range: 50-79), n = 1924

Adjusted for age, sex, and other risk factors

P = probability for coefficients

Cardiovascular Risk Associated with Increasing SBP at Fixed Values of DBP

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.

EWPHE (n = 840)SYST-EUR (n = 4695)SYST-CHINA (n = 2394)

SBP (mm Hg)

2-ye

ar r

isk

of

en

dp

oin

t

240220200180160140120

0.04

0.08

0.12

0.16

0.20

0.24

0.287580859095

DBP(mm Hg)

Blood Pressure and CHD RiskDual BP Component Models

Chi Sq. Hazard Ratio P Value

Model 1SBP 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

† 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.

CH

D H

azar

d R

atio

/10

mm

Hg

(CI)

Age (y)

<50 50-59 600.0

0.4

0.8

1.2

1.6

2.0SBP (10 mm Hg)

DBP (10 mm Hg)

PP (10 mm Hg)

***

***

*** * ***

***

1.0

Rohrscheib MP et al CJASN 2008;3:1407

Evolution of Systolic and Diastolic BP in CKD patients

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

0

2

4

6

8

10

12

14

16

18

20

20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100

100-110

>110

Categories of Pulse Pressure (mmHg)

Haz

ard

Rat

io f

or D

eath

Predialysis PP

Postdialysis PP

Adjusted for level of systolic blood pressure

Ref

Klassen et al. JAMA 2002;287:1548-1555

n = 37,069

0.000

0.250

0.500

0.750

1.000

0.0 28.0 56.0 84.0 112.0 140.0

Brachial Pulse Pressure and Cardiovascular mortalityin ESRD patients

Follow-up (months)

Car

dio

vasc

ula

r fr

ee e

ven

ts PPbr 55 mm Hg≦

PPbr 75 mm Hg≦

PPbr 75 mm Hg≧

Cox model: P=0.033adjusted for age and mean BP

P<0.001

NS

Safar ME et al Hypertension 2002

0.00

0.25

0.50

0.75

1.00

0.0 28 56 84 112 140

Common Carotid Pulse Pressure and Cardiovascular mortalityin ESRD patients

Follow-up (months)

Car

dio

vasc

ula

r fr

ee e

ven

ts

Cox model: P=0.0049adjusted for age and mean BP

PPcc <50 mm Hg

PPcc 75 mm Hg≦

PPcc 70 mm Hg≧

P<0.05

P<0.001

P<0.00001

Safar ME et al Hypertension 2002

1-year Mortality predicted by SBPExperience at 782 US dialysis facilities

0

0.5

1

1.5

2

2.5

< 115 115 -125

125 -135

135 -145

145 -155

155 -165

165 -175

> 175

Categories of SBP (mmHg)

Haz

ard

Rat

io f

or D

eath

Predialysis SBP

Postdialysis SBPRef

Klassen et al. JAMA 2002;287:1548-1555

n = 37,069

1-year Mortality predicted by DBPExperience at 782 US dialysis facilities

0

1

2

3

4

5

6

30-40 40-50 50-60 60-70 70-80 80-90 90-100100-110> 110

DBP (mmHg)

Predialysis

Postdialysis

Klassen et al. JAMA 2002;287:1548-1555

Adjusted for level of systolic blood pressure

n = 37,069

Haz

ard

Rat

io F

or D

eath

Prop

orti

on s

urvi

ving

Survival curves in hemodialysis patientsfor each baseline level of diastolic BP

ISEKI K. et al. Kidney Int 1997

Duration of observation, months

0 12 24 36 48 60

1.0

0.8

0.6

0.4

100+

90-9980-89

70-79-69

Baselined BP (mm Hg)

Hypertension 2005;45:811

Fouque D et al Observatoire National

N = 5692

P<0.01

All cause mortality according Systolic blood pressure (PAS)

Adjusted Cox Z-value –2.23; p=0.02

0.992 (0.988-0.991) for 1 mmHg increase

All cause mortality according Diastolic blood pressure (PAd)

N = 5692

P<0.01

Fouque D. et al Observatoire NationalAdjusted Cox: Z-value = –6.73; p<0.001

0.977 (0.971-0.984) for 1 mmHg increase

80

140

Mean BP

Pulse pressure

Mean BP: Cardiac output peripheral resistance

mm

Hg

Systolic pressure: ventricular ejection (stroke volume and ejection time) arterial stiffness wave reflectionDiastolic pressure: arterial resistance arterial Stiffness Diastolic decay time

Systolic pressure

Diastolic pressure

Augmentation Index (%)

20

48

76

104

132

160

500 1000 1500 2000 2500

Aortic pulse wave velocity (cm/s)

Syst

olic

e P

ress

ure

(mm

Hg)

20

48

76

104

132

160

20 55 90 125 160Stroke volume (ml)

Sys

toli

c P

ress

ure

(m

m H

g)

20

48

76

104

132

160

-40 -15 10 35 60

Sys

toli

c P

ress

ure

(m

m H

g)

R=0.47p<0.0001

R=0.60p<0.0001

R=0.17P <0.05

Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity and stroke volume (n=230)

London et al KI 1996

.... .. ... .. . .

Time (sec)

80

140

4.6

4.38

. . . . . . . .

... .

Blo

od p

ress

ure

= R.C

=1/ = 1/R.C

Blo

od p

ress

ure

*

* log scale-time constant of diastolic decay

-slope of diastolic decay

Relationship of Resistance ®, Compliance (C) and Stiffness (S=1/C)with diastolic pressure decay

Adapted from Simon et al. Am J Physiol 1979

=S/R

80

110

140

170

200

230

0.5 1.1 1.7 2.3 2.8 3.4 4.0

Interdialysis body weight changes (kg)

Sys

toli

c p

ress

ure

(m

m H

g)

400

680

960

1240

1520

1800

0.5 1.1 1.7 2.3 2.8 3.4 4.0

Interdialysis body weight changes (kg)

Aor

tic

pu

lse

wav

e ve

loci

ty-P

WV

(cm

/s)

60

84

108

132

156

180

0.5 1.1 1.7 2.3 2.8 3.4 4.0

Interdialysis body weight changes (kg)

Str

oke

volu

me

- S

V (

mL

)r = 0.21

P = 0.015

NS-PWV and SV adjusted

r = 0.284

P < 0.01

Adjust. For Systolic BP

and PWV

r = 0517

P < 0.0001

Adjust for Systolic BP

Age and SV

London et al Kidney Int 1989

Diagrammatic representation of pressure-volume relationships

Volume

Pre

ssu

re

dP/dV

Einc=1Einc=2

Mean BP

0.00

0.25

0.50

0.75

1.0

0.00 0.25 0.50 0.75 1.0

1-Specificity

Sen

siti

vity

Pulse PressureAUC 72.7±3.2

Aortic PWVAUC 83.4±2.7

Brachial PWVAUC 58.9±3.9

Femoral PWVAUC 56.2±4.0

ROC Curves of CVdeath

Pannier B et al Hypertension 2005

Correlation between Age and Aortic Pulse Wave Velocityin General population ( ) and ESRD patients ( )

5

10

15

20

25

25 50 75 100

Age (years)

Aor

tic

PW

V (

m/s

)

r=0.625p<0.00001

r=0.719p<0.00001

0

100

200

300

400

500

600

10 20 30 40 50 60 70 80 90 100

Age (years)

Ch

arac

teri

stic

imp

edan

ce

(dyn

es.s

.cm

-5)

r=0.525P<0.00001

r=0.340P<0.01

Pannier et al Artery 2007;1:78-89

5

6

7

8

9

10

11

12

20 30 40 50 60 70 80 90

Age (years)

Car

otid

art

ery

dia

met

er (m

m)

2.5

3.2

3.8

4.5

5.2

5.8

6.5

20 30 40 50 60 70 80

Age (years)

Bra

chia

l art

ery

dia

met

er (m

m)

Controls

ESRD patients

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)

Age related changes in arterial internal diameters

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1.10

10 20 30 40 50 60 70 80 90

Age (years)

Com

mon

car

otid

art

ery

IMT

h(m

m)

Controls

ESRD patients

Age related changes in Carotid IMTh

Pannier et al Hypertension 2005

Probability of overall survival in hemodialysispatients according to aortic PWV

Duration of follow-up (months)

0

1

0 35 70 105 140

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

Pro

bab

ilit

y of

ove

rall

su

rviv

al

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.

Decreased PWVDecreased PWV

0.250.25

0.500.50

0.750.75

11

00

00 3535 7070 105105 140140

Unchanged or Unchanged or PWV PWV

Duration of follow-up (months)Duration of follow-up (months)

Survival rate

Changes of mean blood pressure and aortic PWV

Guérin and al. circulation 2001 ; 103 : 987 - 92

9

10

11

12

13

14

Survivors

110

120

InclusionInclusion At targetAt targetBPBP

End of End of follow upfollow up

MBPMBP(mmHg)(mmHg)

PWVPWV(m/s)(m/s)

9

10

11

12

13

14

Non Survivors

100

110

120

InclusionInclusion At targetAt targetBPBP

End of End of follow upfollow up

MBPMBP(mmHg)(mmHg)

PWVPWV(m/s)(m/s)

100

0.00

0.25

0.50

0.75

1.00

0.00 0.25 0.50 0.75 1.00

1-Specificity

Sen

siti

vity

Criterions

Age; AUC 72±5%

Pulse Pressure; AUC 72±5%

Carotid IMT;AUC 68±6%

LVmassix; AUC 72±5%

Calcification score; AUC 82±4%

Aortic PWV; AUC 82±4%

ROC Curve of CV mortality

PWV2 = Einc x arterial IMT/arterial radius wher Einc is incremental elastic modulus

London et al. Cur Op hypertens Nephrol 2006

0 1 2 3 4 5 6 7 8 9 10 11

baseline occlusion postocclusion Time,min

******A = Flow debt mL/100 mL

*

*

******* ***** * ** *

Duration of hyperemia

Peak flow

B = Excess hyperemic flowml/100ml

Flow debt repayment=B/A

For

earm

blo

od f

low

ml/

100

ml/

min

0

10

20

30

40

Schematic representation of reactive hyperemic response in the humanforearm after five minutes of ischemia

*

0

100

200

300

400

Controls ESRDT

ime

to d

ebt

rep

aym

ent

(s)

0

63

125

188

250

Controls ESRD

Flo

w d

ebt

rep

aym

ent

(%)

Pannier B et al. Kidney Int 2001

P<0.0001 P<0.0001

0.00

0.25

0.50

0.75

1.00

0 20 40 60 80 100

Follow-up (months)

Su

rviv

orsh

ip

Probability of survival in ESRD patients according to postischemic forearm flow debt repayement (FDR)

FDR>85%

FDR<85%

²=17.9P<0.001

London GM et al. Kidney Int 2003

Mullen, M. J. et al. Circ Res 2001;88:145-151

Methods of stimulating increased blood flow

2 D TM RF Signal

IMT

Signal averaging 10-10 000 RF lines

Spatialresolution

200-400 µm 20-40 µm

Echotracking is 3 to 10 x more precise than image based techniques

Ghiadoni, L. et al. Hypertension 2003;41:1281-1286

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)

Traub, O. et al. Arterioscler Thromb Vasc Biol 1998;18:677-685

Endothelial cell biology and shear stress

Baseline BA diameter (mm) 4.12 0.13 4.56 0.11 < 0.01

BA compliance (m2.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.103) 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

Controls ESRD

Brachial artery characteristics

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

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

Controls ESRDTN

T-

Bra

chia

l art

ery

dia

met

er (

%)

P < 0.05

0

7

14

21

28

35

0 1 2 2 3 4 5 5 6Brachial artery distensibility (kPa10-3)

TN

T-M

D (

% f

rom

bas

elin

e)

Verbeke et al . JASN 2007