Arterial Stiffness: pathophysiology and clinical impact · Arterial Stiffness: pathophysiology and clinical impact ... d essure Systole Diastole Mean ... R C R C P P Z Z Z

Arterial Stiffness: pathophysiology

and clinical impact

Gérard M. LONDON

Manhès Hospital

Fleury-Mérogis/Paris, France

Determinants of vascular overload (afterload) on the heart

Wave

reflection

PeripheralResistance

Inertance

Arterial

Stiffness

Arterial Impedance as a determinant of afterloadGradients

Aorta

Resistance vessels

Pf

Pb

Pt

Zr - Zc

-Zr -Zc

+

=Reflection

Coefficient

Zc ZR

PWV= Zc

Zc-characteristic impedance

Zr-peripheral resistanceREFLECTION

STIFFNESS

RESISTANCE

ZR

80

140

Mean BP

Pulse pressure

Mean BP: Cardiac output

peripheral resistance

mm

Hg

Pulse pressure: ventricular ejection

arterial stiffness

wave reflection

Systolic pressure

Diastolic pressure

Flow

Pre

ssu

re

Steady -mean

flow

Pulsatile flow

1 Hz

Pulsatile flow

2 Hz

Pulsatile flow

3 Hz

Flow-Pressure relationship - influence of the fraquency

(Resistance = slope of the relationship)

R=8. L/r4 (-viscosity; L length; r= radius - number of vessels)

R= Mean Blood Pressure/Cardiac output

Perfusion pressure (mm Hg)

Flo

w (

ml/

min

)

Pressure-flow relationship - influence of the fraquency

(Resistance = slope of the relationship)

Ringer

Blood Blood +

Noradrenaline

Autogegulation

Diagrammatic representation of volume-pressure relationship

PRESSURE

VO

LU

ME

P

V

V/P=Compliance

P/V=Elastance (Stiffness)

Transition zone

Diagrammatic representation of volume-pressure relationship

Vo

lum

e

Pressure

P

V

V/P=Compliance P/V=Elastance (Stiffness)

Transition zoneP

ress

ure

P

P

V

V

Volume

A.Tedgui and B. Levy , 1994

The arterial wall is a heterogeneous material

Distensible balloon

(rubber=elastin)

Rigid/stiff net

(steel=collagen)

A.Tedgui and B. Levy , 1994

The arterial wall is a heterogeneous material

Diagrammatic representation of pressure-volume

relationships

Volume

Pre

ss

ure

dP/dV

Einc=1Einc=2

Arterial function and blood pressure

Pure Conduit Function Conduit and Cushioning

Function

Blo

od

pre

ssu

re

Systole Diastole

Mean

pressure

Blo

od

pre

ssu

re

Systole Diastole

Mean

pressure

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

Time (sec)

80

140

4.6

4.38

. . . . . . . .

....

Blo

od

pre

ssu

re

= R.C

=1/ = 1/R.C

Blo

od

pre

ssu

re *

* log scale

-time constant of

diastolic decay

-slope of diastolic

decay

Relationship of Resistance (R) and Compliance (C) with

diastolic pressure decay

Adapted from Simon et al. Am J Physiol 1979

The diameter-pressure curve

Local pressure

Time (sec)

75

100

125

150

0 17

7.1

7.2

7.3

0 1Time (sec)

diameter (mm)

7.00

7.15

7.30

70 90 110 130 150

Diameter (mm)

High-definition

echotracking devices

• Wall Track system

• NIUS system

Aplanation

Tonometry

• Millar Instruments

Pressure-diameter relationship :

a thermodynamic analysis

2.2

2.4

2.6

2.8

70 90 110 130 150

Art

eria

l D

iam

eter

(m

m) Dissipated energy

Exchanged energy

Viscosity =

Distensibility =

Arterial Pressure (mm Hg)

Pressure/arterial luminal cross-sectional area and hysteresis loop

in vivo before and after desendothelisation

Intact endothekium

Desendothelisation

Boutouyrie P et al. Arterioscler Thromb Vasc Biol 1997;17:1346-55

Carotid-femoral pulse wave

velocity

tL

PWV²=Einc*IMTh/D

PWV=L/t

450

860

1270

1680

2090

2500

0 20 40 60

CCA distensibility (kPa 10-1.10-3)

Ao

rtic

PW

V (

cm/s

)

Correlation between common carotid artery (CCA) distensibility

and aortic pulse wave velocity (PWV)in human population

r=-0.825

p<0.0001

W W Nichols & M O’Rourke, Mc Donald’s blood flow in

arteries, Arnold ed,1998

measured pressure wave

forward/incident pressure wave

reflected pressure wave

pulse wave velocity

Pressure wave analysis

Effect of arterial stiffness on timing of forward

and reflected Waves

Systolic

Augmentation

Pressure (Aix)

PWV 8 m/sec PWV 12 m/sec

.

Forward-traveling waveBackward-traveling reflected waveActual (composite) wave

T T

T - traveling time of pressure wave to reflecting sites and back

Negative

Aix

Positive

Aix

Aortic versus Peripheral pulse pressure

Peripheral

Artery

.

Forward-traveling waveBackward-traveling reflected waveActual (composite) wave

T

T - traveling time of pressure wave to reflecting sites and back

Aorta amplification

Energy dissipation

Pressure Waves Recorded Along the Arterial Tree

Femoral artery

Iliac artery

Abdominal aorta

Ascending aorta

Renalartery

Thoracic aorta

50

100

150

50

100

150

50

100

150

Nichols WW, et al. Arterial Vasodilation. Philadelphia,1993;32.

(mm

Hg

)(m

m H

g)

(mm

Hg

)

Age 68 years

Age 54 years

Age 24 yearsMaximum

Amplification

Maximum

Early Wave

Reflection

Aortic (carotid) pressure waveforme

.

Forward- waveReflected waveActual wave

Tsh

LVET

P

PP

Augmentation index=P/ PP

P= augmented pressure

PP=pulse pressure

Tsh= time to shoulder

LVET=left ventricular

ejection time

Tsh

50

85

120

155

190

225

500 825 1150 1475 1800

aortic PWV (cm/s)

Tim

e to

sh

ou

lder

(T

Sh

ms) R=-0.671

p<0.0001

Relationship between the time of appearance of reflected wave on the pressure wave

in central artery (time to shoulder - TSh) and aortic pulse wave velocity (PWV)

50

85

120

155

190

225

130 140 150 160 170 180 190 200

Body height (cm)

Tim

e to

sh

ou

lder

(T

Sh

ms)

R=0.585

p<0.0001

Relationship between the time of appearance of reflected wave

on the pressure wave in central artery (time to shoulder - TSh) and body height

Arterial Impedance Gradients

Zc-characteristic impedance; Zr-peripheral resistance

Aorta Muscular arteriesResistance

vessels

Pf P

tPb

Pf

Pb

Pt

( )f

b

CR

CR

P

P

ZZ

Z-Z=

+=CoefficientReflection

Zc ZR

PWV=6 m/s PWV=10 m/s


Pressure = 0+P1+P2+P3…= a1 cos(t+1) + a2 cos(t+2)+ a3 cos(t+3)...

Fourier series - the mean terma and first 6 harmonics of a

presure wave from ascending aorta (Westerhof et al 1979)

Pressure and flow waves broken down into mean term and Fourier series

Modulus is the amplitude of pressure harmonic divided by the amplitude of corresponding

flow harmonic, and phase as the delay between corresponding harmonics

Modulus and phase of impedance in the ascending aorta

McDonald blood flow in the arteries 1994

Mod

ulu

s (d

yn

es s

ec c

m-5

)

Frequency (Hertz)

0 1 2 3 4 5 6 7

0

500

1000

1500

Peripheral

resistance (Zr)

(Heart rate)

First minimum of

impedance modulus - fmin

(lowest pressure for a given flow)

Zc

Characteristic

impedance

Schematic representation of vascular impedance (Modulus= Pressure/flow)

Best coupling

L=/4=PWV/4f

L=/4

Pressure and flow waves along the tubular model completely occluded. At the

closed end the pressure is maximal and flow zero. The best coupling minimal

pressure for maximal flow is at 1/4 of the wavelength ( =PWV/frequency ) equal

to the distance L to site of reflection

Pressure

Flow

T

L = PWV* tp/2

fmin=1/2 tp

Exemple: tp = 0.125s, 2 tp=0.25s, fmin=1/0.25=4Hz

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

130.0 145.0 160.0 175.0 190.0

Body height (cm)

Fir

st m

inim

um

of

imp

eda

nce

(H

z)

Relationship between the first minimum of impedance modulus and body height

London GM personal data

r=-0.546

P<0.0001

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

600.0 900.0 1200.0 1500.0 1800.0

Aortic PWV (cm/s)

Fir

st m

inim

um

of

imp

eda

nce

(H

z)

Relationship between the first minimum of impedance modulus and aortic PWV

r=0.495

P<0.0001


Mod

ulu

s (d

yn

es s

ec c

m-5

)

Frequency (Hertz)

0 1 2 3 4 5 6 7

0

500

1000

1500

Zr=Zr

(Heart rate)

fmin

Zc

Schematic representation of vascular impedance (Modulus= Pressure/flow)

2000

fmin

Zc

Control

ESRD

Mod

ulu

s (d

yn

es s

ec c

m-5

)

Cycles (multiples of 1st in Hertz)

0 1 2 3 4 5 6 7

0

500

1000

1500

(1st = Heart rate)

First minimum of

impedance modulus

Representation of the impedance modulus

and amplitude (power) of flow harmonics

Flow (ml/m) for different

frequencies

Mod

ulu

s (d

yn

es s

ec c

m-5

)

Cycles (Hertz)

0 1 2 3 4 5 6 7

0

500

1000

1500

(Heart rate)

Impedance modulus and flow harmonics during exercise

(shift of flow harmonics with increased heart frequency)

Flow (ml/m)

Heart rate - 200 (3.3Hz)

1st minimum of impedance is

close to heart rate (i.e.

frequency of the highest flow

harmonic for lowest pressure

harmonic)

Heart rate 60 (1Hz)

heart rate is far from 1st min.

of impedance

(flow develops a high pressure)

2.0

3.0

4.0

5.0

6.0

7.0

600

1.66 Hz

800

1.25 Hz

1000

1 Hz

1200

0.83 Hz

1400

0.71 Hz

Heart Period (ms)

Fir

st m

inim

um

of

imp

edan

ce (

Hz)

R=-0.240

p=0.003

Relationship between the first minimum of impedance modulus and heart period


2.0

3.0

4.0

5.0

6.0

7.0

130.0 145.0 160.0 175.0 190.0

Body Height (cm)

Fm

in/H

eart

fre

qu

ency

(ra

tio)

R=-0.280

P<0.0001

Relationship between the ratio of the first minimum of impedance modulus

and heart period and body height (better coupling between heart rate and

arterial properties in tall subjects


0.6

0.9

1.2

1.4

1.7

2.0

2.0 4.0 6.0 8.0 10.0

Fmin/heart frequency (ratio)

LV

vel

oci

ty o

f fi

ber

sh

ort

enin

g (

c/s)

Correlation between Fmin/heart frequency and Left Ventricular

velocity of fiber shortening

r=-0.338

P<0.001


Reflected Wave

SPTI DPTI SPTI DPTI

Superimposed simultaneous phasic recording of aortic (Ao),

left ventricular (LV) pressures and coronary blood flow (CBF)

(Buckeberg et al. Circ Res. 1972)

100

0

LV

Ao

STTI

DPTI

100

LA or PA

Wedge

Ao

STTI

DPTIBP

(mm

Hg

)

CB

F

(ml/

min

)

0.2

0.4

0.6

0.8

1.0

1.2

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

DPTI/SPTI

LV

en

do:e

pi

flow

rati

o

Adapted from Buckberg et al 1972

DPTI/SPTI plotted against Left Ventricular flow distribution

between endocardium and epicardium

200

100

Aortic pulse wave velocity (cm/sec)

Left

ventricular

mass

(g/m2)

500 1000 1500 2000

r = 0.52

p < 0.001

Correlation between left ventricular mass

and aortic pulse wave velocity

150

London et al KI 1989

Aortic stiffness and all-cause mortality in general population

(Laurent et al Hypertension 2001)

0.70

0.80

0.90

1.00

0 5 10 15 20

Follow-up (years)

Su

rviv

al

Low PWV tertile

Medium PWV tertile

High PWV tertile

Kaplan-Meier P<0.0001

Wave reflection (Aix) and cardiovascular survival

• Log rank test for cardiovascular mortality. Chi square =23.11 ; P<0.0001.

AIX : 1st quartile

0.25

0.50

0.75

1

0

0 35 70 105 140

AIX : 2nd quartile

AIX : 3rd quartile

AIX : 4th quartile

Duration of follow-up (months)

Card

iovascu

mar

su

rviv

al

London et al Hypertension 2001

<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

Hypertensive Population in NHANES III by AgeISH (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

(%)

Evolution of Untreated Systolic and Diastolic BP:

The Framingham Heart Study

Adapted from Franklin et al. Circulation 1997;96:308.

n=2036

160

140-159

120-139

<120

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-y

ear

risk

of

en

dp

oin

t

240220200180160140120

0.04

0.08

0.12

0.16

0.20

0.24

0.2875

80

85

90

95

DBP

(mm Hg)

Augmentation Index (%)

20

48

76

104

132

160

500 1000 1500 2000 2500

Aortic pulse wave velocity (cm/s)

Pu

lse

Pre

ssu

re (

mm

Hg

)

20

48

76

104

132

160

20 55 90 125 160

stroke volume (ml)

Pu

lse

Pre

ssu

re (

mm

Hg

)

20

48

76

104

132

160

-40 -15 10 35 60

Pu

lse

Pre

ssu

re (

mm

Hg

) R=0.47

p<0.0001

R=0.60

p<0.0001

R=0.15

p=0.035

Correlation between arterial pulse pressure, wave reflexion (Augmentation index)

aortic pulse wave velocity and stroke volume (n=230)

Adapted from London et al KI 1996

Pulse wave analysis:

Mitchell, G. F. et al. Hypertension 2001;38:1433-1439

Definition of waveform landmarks, AI, and characteristic impedance

Arterial Pressure Waves Recorded

in Young Subjects

Normotensiv

e Subjects

Pseudo-

Hypertensio

n

Essential

Hypertensio

n

Mahmud A, Feely J. American J Hypertens 2003;16:229-232

M O’Rourke, Eur Heart J, 1990

-25

-20

-15

-10

-5

0

SBP DBP MBP PP

Per/Ind (n=204) atenolol (n=202)

BRACHIAL BLOOD PRESSURES at 1 year

NSp<0.001

-23.1

-16.2

-13.3

-12.9

-16.6

-14.0

-9.9

-3.3

p=0.019

p<0.001

Asmar R, London G, O’Rourke M et al. Hypertension 2001;38 : 922-7

-24

-20

-16

-12

-8

-4

0

-22.5

SBP

(mmHg)

-8.0

Per/Ind

(n=65)

Aténolol

(n=65)

p<0.001 p<0.001

p<0.001

AORTIC SBP ( At 1 year)


-10

-6

-2

2

-9.3 PP

(mmHg)

2.3

Per/Ind

(n=65)

Aténolol

(n=65)

p<0.001

NS

p<0.001*

AORTIC PP (At 1 year)


-2

-1,5

-1

-0,5

0

-0.79 -0.99

PWV

(m/s)

Per/Ind atenolol

p<0.001 p<0.001

NS*

PWV (carotido-femoral)


-4

-3

-2

-1

0

1

2

-3.06 AIX (%)

1.83

Per/Ind atenolol

p=0.002

NS

p<0.001*

*

AUGMENTATION INDEX (aortic)


-12

-9

-6

-3

0

-11.3

LVH (g/m2)

-5.3

Per/Ind Aténololp<0.001 p=0.012

p=0.031

LEFT VENTRICULAR HYPERTROPHY


Arterial Impedance Gradients

Zc-characteristic impedance; Zr-peripheral resistance

Aorta Muscular arteriesResistance vessels

Pf P

tPb

Pf

Pb

Pt

( )

Zr - Zc

-Zr -Zc

+

=CoefficientReflection

Zc ZR



Documents

Arterial Stiffness: pathophysiology and clinical impact · Arterial Stiffness: pathophysiology and clinical impact ... d essure Systole Diastole Mean ... R C R C P P Z Z Z