nature publishing group STATE OF THE ART

Arterial Stiffness, Its Assessment, Prognostic Value,

and Implications for Treatment
Audrey Adji1,2, Michael F. O’Rourke1,3,4 and Mayooran Namasivayam1,3

Arterial stiffness has been known as a sign of cardiovascular risk since use of angiotensin-converting enzyme inhibitors, angiotensin-

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the 19th century. Despite this, accurate measurement and clinical receptor blockers, and calcium-channel blockers, as well as
utility have only emerged in recent times. Arterial stiffness and its vasodilating β-blockers. Arterial stiffness will undoubtedly contribute
hemodynamic consequences are now established as predictors to cardiovascular assessment and management in future clinical
of adverse cardiovascular outcome. They are easily and reliably practice. Reviews such as this will hopefully increase awareness of
measured using a range of noninvasive techniques, which can be the mounting evidence underlying this transition, and the relevant
used readily by risk assessment facilities or individual practitioners. theory and methodology. As we begin the second decade of the 21st
The techniques described in this review are based on the pulsatility century, we are finally collectively coming to realize what pioneers
of the cardiovascular system, utilizing the timing of pulse travel such as Osler, Roy, Bramwell and Hill foresaw in the 19th and 20th
along major arteries and the magnitude of wave reflection. These centuries.
have enabled better understanding of the ill effects of arterial
stiffening, not only on large arteries and the left ventricle, but also Keywords: arterial stiffness; blood pressure; hemodynamics;
on tiny arteries in highly perfused organs such as brain and kidneys. hypertension; systolic blood pressure
Treatment options, which directly target the consequences of
arterial stiffening, as opposed to arbitrary reduction of brachial blood American Journal of Hypertension, advance online publication 9 September 2010;
doi:10.1038/ajh.2010.192
pressure, have proved clinical superiority; optimal therapy entails

“The amount of energy expended by the heart ... is ... High systolic pressure was considered to be a good sign and to
­proportional to the pressure developed; hence the amount of be evidence of strong cardiac contraction.3
energy which the heart has to expend per beat, other things Internship and Fellowships in Physiology with pioneers of
being equal, varies ... with the elasticity of the arterial system.” arterial function caused this author to reconsider his views,
Bramwell and Hill, 1922.1 when indexes of arterial function, including the raw pressure
“Only in the case of young children do we find that the elas- wave in mature humans were seen to be markedly different
ticity of arteries is so perfectly adapted to the requirements from those recorded in corresponding arteries of experimen-
of the organism as it is in the case of the lower animals.” Roy, tal animals. Studies of ascending aortic impedance as left ven-
1880.2 tricular load brought this home strongly, as impaired tuning
When the senior author entered medical practice 50 years between ascending aortic impedance, and left ventricular
ago, arterial stiffness had no place in views of arterial hyper- flow harmonics (Figure 1). The ascending aortic impedance
tension, which was considered to be due to a fault in arteriolar of mature middle-aged humans, studied by Murgo et al.,4 was
tone, causing elevation of peripheral resistance, and resulting virtually identical to that in rabbits, despite huge difference
in raised mean and diastolic pressure. Diastolic pressure eleva- in body size and heart rate. Impedance patterns in the rab-
tion was considered the only manifestation of the silent killer bit appeared ideal to cushion pulsatile flow from the heart, as
in its early stages, and systolic pressure elevation was consid- the minimal value of impedance modulus was close to the fre-
ered a manifestation of cardiac strength (after Mackenzie and quency of resting heart rate (~4/s) and high modulus of the
Orr,3 who considered this as a good sign). O’Rourke’s mater- first harmonic of aortic flow, whereas there was gross detun-
nal grandmother’s lament at the dinner table that salt hardens ing in humans as human resting heart rate was about 1/s while
arteries was considered quaint, as hardening of arteries was the minimum of impedance was around 4 Hz. This was an
considered of no importance in elevation of arterial pressure. excellent illustration of Roy’s point,2 but what was the cause?
Pursuing this, we came to appreciate that it was attributable
1St. Vincent’s Clinic, Sydney, Australia; 2Australian School of Advanced Medicine,
to the marked increase with age in aortic pulse wave veloc-
Macquarie University, Sydney, Australia; 3Faculty of Medicine, University of New
South Wales, Sydney, Australia; 4Victor Chang Cardiac Research Institute, Sydney,
ity (PWV) of humans over decades but which are not seen
Australia. Correspondence: Michael F. O’Rourke (m.orourke@unsw.edu.au) in the lifetime of most experimental ­animals. The PWV, and
Received 25 May 2010; first decision 20 June 2010; accepted 8 August 2010. subsequently characteristic impedance, changes with age in
© 2011 American Journal of Hypertension, Ltd. humans were gross: two- to fourfold from 20–80 years of age

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 1 | 5-17 | January 2011 5

 STATE OF THE ART Ill-Effects of Arterial Stiffening

Modulus (normalized IZI/Z0)

Modulus (× 103 dyne·s/cm3)

2 Rabbit Man

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1
2
10 10
cm/s cm/s

0 0
0 5 10 15 0 5 10 15
Frequency (Hz) Frequency (Hz)
Phase (rads)

Phase (rads)

1.0 1.0

0 0

−1.0 −1.0

Figure 1 | Ascending aortic impedance measured in rabbits113 (left) and in a group of adult humans4 (right), together with (inset) amplitude of the first 2–9
harmonics of typical ascending aortic flow waves for rabbits and humans (from ref. 14). Ascending aortic impedance takes the form of a graph of modulus (top),
which is pressure amplitude/flow amplitude, and phase (bottom), which is the delay (in radians) between pressure and flow. The modulus at zero frequency is
peripheral resistance (mean pressure/mean flow). Modulus and phase of impedance are determined from frequency component of pressure and flow waves.
Impedance is similar in rabbits and man, indicating similar timing of wave reflection from the vascular bed. With far shorter body length in rabbit than man,
similarity is attributable to faster pulse wave velocity in man. The specked area up to 10 Hz represents where energy of the flow wave is normally located. This is
appropriate in the rabbit—highest flow energy at lowest impedance modulus—but inappropriate in man.

and out of proportion to the minor increase of brachial systo- occurred with increasing age in both macroscopic and micro-
lic or pulse pressure with age, but accompanied by marked scopic level.8
change in ­arterial pulse wave contour. Further studies reinforced the Framingham results (and
These findings emerged in the 1970s when Dawber and grandma’s views) that hardening of arteries was bad and could
­colleagues from Framingham5 reported their changes in arte- be worsened by high salt intake. Better measures of arterial
rial pressure with age, and noted a more robust relationship stiffness were sought, but none, as recorded noninvasively,
between systolic pressure and cardiovascular events than with were found more useful than aortic PWV—as measured in
diastolic pressure; they questioned the dogma that diastolic animals and humans in the 19th and 20th centuries.9 Aortic
pressure elevation with age was the sine qua non of hyperten- PWV was found related to cardiovascular events, initially in
sion, and drew attention of arterial rigidity to risk of cardiac persons with high risk—those with end-stage renal failure, in
and vascular events, especially stroke.6 Then followed the land- persons with hypertension, the elderly, with diabetes, and in
mark Systolic Hypertension in the Elderly Project (SHEP)7 trial, normal populations. This work has recently been summarized
which showed that reduction in systolic pressure in old per- by Vlachopoulos et al.10 Aortic stiffening measured as carot-
sons with normal (or low) diastolic pressure reduced the risk id–femoral PWV is strongly related to cardiovascular events,
of cardio­vascular events, especially cardiac failure and stroke. independent of age, arterial pressure, and conventional risk
SHEP7 began the revolution on views of treating hypertension. factors of cardiovascular disease.
Persons could have hypertension even when diastolic pressure
was normal (or low). Until the publication of SHEP, no trials Measurement of Arterial Stiffness
had been conducted on isolated systolic hypertension in the PWV
elderly—the most common type of all. There was an excellent As foreshadowed, stiffness of an artery is best measured as
review from National Institute of Aging summarizing changes PWV over a segment of that artery. PWV was measured

6 January 2011 | VOLUME 24 NUMBER 1 | AMERICAN JOURNAL OF HYPERTENSION

Ill-Effects of Arterial Stiffening STATE OF THE ART

∆x
Pressure

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∆t

Time
↔
∆t
∆x
PWV =
∆t

Figure 2 | Pulse wave velocity calculated from distance between two points (Δx) where the pulse is measured divided by the time required for the pulse to travel
between these two points (Δt). Transit time is usually measured from the foot of the waves. PWV, pulse wave velocity

using this method by pioneers in physics, including Thomas

Young (who was also a physician) >200 years ago.11,12 The link
between physiology and medicine was not deliberate, but a 5
consequence of ready availability of animal aortas and elastic
10
ligaments on which experiments could be conducted. Blood
pressure was first measured in a horse by Stephen Hales13 15
just beforehand. The theory connecting arterial elasticity (as 20
Young’s modulus) with pressure and flow was established by
25
Moens and Korteweg as:
30

Eh 35
Zo =
2r 

where E is Young’s modulus in dynes.cm−2, h is wall thickness 40

in cm (assuming a homogeneous material of wall), r is radius 45

(cm), and ρ is the density of blood (grams.cm−3). A direct link 50
20 mm Hg
between characteristic impedance (Z0) and PWV was later
established as Z0 = ρ·PWV.13 Because ρ is almost unity, Z0 Distance from aortic valves
0.5 S
expressed in terms of pressure (dynes cm−2/flow velocity) is
virtually identical to PWV (in cm/s).
Figure 3 | Pressure recorded consecutively at 5-cm intervals between aortic
Figure 2 shows how PWV is measured as distance in the arch and external iliac artery of a 16.5 kg wombat,15 an Australian marsupial of
line of travel between two points at which the pulse is meas- similar size to a dog, but with short stubby legs (from ref. 14).
ured (cm) divided by the time required for the pulse to travel
between these two points. Usually time is measured from the (Figure 3) or from high frequencies imposed on the pulse (as
foot of the wave, usually the point of intersecting tangents by Anliker et al.16 or Hermeling et al.17). There is reasonable
from the decline of the previous pulse and the sharp upstroke correspondence between the last two methods with the PWV
of the following pulse (which usually is linear over the mid- measured from the pulse wavefoot. There is also correspond-
dle third of the pulse upstroke). The peak of the pulse cannot ence between these methods and the apparent phase velocity
be used for this purpose because it is affected considerably by at high frequencies—i.e., the phase of the transfer function of
wave reflection.14,15 However, as high-frequency components the pulse at high frequencies.14 The very precise new method
of the pulse are attenuated rapidly, PWV can be measured from of Hermeling et al.17 permits PWV to be determined for the
high-frequency components of the pulse such as the incisura higher pressure at which the impulse is imposed.

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 1 | january 2011 7

 STATE OF THE ART Ill-Effects of Arterial Stiffening

One can obtain very precise values of PWV over short issues related to the measurement of pressure change, ­diameter
distances noninvasively with magnetic resonance ­imaging change, and wall thickness. Pressure change can be measured
(MRI),18 even though intervals between sampling are by brachial cuff sphygmomanometry (as pulse ­pressure) by
16–32 ms and time of transit is perhaps just 10 ms.18 The a $50 instrument. Brachial pulse pressure, however, is much,
method requires measurement of the flow pulse at two sites and variably, higher than pressure change per beat in the aorta
over multiple cycles so that distinct ensemble-averaged flow or carotid artery.14 As the instrument contains metal, it cannot
pulses can be generated. Unfortunately, some values of MRI- be used at the same time as when diameter change is meas-
determined PWV in the aorta have not considered this issue, ured by MRI. Diameter change is very small in relation to total
and have been reported (and editorialized) without the error diameter, and may be just 2–5%. Besides being small, dia­

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being recognized (need for ensemble-averaging).19–21 MRI meter change cannot always be assumed as perpendicular to
also permits correct measurement of distance in three dimen- the aorta or carotid artery, or to exclude kinking and bending.
sions, so that elongation of the aorta with age (which is far Then there is measurement of wall thickness noninvasively.
greater than dilation with age22,23) can be shown. The MRI Certainly, intima–media thickness can readily be measured
techniques, used appropriately, give lower values of ascending by ultrasound, but is this the appropriate measure for calcu-
aortic PWV in youth, and ascending aortic PWV change with lation of Young’s modulus?14 Calculation of Young’s modulus
age, which are much greater18 (~4× from age 20–80 years) assumes homogeneity of the artery wall. The wall, however, is
than measured over long distances—from root to aortic bifur- grossly inhomogeneous. The intima has no components that
cation24 or to femoral artery, 14 as measured by Doppler flow bear stresses in the wall. The intima cannot be distinguished
or arterial tonometry. This finding has also been confirmed from the media with ultrasound. Most of the increase in
by an invasive study from Choi et al.,25 where both central intima–media thickness with age is due to hyperplasia of the
blood pressure and central PWV were increased considerably intima.32 In the media (where thickness cannot be measured
with age. noninvasively), the elastin and collagen elements determine
In a consensus statement from the Working Group of stiffness, with elastin components predominant at low pres-
Arterial Structure and Function of the European Society of sures and at young ages, and the collagen at high pressures,
Hypertension, Laurent et al.26 considered all methods used to and in older subjects. The elastin fibers in aortas are thick,
that time, and described PWV from carotid (C) to femoral (F) concentric, and homogeneous in youth and are stretched,
artery to be the “Gold Standard” for noninvasive measurement thinned, and fractured in older subjects such that they com-
of aortic stiffness. This opinion was based on many ­­factors prise a smaller part of the media.14,32 Measurement of Young’s
including reproducibility, heritage and mechanism, ease of modulus in a young person compared to an old person will
use, expense, and ability to predict outcome. There are more give entirely different values based on the make-up of the arte-
data available for “aortic” (C–F) PWV as a measure of outcome rial wall, and calculations will be entirely unreliable if values
than any other stiffness measure, and there is no doubt that it of intima–media thickness are used from MRI or ultrasound
is at present the best predictor of outcome.26 In Cruickshank’s measurements. Yet they are, and changes in Young’s modulus
study, aortic PWV replaced systolic and pulse pressure as a with age are often confidently given in large trials without con-
predictor of outcome. 24 In more recent studies,27,28 summa- sideration of these practical issues—i.e., the reality of applying
rized by Vlachopoulos et al.,10 PWV predicted outcome inde- precise physical equations to imprecise measurements of pres-
pendent of all measures of arterial blood pressure. There is sure, diameter, and above all thickness and composition of the
now a recent article by the European group on reference and arterial wall.
normal values of PWV in a healthy European population in From what has been said, it should come as no surprise that
over 11,000 individuals.29 This article includes adjustment of direct measures of arterial elasticity at any given site—aorta,
different methods to calculate pathway length, as previously carotid, or other arteries—are not related to cardiovascular
discussed by Weber et al.30,31 outcomes.26 They were consigned to low and uncertain value
in the European consensus document of Laurent et al.,26 and
Direct measurement of arterial stiffness remain so now.10,33
Young’s modulus—the acknowledged physical measure of
elasticity or stiffness—is the (theoretic) pressure per cm2 of a Indexes of the pressure waveform at central
material required for reversible elongation of 100%. This can and peripheral sites
be calculated for an arterial segment if pressure change, dia­ The pressure waveform is markedly altered with aging.34,35
meter change, and wall thickness are measured, and has been This is attributable to aortic stiffening after full body height
presented in many trials.14 The practical problems in using is achieved at age,17,18 and by previous change in body height
this as a noninvasive measure of stiffness are methodological from birth to attainment of full body height at age 17.34,36

8 January 2011 | VOLUME 24 NUMBER 1 | AMERICAN JOURNAL OF HYPERTENSION

Ill-Effects of Arterial Stiffening STATE OF THE ART

Augmented pressure
Alx advance of the catheter from the groin or arm to the aorta. An
Pulse pressure alternative—though dependent on cuff brachial pressure for
Augmented calibration—entails use of a transfer function applied to the
pressure radial arterial wave, measured noninvasively by applanation
tonometry.47 Another approach entails measurement of the
carotid pressure waveform, calibration from cuff pressure, and
use of the calibrated carotid wave as a surrogate of the aortic
Pressure Pulse pressure pressure waveform.48,49 This method was later expanded by
Kelly and Fitchett,48 then Mitchell et al.,50 and Segers et al.51

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for use with Doppler aortic flow waveforms to generate ­aortic
TR Time
impedance. Discussion of the latter techniques is set out below.
Before proceeding onto this, and then to prognosis, one should
Figure 4 | Aortic AIx calculated from the ratio of augmented pressure divided note that measures of stiffness obtained from the waveforms
by pulse pressure. AIx, augmentation index; TR, time to beginning of reflected are indirect, and so, not as accurate as PWV.14,24,52 Baksi et al.53
waveform. sought to describe changes in the pulse with aging through
meta-analysis of clinical trials of patients with disease; results
Hence, arterial stiffness has a great impact on amplitude are at variance to others, such as the study of Freis et al.,54 and
and shape of the arterial pressure wave, and should ­provide that of Kelly et al.35 who included >1,000 normal subjects with
­information on arterial stiffness in humans. This is the case, and an age span of 2–91 years. This study was dismissed by us55 on
was first so recognized from studies of Marey,37 Mahomed,38 this basis.
and Mackenzie39 in the late 19th and early 20th century and The particular relevance of “pulse wave analysis” stems from
was used by medical examiners to diagnose accelerated arte- the effects of wave reflection, as well as its timing on the pulse
rial senility in applicants for life insurance, and to decline such waveform. Timing is determined by PWV, being earlier when
subjects for coverage.40 It is not surprising that such manifesta- aortic PWV is high, and later when PWV is low. This must be
tions of arterial stiffness should now be used to measure arte- considered, and when it is, pulse wave analysis can be seen as
rial stiffness and its ill effects.33 The first ­modern study of this potentially more useful than PWV in studying the ill effects of
subject was by Dawber et al. as part of the Framingham study.5 disease, and the benefits of drugs in management of hyperten-
Such studies have recently been pursued by our group,35 and sion, aging, heart failure and of disease.43
by others,41–43 and have been included in studies initiated up The principal problem with indexes of the pulse waveform—
to 20 years ago by Safar and colleagues in France,44,45 initially central systolic and pulse pressure, AIx, and amplification—
in patients with end-stage renal disease,44 then in hyperten- are that they are dependent on heart rate through ejection
sive patients,46 the elderly and normal subjects.27,28,33,46 The duration and on left ventricular performance, i.e., on the
vast majority of these have shown independent value of “pulse heart’s ability to contract and expel blood.14,43 Timing is rela-
wave analysis” for predicting cardiovascular outcomes.33 These tively simple to explain, with early return of wave reflection,
are discussed below and their outcome value set out in the next caused by increased pulse wave velocity. Effects of change in
section. These measures include aortic pressure augmentation, ventricular performance are more difficult to explain, as dis-
augmentation index (AIx) (relation of aortic augmented pres- cussed below.
sure to pulse pressure,14 Figure 4), central aortic systolic, and With increase in heart rate, ejection duration is shortened.14
pulse pressure, and amplification of the pulse wave between Hence, the incident and reflected waves are shortened, and the
the ascending aorta and radial artery.33,34 Amplification of latter can have less effect on late systolic pressure and more
the pulse (peripheral pulse pressure/aortic pulse pressure) is effect on the diastolic part of the wave. AIx will be decreased,
inversely related to AIx, but is measured more accurately as it central pulse pressure decreased, and amplification increased.14
does not require identification of a shoulder on the rising limb These changes can be corrected to a degree by allowance for
of the pressure wave in systole. heart rate56 or by collecting data at the same heart rate during
Ill effects of arterial stiffening with age are best understood any intervention.
from studies of the aortic pressure waveform.34 The aortic The second issue is the effect of wave reflection on aortic
pressure during systole is virtually identical to that in the left pressure and ejection of blood from the left ventricle (­measured
ventricle, whereas the pressure during diastole at the coronary as aortic flow velocity during systole). AIx will increase almost
ostia is a major determinant of coronary perfusion. This is dif- linearly with age up to about age of 60 years, where the increase
ficult to measure in clinical practice and is usually undertaken, will be less as it approaches value of 50%. The curvilinear
where indicated, through arterial cannulation. This entails ­pattern of the increase in AIx with age has been described as

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 1 | january 2011 9

STATE OF THE ART Ill-Effects of Arterial Stiffening

a Young Old

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b YOUNG

Flow
Flow Brain / Other
kidney

OLD

Other Flow
Flow Brain /
kidney

Figure 5 | Relation between aortic stiffening and microvascular flow in brain and kidney (a) Ascending aortic pressure waves shown schematically in a young
subject (left) and older patient with left ventricular (LV) hypertrophy and diastolic LV dysfunction (right).34 (b) Schematic diagram of pulsatile peripheral flow in a
young (top) and old subject (bottom). A lumped “windkessel” model is used to simulate function of large arteries for cushioning pressure pulsations. In a young
person (top), as the arteries are distensible, the cushioning function of the arteries absorbs most of the pulsatility. In the older subject, however, stiffening of the
arteries causes loss of their ability to cushion pulsatility of the blood flow, thus this will extend further into highly perfused organs such as brain and kidneys.
Flow through normally perfused vascular beds is represented at the right of each model, and is nonpulsatile. Flow to highly perfused vascular beds such as brain
and kidneys is represented at left. Perfusion of these beds becomes highly pulsatile when arteries are stiff (bottom left).34

mathematical phenomenon, as a ratio of two linear regression ­ aradoxical reduction in pressure augmentation.14 These find-
p
lines.57 If the heart contracts strongly (i.e., acts in engineering ings are readily apparent as an ­aortic pressure wave with little or
terms as a “flow source”14,58,59), generating flow irrespective no systolic augmentation, short ejection duration, and promi-
of afterload, the reflected wave will be apparent as augmenta- nent reflected wave in diastole; i.e., a “dicrotic” wave,14,59,60–63
tion of pressure and AIx will be a good measure of wave reflec- and with reduced late systolic flow and abbreviated ejection in
tion, and indirectly, an index of arterial stiffness.14,59 This is the the flow wave.58,59 Under these conditions, augmented pres-
response of the normal left ventricle. If, however, there is systo- sure, AIx, central pulse pressure, and amplification will not be
lic dysfunction of the left ventricle, and it acts in any way as a ­reliable indexes of arterial stiffness. A lesser degree of impair-
“pressure source”—i.e., with ejection dependent on afterload,60 ment in left ventricular systolic function in diabetic subjects has
wave reflection will be apparent not as augmentation of pres- been invoked to explain why, in diabetes mellitus, aortic PWV,
sure, but relative decrease of flow in late systole,14,59 with and AIx are not increased to a corresponding degree.14,64

10 January 2011 | VOLUME 24 NUMBER 1 | AMERICAN JOURNAL OF HYPERTENSION

Ill-Effects of Arterial Stiffening STATE OF THE ART

PP and clinical outcome

Author RR (95% CI)
Central PP Dart 2006
Jankowski 2008
Pini 2008
Roman 2007
Safar 2002 Central vs.
Pooled (central PP) brachial PP:
Brachial PP Dart 2006 Q = 3.61,
Jankowski 2008 P = 0.057

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Pini 2008
Roman 2007
Safar 2002
Pooled (brachial PP)

0.5 1 2

SBP and clinical outcome

Author RR (95% CI)
Central SBP Dart 2006
Pini 2008
Roman 2007 Central vs.
Safar 2002 brachial SBP:
Pooled (central SBP) Q = 0.25,
Brachial SBP Dart 2006 P = 0.62
Pini 2008
Roman 2007
Safar 2002
Pooled (brachial SBP)

0.5 1 2

Figure 6 | Relative risk (RR) and 95% confidence interval (CI) of clinical events for every 1 s.d. increase in pulse pressure (PP) (top) and systolic pressure (bottom),
calculated from brachial and aorta. Boxes represent the RRs and lines represent the 95% CI for individual studies. The diamonds and their width represent the
pooled RR and the 95% CI, respectively (from ref. 33). SBP, systolic blood pressure.

In practice, these issues are not a major problem. Certainly, answered appropriately and fully by himself and others. By
one cannot rely on indexes of wave reflection in the pressure now (2010) challenges have evaporated.
wave as measures of stiffness when left ventricular function The technique of transfer functions may also be used to
is impaired. However, as severe left ventricular impairment describe the relationship between pressure waveforms at dif-
is usually recognized in clinical trials and affected patients ferent sites: specifically, the relationship between pressure
excluded, this is not major issue. Further, pulse waveform waveforms in the ascending aorta and peripheral arteries in
indexes should be taken at resting heart rate, and allowance the upper limb. We had reason to believe from our own and
made for change when heart rate is different. other studies (relatively constant upper limb PWV with age
and pressure changes, and corresponding pressure waveforms
Use of a generalized transfer function to generate ascending change at central and peripheral sites with vasodilating drugs)
aortic from radial artery pressure waveforms that such a transfer function may be sufficiently stable under
The central concept underlying the generalized transfer func- different conditions to generate central from brachial or radial
tion is the description of pulsatile pressure/ flow waveforms pressure in all adult humans. Detailed studies were done and
as vascular impedance. This was first introduced by Michael confirmed this view.49,67 Applications to the US Food and
Taylor, who showed that ascending aortic impedance may Drug Administration for use on invasively recorded radial
be used to characterize left ventricular load, to describe and waveforms were successful as K002742 and for noninvasively
quantify the effects of wave reflection in vascular beds under recorded radial artery waveforms under K012487.68 The US
different conditions, and to explain contour of pressure and Food and Drug Administration declared that the process had
flow waves in systemic arteries.65,66 As with any new approach, the effect of measuring the central ascending aortic pressure
Taylor’s concepts were subject to robust challenge, which was waveform without the need to catheterize that vessel.

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 1 | january 2011 11

STATE OF THE ART Ill-Effects of Arterial Stiffening

0.20 150
Survival Placebo BP response
composite outcome
Proportion of patients

0.15 140 Placebo

P < 0.001
Ramipril

mm Hg
0.10 130

Ramipril
0.05 120

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0.00 110
0 500 1000 1500 0 1 24 50
Days of Follow-up Time (months)

20 Peripheral SBP
Total cardiovascular events and procedures 140
Atenolol
Atenolol Amlodipine
Proportion of events (%)

15 135 133.9
133.2
130
mm Hg

10
Amlodipine
125 125.5

5
HR = 0.84 (95% Cl 0.78–0.90), P < 0.0001 121.2
120
Central SBP
0 115
0 1 2 3 4 5 6 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 AUC
Time (years) Time (years)

160
16 ARB combination
Patients with primary events (%)

14 Benazepril plus hydrochlorothiazide 150

ACEI combination
12 140
10
mm Hg

130
8
6 120
Benazepril
4 plus amlodipine 110
2
0
0 6 12 18 24 30 36 42 0 3 6 12 18 24 30 36 42
Months Time (months)

Figure 7 | A comparison of the effects of treatment arms in the HOPE (top panel), ASCOT/CAFE studies (middle panel), and ACCOMPLISH (bottom panel);
with outcome shown on the left panels and blood pressure response on the right panels. From the HOPE study114 (top left panel), survival of patients in
ramipril group (solid line) was significantly higher than those in placebo group (dashed line). On the top right panel, brachial systolic pressure response of
placebo (dotted line) only differed around 3 mm Hg with ramipril group (solid line); however, acute study115 has shown greater decrease in brachial systolic
pressure (dashed line) and even greater fall in aortic systolic pressure (grey line); pressure was extrapolated from acute study. From the ASCOT study116
(middle left panel), there was significantly lower events with patients with amlodipine (light blue line) compared to those with atenolol (dark blue line). This
was explicable from the result of CAFE (substudy of ASCOT) study117 (middle right panel); while peripheral systolic pressure fell for both groups, amlodipine
group showed consistent lower central systolic pressure throughout the study period (shaded area). Similar result found in the ACCOMPLISH study118 (bottom
left panel), where patients in the combination of ACEI+CCB (dotted line) had lower events than those of ACEI+diuretic (solid line). As in the two other studies,
peripheral systolic pressure decreased to the same level (bottom right panel118,119) (red solid line: ACEI+diuretic, blue dotted line: ACEI+CCB, black solid
line: combination with ARB), however, central systolic pressure showed greater fall with combination of ARB and CCB (dashed line) compare to ARB+diuretic
(dotted line); pressure was extrapolated from the latter study. The benefit of peripheral arterial vasodilation for survival is greater than would be expected
from analysis of brachial cuff pressure measurements, but can be explained on the basis of greater systolic and pulse pressure reduction in the central aorta.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; AUC, area under curve; BP, blood pressure; CCB, calcium-channel blocker;
CI, confidence interval; HR, hazards ratio; SBP, systolic blood pressure.

12 January 2011 | VOLUME 24 NUMBER 1 | AMERICAN JOURNAL OF HYPERTENSION

Ill-Effects of Arterial Stiffening STATE OF THE ART

ACEI

CCB
ARB
proximal aorta suffers most because it expands more with each

αBL

Diur

βBL
cycle of stress than other less elastic (distal aorta) or muscular
arteries.12,75 Fatigue and fracture of nonliving elastin and colla-
0
gen fibers are determined by the extent of strain (­linear), and the
number of cycles (heart beats) in a ­logarithmic relationship.14
Ill effects of aortic stiffening in humans was described by
Mackenzie in 1902,39 and by Bramwell and Hill in 1922.1
∆SBP2 (mm Hg)

These ill effects explain why arterial stiffening predisposes to

−10 cardiovascular events and death, and so why stiffness (and

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its manifestations) are risk factors for cardiovascular events.
Mackenzie and Bramwell and Hill, focused on cardiac ill
effects, Mackenzie noting that progressive arterial stiffen-
ing with age is responsible for lessening exercise tolerance of
−20 apparently normal people by the fourth decade of life, while
Bramwell and Hill showed that arterial stiffening caused
greater pressure for the left ventricular to face during systole,
with consequent increased left ventricular oxygen and blood
demands, left ventricular hypertrophy and ultimately car-
diac failure. Subsequent studies have endorsed these views,76
quantifying them and describing development of dyspnea and
P < 0.001 (K–W) heart failure on the basis of systolic and diastolic dysfunction
via the “cardiomyopathy of overload” mechanism proposed
Figure 8 | Comparison of ΔSBP2 across different antihypertensives class (from by Katz.77,78 Aortic stiffness rather than left ventricular pump
ref. 100). The newer generation of antihypertensives (ARBs, ACEIs, CCBs and function appears to be the predominant cause of cardiac failure
α-blockers) showed significantly lower central systolic pressure than the older
antihypertensives (diuretics and β-blockers). ACEI, angiotensin-converting
with age.79 This can present as “diastolic” heart failure when
enzyme inhibitor; ARB, angiotensin-receptor blocker; CCB, calcium-channel the left ventricle continues to pump strongly, or as “systolic”
blocker; Diur, diuretics; SBP, systolic blood pressure; α-BL, α-blockers; β-BL, heart failure when contraction is impaired.14
β-blockers; ΔSBP2, difference between central and radial systolic pressure. There are two ways that arterial stiffening predisposes to
cardiac dysfunction, and these are most relevant to therapy.
The transfer function approach corrects the distortion of Stiffening causes the incident and reflected waves to travel
the upper limb pressure waveform as it is transmitted from faster, leading to early return of the reflected wave so that
the heart, so enabling pressure to be measured where it has its this boosts aortic and left ventricular pressure in systole
ill effects on central (carotid, cerebral, coronary, renal) arter- (Figure 5a). A high left ventricular load predisposes to the
ies and on the left ventricle of the heart (whose pressure is development of left ventricular hypertrophy, progressing to
identical to the aortic during systole while the aortic valve is left ventricular dysfunction and cardiac failure, and creating
open). an unfavorable oxygen supply/demand ratio. The other factor
The process we developed was checked by others, and is reduction in aortic pressure during diastole. This decreases
­validated69–74 as being accurate in measuring aortic from the coronary perfusion pressure, and contributes to myocar-
radial pressure waveform under different conditions including dial ischemia even in the absence of coronary artery athero-
Valsalva manoeuvre, with marked change in blood pressure sclerotic narrowing.80 Central pulse pressure elevation has
and heart rate, during exercise and with drugs. been highlighted to predict cardiovascular risk to conventional
The transfer function process is now widely used to gener- risk assessment in large cohorts.43,81,82
ate aortic pressure waveforms and indexes from the noninva- Another ill effect of arterial stiffening has recently become
sive measurement of the radial pulse waveform by applanation apparent. This is the increase in pulsatile flow and pressure pat-
tonometry.14,41,42 terns in the microvasculature of highly perfused organs—spe-
cifically brain and kidneys. With pulsations generated by the
Implications of Arterial Stiffness heart unable to be cushioned and absorbed in stiffened arteries,
Aortic stiffness increases with age in all animals. Because they enter into the microvasculature, predisposing to rupture
humans live longer than laboratory animals, and so, their arter- of the arterial walls and microhemorrhages, and to endothe-
ies are subjected to more cycles of stress, they degenerate to a lial denudation and thrombotic obstruction of tiny arteries
far greater degree than seen in experimental animals. In all, the with resultant microinfarcts in brain and ­kidneys (Figure 5).

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 1 | january 2011 13

STATE OF THE ART Ill-Effects of Arterial Stiffening

The result is predisposition to dementia and to strokes (hem- ies and these dilate by ≥20% with relatively small doses.95–97
orrhagic and thrombotic) in the brain and to deterioration of Such dilation is responsible for the marked reduction in ampli-
glomerular function in the kidney.36,83 Detection of arterial tude of the reflected wave,98 and so the decrease in aortic
stiffness, and reduction in pulsatile central pressure, can lead augmentation, AIx, central systolic, and pulse ­pressure, and
to prevention of microvascular damage and could delay or increased amplification of the pulse between aortic and radial
present ill effects in these highly perfused organs.36 artery.98,99
This is the preferred mechanism of action of antihyperten-
Prognosis in Arterial Stiffening sive agents, with angiotensin-converting enzyme inhibitors,
The key articles of Laurent et al.26 and Agabiti-Rosei et al.84 angiotensin-receptor blockers, and calcium-channel blockers

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presented data from patients with renal failure, diabetes (Figures 7 and 8) exhibiting the same action100,101 together
­mellitus, and hypertension, from elderly subjects and normal with vasodilating β-blockers,47,102 but not diuretics or conven-
population, which linked “aortic” or carotid–femoral PWV tional β-blockers such as atenolol.101
and aortic AIx with cardiovascular events. These are now When first noted, these differential actions of vasodila-
supplemented by more, from Vlachopoulos et al.,10,33 and by tor drugs on the aorta and muscular arteries caused sur-
Roman et al.,81 Wang et al.,41 Weber et al.,42 and Benetos et prise. We were able to show, however, that nitrates have
al.,43 The earlier data were sufficient for carotid–femoral PWV dose-­dependent action on muscular arteries, veins, and
to be accepted as evidence of target organ damage in the arte- arterioles,98 as well as on arteries of different size and
rial circulation in the Guidelines of the European Society of structure.91–99 Effects of nitrates on arterioles in therapeu-
Hypertension and European Society of Cardiology for man- tic doses are minimal. Effective modern antihypertensives
agement of hypertension in 2007.85 Data at that time were are not characterized by their value for reducing peripheral
inconclusive for value of central pressure, Aix, and amplifica- arteriolar resistance and increasing cardiac output. Drugs
tion of the pressure waveform in the upper limb. These pro- that have such an effect, i.e., α-blocking agents do not have
vide strong evidence for indexes of wave reflection as risk the same value as angiotensin-converting enzyme inhibitors
factors for cardiovascular disease (Figure 6). The only dis- or calcium-channel blockers.101 The effectiveness of new
senting study (by Mitchell et al.50) from Framingham can be generation of ­antihypertensives has been shown previously
explained on the basis of flawed technique86—­inappropriate in studies in patients with renal failure and hypertension,
use of applanation tonometry on an artery (brachial) that independent of blood pressure.103–105
cannot be applanated with confidence.87,88 Similar issue is One does expect that dilation of an artery would always
present in relation to pressure amplification in the upper make that artery stiffer as it is expected that tension would be
limb as published by the Asklepios group,89 however, it may transferred from elastin to collagen fibers. This is seen when
be again due to measurement of pressure using brachial tono­ pressure in the artery increases, or when the aorta dilates with
metry as pointed previously.86,88,90 aging. The behavior of the muscular arteries, however, can
readily be explained on the basis of smooth muscle cells being
Treatment in series with collagen and in parallel with elastin fibers, such
Pharmacological treatment of aortic stiffness appears impos- that reduction in muscular tone transfers stresses to the elastic
sible. Attempts have been made with various drugs, includ- from muscular fibers in the wall.14
ing advanced glycation end-product crosslinking breakers,
aimed to restore elasticity to the disorganized elastic fibers of Other Issues
the thoracic aorta.91,92 In the aged aorta, elastin fibers show Direct or indirect measures of arterial stiffness are valuable
fracture, fragmentation, and splitting, such that they appear addition to the clinical evaluation, and further research can
not to play any appreciable role in bearing pulsatile pressure only help to improve their utility. Further research is needed
stresses. Their connections to smooth muscle appear to be to optimize the benefits yielded by arterial stiffness in clini-
disorganized. Drugs such as nitroglycerine, which have such cal practice. Race- and gender-related differences have been
a dominant effect on muscular arteries, have no effect on the observed in arterial hemodynamics.106,107 Thus, specific risk
aorta as gauged by the amplitude of the primary incident wave predictive value in different ethnic populations and differences
in the aorta,93 or on characteristic impedance or PWV.14 Even in thresholds for clinical intervention need to be determined.
in young experimental animals with normal medial anatomy, Studies have repeatedly observed gender differences in arterial
tiny changes only of characteristic impedance have been seen stiffness and hemodynamics.108–112 Although height differ-
with nitrates.94 ences have been proposed as the major mediators,109 the role of
In contrast to elastic arteries such as the proximal aorta and other factors including arterial taper and hormones need to be
carotid artery, nitrates have powerful effects on muscular arter- assessed.112 Although assessment, prognostication, and treat-

14 January 2011 | VOLUME 24 NUMBER 1 | AMERICAN JOURNAL OF HYPERTENSION

Ill-Effects of Arterial Stiffening STATE OF THE ART

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pulse wave analysis system. Other authors report no disclosures. Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network

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