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Brief Review
Aortic Diameter, Aortic Stiffness, and Wave Reflection
Increase With Age and Isolated Systolic Hypertension
Michael F. O’Rourke, Wilmer W. Nichols
T
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he October 2004 High Blood Pressure Research Council
meeting of the American Heart Association included a
debate on the proposition that “aortic diameter, aortic stiffness, and wave reflection all increase with age and in isolated
systolic hypertension.” This was stimulated by a series of
articles1–5 that took a contrary position to change in aortic
diameter and wave reflection and placed emphasis on aortic
stiffness over wave reflection with aging and isolated systolic
hypertension. The purpose of this review is to summarize the
conventional view that has evolved over decades6 –12 but is
not precisely argued in recent literature. According to this
view, early wave reflection from peripheral arteries is the
dominant ill effect of aging and the most logical target for
therapy.12–14
between ages 20 and 80 years. Recent studies on central and
aortic pressure allow for the normally high amplification of
upper limb systolic pressure in youth and show that central
(aortic) systolic and pulse pressure increase by 35 to
40 mm Hg between 20 and 80 years of age (ie, systolic by
⬇40% and pulse pressure by ⬎100%12,17 (Figure 2). Such
change is generally attributed to arterial stiffening with age
and return of reflected waves from the periphery to the
heart.12 When stiffening is measured as “aortic” pulse wave
velocity, there is an ⬇100% increase between ages 20 and 80
years18 (Figure 3). However, in contrast, there is little
increase with age in pulse wave velocity within muscular
conduit arteries of the limbs.5,18,19 There is also little difference between males and females.5,18,19
Increase in aortic diameter with age is usually invoked to
explain progressively increasing prominence of the aortic
knuckle in routine chest radiographs. Autopsy studies have
shown a clear-cut increase in aortic surface area with age20
(Figure 4), whereas cross-sectional studies of aortic diameter
by angiography21 and ultrasound22–26 have shown lesser, but
still definite, increase with age, except in the most proximal
part of the ascending aorta. Gender differences are largely
explicable on the basis of smaller body size in women.12,19
There is some controversy on the competing effects of age,
and of blood pressure change accompanying age, on aortic
dilation. Cross-sectional studies cannot be expected to resolve
this issue. A comparison between hypertensive and matched
normotensive subjects showed a greater degree of aortic
dilation in the latter.26 Longitudinal studies in patients with
Marfan syndrome and cystic aortic necrosis have shown
progressive aortic dilation with age but with rate of dilation
decreased by antihypertensive therapy.27 Cross-sectional
studies have shown aortic dilation in cystic aortic necrosis
with Marfan syndrome related to central but not brachial
pulse pressure.28
Pathological studies of the aging human aorta29,30 have
shown that thickness of the load bearing media remains
relatively constant throughout life and that wall thickening is
attributable predominantly to increased width of the intimal
layer. There is thinning, fraying, and fracture of the elastin
fibers, together with collagenous remodeling (Table), and
Observations and Measurements
“Premature arterial senility” as a cardiovascular risk factor
has long been of intense interest in actuarial studies, even
before introduction of the cuff sphygmomanometer,6 as it had
been in clinical medicine. The latter is apparent in the
textbooks of Osler and Mackenzie ⬎100 years ago.7,8 In
these, premature arteriosclerotic change was assessed from
the pulse waveform palpated at the wrist or measured from
the radial artery by sphygmography. The first graphic recording studies of the arterial pulse by Marey in 18639 noted
characteristic differences between young and old persons
(Figure 1), with prominent late systolic augmentation (“tidal
wave”) in the latter. Mahomed10,11 confirmed these changes
in the 1870s, stressing that “the tidal wave is prolonged and
too much sustained,” and noting similar pulse waveform
changes in asymptomatic persons with elevated arterial pressure as well as in the elderly. By 1900, these findings were
used by life insurance companies to decline applicants on the
basis of premature arterial senility.6
The cuff sphygmomanometer was introduced in the early
1900s, and by 1916, data had been presented to show the
relationship between risk of death and systolic pressure in
asymptomatic persons.6 For decades thereafter, aging change
in arteries was gauged by change in arterial pressure, especially systolic and pulse pressure.15,16 But brachial systolic
pressure increases by only ⬇25 mm Hg on average (⬇22%)
Received October 10, 2004; first decision November 11, 2004; revision accepted December 8, 2004.
From the VCCRI/University of New South Wales/St. Vincent’s Clinic (M.O.), Sydney, Australia; and the Departments of Medicine and Physiology
(W.N.), University of Florida, Gainesville.
Correspondence to M. O’Rourke, Suite 810, St. Vincent’s Clinic, 438 Victoria St, Darlinghurst, NSW 2010, Australia. E-mail
[email protected]
(Hypertension. 2005;45[part 2]:652-658.)
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000153793.84859.b8
652
O’Rourke and Nichols
Aortic Change With Age
653
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Figure 1. Tracings from Marey’s original
publication on the sphygmogram.9 Top,
The original instrument, with base-plate
applied over the radial artery, with long
stylus, pivoting near the site of recording, drawing an amplified signal on
smoked paper that was moved by a
wind-up, clockwork mechanism. Inset is
a “square wave” test to establish frequency response and instrumental artifact. Center, Sphygmograph tracings in 2
young adults, showing patterns still
regarded as typical for the radial artery.
Bottom, Sphygmograph tracings in 4 old
men (left) and old women (right), showing
typical patterns of senescence with
accompanying arteriosclerosis.
progressive disorganization of the media with, ultimate development of cystic medial necrosis. Such medial necrosis in
the elderly is described in pathology textbooks as similar to
that seen in an early age in Marfan syndrome and to be the
substrate of aortic dissection, dilation, and rupture.31,32
Interpretations and Explanations
Conventional explanations of all aortic changes with age are
based on the physical principles of fatigue and fracture
because these affect the inert elastin fibers within the aortic
media.12 Elastin is the most inert substance in the body, with
a chemical half life measurable in decades. The same principles of a material fatigue, as applied to natural rubber, predict
fracture after some 109 cycles of 8% stretch, which is
achieved in the proximal aorta within 40 years of life.
Fracture is not expected within this time span, when stretch is
⬍5%, which explains relative immunity of the peripheral
muscular arteries from this process.5,18,33
Fracture of the elastin fibers readily explains dilation and
stiffening of the aorta with age.12 Elastin fibers normally bear
aortic stresses. When they give way, the wall stretches and the
vessel dilates; stresses are then transferred to the less extensible collagenous elements in the wall, just as stresses are so
transferred when pressure rises in the normal artery. The
latter phenomenon explains the well-known nonlinear pressure/diameter relationship in arteries.
Increased stiffness of the aortic wall causes corresponding
increase in aortic pulse wave velocity. Such increase in wave
velocity causes the reflected wave from the peripheral arterioles to return earlier to the heart and to boost (augment)
pressure in late systole rather than in early diastole.12 Such
increase in wave velocity, with movement of the reflected
wave from diastole into systole, explains the change in pulse
waveform with age, as described by Marey, Mackenzie,
Mahomed et al, and referred to above. Mahomed pointed out
in 1872 that late systolic augmentation of the pulse was
always greater in the brachial than radial artery and greater
still in the carotid artery. This was confirmed by Kelly et al,34
who also showed in normal subjects that from 30 years
onward, the late systolic peak dominates over the early
systolic peak in the carotid and other central arteries;35,36
whereas the early peak or shoulder corresponds with peak
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Figure 2. Change in brachial systolic
pressure with age in multiple population
studies70 –74 shows a steep rise from age
5 years to plateau when full body height
is reached at age 18, then a subsequent
rise after age 45. Aortic systolic pressure, measured at cardiac catheterization,19 increases progressively with age.
After Nichols and O’Rourke.12
systolic flow. In older subjects, this shoulder on the upstroke
of the pressure wave is followed by a surge of pressure in late
systole caused by early return of wave reflection (Figure 5).
In the elderly, the reflected wave arrives even earlier in
systole and merges (or blends) with the incident (or forward)
pressure wave so that there is no inflection point.12,21 These
clinical studies confirmed earlier studies in experimental
Figure 3. Changes in aortic pulse wave velocity (PWV; between
the aortic root and the femoral artery at the groin) with age in a
group of 480 human subjects with low prevalence of atherosclerosis in urban Beijing. From Avolio et al.18
animals and in computer models of the systemic arterial
tree.37– 40 These expressed pulsatile pressure/flow relationships as vascular impedance and showed that the ill effects of
aortic stiffening could be explained on the basis of increase in
stiffness of the proximal aorta (increased characteristic impedance) and early wave reflection, which shifted impedance
curves to higher frequencies12,37– 41 (Figure 5). The combined
effect was to increase markedly the impedance to left ventricular ejection over the frequency band (1 to 4 Hz), which
normally contains the greatest energy of the left ventricular
ejection (flow) wave.
Figure 4. Increase in surface area of the thoracic aorta with age
in men (left) and in women (right), from the unselected autopsy
study of Mitchell and Schwartz.20
O’Rourke and Nichols
Aortic Change With Age
655
Age-Related Changes of Elastin Lamellae in the Human
Mid-Thoracic Aorta for Young (18 – 40 years) and Old (56 –58
years) Persons who Died From Noncardiovascular Disease
Young
Old
Measurement
Mean
SE
Mean
SE
D (mm)
17.0
1.1
22.4
0.7
31.8
0.03
49.1
⬍0.001
P
⬍0.01
WT (mm)
0.94
0.01
ILS (␮m)
8.7
1.1
12.0
0.9
37.8
⬍0.05
EFD (LU/mm)
125
15
36
6
⫺71.2
⬍0.05
0.79
0.01
1.00
0.02
26.4
⬍0.001
1236
162
1891
107
53.0
⬍0.01
MT (␮m)
T/LU (dyne/cm2
1.40
Change %
D indicates, pressure-fixed external diameter; WT, wall thickness; ILS,
interlaminar spacing; EFD, elastin fiber density (lamellar units/ mm); MT,
medial thickness; T/LU, calculated (at mean pressure 100 mm Hg) tension per
lamellar unit.
*From O’Rourke et al.30
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Implications
Effects of wave reflection are readily measured in terms of
augmentation of the central (carotid, aortic, and left ventricular) pressure waveform. The aortic and left ventricular
waveforms may be measured invasively during cardiac catheterization41– 43 or synthesized from the radial pressure waveform recorded by applanation tonometry using a Food and
Drug Administration–approved process.12,44 The carotid
waveform may be recorded directly by applanation tonometry1–5,34 –36,44,45 or approximated from the carotid diameter
waveform.46 Measurement of augmentation requires identification of the localized peak, systolic shoulder, or inflection,
which corresponds to peak aortic flow34,41 (Figure 5). This
requires accurate dynamic frequency response of sensor,
recorder, and convolutional process and has not been
achieved in some clinical studies, as discussed specifically by
Chen et al47 and Smulyan et al.43
The principal implications of aortic change with age relate
to their magnitude, their effects on left ventricular function,
and opportunities for therapeutic modification. It is clear
(Figure 2) that conventional measurements of brachial systolic and pulse pressure underestimate the aging effect, and
that aortic systolic and especially aortic pulse pressure increase far more with age than is usually perceived.12,16,17 Such
changes are largely responsible for development of left
ventricular hypertrophy and left ventricular dysfunction with
age48 as well as renal dysfunction49,50 and progression of
atherosclerosis.51 Changes can be best quantified from measurements of vascular impedance or inferred from augmentation of the central arterial pressure pulse. Augmentation of
the pulse depends on the pattern of left ventricular ejection as
well as on wave reflection and is decreased when left
ventricular systolic function is impaired.52 Inability to maintain late systolic ejection with age12,21 may be responsible for
the relative flattening of carotid34 and of calculated aortic
augmentation53 with age.
Knowledge of arterial change with age permits a more
logical approach to drug therapy of the diseases associated
with age, such as isolated systolic hypertension, cardiac
failure, and angina pectoris. From what has been described
Figure 5. Effects of aging on aortic pressure wave contour (time
domain) and aortic impedance modulus (frequency domain).
Top shows aortic pressure waves (above) and flow waves
(below) in a young (left) and old (right) adult. Bottom shows
impedance modulus (vertical axis) plotted against frequency in a
young (at left) and old subject (at right). Increased proximal aortic stiffness with age causes increased amplitude of the initial
pressure peak and increase in characteristic impedance (arrow
1). Earlier return of reflected waves from arterial terminations
causes the pressure peak to move into late systole and the
impedance curve to shift to the right (arrow 2). The peak of flow
corresponds to the early systolic pressure peak in the young
subject and to the inflection on the rising limb of pressure in the
older subject. After O’Rourke.39
from pathological aortic change, it is difficult to envisage that
drugs would have any major direct effect on the disorganized
aged aorta. Such beneficial effects have been sought and
described for the vasopeptidase inhibitor omapatrilat2 and for
the age cross-link breaker AT711,54 but effects have not been
substantial. No direct effect on aortic stiffness has been found
for nitrates in older human adults.55–57 In very carefully
controlled experimental studies on animals, nitrates have
shown no direct effect on aortic characteristic impedance,
despite marked effect on peripheral muscular arteries.58
In contrast to inefficacy on aortic stiffness, nitrates and
other arterial dilators have marked effects on wave reflection
and can virtually eliminate the late systolic augmentation
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April 2005 Part II
caused by early wave reflection.56,59 Because this effect is
confined to wave reflection, it may not be apparent when
pressure is measured in the upper limb.60,61 Beneficial effect
of nitrates on wave reflection14,56 can be explained on the
basis of arterial dilation and of “trapping” of reflected waves
in the peripheral vessels so that they do not return to the heart.
Such reduction in wave reflection is achievable in low dosage
without any effect on arterioles or on peripheral resistance.56,59 Most data on wave reflection have come from use
of nitrates because the effect is immediate and dramatic.
However, similar effects been described for perindopril and
other drugs used for treatment of hypertension.13,62
Reservations on a Contrary View
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There is no argument that the aorta and proximal arteries
stiffen with age, whereas peripheral muscular arteries are less
affected.5,18,19 There is no argument that the more distal
segments of the proximal thoracic aorta dilate with age, but
there is debate over whether this change is induced by age or
by arterial pressure. Mitchell et al3,63 argue that “effective
aortic diameter” measured indirectly using the water hammer
equation is reduced in persons with isolated systolic hypertension. Such a view gains some support from Framingham
data,24 which showed, after correction for age, that there is an
inverse relationship between aortic diameter and brachial
pulse pressure; similar findings were reported by Agmon et al
from Mayo.25 In both of these studies, any pressure effect was
trivial after correction for age, body size, and gender. Such a
pressure-related effect may have been related to therapy
(more than one third of the Agmon study group were
receiving antihypertensives) or to the measuring site for
pressure. Jondeau et al28 found no association between aortic
diameter and brachial pulse pressure but a definite relationship of diameter with aortic pulse pressure in patients with
Marfan syndrome. The Framingham group24 noted that an
initially narrow aorta predisposes to higher pulsatile flow and
higher pulse pressure. The concept of effective aortic diameter and its derivation was challenged by us64 on multiple
grounds. The water hammer formula is only valid in a
reflectionless system and must have pressure and flow measure at the same site and pulse wave velocity measured
locally.12,64 Mitchell et al3 measured pressure in the carotid
artery, blood flow velocity in the left ventricular outflow
tract, and pulse wave velocity from the central aorta to the
femoral artery.
Mitchell et al5 downplayed the effect of wave reflection
with age, noting in a select healthy population within the
Framingham group (⬍20% of all) that carotid augmentation
index decreased with age in women, although increasing in
men, whereas amplitude of the forward wave increased in
both genders with age. Such discordant gender differences for
augmentation have not been reported previously, nor has
decrease in augmentation with age. There were other anomalies in this article that we have questioned,64 – 66 including the
calculation of forward pressure amplitude, reflected wave
transit time, and greater distance to reflecting site (rather than
reduced distance that we have described).12,21 All of these
measurements depend on correct determination of the inflection point34,41 (Figure 5).
Anomalies in the Mitchell articles may be methodological
and related to the detection of the initial systolic shoulder in
the carotid tracing (or inflection point; Figure 5). We have
experienced problems with our processing of the carotid
pressure waveform and have noted far greater variability with
such waveforms than when we have synthesized the aortic
waveform from the radial wave.67 In the second Australian
High Blood Pressure (ANBP2) study, the experienced group
of Cameron et al45 noted wide variation in the time from wave
foot to inflection point of 5 to 300 ms and corresponding wide
variation in calculated augmentation index. Their average
value of 80 ms was half the value for their invasive study of
aortic pressure in which augmentation index was unusually
low.68 As reported by the ANBP2 group, there was no
relationship between augmentation index and cardiovascular
events, whereas others69 have found a positive association.
This important issue comes down to the accuracy with which
one can identify the inflection point or shoulder that corresponds to the peak of flow in the artery and that may be
blended with the foot of the reflected wave.12,21 If this is
identified too early, augmentation will be calculated high and
characteristic impedance low; if identified too late, augmentation will be low and characteristic impedance falsely high.
It is not possible to exclude such problems in interpretation of
the Mitchell data.
Until and unless the problems raised above can be excluded, the conventional approach, discussed here (with
mutually supportive data from a variety of sources, all
logically explicable) remains strong.
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Aortic Diameter, Aortic Stiffness, and Wave Reflection Increase With Age and Isolated
Systolic Hypertension
Michael F. O'Rourke and Wilmer W. Nichols
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Hypertension. 2005;45:652-658; originally published online February 7, 2005;
doi: 10.1161/01.HYP.0000153793.84859.b8
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