You are on page 1of 11

American Journal of Hypertension Advance Access published July 12, 2016


Arterial Stiffness: Going a StepBeyond

BenjaminGavish1 and Joseph L.Izzo Jr1
can be estimated from the variability of within-individual BP measurements (24-h ambulatory, home BP, or BP measured at different arm
heights) and can be expressed as the pulse stiffening ratio (PSR)=[systolic stiffness]/[diastolic stiffness] or the ambulatory arterial stiffness
index (AASI or its symmetric form, sAASI). High arterial stiffness (PWV)
and stiffening (, stiffness index, cardio-ankle vascular index, AASI, and
PSR) are associated with increased cardiovascular disease risk, but it
remains unclear whether these indicators are useful in improving
medical care quality; the standard of care remains stringent BP control.

Aging and increasing systolic blood pressure (BP) are

linked together by increasing arterial stiffness, defined
loosely as the resistance of the arterial wall to expansion
by an increment in volume. Arterial stiffness is the tangent
slope of the nonlinear relationship between arterial pressure and arterial volume (or cross-sectional area). Pulse
wave velocity (PWV), the most common surrogate for
arterial stiffness, is commonly misinterpreted as a static
indicator of arterial wall properties. In reality, stiffness
varies with any change in distending pressure or input
volume, including each cardiac systole. We describe this
dynamic property as arterial stiffening, which is not fully
predicted by knowing the diastolic stiffness of the artery.
The goal of this work is to provide a conceptual basis for
interested clinicians and researchers to interpret existing
literature and to anticipate future developments in the
study of arterial function. We also include editorial commentary on the scientific and clinical use of available arterial function indicators.

BP configuration changes with aging. Until middle

age, systolic BP (SBP) and diastolic BP (DBP) increase
in tandem but thereafter DBP declines while SBP continues to increase, leading to a widened pulse pressure
(PP, SBP minus DBP) and often to systolic hypertension.1,2 This age-related SBP-DBP divergence also signals

a change in the pathophysiology of hypertension, where

increasing arterial stiffness is progressively superimposed upon the basic hemodynamic profile of hypertension: the product of inappropriately high cardiac output
and inappropriately high systemic vascular resistance.37
In older individuals, both the increase in systolic BP
and the decrease in diastolic BP increase cardiovascular risk. Histopathologic changes in the arterial wall
that underlie these hemodynamic patterns include deterioration of the elastin network, vascular smooth muscle
hypertrophy, and increased medial and adventitial collagen deposition.8,9 This diffuse process of adventitial
and medial fibrocalcific change or pure arteriosclerosis is largely independent of atherogenesis, the atherothrombotic occlusive process caused by endothelial and
medial deposition of oxidized cholesterol, focal endothelial inflammation/ulceration, plaque remodeling, and
From a mechanical perspective, aging is associated with
reduced effectiveness of the aortic Windkessel, the arterial volume reservoir that dampens cardiac pulsation. Loss
of elasticity causes increased SBP, reduced diastolic flow
and DBP, and widening of PP, the cardinal clinical sign of
increased arterial stiffness.1012 With aging, the aorta and
major arteries lose elasticity, but also undergo compensatory
dilatation,6,1316 probably caused by the lifetime burden of
cyclic pulsatile pressure stress. This dilation helps maintain
total arterial compliance (the Windkessel function) by substituting increased arterial volume (or cross-sectional area)

Correspondence: Joseph L.Izzo Jr (

1Department of Medicine, University at Buffalo, Buffalo, New York, USA



Initially submitted December 14, 2015; date of first revision January 11,
2016; accepted for publication May 23, 2016.

Keywords: arterial stiffening; arterial stiffness; blood pressure; blood

vessels; biomarkers; hypertension; methods.

American Journal of Hypertension, Ltd 2016. All rights reserved.

For Permissions, please email:

American Journal of Hypertension 1

Downloaded from at United Arab Emirates University on July 18, 2016

Interest in arterial stiffness has been fueled by the scientific and

clinical implications of its vicious cycle relationship with aging and
systolic blood pressure. In physical terms, stiffness is the slope of the
relationship between an arterys distending pressure and its crosssectional area or volume. Pulse wave velocity (PWV, in m/s), the most
common arterial stiffness indicator, is usually measured by the foot-tofoot time and distance method and is proportional to [stiffness area
(or volume)]1/2 at a given pressure. Its intrinsic pressure dependency
and other flaws in current PWV methods limit its utility. In contrast,
the arterial stiffnessarterial pressure relationship is near-linear, with a
slope , the exponent of the curvilinear arterial pressurearterial volume relationship. The concept of arterial stiffening is related to and
describes a more functionally relevant aspect of arterial behavior: the
change in stiffness for a given change in pressure. Arterial stiffening

Gavish and Izzo

Basic concepts: Age and arterial caliber, pressure, and

A number of important arterial properties can be derived

from the curvilinear relationship between arterial pressure
and lumenal cross-sectional area (or arterial volume for a
given segment) as shown in Figure1 for normal and clinically elevated BP23:

Pressure = + exp ( Area ) (1)

where , , and are pressure-independent constants. Afull

discussion of the unique aspects of these constants is beyond
the scope of this paper, but in general, is related to intrinsic
properties of an artery to remain patent at very low pressures
2 American Journal of Hypertension

Figure 1. Arterial pressure vs. cross-sectional area in younger and

older people. Curves fitted to equation (1) using US cross-sectional BP
data for two age-groups (younger, age 2831, BP 115/73 and older, age
7178, BP 145/76mm Hg)1 and aortic size (area) from groups with similar age obtained from autopsy studies23 as best fit exponential pressure
vs. area relationship (equation (1)), for the normal and higher pressure
range (r > 0.999), with = 53 and 43mm Hg, = 1.43 and 3.42cm2,
and =1.07 and 1.05103 mm Hg for the younger and older groups,
respectively. Gray shaded boxes highlight the pulse pressures (systolic
[S] diastolic [D] BP) and corresponding pulse areas (or pulse volumes),
which are also marked by vertical and horizontal arrows, respectively.
Arterial stiffness at any point along either curve is the tangent slope
(diagonal lines) of the nonlinear pressure vs. area curve for a given pressure (filled circle) in mm Hg/cm2. In older people, the curve is shifted
downward and rightward as aortic diameter and stiffness increase.
BP=blood pressure.

and is a scaling factor for the y-intercept. Higher signifies greater stiffening (a greater pressure increase for a
given increment in arterial volume). Equation (1) has been
used for fitting similar data with 24 and without it,25,26 and
for describing pressurevolume relationships in the left
An important principle is that arterial distending pressure and arterial caliber combine with arterial wall characteristics to determine arterial stiffness;
another component, blood density, is usually ignored.
Caliber refers to the cross-sectional area of the artery
but volume and area are often interchangeable (i.e., if
area equals volume/length for an arterial segment).24,28
Figure 1 defines the pressurearea relationship for two
groups of individuals: a younger group with lower BP
and an older group with higher BP; aortic caliber is also
greater in the older group, as observed by Hallock and
Benson.23 To construct this figure, aortic size data were
taken from autopsy studies23 in which five age-groups
were represented; data from two of these groups are
embedded in Figure1. BP values corresponding to these
age-groups were taken from more recent US population
data.1 It could be argued that in vivo aortic caliber might
have been more appropriate14,29 but results would have
been similar to those depicted. Aortic size data and the
corresponding BP data were then fit to equation (1). The
most clinically relevant BP range is above 75mm Hg,
where both curves can be described remarkably well. The
effect of aging (and increased vessel caliber) on arterial
pressurearea curves is to cause a downwardrightward

Downloaded from at United Arab Emirates University on July 18, 2016

for the lost wall elasticity. The effectiveness of this compensation is limited by the greater relative arterial stiffening
during systole in the larger stiffer artery, which also reduces
arterial volume expansion at any givenPP.
Arterial stiffness is often discussed as if it were a static
property of a given artery (or region) but this is not the
case. Arterial wall characteristics directly affect arterial
stiffness but the term stiffness is intrinsically dynamic
in that it also depends on arterial size and distending
pressure. Thus, arterial stiffness is not constant within
an individual, not even within a single cardiac cycle. The
change in stiffness that results from a given increment in
distending pressure is termed arterial stiffening. This
property has been demonstrated in many animals17 and
is an important clue to the dynamic process of arterial
accommodation to physiologic and pathologic changes in
the arterial tree. The arterial stiffening concept underlies
many of the newer techniques to assess optimal and suboptimal arterial function that are discussed in subsequent
One of the most significant of the current debates is
whether increased arterial stiffness precedes systolic hypertension, or perhaps whether the relationship is best viewed
as a vicious cycle where each is both cause and effect.5 It
would seem that the vicious cycle concept is a very good
explanation for the observed age-related pathophysiologic
changes. For example, in chronic hypertension, when brachial BP is normalized by external compression, the high
brachial artery stiffness is also normalized.13 However,
older normotensives have higher arterial stiffness than
young normotensives but also have higher SBP and PP for
the same mean arterial pressure.18 As PP increases with
age and hypertension, diverse organ-related changes also
occur, such as increased cardiac afterload and left ventricular hypertrophy.19 Accompanying microcirculatory rarefaction and increased microcirculatory pulsatility reduce the
efficiency of oxygen and nutrient delivery and promote
glomerulosclerosis and chronic kidney disease progression20 as well as cerebral microvascular disease21 and cognitive impairment.22 This integrated model of age-systolic
BPstiffnesstarget organ damage is not fully proven but is
consistent with many observations.

Arterial Stiffness

Pulse wave velocity

The oldest and simplest indicator of arterial stiffness is

the velocity of the arterial pressure wave (PWV). According
to the formula derived over 100 years ago by Moens and
Korteweg and modified later by Bramwell and Hill,34 PWV
can be writtenas:

Incremental bulk modulus 
PWV = k

where k is a constant and is the blood density. The original

BramwellHill equation can be writtenas:


PWV m s = 0.357 V



where dP/dV is stiffness, i.e., the tangent slope of the pressurevolume curve (Figure 1). Equations (2a) and (2b)
require inclusion of a reference (basal or initial) cross-sectional area (or volume), which is largely its diastolic value.
Assessment of arterial stiffness has been both direct and
indirect but for clinical purposes, only the indirect techniques are relevant.
Foot-to-foot method. The standard clinical method
for PWV is to measure the distance between two distal
arterial sites and then to divide this distance by the difference in pulse arrival times. Because of distortion of the

systolic peak by differential wave propagation speeds,3537

the foot-to-foot method is used for the determination of
pulse arrival times.38 The foot-to-foot method is more
closely related to diastolic than systolic pressure,39 i.e., it
predominantly reflects diastolic stiffness but may also contain a component of systolic stiffness. Of substantial concern
is the routine practice of ignoring the baseline (diastolic)
arterial cross-sectional area that confounds the interpretation of compliance (change in volume/change in pressure) and its reciprocal, stiffness. Instead, it would be more
appropriate to consider arterial distensibility (dV/VdP) or
its reciprocal, the elastic modulus (elastance). This is especially true because a stiffer artery could simply be smaller
(reduced volume or area) or it could have altered wall composition (excess collagenous deposition). Finally, equation
(2b) suggests that the pressure dependence of PWV is not
the same as that of stiffness because of the square root function; PWV2 increases with pressure to a greater degree than
stiffness does.
PWV, which is most commonly measured between the
carotid and femoral arteries (cfPWV), has been used in
pathophysiological studies as well as large observational
and follow-up investigations. Many investigators and
some guidelines40,41 favor routine clinical use of PWV as
a cardiovascular disease risk assessment tool because of
its proven association with cardiovascular and renal disease morbidity4246 and mortality4749 and the incremental improvement over standard cardiovascular disease
risk factors that it may provide.44,5053 PWV is now widely
available, reimbursable (United States) and is endorsed by
the European Society of Hypertension and the European
Society of Cardiology.38 Consensus statements summarizing traditionally accepted concepts of arterial stiffness and
PWV measurement provide an exhaustive bibliography for
interested individuals.5254
The authors of this review have a less positive opinion
of standard PWV measurement due to the many questionable hidden assumptions, complex confounding relationships, and problems of measurement it represents.
Nonstandardization of PWV methods makes it difficult to
compare values between studies, although these methodological artifacts do not necessarily alter conclusions when
a particular device is used in a single study that employs
population stratification or follow-up strategies. Major
confounders of PWV are treated inconsistently; PWV varies directly with age,16,5558 and arterial pressure49,59,60 and
inversely with heart rate.6164 Most studies ignore these
interactions, which are not fully independent: older age
is associated with greater stiffness (higher PWV) but also
with lower diastolic pressure (reduced Windkessel function). The close relationship between age and PWV has
led some investigators to suggest age normalization,65 and
a similar rationale could be offered for BP normalization.
Better standardization is essential; at the very least, the
dependence of PWV on BP dictates strict criteria for its
There are other substantial theoretical and technical
measurement problems. PWV is a lumped parameter that
is an admixture of properties of different arteries (e.g., the
aorta, carotid, and femoral arteries in cfPWV) that are
American Journal of Hypertension 3

Downloaded from at United Arab Emirates University on July 18, 2016

curve shift; note again that arterial cross-sectional area

(and diameter) is greater in the older group, particularly
at lower pressure levels. Below the operating pressure
region, in which equation (1) is fully valid, the younger
subject curve displays a transition at a point where the
slope reaches a minimal value; this change in arterial
behavior will be explained subsequently.
Stiffness (or more properly, elastance), the slope of the
pressure vs. area (or volume) curve at any point, represents
the ratio between a small incremental pressure change and
the corresponding area (volume) change. Stiffness becomes
incremental elastic modulus if the area (volume) change
is expressed relatively.30 Stiffness is the reciprocal of arterial compliance.31 Ahighly compliant artery can store more
blood with a lesser increase in pressure than one that is
stiffer but a larger artery will have greater compliance than a
smaller one if the arterial wall composition is similar. It can
be seen from Figure1 that in the normal and higher blood
pressure range, stiffness increases directly with pressure; it
also increases during each systole and decreases during each
diastole. The concave part of the pressurearea curves shown
in Figure1 and the resulting changes in pressure-dependent
stiffness stem from the structure, organization, and behavior
of the constituent arterial wall components (elastin, collagen, and smooth muscle) and their interaction with arterial
caliber, all of which change with age.9,32,33 Thus, different
arteries with different sizes and proportions of wall constituents may display different relationships between stiffness
and pressure.

Gavish and Izzo

Systolic stiffness. Systolic PWV is always greater than

diastolic PWV because of the pressure dependence of PWV.
However, systolic PWV is more likely to be of clinical significance than diastolic PWV because it represents the most
stretched state of the artery. This principle is embedded in
the concept of arterial stiffening as will be discussed in detail
in the next section. One device (MobilOGraph with ARC
Solver) uses 24-h ambulatory oscillometry with pulse wave
analysis to create a proprietary transfer function-derived
central pressure waveform and a corresponding PWV (said
by the manufacturer to depend on age, central BP, and aortic
impedance). Aortic PWV values by this method are much
closer to invasively determined aortic PWV but other information suggests that the method tracks systolic rather than
diastolic PWV. In our studies, about 90% of the intraindividual variation in PWV throughout the day can be explained
by the corresponding variation in systolic BP, while 92% of
the interindividual variation in PWV can be explained by
age (85%) and systolic BP (7%).73 In other studies, end-systolic PWV (BP measured at the dicrotic notch) has a much
stronger association with PP and age than does standard
(diastolic) PWV.74
Pulse pressure amplification and AIx. Pulse wave analysis allows estimation of other central BP and other potential indicators of arterial function. Another phenomenon
related to PWV is pulse pressure amplification (higher distal than central PP and systolic BP), which is at least part
due to the distortion of the systolic pulse waveform by variations in PWV during systole. High pulse pressure amplification can be caused by anatomical differences in artery
4 American Journal of Hypertension

caliber even if the wall elastic properties are normal; in

smaller peripheral arteries that taper, there is a progressive
increase in systolic BP, impedance and PWV even if the wall
composition is perfectly normal.36,37,75 Historically, late systolic pressure augmentation (augmentation index (AIx))
was used as an indirect index of arterial stiffness but more
recent thinking suggests that this practice should be reconsidered.76,77 AIx and PWV both tend to be high in older
individuals and therefore are often correlated; this does not
mean, however, that AIx is a reliable indicator of arterial
stiffness. This misunderstanding was largely related to outdated concepts of wave reflection theory which held that
decreased pulse transit time in stiff arteries (high PWV)
caused the backward arterial pressure wave to appear prematurely in late systole, where it caused enhanced summation with the forward pressure wave. However, several
investigators have now refuted this model of pressure wave
reflection;7884 the return wave can be found in all individuals in late systole. AIx is more dependent on the reflection
coefficient, which in turn is influenced heavily by distal
vascular resistance.

Arterial stiffness indicators provide limited predictive

information about the dynamic behavior of arteries over the
range of physiologic and pathophysiologic changes observed
in the population. Although PWV varies with aging and
disease, it fails to capture the dynamic essence of arterial
mechanics. As depicted in Figure1, full appreciation of the
implications of the nonlinear pressurearea relationship
requires a more inclusive approach.
Stiffnesspressure relationship

The nonlinear concave form of the pressurearea curves

shown in Figure1 and the variations with aging and disease
stem from the structure and organization of the wall components: elastin, collagen, and smooth muscle and their
dissimilar pressure and size-dependent interactions.8,9,32,33
Arterial stiffness is the slope of the pressurearea (or volume) curve, but arterial stiffening is the nearly constant
slope of the arterial stiffnesspressure curve () over the
usual operating range of pressures in man.25,85 Stiffening
also can be described as the change in stiffness that accompanies a given pressure increment. Figure 2 is derived
directly from Figure1; in the usual operating range, from
Stiffness = ( P ) (3)

ln (SBP ) (DBP )
Pulse area


The dimensions of are 1/area (or 1/volume). Current

clinical estimation of involves modified forms of equation
(4). Differences in between individuals strongly depend
on arterial wall characteristics; zero corresponds to a
purely elastic artery, i.e., stiffness is a pressure-independent

Downloaded from at United Arab Emirates University on July 18, 2016

structurally dissimilar. The use of different measurement

regions to represent the aorta (e.g. heartfemoral vs. brachialankle) is an intrinsic problem made worse by grossly
incorrect height-based algorithms68 and inconsistencies
in the anatomic landmarks chosen to represent arterial
path length.69 For example, the most widely used method
of PWV estimation, cfPWV (often mislabeled as aortic
PWV using the Complior, Colin, or similar devices) has
been calculated several different ways with dramatically
different results. For a known mean catheter-based aortic
PWV of 8.5 m/s, the corresponding carotidfemoral value
was 11.5 m/s (35% higher) if arterial length was assumed as
the uncorrected carotidfemoral distance (the most common approach).69 If a more appropriate distance correction
was used (carotidsuprasternal notch distance subtracted
from suprasternal notchfemoral distance), the PWV value
was 8.7 m/s, similar to the invasive value.69 The problem
is even worse for distal measurement sites; brachialankle
PWV, although correlated with central measurements,70
exceeds true aortic PWV by at least 50%.71,72 Because of
these vagaries, newer PWV techniques continue to arise.
One method estimates heartfemoral PWV (Colin VP
1000/2000) from the timing of aortic valve closure (by
phonocardiography and electrocardiography) and the foot
of the femoral pulse wave measured by arterial tonometry.
The Colin device also measures standard cfPWV and brachialankle PWV.

Arterial Stiffness

constant, while higher implies stiffening. Conceptually,

stiffness and stiffening are independent measures; arteries
may display high or low stiffness independent of pressure,
while others may demonstrate a close relationship of stiffness and stiffening in part due to alterations in elastin and
collagen content.
Figure 2 also demonstrates that at low pressures (and
minimum stiffness), stiffening (defined by the tangent slope)
can be low, zero, or even negative (see shaded area for the
younger group). These phenomena reflect different structurefunction characteristics that vary with arterial pressure
and age and arterial wall composition. The pressure at the
point of minimum stiffness (maximum compliance) represents a complex transition between a normally distended
vs. collapsed (more properly buckled) configuration of
the artery. Buckling is a term that refers to a conformational
shift in the vessel (e.g. convex to crescentic) where there
is a large reduction in the lumen area for a relatively small
pressure reduction.24,28,87 This shift is manifested by the disappearance of the buckling phenomenon and appearance
of an older type artery that never collapses fully, instead
remaining ovoid with a finite diameter and stiffness even
at zero pressure. The younger type curve is more common
in the thoracic and abdominal aorta,88 while the older type
is more common in peripheral conduit arteries, including
the brachial and radial arteries.89,90 The buckling aspect in
pressurearea relationships has been used to model ex vivo
and in vivo pressure dependence of arterial compliance.88
Finally, if the linear stiffnesspressure relationship (equation (4)) observed at higher pressures is extrapolated back
to zero stiffness (see Figure2), the line crosses the pressure
axis at a value of approximately 4055mm Hg. The same
range was obtained by Cox using data from six different
types of arteries.91 Our interpretation of this information is
that is an estimate of collapsibility of an artery, which in
turn is related to its structural characteristics (e.g., collagen
content) and to its stiffness. These and other aspects of low
pressure arterial behavior deserve further investigation.

Clinical estimation of

Stiffness index. Stiffness index (SI) is a dimensionless

index defined as follows86:

SI =


Pulse diameter

) (Diastolic diameter ) (5)

Equation (5) can be obtained from equation (4) by ignoring

, thus expressing cross-sectional area relative to its diastolic
value, and approximating the relative pulse area (i.e., [systolic minus diastolic area]/[diastolic area]) as twice the relative pulse diameter.92 This approximation makes SI roughly
equal to 2/[diastolic area]. Systolic and diastolic diameters
can be measured noninvasively by echo tracking. Since the
diastolic diameter varies with pressure, SI is clearly not a
pressure-independent constant. The omission of causes
further severe limitations in its use; e.g., if BP is 140/80mm
Hg and = 40mm Hg, in equation (4) is ln[(140 40)
/(80 40)]=0.92, whereas SI in equation (5) is 0.56 (i.e., about
40% smaller). SI was originally suggested as an expression of
arterial stiffness,86 and it does increase with age, hypertension,
smoking and their interaction,25,93 and type 2 diabetes94 and is
an independent risk factor for recurrent acute coronary events.95
Cardio-ankle vascular index (CAVI). This proprietary
index has been claimed to be a pressure-independent estimate of 96,97 and is derived from cuff BP and standard
PWV98 according to the following formula:

) (

CAVI = a PWV 2 2 PP ln SBP DBP + b (6)

where a and b are adjustable constants. Derivation of equation
(6) from equation (4) ignores and replaces the required small
pressure and volume changes in the BramwellHill equation
(equation (2b)) with central PP and pulse volume estimates
that are not small. This may explain the observed relationship between CAVI and SI.99 Equation (6) involves the unverified derivation of the constants a and b. Clinical applications of

American Journal of Hypertension 5

Downloaded from at United Arab Emirates University on July 18, 2016

Figure2. Arterial stiffness vs. arterial pressure. These relationships are derived directly from Figure1. In contrast to the curvilinear pressurevolume
relationship (Figure1), stiffness is linearly related to arterial pressure, at least for pressures in the usual physiologic and pathophysiologic range. The
degree of stiffening is the slope , which differs from the dimensionless stiffness parameter,86 and has dimensions of 1/area or 1/volume). PSR (pulse
stiffening ratio) is the ratio between systolic and diastolic stiffness that can be defined for any pressure range, including an individuals pulse pressure
(horizontal and vertical arrows); S is systolic BP and D is diastolic BP. Stippled areas identify the lowest pathophysiologic pressure ranges, where stiffness
vs. pressure deviates from linearity due to phenomena such as buckling. Dashed lines that cross the x-axis (representing =4055mm Hg) are given by
equation (3). Markings are similar to Figure1.

Gavish and Izzo

CAVI were recently reviewed,100 and it has been claimed that

this proprietary index yields prognostic information about
cerebrovascular and coronary artery disease.101,102 Whether
CAVI offers clinically useful incremental risk stratification or
whether it is truly pressure independent remains to be proven.
BP-derived arterial stiffening indicators

Stiffening indicators can be derived from repeated BP

measurements alone: pulse stiffening ratio (PSR) and two
forms of ambulatory arterial stiffness index (AASI). They
share a common purpose: providing easily measured,
(largely) pressure-independent information with diagnostic
and prognostic significance.



DBP = C + 1 PSR SBP 


There is no a priori assumption that PSR, C, or C are constants

but the highly linear relationship between SBP and DBP in
all individuals has been observed (Figure3) for intra-arterial
pressures,110 brachial 24-h ambulatory pressures,104,111113
home BP monitoring,114 and gravitational-induced brachial BP
change.107 This indicates that PSR is also pressure independent. When estimated from BP data using symmetric regression,115 PSR can be expressed as the ratio of SBP variation to
DBP variation:





Figure 3. Linearity of systolic vs. diastolic BP. The slope is interpreted as an estimation for the PSR, see equation (7a) given as mean SD, using:
(a) 24-hour ambulatory BP monitoring106 or (b) digital BP monitoring with gravitational method (see text).109 Data were reproduced with permission.
BP=blood pressure; PSR=pulse stiffening ratio.

6 American Journal of Hypertension

Downloaded from at United Arab Emirates University on July 18, 2016

Pulsatile stiffening ratio. Asimple and convenient way

to express stiffening is the ratio [systolic stiffness]/[diastolic
stiffness] or PSR (see Figure2) as originally proposed by
Gavish.103 Other names for PSR in past communications
were: Sym-slope,104 s-slope,105 BP variability ratio (BPVR),106
S-D slope,107 and dSdD.108 Equation (3), PSR=(SBP )/
(DBP ), leads to the following predicted relationships:

where SD is standard deviation.106 Equation (8) suggests

that PSR can be determined theoretically from any type of
consistently measured repeated BP values with sufficient
range and variation. By definition, PSR=1 for a purely elastic artery. Asubject with greater variability of systolic than
diastolic BP (PSR > 1) displays greater stiffening over the
observed pressure range. The newer gravitational method
for PSR determination also has promise (Figure3). With a
digital BP monitor and standard arm cuff, readings are taken
at four different vertically displaced arm positions. The
resulting 20mm Hg of BP variation, the corresponding good
SBP-DBP correlation (mean R = 0.94), and the minimal
heart rate variation all contribute to reasonable reproducibility.109 In contrast to current belief, BP variation in response
to changing arm cuff height cannot be explained solely by a
hydrostatic effect.116 From our 24-h ambulatory monitoring
data, mean PSR was 1.390.33 (mean SD), range 0.593.5,
mean error of determination 6%, mean SBP-DBP correlation of 0.76, and about 5% of the PSR values were <1).106 The
negative stiffening in the low pressure range (as predicted in
Figures 1 and 2)deserves furtherstudy.
There are other important implications of the highly
linear relationship between SBP and DBP and the derivation of PSR. Stated differently, the model assumes that the
linear SBP-DBP relationship is a physiological law and not
just a statistical correlation. It predicts the observed exponential pressurearea relationship (Figure 1, equation (1))
and the associated linear stiffnesspressure relationship
(Figure2, equation (2)).103 Since PSR=exp ([Pulse area]),
by combining equations (1) and (3), both PSR and appear
to be pressure independent. Pulse area (volume) and the
Windkessel function (aortic volume reservoir) are also pressure independent. Several factors can alter PSR physiologically; Figure 4 shows that PSR varies inversely with heart
rate, increasing more steeply for heart rates <70 bpm (along
with DBP117 and diastolic stiffness). Figure4 also shows that
PSR increases gradually at younger ages (<55 years) and
more steeply in older individuals, consistent with our knowledge of arterial stiffness and stiffening. PSR is an independent predictor of all-cause mortality in the general population

Arterial Stiffness

(after adjusting for confounding factors)109 and especially for

the cohort of elderly hypertensive patients (age >60 years)
with slow heart rate (<70 bpm).108
AASI and sAASI. These indicators, like PSR, are derived
from the observed linear relationship between SBP and DBP.
AASI was originally defined as 1 [diastolic-on-systolic
slope] and was originally calculated using standard regression of 24-h ambulatory systolic and diastolic pressures.94
The formula for AASIis:
where R is the standard Pearson SBP-DBP correlation coefficient and PSR is given by equation (8).106 The dependence
of AASI on R (also observed experimentally)104,115,118 is a bias
caused by the asymmetric characteristics of standard regression methodology that can be eliminated using symmetric
regression technique,104,115 resulting in ansAASI:

AASI = 1

sAASI = 1


Zero sAASI (but not AASI) corresponds to purely elastic

artery. AASI can be easily converted to sAASI using the formula sAASI=1 (1 AASI)/R,106 and the latter to PSR using
the formula 1/(1 sAASI); AASI and sAASI strongly correlate with PSR118 at least in part due to the common terms
involved (Equations (9) and (10)). Reproducibility of AASI
and sAASI using self-measured home BP values was somewhat lower than using automated 24-h monitoring.118,119
AASI is also substantially affected by physiologic variations
in vascular resistance and heart rate120 (see Figure4). PSR,
sAASI, and especially AASI are also affected by nocturnal BP
dipping (higher in non-dippers).104
AASI and sAASI are primarily indicators of stiffening
as supported by computer simulation.120,121 Due to the
close mathematical relationship between PSR and sAASI,
both would be expected to display similar diagnostic and
prognostic significance; this is true for all-cause mortality.105,106 PSR and AASI (or sAASI) are positively correlated with high collagen/elastin ratio (in rats),122 and it

should not be surprising that both may correlate with

arterial stiffness indicators, at least in some instances.
High sAASI is associated with microalbuminuria and
reduced renal function.123 AASI predicts cardiovascular
mortality and events, especially stroke124,125 but sAASI has
stronger predictive power than AASI.105,106,126128 Finally,
using ambulatory BP measurements, PSR, sAASI, and
AASI were reduced by 8 weeks of daily treatment with
device-guided breathing but were unaffected by 6-month
potassium chloride-enriched diet or seasonal BP change
suggesting that stiffening may be affected by certain
therapeutic interventions.129 Alternatively, there may be
a degree of hidden pressure dependency of these stiffening indicators that is not apparent in the concepts or
formulas used to derive them.

A main goal of this work is to spark necessary discussion and debate about future needs and directions. From a
scientific perspective, historical methods for arterial stiffness (mainly PWV) are limited in the information they
provide. The first section of this review detailed a comprehensive framework for understanding arterial stiffness
and its consequences. Subsequent discussion emphasized
the intrinsic pressure dependence of arterial stiffness and
the need for a more dynamic term (arterial stiffening) to
describe clinically relevant, largely pressure-independent
arterial behavior. There are now several approaches that
yield information on arterial stiffness and stiffening. In
describing the dynamic relationship between the arterial
wall and the corresponding arterial pressure, PSR is attractive because it is an indicator that is particularly relevant to
a single cardiaccycle.
Newer practical techniques to estimate stiffening-related
parameters, such CAVI, may have a place or it may be that
other new indicators that may be more pressure independent
(PSR, AASI, and sAASI) may be most useful. Not all of these
techniques are fully validated, so refinements may be necessary. All techniques contain assumptions that can be seriously
American Journal of Hypertension 7

Downloaded from at United Arab Emirates University on July 18, 2016

Figure4. Age and heart rate dependence of stiffening (PSR). Mean values for age and heart rate groups (n=3,433) taken with permission.106 The
dashed lines are best fit models of the trend of the four youngest age-groups and the trend of the four highest heart rate groups, respectively. PSR=pulse
stiffening ratio.

Gavish and Izzo


The authors wish to thank Prof. Michael Burstyn for the

permission to use the data for Figures 3a and4.
8 American Journal of Hypertension


The authors declared no conflict of interest.

1. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan
MJ, Labarthe D. Prevalence of hypertension in the US adult population.
Results from the Third National Health and Nutrition Examination
Survey, 1988-1991. Hypertension 1995; 25:305313.
2. Franklin SS, Gustin W 4th, Wong ND, Larson MG, Weber MA, Kannel
WB, Levy D. Hemodynamic patterns of age-related changes in blood
pressure. The Framingham Heart Study. Circulation 1997; 96:308315.
3. Izzo JL, Jr. Hemodynamics of hypertension. In Lip GYP, Hall JE (eds),
Comprehensive Hypertension. Mosby-Elsevier: Philadelphia, 2007,
4. Izzo JL, Jr. Arterial stiffness and the systolic hypertension syndrome.
Curr Opin Cardiol 2004;19:341352.
5. AlGhatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P,
Scuteri A, Najjar SS, Ferrucci L, Lakatta EG. Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore
Longitudinal Study of Aging. Hypertension 2013; 62:934941.
6. Simon AC, Levenson J, Bouthier J, Safar ME, Avolio AP. Evidence of
early degenerative changes in large arteries in human essential hypertension. Hypertension 1985; 7:675680.
7. Benetos A, Waeber B, Izzo J, Mitchell G, Resnick L, Asmar R, Safar
M. Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications. Am J Hypertension
8. Avolio A, Jones D, Tafazzoli-Shadpour M. Quantification of alterations
in structure and function of elastin in the arterial media. Hypertension
1998; 32:170175.
9. Bank AJ, Wang H, Holte JE, Mullen K, Shammas R, Kubo SH.
Contribution of collagen, elastin, and smooth muscle to in vivo human
brachial artery wall stress and elastic modulus. Circulation 1996;
10. Mitchell GF, Lacourcire Y, Ouellet JP, Izzo JL Jr, Neutel J, Kerwin LJ,
Block AJ, Pfeffer MA. Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension:
the role of proximal aortic diameter and the aortic pressure-flow relationship. Circulation 2003; 108:15921598.
11. Mitchell GF, Gudnason V, Launer LJ, Aspelund T, Harris TB.

Hemodynamics of increased pulse pressure in older women in the
community-based Age, Gene/Environment Susceptibility-Reykjavik
Study. Hypertension 2008; 51:11231128.
12. Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003; 107:28642869.
13. Smulyan H, Vardan S, Griffiths A, Gribbin B. Forearm arterial distensibility in systolic hypertension. J Am Coll Cardiol 1984;3:387393.
14. Lam CS, Xanthakis V, Sullivan LM, Lieb W, Aragam J, Redfield MM,
Mitchell GF, Benjamin EJ, Vasan RS. Aortic root remodeling over the
adult life course: longitudinal data from the Framingham Heart Study.
Circulation 2010; 122:884890.
15. Mitchell GF, Conlin PR, Dunlap ME, Lacourcire Y, Arnold JM, Ogilvie
RI, Neutel J, Izzo JL Jr, Pfeffer MA. Aortic diameter, wall stiffness, and
wave reflection in systolic hypertension. Hypertension 2008; 51:105111.
16. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME.
Pulsatile diameter and elastic modulus of the aortic arch in essential
hypertension: a noninvasive study. J Am Coll Cardiol 1989; 13:399405.

Shadwick RE. Mechanical design in arteries. J Exp Biol
18. Franklin SS, Lopez VA, Wong ND, Mitchell GF, Larson MG, Vasan RS,
Levy D. Single versus combined blood pressure components and risk
for cardiovascular disease: the Framingham Heart Study. Circulation
2009; 119:243250.
19. Bouthier JD, De Luca N, Safar ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Heart J

Downloaded from at United Arab Emirates University on July 18, 2016

questioned and none are necessarily applicable to all experimental questions or are valid over the entire range of BP values encountered in clinical medicine. For example, PWV is
highly pressure dependent, but current convention does not
consistently account for this important phenomenon. CAVI
utilizes cfPWV, itself a hypothetical construct that does not
correspond to the anatomy or function of any recognizable
arterial segment, instead comprising mixed measurements
taken from different parts of the circulation. SI is intrinsically
local. PSR, AASI, and sAASI involve only BP measurements
and may be more global measures, but may be relatively
insensitive or too lumped to be clinically useful.
For clinicians, the central question about any arterial stiffness/stiffening indicator is: Does knowing it add value?
or What would Ido differently or better in my patients if
Iknew these parameters? It appears that the general answer
to both questions is not too much for existing techniques
and too early to tell for newer ones. Currently, the standard argument from supporters of universal PWV measurement is that it provides incremental cardiovascular disease
risk stratification beyond age, BP, and other readily available risk factors. This may be true in a statistical sense but
it is extremely difficult to see how such knowledge translates
into better patient care. High BP is closely related to stiffness and is universally recognized by patients as a cardinal
risk factor that requires therapy. There is no justification for
monitoring arterial stiffness in response to therapy, principally because there are no drugs that target arterial stiffness
directly. Earlier claims that arterial stiffness is reduced by
chronic ACE inhibition independent of antihypertensive
effects130 were almost certainly overstated. In more recent
studies, chronic reninangiotensin blockade (olmesartan)
has been said to lower arterial stiffness partly independent of the corresponding BP reduction,131 and there is an
ongoing European trial that investigates this point further
(SPATE). However, all drugs that lower arterial pressure also
lower arterial stiffness. There is also the very real likelihood
of misunderstanding and misrepresentation of arterial stiffness by clinicians with insufficient background knowledge
or expertise. If arterial stiffness information is presented
routinely to patients, the clinician must take care to convey
the message that there is no specific treatment for stiff arteries and that stringent BP control is the only current answer.
Finally, although relatively inexpensive, a costbenefit analysis is needed for arterial stiffness/stiffening indicators that
should include such hidden expenses as the impact of diagnostic inaccuracy (including false positives and negatives)
and the costs of professional education and quality monitoring programs. Much better understanding of the clinical
and pathophysiologic information provided by stiffness and
stiffening indicators is needed before their universal use by
enlightened and responsible practitioners is fully warranted.

Arterial Stiffness
Expert consensus document on arterial stiffness: methodological issues
and clinical applications. Eur Heart J 2006; 27:25882605.
41. Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank
JK, De Backer T, Filipovsky J, Huybrechts S, Mattace-Raso FU,
Protogerou AD, Schillaci G, Segers P, Vermeersch S, Weber T, Artery
S; European Society of Hypertension Working Group on Vascular S;
Function and European Network for Noninvasive Investigation of
Large A. Expert consensus document on the measurement of aortic
stiffness in daily practice using carotid-femoral pulse wave velocity. J
Hypertens 2012; 30:445448.
42. McEniery CM, Yasmin, Wallace S, Maki-Petaja K, McDonnell B,

Sharman JE, Retallick C, Franklin SS, Brown MJ, Lloyd RC, Cockcroft
JR, Wilkinson IB; ENIGMA Study Investigators. Increased stroke volume and aortic stiffness contribute to isolated systolic hypertension in
young adults. Hypertension 2005; 46:221226.
43. Mitchell GF, Vita JA, Larson MG, Parise H, Keyes MJ, Warner E, Vasan
RS, Levy D, Benjamin EJ. Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: the Framingham Heart Study. Circulation 2005; 112:37223728.
44. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg
NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular
events: the Framingham Heart Study. Circulation 2010; 121:505511.
45. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave
velocity as a marker of cardiovascular risk in hypertensive patients.
Hypertension 1999; 33:11111117.
46. Sutton-Tyrrell K, Najjar SS, Boudreau RM, Venkitachalam L, Kupelian
V, Simonsick EM, Havlik R, Lakatta EG, Spurgeon H, Kritchevsky
S, Pahor M, Bauer D, Newman A; Health ABC Study. Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 2005;
47. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG.
Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function?
Circulation 2002; 106:20852090.
48. Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse
wave velocity predicts cardiovascular mortality in subjects >70years of
age. Arterioscler Thromb Vasc Biol 2001; 21:20462050.
49. Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs
L, Ibsen H, Jeppesen J. Prognostic value of aortic pulse wave velocity as
index of arterial stiffness in the general population. Circulation 2006;
50. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L,
Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients.
Hypertension 2001; 37:12361241.
51. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic
review and meta-analysis. J Am Coll Cardiol 2010; 55:13181327.
52. Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin
EJ, Boutouyrie P, Cameron J, Chen C-H, Cruickshank JK, Hwang S-J,
Lakatta EG, Laurent S, Maldonado J, Mitchell GF, Najjar SS, Newman
AB, Ohishi M, Pannier B, Pereira T, Vasan RS, Shokawa T, SuttonTyrell K, Verbeke F, Wang K-L, Webb DJ, Willum Hansen T, Zoungas
S, McEniery CM, Cockcroft JR, Wilkinson IB. Aortic pulse wave velocity improves cardiovascular event predictionan individual participant
meta-analysis of prospective observational data from 17,635 subjects. J
Am Coll Cardiol 2014; 63:636646.
53. Vlachopoulos C, Xaplanteris P, Aboyans V, Brodmann M, Cfkov R,
Cosentino F, De Carlo M, Gallino A, Landmesser U, Laurent S, Lekakis
J, Mikhailidis DP, Naka KK, Protogerou AD, Rizzoni D, SchmidtTrucksss A, Van Bortel L, Weber T, Yamashina A, Zimlichman R,
Boutouyrie P, Cockcroft J, ORourke M, Park JB, Schillaci G, Sillesen
H, Townsend RR. The role of vascular biomarkers for primary and
secondary prevention. A position paper from the European Society
of Cardiology Working Group on peripheral circulation: Endorsed by
the Association for Research into Arterial Structure and Physiology
(ARTERY) Society. Atherosclerosis 2015; 241:507532.
54. Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA,
Cockcroft JR, Heffernan KS, Lakatta EG, McEniery CM, Mitchell
GF, Najjar SS, Nichols WW, Urbina EM, Weber T. Recommendations
for improving and standardizing vascular research on arterial

American Journal of Hypertension 9

Downloaded from at United Arab Emirates University on July 18, 2016

20. Briet M, Boutouyrie P, Laurent S, London GM. Arterial stiffness and

pulse pressure in CKD and ESRD. Kidney Int 2012; 82:388400.
21. Mitchell GF. Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage.
J Appl Physiol. 2008;105:16521660.
22. Hanon O, Haulon S, Lenoir H, Seux M-L, Rigaud A-S, Safar M, Girerd
X and Forette F. Relationship between arterial stiffness and cognitive
function in elderly subjects with complaints of memory loss. Stroke
23. Hallock P, Benson IC. Studies on the elastic properties of human isolated aorta. J Clin Invest 1937; 16:595602.
24. Drzewiecki G, Field S, Moubarak I, Li JK-J. Vessel growth and collapsible pressure-area relationship. Am J Physiol Heart Circ Physiol
25. Pagani M, Mirsky I, Baig H, Manders WT, Kerkhof P, Vatner SF. Effects
of age on aortic pressure-diameter and elastic stiffness-stress relationships in unanesthetized sheep. Circ Res 1979; 44:420429.
26. Armentano R, Megnien JL, Simon A, Bellenfant F, Barra J, Levenson J.
Effects of hypertension on viscoelasticity of carotid and femoral arteries
in humans. Hypertension 1995; 26:4854.
27. Glantz SA, Parmley WW. Factors which affect the diastolic pressurevolume curve. Circ Res 1978;42:171180.
28. Liu SQ, Fung YC. Zero-stress states of arteries. J Biomech Eng

29. Vasan RS, Larson MG, Levy D. Determinants of echocardiographic
aortic root size. The Framingham Heart Study. Circulation 1995;
30. Chirinos JA. Arterial stiffness: basic concepts and measurement techniques. J Cardiovasc Transl Res 2012;5:243255.
31. ORourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE.
Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertens. 2002;15:426444.
32. Roach MR, Burton AC. The reason for the shape of the distenstensibility curves of arteries. Can J Biochem Physiol 1957;35:681690.
33. VanBavel E, Siersma P, Spaan JAE. Elasticity of passive blood vessels: a
new concept. Am J Physiol Heart Circ Physiol 2003;285:H1986H2000.
34. Bramwell JC, Hill AV. The velocity of the pulse wave in man. Proc R Soc
Lond B. 1922;93:298306.
35. Anliker M, Histand MB, Ogden E. Dispersion and attenuation of small
artificial pressure waves in the canine aorta. Circ Res. 1968;23:539551.
36. Barnard AC, Hunt WA, Timlake WP, Varley E. A theory of fluid flow in
compliant tubes. Biophys J 1966;6:717724.
37. Safar ME. Epidemiological aspects of pulse pressure and arterial stiffness. J Hypertens 1999;17:S37S40.
38. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bhm M,
Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M,
Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ,
Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa
M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson
PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A,
Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL,
Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol
C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P,
Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P,
Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S,
Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni
E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De
Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C,
Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T,
Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G,
Perk J, Polonia J, Popescu BA, Reiner Z, Rydn L, Sirenko Y, Stanton
A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos
C, Volpe M, Wood DA. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of
Arterial Hypertension of the European Society of Hypertension (ESH)
and of the European Society of Cardiology (ESC). Eur Heart J 2013;
39. Rothe CF. Mean circulatory filling pressure: its meaning and measurement. J Appl Physiol 1993; 74:499509.
40. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C,
Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier
H; European Network for Non-invasive Investigation of Large A.

Gavish and Izzo

10 American Journal of Hypertension

augmentation index in patients with diabetes. J Hypertens 2004;

79. McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft
JR; ACCT Investigators. Normal vascular aging: differential effects
on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff
Collaborative Trial (ACCT). J Am Coll Cardiol 2005; 46:17531760.
80. Baksi AJ, Treibel TA, Davies JE, Hadjiloizou N, Foale RA, Parker
KH, Francis DP, Mayet J, Hughes AD. A meta-analysis of the mechanism of blood pressure change with aging. J Am Coll Cardiol 2009;
81. Tyberg JV, Davies JE, Wang Z, Whitelaw WA, Flewitt JA, Shrive NG,
Francis DP, Hughes AD, Parker KH, Wang JJ. Wave intensity analysis
and the development of the reservoir-wave approach. Med Biol Eng
Comput 2009; 47:221232.
82. Davies JE, Alastruey J, Francis DP, Hadjiloizou N, Whinnett ZI,

Manisty CH, Aguado-Sierra J, Willson K, Foale RA, Malik IS, Hughes
AD, Parker KH, Mayet J. Attenuation of wave reflection by wave entrapment creates a horizon effect in the human aorta. Hypertension 2012;
83. Schultz MG, Davies JE, Hardikar A, Pitt S, Moraldo M, Dhutia N,
Hughes AD, Sharman JE. Aortic reservoir pressure corresponds to
cyclic changes in aortic volume: physiological validation in humans.
Arterioscler Thromb Vasc Biol 2014; 34:15971603.
84. Izzo JL, Gawri K, Sheikh FM, Younus U, Osmond PJ. Effects of aging
and blood pressure on timing and amplitude of central pulse contour
landmarks. J Am Soc Hypertens 2015; 9:e13.
85. Mourad JJ, Girerd X, Boutouyrie P, Laurent S, Safar M, London G.
Increased stiffness of radial artery wall material in end-stage renal disease. Hypertension 1997; 30:14251430.
86. Hayashi K, Handa H, Nagasawa S, Okumura A, Moritake K. Stiffness
and elastic behavior of human intracranial and extracranial arteries. J
Biomech 1980; 13:175184.
87. Han H-C, Chesnutt JW, Garcia J, Liu Q, Wen Q. Artery buckling:
new phenotypes, models, and applications. Ann Biomed Eng 2013;
88. Langwouters GJ, Wesseling KH, Godehard WJA. The static mechanical
properties of 45 human thoracic and 20 abdominal aortas in vitro and
the parameters of a new model. J Biomech 1984; 17:425435.
89. Bank AJ, Wilson RF, Kubo SH, Holte JE, Dresing TJ, Wang H. Direct
effects of smooth muscle relaxation and contraction on in vivo human
brachial artery elastic properties. Circ Res 1995; 77:10081016.
90. Giannattasio C, Cattaneo BM, Mangoni AA, Carugo S, Stella ML, Failla
M, Trazzi S, Sega R, Grassi G, Mancia G. Cardiac and vascular structural changes in normotensive subjects with parental hypertension. J
Hypertens 1995; 13:259264.
91. Cox R. Arterial wall mechanics and composition and the effects

of smooth muscle activation. Am J Physiol Legacy Content 1975;
92. Kawasaki T, Sasayama S, Yagi S-I, Asakawa T, Hirai T. Non-invasive
assessment of the age related changes in stiffness of major branches of
the human arteries. Cardiovasc Res 1987; 21:678687.
93. Liang YL, Shiel LM, Teede H, Kotsopoulos D, McNeil J, Cameron JD,
McGrath BP. Effects of blood pressure, smoking, and their interaction
on carotid artery structure and function. Hypertension 2001; 37:611.
94. Toutouzas K, Stefanadis C, Tsiamis E, Vlachopoulos C, Tousoulis

D, Tsioufis C, Toutouzas P. Aortic pressure-diameter relation in
patients with non-insulin dependent diabetes mellitus: new insights.
Diabetologia 2000; 43:10701075.
95. Stefanadis C, Dernellis J, Tsiamis E, Stratos C, Diamantopoulos L,
Michaelides A, Toutouzas P. Aortic stiffness as a risk factor for recurrent acute coronary events in patients with ischaemic heart disease. Eur
Heart J 2000; 21:390396.
96. Shirai K, Hiruta N, Song M, Kurosu T, Suzuki J, Tomaru T, Miyashita
Y, Saiki A, Takahashi M, Suzuki K, Takata M. Cardio-Ankle Vascular
Index (CAVI) as a novel indicator of arterial stiffness: theory, evidence
and perspectives. J Atheroscler Thromb 2011; 18:924938.
97. Sun CK. Cardio-ankle vascular index (CAVI) as an indicator of arterial
stiffness. Integr Blood Press Control 2013; 6:2738.
98. Shirai K, Utino J, Otsuka K, Takata M. A novel blood pressure-independent arterial wall stiffness parameter; cardio-ankle vascular index
(CAVI). J Atheroscler Thromb 2006; 13:101107.
99. Takaki A, Ogawa H, Wakeyama T, Iwami T, Kimura M, Hadano

Y, Matsuda S, Miyazaki Y, Matsuda T, Hiratsuka A, Matsuzaki M.

Downloaded from at United Arab Emirates University on July 18, 2016

stiffness: a scientific statement from the American Heart Association.

Hypertension. 2015; 66:698722.
55. Hallock P. Arterial elasticity in man in relation to age as evaluated by
the pulse wave velocity method. Arch Int Med 1934; 54:770798.
56. Simonson E, Nakagawa K. Effect of age on pulse wave velocity and
aortic ejection time in healthy men and in men with coronary artery
disease. Circulation 1960; 22:126129.
57. Vaitkevicius PV, Fleg JL, Engel JH, OConnor FC, Wright JG, Lakatta
LE, Yin FC, Lakatta EG. Effects of age and aerobic capacity on arterial
stiffness in healthy adults. Circulation 1993; 88:14561462.
58. Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME.

Comparative effects of aging in men and women on the properties of
the arterial tree. J Am Coll Cardiol. 2001; 37:13741380.
59. Asmar R, Topouchian J, Pannier B, Benetos A, Safar M; Scientific
QCC and Investigation Committees of the Complior S. Pulse wave
velocity as endpoint in large-scale intervention trial. The Complior
study. Scientific, Quality Control, Coordination and Investigation
Committees of the Complior Study. J Hypertens 2001; 19:813818.
60. Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac AM,
Target R, Levy BI. Assessment of arterial distensibility by automatic
pulse wave velocity measurement. Validation and clinical application
studies. Hypertension 1995; 26:485490.
61. Albaladejo P, Asmar R, Safar M, Benetos A. Association between
24-hour ambulatory heart rate and arterial stiffness. J Hum Hypertens
2000; 14:137141.
62. Lantelme P, Mestre C, Lievre M, Gressard A, Milon H. Heart rate: an
important confounder of pulse wave velocity assessment. Hypertension
2002; 39:10831087.
63. McGrath BP, Liang YL, Kotsopoulos D, Cameron JD. Impact of physical and physiological factors on arterial function. Clin Exp Pharmacol
Physiol 2001; 28:11041107.
64. Wilkinson IB, Mohammad NH, Tyrrell S, Hall IR, Webb DJ, Paul VE,
Levy T, Cockcroft JR. Heart rate dependency of pulse pressure amplification and arterial stiffness. Am J Hypertens 2002; 15:2430.
65. Khoshdel AR, Thakkinstian A, Carney SL, Attia J. Estimation of an agespecific reference interval for pulse wave velocity: a meta-analysis. J
Hypertens 2006; 24:12311237.
66. Tomlinson LA. Methods for assessing arterial stiffness: technical considerations. Curr Opin Nephrol Hypertens 2012; 21:655660.
67. Cameron J. Estimation of arterial mechanics in clinical practice and as
a research technique. Clin Exp Pharmacol Physiol 1999; 26:285294.
68. Sugawara J, Hayashi K, Tanaka H. Arterial path length estimation on
brachial-ankle pulse wave velocity: validity of height-based formulas. J
Hypertens. 2014; 32:881889.
69. Weber T, Ammer M, Rammer M, Adji A, ORourke MF, Wassertheurer
S, Rosenkranz S, Eber B. Noninvasive determination of carotidfemoral pulse wave velocity depends critically on assessment of travel distance: a comparison with invasive measurement. J Hypertens 2009;
70. Sugawara J, Hayashi K, Yokoi T, Cortez-Cooper MY, DeVan AE, Anton
MA, Tanaka H. Brachial-ankle pulse wave velocity: an index of central
arterial stiffness? J Hum Hypertens 2005; 19:401406.
71. Sugawara J, Tanaka H. Brachial-ankle pulse wave velocity: myths, misconceptions, and realities. Pulse 2015; 3:106113.
72. Hussain T, Yedlapati SH, Osmond PJ, Izzo JL. Relationships between
peripheral and central blood pressures and pulse wave velocities. J Am
Soc Hypertens. 2014; 8:e39e40.
73. Basta S, Hussain T, Osmond PJ, Izzo JL. Dependence of ambulatory
oscillometric brachial pulse wave velocity (Mobil-O-Graph) on systolic
blood pressure. J Am Soc Hypertens 2014; 8:e36e37.
74. Hermeling E, Reesink KD, Kornmann LM, Reneman RS, Hoeks AP.
The dicrotic notch as alternative time-reference point to measure local
pulse wave velocity in the carotid artery by means of ultrasonography. J
Hypertens 2009; 27:20282035.
75. Hisland MB, Anliker M. Influence of flow and pressure on wave propagation in the canine aorta. Circ Res 1973; 32:524529.
76. Yasmin, Brown MJ. Similarities and differences between augmentation
index and pulse wave velocity in the assessment of arterial stiffness.
QJM 1999; 92:595600.
77. ORourke MF, Pauca AL. Augmentation of the aortic and central arterial pressure waveform. Blood Press Monit 2004; 9:179185.
78. Lacy PS, OBrien DG, Stanley AG, Dewar MM, Swales PP, Williams
B. Increased pulse wave velocity is not associated with elevated

Arterial Stiffness
118. Stergiou GS, Kollias A, Rarra VC, Roussias LG. Ambulatory arterial
stiffness index: reproducibility of different definitions. Am J Hypertens
2010; 23:129134.
119. Stergiou GS, Kollias A, Rarra VC, Nasothimiou EG, Roussias LG.
Arterial stiffness index based on home (HASI) vs. ambulatory
(AASI) blood pressure measurements. Hypertens Res Clin Exp 2010;
120. Kips JG, Vermeersch SJ, Reymond P, Boutouyrie P, Stergiopulos N,
Laurent S, Van Bortel LM, Segers P. Ambulatory arterial stiffness
index does not accurately assess arterial stiffness. J Hypertens 2012;
121. Craiem D, Graf S, Salvucci F, Chironi G, Megnien J-L, Simon A,
Armentano RL. The physiological impact of the nonlinearity of arterial
elasticity in the ambulatory arterial stiffness index. Physiol Meas 2010;
122. Li Z-Y, Xu T-Y, Zhang S-L, Zhou X-M, Xu X-W, Guan Y-F, Lo M, Miao
C-Y. Telemetric ambulatory arterial stiffness index, a predictor of
cardiocerebrovascular mortality, is associated with aortic stiffnessdetermining factors. CNS Neurosci Ther 2013; 19:667674.
123. Robles NR, Mena C, Macias R, Garcia de Vinuesa E, Herrera J, Macias
JF. Symmetrical ambulatory arterial stiffness index: Relationship
with microalbuminuria and renal function. Eur J Int Med 2010;
124. Kollias A, Stergiou GS, Dolan E, OBrien E. Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis 2012;
125. Dolan E, Thijs L, Li Y, Atkins N, McCormack P, McClory S, OBrien
E, Staessen JA, Stanton AV. Ambulatory arterial stiffness index as a
predictor of cardiovascular mortality in the Dublin Outcome Study.
Hypertension 2006; 47:365370.
126. Liu Z, Peng J, Lu F, Zhao Y, Wang S, Sun S, Zhang H, Diao Y. Salt loading
and potassium supplementation: effects on ambulatory arterial stiffness
index and endothelin-1 levels in normotensive and mild hypertensive
patients. J Clin Hypertens 2013; 15:485496.
127. Matsui Y, ORourke MF, Ishikawa J, Shimada K, Kario K. Association of
changes in ambulatory arterial stiffness index and pulse wave velocity
during antihypertensive treatment: the J-CORE study. Am J Hypertens
2012; 25:862868.
128. Schillaci G, Maggi P, Madeddu G, Pucci G, Mazzotta E, Penco G,
Orofino G, Menzaghi B, Rusconi S, Carenzi L, Celesia BM, Martinelli
C, Bonfanti P, De Socio GV; Group ftCS. Symmetric ambulatory arterial stiffness index and 24-h pulse pressure in HIV infection: results of
a nationwide cross-sectional study. J Hypertens 2013; 31:560567.
129. Gavish B, Alter A, Barkai Y, Rachima-Maoz C, Peleg E; Rosenthal T.
Effect of non-drug interventions on arterial properties determined
from 24-h ambulatory blood pressure measurements. Hypertens Res
Clin Exp 2011; 34:12331238.
130. Tropeano AI, Boutouyrie P, Pannier B, Joannides R, Balkestein E,
Katsahian S, Laloux B, Thuillez C, Struijker-Boudier H, Laurent S.
Brachial pressure-independent reduction in carotid stiffness after longterm angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension 2006; 48:8086.
131. Laurent S, Boutouyrie P; Vascular Mechanism Collaboration. Dosedependent arterial destiffening and inward remodeling after olmesartan in hypertensives with metabolic syndrome. Hypertension 2014;

American Journal of Hypertension 11

Downloaded from at United Arab Emirates University on July 18, 2016

Cardio-ankle vascular index is a new noninvasive parameter of arterial

stiffness. Circ J 2007; 71:17101714.
100. Hayashi K, Yamamoto T, Takahara A, Shirai K. Clinical assessment of
arterial stiffness with cardio-ankle vascular index: theory and applications. J Hypertens 2015; 33:17421757.
101. Saji N, Kimura K, Shimizu H, Kita Y. Silent brain infarct is independently associated with arterial stiffness indicated by cardio-ankle vascular index (CAVI). Hypertens Res 2012; 35:756760.
102. Nakamura K, Tomaru T, Yamamura S, Miyashita Y, Shirai K, Noike H.
Cardio-ankle vascular index is a candidate predictor of coronary atherosclerosis. Circ J 2008;72:598604.
103. Gavish B. B012: Repeated blood pressure measurements may probe
directly an arterial property. Am J Hypertens 2000; 13:190A191A.
104. Gavish B, Ben-Dov IZ, Bursztyn M. Linear relationship between systolic and diastolic blood pressure monitored over 24 h: assessment and
correlates. J Hypertens 2008; 26:199209.
105. Ben-Dov IZ, Gavish B, Kark JD, Mekler J, Bursztyn M. A modified
ambulatory arterial stiffness index is independently associated with allcause mortality. J Hum Hypertens 2008; 22:761766.
106. Gavish B, Ben-Dov IZ, Kark JD, Mekler J, Bursztyn M. The association
of a simple blood pressure-independent parameter derived from ambulatory blood pressure variability with short-term mortality. Hypertens
Res Clin Exp 2009; 32:488495.
107. Gavish B. The relationship between systolic and diastolic pressures: a
possible link between risk-related clinical measures and arterial properties. Hypertens Res Clin Exp 2010; 33:657658.
108. Gavish B, Bursztyn M. Blood pressure and heart period variability
ratios derived from 24-h ambulatory measurements are predictors of
all-cause mortality. J Hypertens 2015; 33:491498; discussion 498.
109. Gavish B, Gavish L. Simple determination of the systolic-diastolic pressure relationship from blood pressure readings taken at different arm
heights. Blood Press Monit 2013; 18:144150.
110. Tochikubo O, Oota T, Miyazaki N, Kaneko Y. A New Portable Device
for 24-hour Recording of Ambulatory Intra-arterial Blood Pressure and
Heart Rate in Hypertensive Patients. Jap Heart J 1986; 27:661669.
111. Tochikubo O, Ochiai H, Oota T, Miyajima E, Kaneko Y. Measurements
of base blood pressure during sleep and its clinical significance in
hypertensive patients. Jap Circ J. 1987; 51:11741183.
112. Tochikubo O, Hishiki S, Miyajima E, Ishii M. Statistical base value of
24-hour blood pressure distribution in patients with essential hypertension. Hypertension 1998; 32:430436.
113. Li Y, Wang JG, Dolan E, Gao PJ, Guo HF, Nawrot T, Stanton AV, Zhu
DL, OBrien E, Staessen JA. Ambulatory arterial stiffness index derived
from 24-hour ambulatory blood pressure monitoring. Hypertension
2006; 47:359364.
114. Stergiou GS, Kollias A, Giovas PP, Papagiannis J, Roussias LG. Ambulatory
arterial stiffness index, pulse pressure and pulse wave velocity in children
and adolescents. Hypertens Res Clin Exp 2010; 33:12721277.
115. von Eye A. Symmetric regression. In: von Eye A, Schuster C (eds), Regression
Analysis for Social Sciences. Academic Press: San Diego, 1998, 209233.
116. Gavish B, Gavish L. Blood pressure variation in response to changing
arm cuff height cannot be explained solely by the hydrostatic effect. J
Hypertens 2011; 29:20992104.
117. MacWilliam JA, Melvin GS. Systolic and diastolic blood pressure measurement, with special reference to the auditory method. Br Med J 1914;