Brief Review

Interaction Between Hypertension and Arterial Stiffness

An Expert Reappraisal
Michel E. Safar, Roland Asmar, Athanase Benetos, Jacques Blacher, Pierre Boutouyrie,
Patrick Lacolley, Stéphane Laurent, Gérard London, Bruno Pannier, Athanase Protogerou,
Véronique Regnault; for the French Study Group on Arterial Stiffness

O ur current day understanding of the basic principles of

hemodynamics and arterial stiffness has largely ben-
efited from earlier seminal works of 19th-century physicists/
physiologists/physicians1 and the development of noninvasive
methodologies that provide accurate analysis of the pressure
wave in normal and pathological conditions. The mechanical
properties of large arteries are highly complex, and particu-
larly difficult to measure, from both theoretical and technical
perspectives. Arteries have marked anisotropy and nonlinear
viscoelastic properties2,3 that are specific to a single arterial
segment. Although it is difficult to extrapolate segmental arte-
rial properties to the whole arterial tree, simple parameters
derived from either the Windkessel model or that of arterial
wave propagation have been elaborated. Safar and O’Rourke2,4
have contributed extensively to the clinical applications of
these concepts, which have proven their relevance in predict-
ing outcomes and refining therapies.
The present review summarizes extensive research con-
ducted over recent decades on the relation between hyper-
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from personal clinical adaptations of the Guyton model.7 We
observed that, in the same way as hypertension and regard-
less of BP levels, arterial stiffening (demonstrated by reduced
compliance and distensibility) emerged as another distinctive
feature of cardiovascular risk, which was invariably observed
concurrently with endothelial dysfunction.8
The Windkessel model provides accurate assessment of
the extent to which large arteries instantly adjust to the volume
of blood ejected from the ventricles, store part of the stroke
volume during each systole, and drain this volume during
diastole, to maintain adequate cardiac output and continuous
perfusion of peripheral organs and tissues.6,9
Whereas the Windkessel model is a nonpropagative rep-
resentation of arterial circulation, the Moens-Korteweg equa-
tion described both propagation and velocity. Given that pulse
waves travel faster in stiffer arteries, it was suggested in 1987
that pulse wave velocity (PWV) would provide more reliable
insight into arterial stiffness than the Windkessel model.10
PWV was measured in longitudinal portions of large arter-

tension and arterial stiffness. This critical analysis of major
concepts has been developed by key French research groups
in collaboration with numerous international research centers.
Basic Concepts: Hypertension, Windkessel
Model, and Aortic Stiffness
In the 1970s, research in the field of hypertension gave par-
ticular emphasis to cardiac output and particularly the extent
to which it varied from the norm in patients with essential
hypertension. Investigations were limited to the framework of
the negative feedback loop of the Guyton model that was used
to illustrate cardiac output, fluid volumes, and potentially kid-
ney function in patients with normal or elevated blood pres-
sure (BP).5 Although cardiac output levels were shown to be
normal in the majority of hypertensive patients, it became
clear that specific mechanisms—particularly to counteract
the classically normal or low intravascular volume in this
population—were at play to maintain effective output lev-
els.6 Steady-state hemodynamic variables were thus defined
ies, typically between the carotid and femoral arteries, and
considered almost rectilinear. Elevated PWV together with
increased pulsatile diameter were identified as standard fea-
tures of hypertension.11,12 Carotid-femoral PWV (cf-PWV)
soon emerged as the gold standard for assessing aortic stiff-
ness and one of the most valuable independent predictors of
cardiovascular events.6,13,14
Arterial stiffness increases progressively from the heart to
the periphery. This, together with the tapering of the aortic
diameter (impedance mismatch), induces wave reflections.
Figure 1 describes the mechanisms through which imped-
ance mismatch generates reflection of the pressure wave
and protects small arteries from excessive pulsatility, and
how this phenomenon is lost in hypertension.15 Clinical tri-
als have demonstrated that young healthy individuals have
lower central (carotid) than peripheral (brachial) systolic
BP (SBP), whereas mean arterial pressure and diastolic BP
(DBP) are relatively constant throughout the arterial tree.16
This hemodynamic characteristic is called pulse pressure (PP)

From the Diagnosis and Therapeutics Center, Hôtel-Dieu Hospital, Paris, France (M.E.S., J.B.); Foundation-Medical Research Institutes, Geneva,
Switzerland/Beirut, Lebanon (R.A.); Department of Geriatrics, Nancy University Hospital, Université de Lorraine, Inserm U1116, DCAC, France (A.B.);
Department of Pharmacology, Assistance Publique-Hôpitaux de Paris, Georges Pompidou European Hospital; Paris-Descartes University; PARCC-Inserm
U970, Paris, France (P.B., S.L.); Université de Lorraine, Inserm U1116, DCAC, Nancy, France (P.L., V.R.); PARCC-Inserm U970, Paris, France (G.L.,
B.P.); Department of Nephrology, Manhès Hospital, Fleury-Mérogis, France (G.L., B.P.); and Cardiovascular Prevention and Research Unit, Department
of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Greece (A.P.).
Correspondence to Michel E. Safar, Paris Descartes University, APHP, Centre de Diagnostic et de Thérapeutique, Hôtel-Dieu, 1 place du Parvis Notre-
Dame, 75181 Paris Cedex 04, France. Email michel.safar@aphp.fr
(Hypertension. 2018;72:796-805. DOI: 10.1161/HYPERTENSIONAHA.118.11212.)
© 2018 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp DOI: 10.1161/HYPERTENSIONAHA.118.11212

796
 Safar et al   Hypertension and Arterial Stiffness   797

Figure 1. Impedance mismatch and wave pressure reflection. In normotension (NT), the proximal aorta is more distensible than the distal aorta, thus leading
to an arterial stiffness gradient (aortic pulse wave velocity (PWV) < distal aorta PWV). This gradient is equivalent to an impedance mismatch, generating
wave reflections. Partial reflections occur upstream, at a distance from the microcirculation, and return at low PWV to the aorta during diastole. Because the
reflected wave arrives late in systole, there is little superposition of reflected waves to incident waves, and systolic blood pressure (SBP) is not increased.
Central-to-peripheral amplification is maintained. Partial reflections limit the transmission of pulsatile pressure energy to the periphery and protect the
microcirculation. With the disappearance or inversion of the stiffness gradient (aortic PWV > peripheral PWV, less impedance mismatch), pulsatile pressure
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is insufficiently dampened and is transmitted, thus damaging the microcirculation. Less pressure waves are reflected, and although they travel backward at
high velocity because of the elevated arterial stiffness, they arrive at the central aorta in early systole and are superimposed on the incident pressure wave,
a phenomenon which increases SBP. In black, hypertension (HT); in grey, NT. Tapering of the aortic diameter is illustrated. The dotted lines schematically
separate the segments of the arterial tree into proximal elastic aorta, distal less elastic aorta, resistance arteries, and microcirculatory network.

amplification, though it actually refers to a pressure waveform
distortion rather than an amplification, the latter erroneously
implying an energy input into the system. PP amplification
rapidly became a means to evaluate the aortic stiffness gra-
dient, which, when it disappears, is an independent predic-
tor of cardiovascular events that is quite distinct from aortic
stiffening.16 These observations also confirmed the preser-
vation of the Windkessel effect (Figure 1)15 in subjects with
hypertension.
Figure 1 shows how aortic PWV is lower than peripheral
PWV; BP levels change abruptly between resistance arteries
and the microcirculatory network, thus protecting the micro-
circulation.15 A model of elevated BP (hypertensive disease)
illustrates the hypothesis whereby arteriolar modifications of
the endothelium, of vascular smooth muscle (VSM), or both,
operate as an adaptive mechanism to maintain low levels of
capillary pressure, irrespective of BP levels.15,17 Proximal aor-
tic PWV increases up to—and sometimes beyond—the level
of aortic distal PWV, reducing or reversing the physiologi-
cal stiffness gradient. This reduces proximal reflections and
consequently, pulsatile pressure is inadequately dampened as
it reaches the smaller arteries, causing hyperpulsatility and
potential damage to the microcirculation.
In elderly patients, and women in particular,18 these
changes in the mechanical properties of vessels promote
PP augmentation because of early arrival of pressure wave
reflections and excessive PP transmission to the small vascula-
ture, both triggering cardiovascular complications.2,17–20 Three
parameters are largely preserved in subjects with hyperten-
sion, irrespective of sex: cardiac output level, low capillary
pressure, and the Windkessel effect.
Hypertension, Arterial Stiffness,
and VSM Cells
The rationale for assessing aortic stiffness in clinical hyper-
tension is based on 2 primary observations.21–23 First, there is
no intrinsic stiffening of large arteries as assessed by disten-
sibility-pressure curves or elastic modulus-wall stress curves
in patients with essential hypertension.22,23 Second, for a given
level of BP or circumferential wall stress, arterial wall hyper-
trophy typically occurs in the presence of normal arterial stiff-
ness. Recent basic research has clearly established the role of
VSM cells (VSMC) in arterial stiffness.24–26
Glagov published his seminal work on the structural
changes of the aorta in response to high BP in the early 1960s,27
and by the end of the 1980s, clinical measurements of arterial
stiffness were relatively commonplace.6 Much later, abolition
of VSM tone (by potassium cyanide poisoning) was seen to
increase the elasticity of the rat carotid artery, thus highlighting
the major role of VSMC.8 Animal studies showed that loss of
vascular endothelium is correlated with increased carotid artery
diameter and distensibility, both of which are less prominent in
 798  Hypertension  October 2018

Figure 2. Vascular smooth muscle cell (VSMC) mechanotransduction in hypertension. In response to mechanical stimuli, the increase in extracellular matrix
(ECM) stiffness promotes integrin activation and recruitment of talin leading to the formation of focal adhesion (FA) complexes. The talin-to-vinculin binding
reinforces the actin-talin linkage and forms catch bonds. This process increases actin polymerization and cell migration. Activation of GPCRs (G-protein–
coupled receptors) via RhoA-ROCK (ras homolog family member A/Rho-associated protein kinase) pathways results in cell contraction. PDGF (platelet-
derived growth factor) and the SRF (serum response factor)/myocardin axis regulate specific genes encoding contractile proteins. PDGF also triggers VSMC
proliferation and autophagy. FA activation and increased dynamic actomyosin interactions regulate VSMC stiffness. Hypertension-induced changes in
these different signaling pathways (boxes) are highlighted at the level of elastic (EA) and muscular (MA) arteries. At the structural level, ECM, the number of
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musculo-elastic complexes and the elastic potential of the arterial wall are greater in EA than in MA, whereas vascular tone and density of VSMCs are greater
in MA. Ang II indicates angiotensin II; CArG, CC(A/T)6GG; Elk-1, ETS-like transcription factor-1; and KLF4, Krüppel-like factor 4.

spontaneously hypertensive than in normotensive rats. Thus,
in the presence of endothelial cells, powerful constrictive
mechanisms were likely at play to maintain arterial properties
through their equilibrium with nitric oxide bioactivity.8
Research into cellular and molecular determinants of arte-
rial stiffness has recently expanded the classical view attribut-
ing arterial stiffening to components of extracellular matrix
(ECM; mainly elastin and collagen) to proteins regulating
VSMC contractility and cell-ECM interactions, all now linked
at focal adhesions (FA; Figure 2).25 The emerging concept of
VSMC stiffness established their role in controlling arterial stiff-
ness, which involves dynamic actin/myosin interactions with
G-protein and the subsequent signaling pathways.28 VSMC plas-
ticity is controlled by numerous growth factors and transcrip-
tional pathways. Dedifferentiation to synthetic and proliferative
states leads to ECM accumulation or hypertrophy of the vascular
wall, which may directly affect arterial stiffness. The pivotal role
of VSMC plasticity is exemplified in arterial calcification where
a shift from a contractile to a secretory phenotype mediates a
process similar to that of bone formation (see below).
FA are a dynamic process involving adhesion proteins, fibro-
nectin, integrins, and the intracellular talin and vinculin linked to
F-actin filaments (Figure 2).26 Proteins within FA undergo con-
formational changes that mediate cellular mechanotransduction.
On a rigid ECM, the reinforcement of FA because of vinculin
binding to talin constitutes a catch bond leading to a long FA
lifetime. The current hypothesis is that catch bond formation
plays a major role in arterial stiffening. To further investigate
the relation between FA-size and the arterial stiffness gradi-
ent, Dinardo et al29 showed that VSMC from the thoracic aorta
exhibit smaller FA than cells from the femoral artery.
FA are linked to G-protein–related VSMC contractility.25
FA complexes are physically linked to the nucleus via inter-
actions of the cytoskeleton with the nuclear matrix, in a pro-
cess called nuclear mechanotransduction. Tension forces from
ECM are transmitted to the nucleus via the link complex and
the lamina scaffold and affect gene expression. This balances
both extracellular and intracellular forces.30
The assumption that FA site numbers increase the stiff-
ness of wall components is substantiated by the spontaneously
hypertensive rat model in which fibronectin- and α5β1 integ-
rin-expression is greater in the media.31
At the cellular level in spontaneously hypertensive rat,
increased stiffness is only observed in elastic arteries and not in
muscular arteries.32 The specific contribution of VSMC to arte-
rial stiffening and modulation has yet to be elucidated in light of
FA activation coupled with G-protein–regulated contractility.33
End-Stage Renal Disease, Premature Aging,
and Arterial Calcifications
Young patients with end-stage renal disease (ESRD)—who
rapidly develop significant arterial calcifications—were among
the first hypertensive individuals to undergo extensive clinical
investigations.
 Safar et al   Hypertension and Arterial Stiffness   799
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Characteristic Features of ESRD Patients
Premature arterial aging is a characteristic feature of
patients with ESRD and is typically associated with marked
arterial stiffening (Figure 3) and a notable increase in the
diameter of the terminal abdominal aorta. Variations in
Figure 3. Age-associated arterial stiffness in
end-stage renal disease (ESRD). Correlations
between age and (A) aortic PWV, (B) brachial
PWV, and (C) brachial/aortic stiffness gradient
in controls (red) and patients with ESRD (blue).
Adapted from London et al35 with permission.
Copyright © 2016, the American Society of
Nephrology.
cf-PWV can be detected before the onset of overt cardio-
vascular disease. Aortic PWV is an independent predictor
of all-cause and cardiovascular mortality in patients with
ESRD, as well as in those with chronic kidney disease and
hypertension, and as such, differs markedly from the minor
 800  Hypertension  October 2018
changes in PWV that are observed in patients with mild-
to-moderate hypertension (see above). Extreme increases
in aortic stiffness lead to notable reductions in the stiff-
ness gradient and aortic taper.34,35 Aortic stiffening causes
early return of reflected waves, elevates aortic SBP and
PP, reduces coronary perfusion pressure, the arterial stiff-
ness gradient and the reflective properties of the arterial
tree, and exposes small arteries to greater wave transmis-
sion toward the periphery, with subsequent damage to these
vessels (Figure 1).35 Certain BP-lowering drugs, such as
angiotensin-converting enzyme inhibitors that attenuate
aortic stiffness, exert favorable effects and improve survival
in ESRD.35 Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers also slow the progression of
aortic stiffening in hypertensive patients with chronic kid-
ney disease stages 2 to 5. However, neither of these drugs
prevents the carotid artery remodeling and dilation that are
associated with cardiovascular events.35 Variations in aortic
geometry can reveal microvascular dysfunction and are reli-
able predictors of all-cause and cardiovascular mortality.13
Future investigations should provide clearer insight into
the effects of different pharmacological agents in patients
on hemodialysis and after renal transplantation.36 Indeed,
Karras et al37 demonstrated that kidney transplantation was
associated with reversal of aortic stiffening and normaliza-
tion of carotid remodeling.
Arterial Calcifications in ESRD
One distinctive feature of vascular damage in ESRD is the
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presence of arterial calcification—representing the process
of repair and the formation of scar tissue—that is correlated
with cardiovascular morbidity and mortality.38 Numerous
experimental studies have highlighted similarities between
bone development and the process of arterial calcifica-
tion,39–41 which involves VSMC phenotype differentiation
into osteoblast-like cells (with subsequent mineralization),
and is induced and regulated by the equilibrium between
factors that promote and factors such as fetuin-A, matrix
Gla protein, and osteoprotegerin that inhibit calcification.
Clinical data indicate that VSMC phenotype differentia-
tion is influenced by several factors, such as inflammation,
dyslipidemia, oxidative stress, estrogen deficiency, vitamin
D and K deficiencies, hypercalcemia and hyperphosphate-
mia, characterized by the activation of Cbfa1/Runx2-factors
that are essential for osteoblastogenesis of mesenchymal
cells. Calcification develops in 2 stages: first, activation of
macrophages, and second, inflammation and calcification.39
Arterial calcification develops in the intima and medial lay-
ers of large and medium-sized vessel walls, often concur-
rently at both sites. Calcification of the intima progresses
with the evolution of atherosclerotic plaque. The diffuse
mineral deposits in the arterial tunica media that charac-
terize media calcification (Mönckeberg’s sclerosis) are
frequently observed in the elderly but are more distinct in
patients with metabolic disorders, such as metabolic syn-
drome, diabetes mellitus, or ESRD. Management of patients
with evidence of arterial calcifications focuses mainly on
prevention, or stabilization of existing calcifications,
because regression is unlikely. Because intimal calcification
is related to atherosclerosis, the usual treatment approach is
nonspecific as in patients with atherosclerosis. Management
of ESRD patients includes controlling serum calcium and
phosphate levels, thereby avoiding oversuppression of para-
thyroid activity.
Age-Related Changes in Arterial Stiffness and
the BP Curve
Age-Related Changes in Arterial Stiffness and the
BP Curve
The prevailing characteristic of hypertension in elderly indi-
viduals is the progressive change in the BP curve, with both
a higher SBP and a lower DBP.42 This is clearly shown in the
DESIR (Data from an Epidemiologic Study on the Insulin
Resistance Syndrome) study of 4293 nondiabetic and type 2
diabetic volunteers (age, 30–65 years).42 Mean annual SBP
levels increased significantly with age and were higher in men
than in women. Initially, changes in both DBP and SBP were
the same, irrespective of sex, and reaching peak levels around
the age of 45. Subsequently though, annual changes in DBP
were less notable and were even significantly negative in indi-
viduals >60 years. Mean PP level increased markedly with age
and was a significant predictor of cardiovascular risk,42 as was
further PP amplification.43
Because increased PP per se can be influenced by the
extent of heart failure, aortic stiffening was recognized as
a more appropriate marker of vascular damage than PP
measurements.44 Increased aortic stiffness can be associ-
ated with decreased DBP; coronary ischemia and excessive
DBP-lowering are therefore likely consequences, with car-
diovascular accidents as a potential outcome.45 Furthermore,
noninvasive assessment of cf-PWV has shown aortic stiff-
ening to be consistently higher in patients with both hyper-
tension and type 2 diabetes mellitus than in nondiabetic
hypertensive subjects, for the same BP level (Figure 4).46,47
Arterial stiffening can therefore be positively correlated to
overall and long-term cardiovascular risk, but also to the
duration of diabetes mellitus in patients with concomitant
hypertension and type 2 diabetes mellitus. In addition, age-
induced increases in PWV favor the development of arterial
calcifications and adhesive molecules in these patients.9,48,49
Arterial stiffness is related to age, heart rate, and mean arte-
rial pressure, and in hypertensive diabetic subjects, to diabe-
tes mellitus duration and insulin treatment, a finding that is
of major importance.46,49
Although the impact of metabolic disorders on arterial
stiffness is widely acknowledged, the role of high waist cir-
cumference remains questionable, particularly when arterial
stiffness is assessed using the cardio-ankle vascular index.50,51
Recent studies have shown lower arterial stiffness values in
subjects with increased waist circumference.
BP and Arterial Stiffness in Elderly Subjects
The majority of evidence relating to the risks of high BP and
the benefits of BP-lowering is derived by extrapolating data
from younger populations and more recent studies such as
HYVET (Hypertension in the Very Elderly)52 and SPRINT
(Systolic Blood Pressure Intervention Trial).53
 Safar et al   Hypertension and Arterial Stiffness   801

Figure 4. Reference values for pulse wave velocity according to age and cardiovascular risk factors. Mean values are presented for each age decade
according to the presence of diabetes mellitus (1032 subjects) or the number of cardiovascular risk factors (sex, dyslipidemia, and current smoking): no
risk factors (2207 subjects), males (1080 subjects), dyslipidemia (6251 subjects), and current smokers (444 subjects). Threshold values for dyslipidemia
were defined in the 2007 European Society of Cardiology/European Society of Hypertension guidelines (total cholesterol >5.0 mmol/L, HDL [high-
density lipoprotein]-cholesterol <1.0 mmol/L for men and <1.2 mmol/L for women, LDL [low-density lipoprotein]-cholesterol >3.0 mmol/L or triglycerides
>1.7 mmol/L). Adapted from the Reference Values for Arterial Stiffness’ Collaboration47 with permission. Copyright © 2010, the European Society of
Cardiology.

Interestingly, post hoc analysis of the HYVET trial benefits of BP-lowering treatment in frail, polymedicated
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found no relationships between the benefits of antihyperten- octogenarians.61,62

sive treatment and patient frailty.54 More recently, SPRINT53
showed that even in subjects ≥75 years, cardiovascular dis-
ease outcomes and total mortality were reduced with intensive
treatment as compared with standard therapeutic strategies.
However, both HYVET and SPRINT excluded the frailest
subjects such as those with clinically significant cognitive
decline, dementia, and other comorbidities.55 Nevertheless,
in people with major frailty and loss of autonomy, the rela-
tionship between BP (both SBP and DBP) and cardiovascu-
lar events was absent or even negative.56 More recent studies
showed that this negative relationship was mainly observed in
individuals receiving BP-lowering drugs and was highly sug-
gestive of reversed causality.57–59
Interestingly, in these very old, frail individuals, arterial
stiffness remains a determinant of cognitive decline, morbid-
ity, and mortality.43,60 The impact of SBP levels and arterial
stiffness can be very different, possibly because low SBP
levels mainly reflect age-related comorbidities and condi-
tions such as malnutrition, dehydration or frailty, whereas
in relatively younger and more robust individuals, low SBP
levels mainly reflect lower arterial stiffness and better arte-
rial health.
We can also hypothesize that people with marked frailty
and polymorbidity may have impaired circulatory autoregula-
tion, causing tissue hypoperfusion in the presence of low BP,
especially when this low BP is the result of treatment with
multiple antihypertensive drugs.
These considerations may also at least partly explain
why there is currently insufficient evidence about the
Interactions Between Hypertension
and Arterial Stiffness
Arterial Stiffness as a Cause or a Consequence of
Hypertension
Speculation continues as to whether arterial stiffness is a cause
or a consequence of hypertension, and whether large or small
arteries are damaged first (Figures 1 and 5).
An insidious positive feedback loop between local
mechanical and biological responses on one hand and global
hemodynamic results on the other, may explain why central
artery stiffening is both a cause of hypertension and one of
its consequences.63 Intrinsic stiffness of the carotid artery
was only seen to be elevated independently of BP in young
hypertensives, and not in older patients.23 Longitudinal assess-
ment of the temporal relationship between carotid and aortic
stiffness,64 and incident hypertension, suggests that arterial
stiffening is a precursor for future changes to the systolic
hemodynamic load. However, in hypertension, arterial stiff-
ness increases because of increases in distension pressure.
Moreover, sustained increases in BP promote matrix synthesis
causing subsequent increases in vascular thickness and struc-
tural stiffening. In addition, elevated BP increases the load of
stiff components within the arterial wall, reorganizes the spa-
tial distribution of VSMC and ECM,25 and increases arterial
stiffness.
Aortic stiffening may also be paralleled and possibly
influenced by remodeling of small resistance arteries that are
 802  Hypertension  October 2018

Table. Reference Values for PWV According to Age and Blood Pressure Level

Blood Pressure Level, mm Hg

Normal ≥120/80 and High Normal ≥130/85 and Grade I HT ≥140/90 and
Optimal <120/80 <130/85 <140/90 <160/100 Grade II/III HT >160/100
Age, y N PWV, m/s N PWV, m/s N PWV, m/s N PWV, m/s N PWV, m/s
<30 896 6.1 (4.6–7.5) 417 6.6 (4.9–8.2) 220 6.8 (5.1–8.5) 96 7.4 (4.6–10.1) 40 7.7 (4.4–11.0)
30–39 315 6.6 (4.4–8.9) 245 6.8 (4.2–9.4) 184 7.1 (4.5–9.7) 189 7.3 (4.0–10.7) 109 8.2 (3.3–13.0)
40–49 822 7.0 (4.5–9.6) 562 7.5 (5.1–10.0) 385 7.9 (5.2–10.7) 325 8.6 (5.1–12.0) 167 9.8 (3.8–15.7)
50–59 514 7.6 (4.8–10.5) 519 8.4 (5.1–11.7) 434 8.8 (4.8–12.8) 490 9.6 (4.9–14.3) 238 10.5 (4.1–16.8)
60–69 414 9.1 (5.2–12.9) 509 9.7 (5.7–13.6) 485 10.3 (5.5–15.1) 648 11.1 (6.1–16.2) 289 12.2 (5.7–18.6)
≥70 163 10.4 (5.2–15.6) 244 11.7 (6.0–17.5) 333 11.8 (5.7–17.9) 535 12.9 (6.9–18.9) 305 14.0 (7.4–20.6)
Results are means (± 2 SDs). HT indicates hypertension; N, number of individuals; and PWV, pulse wave velocity.
Adapted from the Reference Values for Arterial Stiffness’ Collaboration47 with permission. Copyright © 2010, the European Society of Cardiology.

closely interdependent in sustained grade I hypertension, and
likely during the early phases of prehypertension. Although
it is difficult to establish a temporal relationship, the likely
existence of a cross-talk (as opposed to a linear sequence) was
previously suggested, whereby changes in small arteries affect
the phenotype of larger arteries, and vice versa in a vicious
circle.65 Damage to both small and large arteries contributes
to the rise in central BP by favoring the generation of wave
reflections and their propagation, respectively, as seen in
hypertensive patients where both the media-to-lumen ratio of
subcutaneous small resistance arteries and cf-PWV are inde-
pendent determinants of central SBP. Increased resistance in
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and retinal microcirculation changes are already detectable in
prehypertensive subjects.66
Thus, whether hypertension causes or is caused by cen-
tral arterial stiffening and whether large or small arteries are
damaged first can be considered irrelevant. The main issue is
that progressive aggravation is likely in both cases. The clini-
cal combination of hypertension and arterial stiffness marks a
major step toward the development of cardiovascular disease
and therefore highlights the need for thorough assessment of
cardiovascular risk.
Reference Values for Arterial Stiffness

small arteries elevates mean BP, and then increases arterial
stiffness in the large elastic arteries which, concomitantly with
more pressure wave reflections, increases central SBP and
24-hour ambulatory brachial BP variability, ultimately lead-
ing to target organ damage.65,66 The increased central BP pul-
satility is, in turn, a factor of small resistance artery damage.
This was initially reported in hypertensive animal models and
later in hypertensive patients in whom brachial PP and more
recently central SBP and PP were measured with applanation
tonometry. Interestingly, the wall-to-lumen ratio of retinal
arteries is significantly correlated with 24-hour SBP levels,
In clinical practice, arterial stiffness measured from cf-
PWV is now recommended in the 2013 Guidelines for the
Management of Hypertension, developed by the European
Society of Hypertension and the European Society of
Cardiology.67 Beyond the recommended threshold of 10 m/s
PWV, the risk is considered to be markedly greater. However,
given that both age and BP are major determinants of aor-
tic stiffness, the 10 m/s threshold may not apply to the same
extent in a 30-year-old or a 70-year-old patient, or in grade I
and grade II hypertension. Therefore, reference values have
been established according to age and BP, both in subjects

Figure 5. Interaction of hypertension with large

and small arterial damage. In a vicious circle,
alterations of small arteries, that is, reduced
lumen diameter, impaired vasodilation, and
vessel rarefaction trigger an increase in mean
blood pressure (BP) which in turn contributes
to the stiffening of large arteries leading to an
increase in central systolic and pulse pressure.
The increased central BP aggravates small
artery damage.
 Safar et al   Hypertension and Arterial Stiffness   803
with no cardiovascular risk factors and in patients with car-
diovascular risk factors but no diabetes mellitus, providing a
standardized comparison between observed values and refer-
ence values in age- and sex-matched individuals (Table).
The Reference Values for Arterial Measurements
Collaboration established reference values for cf-PWV in
16 867 individuals from 13 centers across 8 European coun-
tries47: for common carotid stiffness and common femoral
stiffness, obtained by echo tracking in 22 708 and 5069 indi-
viduals, respectively, from 24 and 6 research centers, respec-
tively68,69; and for central BP in 91 588 individuals from 54
research centers worldwide.70
Conclusions
This review summarizes the foremost clinical features of
patients with sustained hypertension, chronic kidney disease,
and elevated arterial stiffness. First, in hypertension, cardiac
output remains within the normal range, and capillary pressure
is as low as in individuals with normal BP. Hypertensive sub-
jects, however, are prone to increased risk of cardiovascular and
renal complications. Second, in the early phases of sustained
hypertension, the resistive components of the vasculature may
exert both a protective and a negative influence by establishing
a balance between vasoconstrictive and vasodilating agents at
the endothelial level and increasing VSMC stiffness.21 Third,
antihypertensive drug treatment significantly increases survival,
particularly in patients with ESRD71 and older individuals.43
Fourth, whether hypertension is a cause or a consequence of
increased arterial stiffness, and whether larger or smaller arter-
Downloaded from http://ahajournals.org by on October 27, 2018
ies are damaged first is an academic discussion.63,66 Any onset
of large artery stiffening or small artery remodeling warrants
specific attention and prompt therapeutic intervention.
Future Perspectives
Future studies should address these more fundamental aspects
of the hypertensive disease and how best to convert them into
effective preventive measures:
1. The primary target is to reduce SBP and DBP to estab-
lished threshold levels, or even lower as is currently rec-
ommended.72 Large observational and interventional
studies are therefore needed to demonstrate that targeting
treatment to reduce arterial stiffness and wave reflections
can reduce cardiovascular complications over and beyond
BP reduction alone.73 Whether earlier assessment of arte-
rial stiffness and wave reflections, leading to earlier initia-
tion of antihypertensive treatment, results in more effec-
tive prevention of cardiovascular complications has yet to
be established.
2. Therapeutic measures of cardiovascular prevention are
recommended in children and adolescents with empha-
sis on the importance of a healthy lifestyle including high
levels of physical activity, and when necessary, calorie re-
striction. In hypertension, they focus on overweight and
diabetes mellitus.74 Clinical evaluations of arterial stiffness
and wave reflections are needed in response to healthy life-
style measures, physical exercise, and body weight reduc-
tion.75 Genetic analyses can provide important insight into
potential underlying mechanisms.76
3. Controlled clinical trials are also needed in older hy-
pertensives, including geriatric patients with cognitive
impairment, functional decline, Alzheimer disease, and
loss of autonomy. This will improve our understanding
of the potential benefits of downtitrating antihyperten-
sive treatment in patients with excessively low BP lev-
els, for example, SBP<130 mm Hg, according to the
level of arterial stiffness and wave reflections.
Acknowledgments
We thank Moyra Barbier for editorial assistance.
Disclosures
None.
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