Large-artery stiffness, hypertension and cardiovascular risk in older patients Jacques Blacher and Michel E Safar* INTRODUCTION
High blood pressure is a powerful cardiovascular
Research studies on hypertension have, so far, generally focused on vascular
risk factor because of its actions on the arterial
resistance and small arteries. The high prevalence of systolic hypertension
wall, and its role in events that affect the heart
in patients older than 50 years and the development of noninvasive Doppler
and the brain. Drug treatment of hypertension
and echotracking techniques have made it possible to determine large-artery
can prevent such complications. Two specific
stiffness with a high degree of reproducibility. Increased arterial stiffness
points of the blood-pressure curve, the peak
and disturbed wave reflections are the basis for understanding reduced
systolic blood pressure and the end-diastolic
aortic elasticity and systolic hypertension, particularly in older people. This
blood pressure, are used to clinically define high
hemodynamic pattern results from mechanical factors and other pressure-
blood pressure (Figure 1). Hemodynamically,
independent risk factors, such as diabetes mellitus, renal failure, obesity and
however, the overall shape of the blood-pressure
severe atherosclerosis. Distinct phenotypes of arterial stiffness and pulse
curve and the cross-sectional area under the curve,
pressure result from specific gene polymorphisms, such as those related
rather than merely its maximum and minimum
to the renin–angiotensin system. The roles of arterial stiffness and wave
values, should be taken into account to describe
reflections in hypertension have been elucidated by modern interpretations
the mechanical effects on the arterial wall and to
of the blood-pressure curve in relation to its propagation, mechanisms of
give an adequate description of hypertension. systolic-blood-pressure amplification, and the pulse-pressure amplitude.
The blood-pressure curve might be consid-
New predictors of cardiovascular risk have been identified, such as increased
ered as the superposition of a steady compo-
pulse pressure and pulse-wave velocity, and disturbed wave reflections, all
nent—mean arterial pressure—and a pulsatile
of which are independent predictors of cardiovascular risk that are more
component—pulse pressure (Figure 1).1 Mean
powerful than either systolic or diastolic blood pressure alone. Therapeutic
arterial pressure is the steady pressure resulting
trials are investigating ways to reduce stiffness, and thereby allow the selective reduction of systolic and pulse pressure in hypertensive patients with or
reach the peripheral tissues and organs. Pulse
without advanced renal failure. Modern pharmacologic agents need to be
pressure is a consequence of the intermittent
identified, which could reduce systolic hypertension in patients older than
ventricular ejection from the heart. The role of
50 years. Here we discuss the structural and functional factors that influence arterial stiffness, wave reflections and pulse pressure in hypertension, as well
large conduit arteries, particularly the thoracic
as their related roles in cardiovascular risk.
aorta, is to dampen the pressure oscillations that result from intermittent ventricular ejection.
KEYWORDS arterial stiffness, cardiovascular risk, hypertension, wave reflections
In addition to cardiac factors, therefore, the main determinants of pulse pressure and peak
REVIEW CRITERIA
systolic blood pressure are the cushioning
We carried out a search for original articles that were focused on “arterial
capacity of arteries, and the timing and inten-
stiffness” and “pulse pressure”, and were published between 1966 and 2005,
sity of WAVE REFLECTIONS.1 The cushioning
in MEDLINE and PubMed. All the papers that were identified were English-language, full-text articles. We also searched the reference lists of identified
capacity of arteries is influenced by the visco-
elastic properties of the arterial wall and, thus, by arterial stiffness, which is usually expressed
J Blacher and ME Safar are physicians and research workers in the Diagnosis
in the quantitative terms of compliance and
Center, Hôpital Hôtel-Dieu, Paris, France.
distensibility. Wave reflections result from the cumulative action of a forward wave coming
Correspondence
from the heart—which propagates at a given
*Diagnosis Center, Hôpital Hôtel-Dieu, 1 Place du Parvis Notre-Dame, 75181 Paris, Cedex 04, France
speed, the pulse-wave velocity (PWV)—and
a backward wave returning towards the heart from particular reflection sites.1
Received 11 March 2005 Accepted 13 June 2005
During the past few years, arterial stiffness and
www.nature.com/clinicalpracticedoi:10.1038/ncpcardio0307
wave reflections have been widely investigated in
450 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE
2005 Nature Publishing Group GLOSSARY WAVE REFLECTION Reflections of the pressure wave generated by the heart, which originate from each discontinuity of the Figure 1 Typical features of a blood-pressure curve. This curve is usually defined by the upper and lower extremities, which show peak systolic blood pressure and end-diastolic blood pressure, respectively. A better way to define blood pressure as shown by the curve is to describe the totality of the curve, which is composed of a steady component (i.e. mean arterial pressure) and a pulsatile component (i.e. pulse pressure); these features represent hemodynamic fluctuations of the curve around the mean arterial pressure and describe the mechanical effects on the arterial wall, thereby giving an adequate definition of hypertension.
elderly patients both with and without hyper-
in the arterial tree. From these sites of discon-
tension. Whereas end-diastolic blood pressure
tinuity, which are mainly located at the origins
was previously considered to be the better guide
of arteriole branches, reflected waves are
for determining disease severity, epidemiologic
generated that travel backwards towards the
studies have shown that peak systolic blood
ascending aorta (Figure 2). Therefore, incident
pressure is a more informative cardio vascular
and reflected waves are in constant interaction
risk factor, particularly in patients older than
along the arterial circuit and are superimposed
50 years.2 Furthermore, it has been shown
so that each becomes a part of the actual blood-
that pulse pressure—calculated as the differ-
pressure wave. The final amplitude and shape
ence between the peak systolic blood pressure
of the measured aortic blood pressure wave are
and the end-diastolic blood pressure—is an
determined by the timing, or phase relationship,
independent predictor of cardiovascular risk,
between the two component waves. This, in turn,
particularly for myocardial infarction.3 Finally,
depends on the PWV, the traveling distance of
although drug control of end-diastolic blood
the pressure waves and the duration of ventric-
pressure to achieve values lower than 90 mmHg
ular ejection. In young people, under physio-
can be consistently obtained in treated hyper-
logic conditions, the backward pressure wave
tensive patients, it remains difficult to control
returns from the distal arterial vessels during
peak systolic blood pressure, and values lower
diastole, which makes the pulse pressure higher
than 140 mmHg are more difficult to achieve.4
in the peripheral arteries than in the central
The purpose of this review, therefore, is to
arteries. This physiologic phenomenon, which is
describe the structural and functional factors
called pulse-pressure amplification (Figure 2),1
that influence arterial stiffness, wave reflections
is highly influenced by the PWV. With an
and pulse pressure in people with hyper tension
increased PWV, the reflecting sites of the distal
and to determine the role of these variables
arterial tree seem to be closer to the ascending
in cardiovascular risk. On the basis of these
aorta, and the reflected waves occur earlier and
considerations, new approaches are proposed
are more closely in phase with incident waves
to further reduce cardiovascular risk in elderly
in this region. The earlier return of wave reflec-
tions means that the reflected wave impacts on the central arteries during systole and not
BASIC CONCEPTS
during diastole. This disturbed signal results in
The ejection of blood into the aorta generates
an augmentation of aortic and ventricular pres-
a pressure wave that is propagated at a given
sures during systole, and reduces aortic pressure
velocity to other arteries throughout the body
during diastole. Hence, the altered mechanical
(Figure 2). Under physiologic conditions, the
properties of the aortic wall influence the levels
aortic PWV is approximately 5–7 m/s. This
of aortic peak systolic blood pressure and end-
forward wave is reflected at all points of structural
diastolic blood pressure, which are increased
discontinuity, functional discontinuity or both
and decreased, respectively, as a consequence of
SEPTEMBER 2005 VOL 2 NO 9 BLACHER AND SAFAR
NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 451
2005 Nature Publishing Group CARDIOVASCULAR RISK FACTORS
Physiologically, mean arterial pressure remains similar throughout the arterial tree, whereas
vessel stiffness increases progressively from the
proximal to the distal part of the vascular trajec-
tion. These changes in elasticity result from a
combination of factors: the continuous decrease
of vessel cross-sectional area along the arterial
tree, the progressive increased rigidity of the
vascular wall material and the physiologic rise
in pulse pressure from the central arteries to
Propagation of the blood-pressure wave. After ventricular ejection, a
forward wave propagates at a given pulse-wave velocity along the arterial
the peripheral arteries. An increase in the stiff-
tree (1). The wave is reflected at any discontinuity of the arterial wall (reflection
ness gradient of the wall material is observed
sites; 2), and superposition of the forward and reflected waves can be
when the proximal arteries are compared with
observed at any point of the arterial tree, but is particularly evident at the site of
the distal arteries because vascular elasticity is
the thoracic aorta (3). The effect of superposition is to make the peak systolic
higher in the proximal arteries. In humans, the
blood pressure and the pulse pressure significantly higher in the peripheral
increase in stiffness between the carotid artery
arteries than in the central arteries.
and the radial artery is approximately 25% in healthy people.1,5 With increasing age, the gradient decreases significantly, because the age-
GLOSSARY
early wave reflections. Finally, a disturbed pres-
mediated increase in arterial stiffness progresses
YOUNG’S MODULUS (E)
sure signal arising from the distal arteries might
more rapidly in the central arteries than in the
alter the heart–vessel coupling through early
peripheral arteries.1,5 This faster increase of
represented by the slope of the stress–strain relationship
wave reflections and lead to increased cardio-
stiffness in the central arteries is independent
vascular risk. This signal, through an increase
of the mean arterial pressure and involves
FOOT-TO-FOOT METHOD
of peak systolic blood pressure, favors cardiac
several changes: enlargement of the mean
hypertrophy and congestive heart failure, and,
diameter, reduction of the pulsatile diameter, an
between successive arrivals of the foot of a pressure
through the decrease of end-diastolic blood
age-mediated reduction in endothelial function,
pressure, reduces coronary perfusion and causes
huge development of the connective tissue; and
the reduction of pulse-pressure amplification
APPLANATION TONOMETRY
Aortic PWV is influenced by many con founding
resulting from the increased stiffness and altered
factors, including age, mean arterial pressure and
reflectance properties of the arterial wall.1
sex, which need to be taken into account during
Aging is the dominant process that alters
of a superficial (radial or carotid) artery, to record the
statistical evaluations. PWV is related to YOUNG’S
vascular stiffness, wave reflections and pulse
MODULUS (E) by the Moens–Korteweg equation,
pressure. There is, however, extreme variability
in these age-mediated changes.5 This variation is influenced by the histopathologic muscular
or musculoelastic peculiarities of arterial tissue,
along with the presence of other cardiovascular
where ρ is the blood density, E is Young’s
risk factors. In middle-aged individuals with
modulus, r is the internal radius of the vessel,
hypertension, the dominant contribution to
and h is the arterial thickness.
changes in arterial stiffness is made by high
mean arterial pressure, whereas in older people
changes in the vascular wall that are independent
to measure aortic PWV by calculating the
of the mean arterial pressure are more impor-
ratio of distance to time.1 In addition, local
tant.1,5 This factor is of particular importance in
arterial stiffness might be determined from
hypertensive patients with endothelial dysfunc-
pulsatile changes in the diameter and blood
tion, including those with diabetes mellitus, end-
pressure of superficial large arteries, such as the
stage renal disease or numerous atherosclerotic
carotid artery. The measurement of changes in
lesions.1,5 Under such conditions, the increases
arterial dia meter requires the use of high-
in stiffness involve not only endothelial dysfunc-
resolution ultrasound techniques, whereas
tion but also increased binding and cross-linking
changes in pulsatile pressure are measured
of molecules within the connective tissue, such
as collagen, proteoglycans and fibronectin.
452 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE
BLACHER AND SAFAR SEPTEMBER 2005 VOL 2 NO 9
2005 Nature Publishing Group
Environmental (sodium) and genetic factors
was 5.4 (95% CI 2.4–11.9) for all-cause mortality
are now considered to have a large influence
and 5.9 (95% CI 2.3–15.5) for cardiovascular
on arterial mechanics. Gene polymorphisms
mortality. For each increase in PWV of 1 m/s
might be related either to the pathophysiology
the all-cause mortality-adjusted OR was 1.39
of hypertension, through effects on the renin–
(95% CI 1.19–1.62). Therefore, aortic PWV was
angiotensin–aldosterone system, or to cardio-
shown to be a strong independent predictor of
vascular aging.1 Combinations of two or three
specific polymorphisms can affect the proper-
Brachial and upper-limb or lower-limb PWVs
ties of the vessel wall more consistently than
do not predict this risk.10 Arterial calcifications,
one polymorphism alone. In elderly individuals
which are simple markers of cardiovascular
with systolic hypertension, the DD genotype
risk,11 do not contribute directly to mortality.
(homozygous deletion) of the angiotensin-
Another index of arterial stiffness, the carotid
converting-enzyme gene (ACE) insertion/
artery incremental elastic modulus, is a strong
deletion (I/D) polymorphism, in association
and independent predictor of cardiovascular
with specific genotypes of the aldosynthase
mortality.12 Finally, the principal predictor of
and α-adducin 1 gene (ADD1) polymorphisms,
cardiovascular risk independent of aortic PWV
involves a consistent increase of arterial stiffness
is the presence of early carotid wave reflections.13
together with an increase of peak systolic blood
Similar predictive results have been reported in
diabetic patients with end-stage renal disease, renal transplant recipients and individuals with
Arterial stiffness and cardiovascular risk
ischemic heart disease,14–16 but such studies are
In people older than 60 years, pulse pressure
is the most powerful mechanical factor that
In a cross-sectional study, 710 patients with
predicts myocardial infarction.3 The predictive
essential hypertension were investigated,17 and
value of this factor applies even in individuals
the presence or absence of atherosclerotic alter-
with hypertension that is successfully main-
ations was detected on the basis of the presence
tained at close to normal values by drug therapy.8
of clinical cardiovascular events. The calculation
Because pulse pressure is influenced by both
of cardiovascular risk using the Framingham
cardiac and arterial factors, increased pulse pres-
data18 was first done for those patients without
sure means greater arterial stiffness only in older
atherosclerotic alterations: in this population,
populations with preserved ejection fractions.
all the calculated cardiovascular risks increased
In young subjects, increased systolic blood pres-
progressively with PWV. In patients of any age
sure and pulse pressure are mainly due to cardiac
with atherosclerotic alterations, aortic PWV was
factors (i.e. increased ventricular ejection).1,2
the best predictor of cardiovascular mortality.
Therefore, aortic PWV should be used as a main
Meaume and colleagues19 reported similar
predictor of cardiovascular risk only in individ-
findings in the elderly after long-term follow-
uals who are older than 50 years of age.1–3 The
up. In middle-aged hypertensive patients and
three populations that have predominantly been
in the elderly, another longitudinal study gave
studied are those with end-stage renal disease,
essential hypertension and diabetes mellitus.
Cardiovascular risk is easy to assess in
stiffness or both, several groups have shown that
patients with end-stage renal disease because
arterial stiffness is significantly elevated in indi-
of the related severe complications, high cardio-
viduals with type 1 or type 2 diabetes, compared
vascular mortality and access to operational
with nondiabetic individuals matched for age
facilities in relation to their regular dialysis. In
and mean arterial pressure. A similar finding
a cohort of 241 patients studied between 1987
has been reported in patients with metabolic
and 1998, 73 deaths occurred, including 48 due
syndrome.21–23 Of the usual functional and
to cardio vascular causes.9 From Cox regression
structural changes of the media and the endo-
analyses, two factors emerged as predictors of
thelium, the most important was the formation
all-cause and cardiovascular mortality—age
of advanced glycation end-products, which are
and aortic PWV. After adjustment for all
responsible for the increased collagen cross-
potentially confounding variables, for values
linkage that results in increased stiffness.22 Data
of PWV higher than 12.0 m/s compared with
from studies in hypertensive patients have shown
PWV lower than 9.4 m/s the odds ratio (OR)
that an advanced glycation end-product breaker,
SEPTEMBER 2005 VOL 2 NO 9 BLACHER AND SAFAR
NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 453
2005 Nature Publishing Group
ALT-711 (alagebrium chloride, Alteon Inc.,
changes, which were observed in patients who
Parsippany, NJ) is able to decrease the amount
were treated with perindopril and indapamide
of collagen cross links,21 thereby improving
but not with atenolol, point to parallel features in
carotid distensibility and reducing pulse pressure
the reduction of peak systolic blood pressure and
without changing the mean arterial pressure. In
pulse pressure, and in the regression of structural
patients with diabetes, both pulse pressure and
arteriolar changes.28 This finding is consistent
aortic PWV have been shown to be markers of
with previous results reported with ACE inhibi-
tion, including changes in reflection coefficients that are usually located at arteriolar branching
NEW STRATEGIES FOR CARDIOVASCULAR
points29 and delays in the return of wave reflec-
tions.28,29 Therefore, complex interactions are
A long-term (>1 year) therapeutic trial that
required between small and large arteries to
investigated the role of arterial stiffness, peak
achieve reductions of peak systolic blood pres-
systolic blood pressure and the control of pulse
sure and pulse pressure through the use of ACE
pressure was performed in patients with end-
inhibitors. Rizzoni and colleagues30 reported that,
stage renal disease.26 The objective was to reduce
in hypertensive patients, structural alterations of
their cardiovascular risk by use of an initial
the small arteries predicted cardiovascular risk
treatment that included salt and water deple-
in association with increased pulse pressure, the
tion. After randomization, the patients were
traditional surrogate of aortic stiffness.
first assigned either ACE inhibition or calcium blockade, followed by administration of the
CONCLUSION
two agents combined, either with or without a
In conclusion, whereas pulse pressure might
β-blocker. During the follow-up of 51 months,
provide effective semiotic information in
the mean arterial pressure, pulse pressure and
clinical practice, the measurement of arterial
aortic PWV were all reduced in the survivors.
stiffness is clinically relevant not only for risk
In the individuals who died from cardiovascular
assessment but also to quantify reductions in
events, the mean arterial pressure was lowered
cardio vascular risk. New therapeutic strate-
to the same extent as that observed in the survi-
gies that selectively reduce pulse pressure and
vors, but the pulse pressure and PWV remained
arterial stiffness should be developed. On the
unmodified by drug therapy. The adjusted
basis of the results of short-term and medium-
relative risk of all-cause death and cardio-
term controlled trials,31 such a regimen should
vascular death in response to blood-pressure
involve a combination of ACE inhibitors and
changes were 2.59 (95% CI 1.51–4.43) and 2.35
diuretics, with the use of new vasopeptidase
(95% CI 1.23–4.51), respectively (P <0.01). In
inhibitors or spironolactone, and might include
this trial, prolonged survival seemed to be more
newly identified or as yet unidentified agents as
closely related to the use of ACE inhibitors than
to β-blockers or dihydropyridine derivatives.
In the Preterax® in Regression of Arterial
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