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AJH
2004; 17:39S– 48S
Vascular Stiffening and Arterial Compliance
Implications for Systolic Blood Pressure
Ernesto L. Schiffrin
Hypertension in older persons is characterized by increased systolic blood pressure, and isolated systolic hypertension (ISH) is the most common type of hypertension
in this population. It is thought that ISH results from
age-associated vascular stiffening and reduced compliance
that can be revealed and quantified by analysis of arterial
pressure waveforms. Evaluation of pulse wave velocity
and other related measures has shown that arterial stiffness
increases with advancing age and other cardiovascular
(CV) risk factors including hypertension, the metabolic
syndrome, diabetes, obesity, hypercholesterolemia, and
elevated C-reactive protein. Many of these relationships
have been demonstrated in patients without clinical CV
disease and are independent of patient age. Arterial stiffness is significantly and independently associated with
both target organ damage and increased risk for CV morbidity and mortality. The mechanisms underlying age- and
disease-related arterial stiffening are not fully understood.
However, assessment of changes in gene expression associated with increased arterial stiffness and gene polymorphisms that increase the risk for vascular stiffening
suggests that components of the renin–angiotensin system,
matrix metalloproteinases, intracellular signaling, and extracellular matrix components may all be involved in this
process. Interventions aimed at these targets may reduce
vascular stiffness, lower systolic blood pressure, decrease
the prevalence of ISH, and improve outcomes for patients
(particularly older patients) with hypertension or other CV
conditions. Am J Hypertens 2004;17:39S– 48S © 2004
American Journal of Hypertension, Ltd.
Key Words: Arterial stiffness, augmentation index,
pulse wave velocity, aging, hypertension, obesity, diabetes, hypercholesterolemia.
ypertension is one of the most common chronic
diseases in the world, and more than one-fourth
of individuals in the United States have this condition.1 The risk for hypertension increases dramatically
with age; 7.2% of individuals 18 to 39 years old are
hypertensive, and this value rises to 30.1% for those 40 to
59 years old and 65.4% for those ⱖ65 years. The lifetime
risk of hypertension for individuals 55 years old is approximately 90%.1,2 Because systolic blood pressure (SBP)
progressively increases and diastolic blood pressure
(DBP) decreases after age 55 years, most older persons
with hypertension develop isolated systolic hypertension
(ISH), which is the most common form of hypertension in
the older population. It is characterized by increased SBP
and reduced DBP, leading to increased pulse pressure
(PP).3 Epidemiologic studies have shown that elevated
SBP is associated with significantly greater cardiovascular
(CV) risk than increased DBP.4,5
Isolated systolic hypertension is thought to result in part
from age-associated vascular stiffening and reduced compliance and distensibility of central conduit blood vessels,
H
such as the aorta. This significantly increases SBP because
the cushioning function to accommodate the systolic volume ejected by the left ventricle (LV) cannot be performed
without a significant rise in peak blood pressure (BP).6
Reflected waves play a critical role in this rise in peak
pressure. These waves originate at different sites that have
not been anatomically localized but that may be generated
as vessels progressively branch out and may occur particularly at the level of smaller resistance arteries at sites of
increased impedance. When vessels are stiffer, these reflections occur earlier in the cardiac cycle as pulse wave
velocity (PWV) is increased. They therefore arrive at the
origin of the aorta increasingly ahead of the dicrotic notch
in the aortic pulse waveform, resulting in summation with
the anterograde wave and increased peak pressure. This
amplification contributes significantly to exaggerated aortic and peripheral SBP and PP. The effect is greater proximally in the aorta where more reflected waves arrive than
distally in peripheral arteries. Increased stiffness of the
central elastic arteries is the primary cause of ISH and
elevated PP in older patients and in patients with CV
Received August 18, 2004. Accepted August 23, 2004.
From the Canadian Institute of Health Research Multidisciplinary
Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Address correspondence and reprint requests to Dr. Ernesto L.
Schiffrin, Clinical Research Institute of Montreal, 110 Pine
Ave W, Montreal, PQ, Canada H2W 1R7; e-mail: ernesto.schiffrin@
ircm.qc.ca
© 2004 by the American Journal of Hypertension, Ltd.
Published by Elsevier Inc.
0895-7061/04/$30.00
doi:10.1016/j.amjhyper.2004.08.019
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AJH–December 2004 –VOL. 17, NO. 12, Part 2
FIG. 1. Propagation of the PP wave from central to peripheral arteries in patients 24, 54, and 68 years of age. In older patients, the more
rapid propagation of PW reduces PP amplification, resulting in nearly identical central and peripheral BP. From ref. 8, reproduced with
permission. PP ⫽ pulse pressure; PW ⫽ pulse wave.
disease (CVD) including systolo/diastolic hypertension.
Measurement of arterial pressure waveforms in hypertension and related conditions increases the information about
underlying disease and risk, because it provides the aortic
systolic pressure and PP that the heart experiences, which
is more informative than peripheral BP.7 This article reviews analysis of the pulse waveform and indices derived
from it, such as augmentation index (AIx) and PWV; the
effects of arterial stiffening on end-organs and survival; the
relationships between arterial stiffening and well-known
CV risk factors; and cellular mechanisms that may be
involved in decreasing the elasticity of the wall of conduit
arteries. It also briefly summarizes interventions that may
affect, slow, or reverse arterial stiffening and reduce the
associated CV risk.
Pulse Wave Analysis, AIx, and
PWV
Although DBP and mean arterial pressure decrease progressively along the arterial tree, the pulsatile component,
PP, increases from central arteries (aorta) to peripheral
vessels as a result of the summation of the incident and the
reflected waves along central and peripheral arteries (Fig.
1). As mentioned earlier, reflections of the pulse wave
occur along the vascular tree at anatomic sites that have
not been located and as a result of changes in the impedance as vessels branch out. One of the main sites of wave
reflection may be the smaller resistance arteries. As these
reflected waves race back, they sum with the advancing
wave and distort it, resulting in paradoxically increasing
systolic pressure as the waves progress from the origin of
the aorta to peripheral vessels. Also as a result, the waveform is different in the aorta and in the periphery. Pulse
pressure increases by 18% to 31% between the aortic arch
and the brachial artery in younger individuals.8 However,
as a consequence of aging, stiffer vessels result in acceleration of both the advancing and the reflected waves. The
reflected waves occur earlier and go back along the aorta
at greater speed, arriving not in diastole but in systole.
Consequently, summation of the advancing and reflected
waves occurs earlier in the cardiac cycle and amplifies the
aortic systolic pressure. Amplification of PP thus changes
dramatically with age (Fig. 1). In younger individuals, the
summation of the forward and the backward wave at each
point of the arterial tree results in progressive elevation of
SBP in peripheral arteries. The more rapid pulse wave
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propagation in older persons results in less amplification
of PP from central to peripheral blood vessels, as the
reflected waves have occurred earlier and traveled back
faster and increased the peak aortic pressure, which is
closer or similar to that in the periphery8 (Fig. 1).
The AIx is a hemodynamic measure related to arterial
stiffness. It is defined as the increment in pressure from the
first systolic shoulder to the peak pressure of the aortic
pressure waveform expressed as a percentage of the peak
pressure. The AIx is thought to be primarily determined by
the intensity and timing of reflected waves. The central
arterial PW is composed of a forward traveling wave
generated by LV ejection and the later-arriving reflected
wave from the periphery. As stiffness of arterial walls
increases, transmission velocities of both forward and
reflected waves increase. This causes the reflected wave to
arrive earlier in the central aorta and augments pressure in
systole, as mentioned earlier here. The increase in pressure
related to the arrival of the reflected wave determines the
AIx. The AIx reflects the load placed on the LV due to
wave reflection, is a surrogate marker for arterial stiffness,
and is thought to have a significant association with CV
risk.9,10
Pulse wave velocity is the velocity of the PW along the
arterial tree (measured with the time difference between the
electrocardiographic R wave and the arrival of the wave to
the carotid and a lower limb vessel, and the distance between
the sites of measurement). Like AIx, PWV is considered to
be an accurate measure of central vascular stiffness. There is
a linear correlation between PWV and AIx in many studies,
and both parameters increase with advancing age9 (Fig. 2).
However, AIx is influenced by the level of BP, heart rate,
gender, age, height (shorter individuals exhibit a greater
AIx),11,12 and vasoactive drugs independent of changes in
stiffness. In contrast, PWV is independent of these factors and
relates to Young’s modulus of thin-walled elastic tubes.
Thus, the two measures cannot be considered as interchangeable markers of vascular stiffness.9 The AIx is obtained by a
transfer function that allows derivation of the aortic pulse
waveform from a peripheral vessel (radial or carotid arteries).
Questions have been raised as to the precision of the calculated AIx as a result of the variability of the transfer functions
for each individual.13 Measurement of AIx is dependent on
higher-frequency signals than BP, and the transfer function
may be less precise and may have greater variability at these
high frequencies. This also results in underestimation of
central systolic pressure and overestimation of central diastolic pressure. In some studies, correlation of AIx and PWV
is accordingly low, and the latter appears to be a more precise
measure of the stiffness of central blood vessels. Some investigators have suggested that AIx could be replaced by
simple calculation of central aortic pressure, which may be
more precise than the derived aortic pulse waveform used to
calculate AIx, or even direct determination of AIx from the
peripheral pulse.14
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FIG. 2. Relationships between Alx, PWV, and age in 50 healthy men
(univariate regression). From ref. 9, reproduced with permission.
PWV ⫽ pulse wave velocity.
Relationship Between Markers for
Arterial Stiffness and Other Risk
Factors for CVD
Results from a number of recent studies have demonstrated significant correlations between measures of arterial stiffness and other well-established risk factors for
CVD.
Hypertension
Not surprisingly, there is a strong correlation between
arterial stiffness and the incidence of hypertension. Liao et
al measured carotid arterial elasticity by high-resolution
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B-mode ultrasonography and expressed their results as
adjusted arterial diameter change, Peterson’s elastic modulus, Young’s elastic modulus, and ␤ stiffness index. They
also assessed the incidence of hypertension (defined as
SBP ⱖ160 mm Hg, DBP ⱖ95 mm Hg, or use of antihypertensive medication). Both sets of measures were taken
from 6992 normotensive men and women 45 to 64 years
of age at baseline who were enrolled in the populationbased Atherosclerosis Risk in Communities (ARIC) Study
and followed for 6 years. Adjusted cumulative incident
rates of hypertension from the highest to the lowest quartiles of arterial elasticity, when measured by adjusted
arterial diameter change, were 6.7%, 8.0%, 7.3%, and
9.6%, respectively. Study results indicated that each standard deviation decrease in arterial elasticity was associated
with a 15% increase in the risk for hypertension, independent of other established risk factors and baseline BP.
These investigators suggested that the loss of arterial elasticity in large and medium arteries and the resulting adverse effects on target organs such as the kidneys may be
responsible for the relationship between greater arterial
stiffness and increased risk for hypertension that was observed in the ARIC cohort.15
Results from a more recent study also suggest that
reduced aortic elasticity, as reflected by increased PP, may
play a primary role in the development of hypertension.
Mitchell et al16 used calibrated tonometry and pulsed
Doppler to assess arterial stiffness and pulsatile hemodynamics in 128 patients with uncomplicated systolic hypertension and 30 age- and gender-matched normotensive
patients in the control group. The PWV was assessed using
tonometry and body surface measurements. Characteristic
impedance (Zc) was calculated from the ratio of change in
carotid pressure and aortic flow in early systole. Hypertensive patients had higher PP than patients in the control
group; this was primarily attributable to higher Zc, which
accounted for nearly one-half of the excess PP in men and
more than two-thirds in women. Increased Zc in hypertensive patients was attributable to decreased effective
aortic diameter. It should be emphasized that aortic diameter was not measured directly, which has generated some
criticism of these results. These findings were considered
to be consistent with the view that aortic function may
play a primary active role in the pathophysiology of systolic hypertension. They also argue against the possibility
that aortic degeneration, dilation, and wall stiffening develop secondary to hypertension. All of these results support the view that central aortic stiffness may be an
attractive target for therapies aimed at reducing hypertension, particularly ISH.
Obesity
Obesity—a well-known risk factor for CVD—is related to
arterial stiffness. Results from one recent correlational
study that included 186 young adults (20 to 40 years old)
and 177 older patients (41 to 70 years old) indicated that
AJH–December 2004 –VOL. 17, NO. 12, Part 2
FIG. 3. Mean PWV in obese (BMI ⬎30 kg/m2), overweight (BMI
⬎25 kg/m2), and normal weight (BMI ⬍25 kg/m2) individuals (adjusted for age, SBP, race, and sex). From ref. 17, reproduced with
permission. BMI ⫽ body mass index; PWV ⫽ pulse wave velocity;
SBP ⫽ systolic blood pressure.
aortic stiffness, as reflected by PWV, was significantly
correlated with higher body weight, body mass index (Fig.
3), waist and hip circumferences, and waist– hip ratio.
These relationships were independent of patient age, SBP,
ethnicity, and sex. One of the most important observations
from this study was the early age at which a significant
relationship between obesity and arterial stiffness became
apparent. Obese individuals as young as 20 to 30 years of
age had a PWV 47 cm/sec higher than that of age-matched
nonobese patients. This corresponds to an increase in
vascular stiffness associated with a 5-year increase in age
and a plateau in middle age.17 Obesity was not associated
with further increases in vascular stiffness in elderly patients.
Metabolic Syndrome
The clustering of CV risk factors referred to as metabolic
syndrome is very common. Recent analysis of results from
the Third National Health and Nutrition Education Survey
(NHANES III) indicated that the age-adjusted prevalence
of metabolic syndrome in the United States is 23.7%. The
prevalence of the metabolic syndrome increases from
6.7% among persons 20 to 29 years of age to 43.5%
among those 60 to 69 years old.18 Presence of the metabolic syndrome is an independent predictor of increased
arterial stiffness. In the Baltimore Longitudinal Study on
Aging analysis of 471 participants without clinical CVD
and not receiving antihypertensive therapy, the metabolic
syndrome was defined as three or more of the following:
impaired glucose tolerance, hypertension, dyslipidemia, or
obesity. The presence of the metabolic syndrome resulted
in a disproportionate increase in carotid stiffness, as determined by B-mode ultrasonography, in multiple regression models that included age, gender, smoking,
low-density lipoprotein cholesterol (LDL-C), and each
individual component of the metabolic syndrome as continuous variables.19
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FIG. 4. Plots of PWV versus SBP for patients with diabetes (a) and patients with normal glucose tolerance (b). From ref. 20, reproduced with
permission. PWV ⫽ pulse wave velocity; SBP ⫽ systolic blood pressure.
Diabetes
Pulse wave velocity is significantly increased in patients
with diabetes. Assessment of 397 individuals with diabetes
and 174 individuals without this disease indicated that at
any SBP, Doppler-derived aortic PWV was higher in
patients with diabetes than in patients in the control group
(Fig. 4). Moreover, PWV was an independent predictor of
all-cause and CV mortality for the individuals enrolled in
this trial.20 These results support the view that PWV is a
powerful independent predictor of mortality across the
entire spectrum of glucose tolerance. In a multivariate
analysis, PWV displaced SBP from the list of other independent risk factors. This suggests that PWV may reflect
a final common pathway on which BP and other risk
factors operate to increase CV risk.20
Schram et al21 also demonstrated that both peripheral
and central arterial stiffness increase with deteriorating
glucose tolerance status. They evaluated total systemic
arterial compliance, aortic AIx, and carotid–femoral transit time (inversely related to PWV) in a population-based
study of 261 individuals with normal glucose metabolism,
170 with impaired glucose metabolism, and 188 with type
2 diabetes. After correction for sex, age, heart rate, height,
body mass index, and mean arterial pressure, type 2 diabetes was associated with decreased total systemic arterial
compliance, increased aortic AIx, and decreased carotid–
femoral transit time. Impaired glucose metabolism was
also correlated, albeit less strongly, with decreased total
systemic arterial compliance. These results are consistent
with the view that deteriorating glucose tolerance is associated with a general increase in arterial stiffness that may
explain, at least in part, the increased risk for CVD associated with both impaired glucose tolerance and diabetes.
Hypercholesterolemia
Assessments of the relationships between lipid profile
abnormalities and arterial stiffness have produced somewhat variable results. Dart et al22 measured plasma cholesterol and indices of arterial stiffness, including AIx,
systemic arterial compliance, and transverse expansion of
the aortic arch (aortic distensibility) in 868 men and
women 65 to 84 years of age who participated in the
Australian National BP2 study. Multiple regression analysis indicated no significant associations between stiffness
parameters and total cholesterol (TC) or high-density lipoprotein cholesterol (HDL-C). Toikka et al23 reported a
significant positive correlation between the HDL-C/TC
ratio and carotid artery compliance (as measured by ultrasonography) and negative correlations between oxidized
LDL-C and compliance for both the carotid artery and the
ascending aorta (as measured by magnetic resonance imaging) in a small cohort of healthy men 29 to 39 years of
age. As in the study of Dart et al, aortic elasticity was not
related to standard lipid variables. These results suggest
that oxidative modification of LDL-C may play a role in
the alteration of arterial wall elastic properties and that
changes associated with this process are apparent in
healthy young men.23
In contrast to the results summarized in the preceding
paragraph, Wilkinson et al24 reported that aortic PP, PWV,
and AIx were all significantly higher in patients with
hypercholesterolemia than in individuals with normal TC
levels.
C-Reactive Protein
C-reactive protein (CRP) is a new marker that has been
proposed to be a sensitive index for increased CVD risk,
although it is not proven to be cardiac- or vascular-specific. In a recent correlational study that included 427
individuals free of clinically apparent CVD, diabetes, and
hypercholesterolemia, there was a significant positive correlation between CRP and brachial and aortic PWV and
PP. These correlations suggest that inflammation may be
involved in arterial stiffening, and that this process may be
ongoing in individuals without other clinically evident
CVD.25
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Table 1. Relative risk (odds ratios [OR]) for cardiovascular (CV) mortality according to pulse wave velocity
(PWV) and other risk factors (modified from ref. 30)
Parameter
PWV (5 m/sec)
Previous CVD (yes/no)
Age (10 y)
PP (10 mm Hg)
SBP (10 mm Hg)
Diabetes (yes/no)
OR
Lower 95% CI
Higher 95% CI
P
2.35
14.81
2.32
1.53
1.26
4.23
1.76
7.98
1.78
1.31
1.12
1.96
3.14
27.47
3.01
1.80
1.42
9.15
⬍.0001
⬍.0001
⬍.0001
⬍.0001
⬍.001
⬍.001
CI ⫽ confidence interval; CVD ⫽ cardiovascular disease.
Arterial Stiffness as a Predictor of
Morbidity and Mortality
Target Organ Damage
Increased arterial stiffness is significantly associated with
target organ damage. These relationships have been demonstrated for both the heart and the kidneys.
Pressure load is a stimulus for LV hypertrophy, and this is
particularly true for aortic systolic pressure and PP. Results
from 276 patients (79 normotensive and 197 otherwise
healthy hypertensive individuals) who underwent echocardiography to assess LV structure, along with carotid ultrasound
and applanation tonometry to determine the pressure-independent arterial stiffness index, ␤, and pressure-dependent
elastic modulus, indicated clear relationships between variables related to arterial stiffness and LV hypertrophy. Elastic
modulus was significantly correlated with LV mass. The ␤
index was inversely related to chamber diameter and directly
related to LV relative wall thickness and to the ratio of wall
thickness to chamber radius.26
Patients with end-stage renal disease have increased
aortic stiffness. Aortic PWV is a strong independent predictor of overall and CV mortality in this population.27 It
has also been suggested that arterial stiffness may be
significantly related to renal function in normotensive and
hypertensive populations.28 This view is supported by
results from a study of 1290 patients with normal or
elevated BP and plasma creatinine values ⱕ130 ␮mol/L.
These patients were divided into three tertiles according to
the calculated creatinine clearance; for each group the BP,
aortic PWV, and standard CV risk factors were determined. Elevated aortic PWV was significantly associated
with reduced creatinine clearance in patients in the lowest
tertile for this measure. This relationship was independent
of mean BP, plasma glucose and cholesterol, obesity, and
smoking habits and was stronger in younger (ⱕ55 years of
age) than in older patients. In a subset of untreated hypertensive patients enrolled in this trial, creatinine clearance
was independently and positively correlated with common
carotid artery compliance. All of these results support the
conclusion that increased stiffness of central arteries is
significantly and independently associated with evidence
of kidney damage in patients with mild-to-moderate renal
insufficiency.29
Cardiovascular Morbidity and Mortality
Aortic stiffness, as reflected by aortic PWV, has been
shown to be an independent predictor of CV and all-cause
mortality in patients with hypertension. Laurent et al30
followed a cohort of 1980 patients with essential hypertension who underwent measurement of carotid–femoral
PWV at study entry. The mean patient age at the time of
enrollment was 50 years and the average follow-up was
112 months. During this period, there were 107 fatal
events with 46 of CV origin. The PWV was significantly
correlated with all-cause and CV mortality (Table 1). Odds
ratios for all-cause and CV mortality for a 5 m/sec increment in PWV were 2.14 and 2.35, respectively. The increased CV risk with higher PWV was independent of
previous CVD, age, and diabetes. The PP was not independently associated with all-cause mortality and was only
marginally associated with CV mortality.
Aortic stiffness is also an independent predictor of
primary coronary events in patients with hypertension.
The predictive value of arterial stiffness for coronary heart
disease (CHD) was assessed in 1045 patients who had
essential hypertension but no other CVD. Aortic stiffness
was determined from carotid–femoral PWV, and the risk
of CHD was calculated using the Framingham equations.
Mean age at entry was 51 years and the average follow-up
was 5.7 years. Study results showed that coronary events
(fatal and nonfatal MI, coronary revascularization, and
angina pectoris) and all CV events were significantly related to increasing PWV (Table 2). The relative risks (RR)
for CHD and CV events associated with an increase in
PWV of 3.5 m/sec were 1.42 and 1.41, respectively. In the
multivariate analysis, after adjustment for Framingham
risk score, PWV remained significantly associated with the
occurrence of coronary events.31
Mechanisms Leading to Stiffening
of the Blood Vessel Wall
Gene Expression
The molecular mechanisms underlying the development of
vascular stiffness are largely unknown. It is generally
believed that the composition and structure of the extracellular matrix and cell-matrix interactions are critical
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Table 2. Relative risk (RR) for primary coronary heart disease (CHD) and cardiovascular (CV) events
according to pulse wave velocity (PWV), Framingham risk score, and classic CV risk factors (modified from ref.
31)
Parameter
CHD events
PWV (3.5 m/s)
FRS (4 points)
Age (10 y)
Hypercholesterolemia (yes/no)
Sex (M/F)
All CV events
PWV (3.5 m/sec)
FRS (4 points)
Age (10 y)
SBP (10 mm Hg)
PP (10 mm Hg)
Hypercholesterolemia (yes/no)
Diabetes (yes/no)
Gender (male/female)
RR
Lower 95% CI
Higher 95% CI
P
1.42
1.51
1.42
2.49
2.32
1.10
1.10
1.12
1.38
1.14
1.82
2.05
1.81
4.48
4.76
⬍.01
⬍.01
⬍.01
⬍.01
⬍.02
1.41
1.57
1.47
1.12
1.16
1.73
2.16
1.64
1.17
1.25
1.23
1.02
1.02
1.09
1.21
1.02
1.70
1.98
1.76
1.22
1.32
2.76
3.84
2.62
⬍.001
⬍.0001
⬍.0001
.015
.019
.017
⬍.01
.036
CI ⫽ confidence interval; CVD ⫽ cardiovascular disease; FRS ⫽ Framingham risk score; PP ⫽ pulse pressure; SBP ⫽ systolic blood pressure.
determinants of arterial stiffness, but the signaling cascades involved in these processes are not fully understood.32 Durier et al33 attempted to relate arterial stiffness,
as reflected by PWV analysis, to gene expression in tissue
samples from the ascending aortas of patients undergoing
bypass surgery. Patients were classified as having either a
distensible or stiff aorta, and gene expression determined
by mRNA analysis was compared in these two groups. A
total of 35 genes had expression patterns that correlated
with PWV (Fig. 5). These included protein phosphatase-1,
catalytic subunit, ␤ isoform (PPP1C␤), also known as the
catalytic subunit of myosin light-chain phosphatase, and
Yotiao, an A kinase anchor protein. Several genes were
also expressed in an all-or-none pattern, including protein
kinase C–␤1 (PKC␤1). This kinase has been reported to be
involved in long-term, sustained contractions and could be
an important determinant in arterial stiffness. There were
also relationships between extracellular matrix molecules
and aortic stiffness. Expression of integrins ␣2b, ␣6, ␤3,
and ␤5 differed between stiff and distensible aortas. The
␣2b and ␣6 integrin transcripts were present in all samples
from stiff aortas and were absent in all samples from
distensible aortas. Expression of proteoglycans and related
proteins also differed between stiff and distensible aortas.
Dermatopontin, neuroglycan-C, and osteomodulin gene
transcripts were less abundant in stiff aortas compared
with distensible aortas, whereas decorin and aggrecan
transcripts were more abundant.
Specific Genotypes
Renin–Angiotensin System Results from clinical and
experimental studies have suggested that actions of the
renin–angiotensin system (RAS) may contribute to the
development of arterial stiffness by altering the extracellular matrix in the vascular media.32,34 Elevated lev-
els of angiotensin-converting enzyme (ACE) have been
observed in individuals with increased thickness of the
carotid wall.35 Benetos et al36 recently evaluated relationships between genetic polymorphisms for the ACE
insertion/deletion (I/D) genes and angiotensin II type 1
receptors (AT1) and aortic stiffness in patients with
hypertension. Their study enrolled 134 patients with
never-treated hypertension who underwent measurement of carotid–femoral PWV and assessment of ACE
I/D and AT1 genotypes. Arterial stiffness was significantly increased in patients in AT1 CC homozygotes
versus AT1 AC heterozygotes and AT1AA homozygotes. There was also a trend toward decreased PWV in
patients with higher numbers of ACE D alleles.
A more recent and much larger study has confirmed the
relationship between the ACE D gene and arterial stiffness. Results from 3001 patients ⱖ55 years old included in
the Rotterdam study indicated that individuals with the
ACE I/D and DD genotypes had significantly greater carotid stiffness than did patients with the II genotype.37
Matrix Metalloproteinases Matrix metalloproteinases (MMP) play a central role in the homeostasis of the
extracellular matrix and vascular remodeling. Substrates for these enzymes include most major constituents of the arterial wall, such as fibronectin, type IV, V,
IX, and X collagens, gelatin, laminin, elastin, and proteoglycans.38 Results from two recent studies have demonstrated significant relationships between MMP-3 and
MMP-9 and increased arterial stiffness. Medley et al
determined whether a common promotor polymorphism
(5A/6A) associated with differences in MMP-3 activity
(the 5A allele has greater promotor activity than the 6A
allele) was correlated with age-related arterial stiffening. They evaluated the MMP-3 5A/6A genotype in 203
patients with low CV risk and related it to ascending
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FIG. 5. Categorization of genes exhibiting differential expression with arterial stiffness. From ref. 33, reproduced with permission.
aortic input impedance. Older (ⱖ61 years of age)
5A/5A homozygotes had higher aortic impedance than
heterozygotes, whereas there was no difference in the
younger group. These results support the view that the
MMP-3 genotype may be an important determinant of
vascular remodeling and age-related arterial stiffening.38 Medley et al also evaluated the relationship between MMP-9 genotype (C-1562T promoter
polymorphism) and arterial stiffness in 84 patients with
CHD. Carotid applanation tonometry was used to assess
central BP, and Doppler velocimetry was used to determine aortic stiffness. Individuals who were T-allele
carriers (CT and TT) had stiffer large arteries and higher
carotid PP and SBP than did those who were CC homozygotes. In aortic samples, MMP-9 gene expression
was fivefold higher and active protein levels were more
than twofold higher in T-allele carriers.39
Potential Interventions to
Decrease Arterial Stiffness
Some drugs have the potential to reduce arterial stiffness
and could be used to decrease the severity of this CV risk
factor. These include the following: agents that increase
vascular levels of nitric oxide (NO) and enhance endothe-
lial function (eg, isosorbide dinitrate, sinitrodil, nebivolol,
cycletanine); drugs that interfere with deleterious extracellular matrix remodeling (eg, agents that interfere with the
actions of the RAS); aminoguanidine derivatives that inhibit collagen cross-linking promoted by advanced glycation endproducts (AGE) (eg, AGE formation inhibitors);
thiazolium derivatives that break AGE cross-links (eg,
AGE cross-link breakers); and medications that decrease
sodium-associated arterial stiffness (eg, thiazide diuretics,
indapamide, spironolactone).8
Conclusions
The results summarized and discussed in this review indicate that increased stiffness of large arteries is closely
associated with aging and is responsible for the very high
prevalence of ISH in older individuals. One important
conclusion that can be drawn is that arterial stiffness is also
related to a large number of CV risk factors including
hypertension, obesity, the metabolic syndrome and diabetes, hypercholesterolemia, and elevated CRP, among others. Many of these relationships have been demonstrated
in patients without clinical CVD and are largely independent of patient age. Arterial stiffness is also significantly
AJH–December 2004 –VOL. 17, NO. 12, Part 2
VASCULAR STIFFENING AND SYSTOLIC BLOOD PRESSURE
associated with both target organ damage and increased
risk for CV morbidity and mortality.
Although the etiologies of age- and disease-associated
arterial stiffening are not completely understood, it is clear
that multiple mechanisms contribute to this process. Assessment of changes in gene expression associated with increased
arterial stiffness and genetic polymorphisms that increase the
risk for this condition suggests that a wide range of molecules, including components of the RAS, intracellular signaling, extracellular matrix components, and MMP may be
involved in the cascade of events that results in arterial
stiffening. The large number of molecules likely to be involved in arterial stiffening suggests that there should be
many potential targets for interventions aimed at stopping or
even reversing this process. Agents that reduce vascular
stiffness may contribute to lower SBP, decreased prevalence
of ISH, and improved outcomes for patients with hypertension or other CV conditions.
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