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REVIEW
URRENT
C
OPINION
Arterial stiffness: insights from Framingham
and Iceland
Gary F. Mitchell
Purpose of review
To examine the putative measures of arterial stiffness and the mechanisms of adverse effects of stiffness on
blood pressure and target organ damage using data from comprehensive hemodynamic profiles obtained
in the Framingham Heart Study and the Age, Gene/Environment Susceptibility-Reykjavik Study.
Recent findings
Once thought to be a consequence of longstanding hypertension, recent evidence suggests that aortic
stiffness antedates and contributes to the pathogenesis of hypertension and target organ damage in the
heart, brain, and kidneys. Carotid–femoral pulse-wave velocity (CFPWV) has emerged as the reference
standard measure of aortic stiffness and a powerful predictor of cardiovascular disease risk. Augmentation
index, a putative measure of arterial stiffness and wave reflection, has complex relations with stiffness and
risk. Recent evidence suggests that wave reflection, which is a normal consequence of impedance
mismatch between compliant aorta and stiff muscular arteries, is protective and limits the exposure of target
organs to potentially harmful pulsatile energy. Aortic stiffening produces impedance matching that reduces
wave reflection and exposes the microcirculation to excessive pulsatile stress, resulting in microvascular
target organ damage and dysfunction.
Summary
CFPWV provides a powerful new tool for risk stratification and elucidation of the pathogenesis of target
organ damage in hypertension.
Keywords
augmentation index, characteristic impedance, pulse pressure, pulse-wave velocity
INTRODUCTION
Our understanding of the relations between hypertension, arterial stiffness, excessive pressure pulsatility, and target organ damage has changed
dramatically in the recent years. In a traditional
paradigm, repetitive pulsatile strain with aging
was thought to break down elastin in the wall of
the aorta, resulting in aortic dilation and increased
engagement of collagen, which is several orders of
magnitude stiffer than the elastic fibers that normally bear most of the load in the aortic wall. The
resulting increase in aortic wall stiffness increases
the pulse-wave velocity (PWV). Progressively higher
PWV was posited to result in increasingly premature
arrival of the reflected pressure wave, progressive
augmentation of the central aortic pressure waveform, and widening of pulse pressure (PP). Importantly, in the foregoing paradigm, excessive aortic
stiffness was viewed as a complication of longstanding hypertension, which was thought to amplify
stress on the aorta and accelerate the process of
aging [1–5]. The clinical implications of these
putative measures of arterial stiffness and wave
reflection, and their relations with blood pressure
(BP) progression and target organ damage, have
been studied by using comprehensive hemodynamic profiling of central aortic pressure-flow
relations, PWV, and wave reflection in the large,
well characterized, community-based cohorts of
the Framingham Heart Study and the Age, Gene/
Environment
Susceptibility
(AGES)-Reykjavik
Study. Findings from these studies and others have
confirmed some of the prior hypotheses and substantially altered our interpretation of others.
Cardiovascular Engineering, Inc, Norwood, Massachusetts, USA
Correspondence to Gary F. Mitchell, MD, Cardiovascular Engineering,
Inc., 1 Edgewater Drive, Suite 201, Norwood, MA 02062, USA.
Tel: +1 781 255 6930; e-mail: [email protected]
Curr Opin Nephrol Hypertens 2015, 24:1–7
DOI:10.1097/MNH.0000000000000092
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Circulation and hemodynamics
KEY POINTS
Increased arterial stiffness and excessive pressure
pulsatility antedate and contribute to the pathogenesis
of hypertension and target organ damage.
Carotid-femoral pulse wave velocity, which can be
assessed in 2 minutes by using arterial tonometry with
relatively inexpensive equipment and nominal training,
has emerged as the gold standard measure of aortic
stiffness and a powerful new risk factor for
cardiovascular disease.
Though often portrayed as deleterious, wave reflection
is a protective phenomenon that limits transmission of
potentially harmful levels of pulsatility into the
microcirculation of high-flow organs such as the brain
and kidneys.
ARTERIAL STIFFNESS AND PRESSURE
PULSATILITY
The gold-standard measure of aortic stiffness is
carotid–femoral PWV (CFPWV), which is optimally
assessed by using arterial tonometry (Fig. 1).
(a)
Although a number of alternative approaches have
been proposed, tonometric CFPWV benefits from a
body of literature that strongly supports its role as
a novel cardiovascular disease (CVD) risk factor
[6 ,7]. Relatively modest equipment and expertise
are required to assess CFPWV, rendering it suitable
for use in a routine clinical setting. In order to
more fully characterize mean and pulsatile load
on the heart, assessment of central-pressure–flow
relations is required [8]. The test can be performed
quickly and robustly by well-trained sonographers.
However, the evaluation requires limited cardiac
ultrasound and moderate expertise, and hence is
suitable for use in a specialty laboratory or research
setting.
We evaluated age relations of BP and key hemodynamic measures in the Framingham Offspring
and Third Generation cohorts, which together span
the full adult age range [8]. Age relations of CFPWV
and PP were complex, and strongly nonlinear.
CFPWV increased modestly with age through midlife and rapidly thereafter. In contrast, PP fell substantially from young adulthood through midlife, as
has been reported by others [9], and then increased
&&
(b)
Carotid
160
SSN-C
Pressure (mmHg)
120
80
SSN-F
∆T
CFTD
40
0
0
200
400
Time (ms)
600
800
Femoral
FIGURE 1. Measurement of carotid–femoral pulse-wave velocity. (a) Using a tonometer, high-fidelity carotid (gray) and
femoral (black) pressure waveforms are acquired noninvasively. The foot of each waveform is identified by finding the point in
which the local pressure derivative (dP/dt) exceeds 20% of peak dP/dt. The foot-to-foot transit time (DT) is determined using
the R-wave of the electrocardiogram as a timing reference. (b) Transit distance is estimated from the body surface
measurements. As a result of the parallel transmission of the waveform up the brachiocephalic and around the arch (black fill),
the direct distance from carotid to femoral site overestimates the true transit distance. Therefore, to estimate the true
carotid–femoral transit distance (CFTD), one measures from the suprasternal notch to the femoral (SSN-F) and carotid
(SSN-C) tonometry sites, and then takes the difference. Then, the carotid–femoral pulse-wave velocity is calculated as
CFPWV ¼ CFTD/DT. CFPWV, carotid–femoral pulse-wave velocity.
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Arterial stiffness: insights from Framingham and Iceland Mitchell
rapidly after the midlife nadir. Augmentation index,
a measure of wave reflection, increased substantially
with age through midlife, at a time when PP was
actually falling, and then fell after midlife, at a time
when PP and CFPWV increased rapidly. The opposing age trends of PP and augmentation index indicated that it was extremely unlikely that age-related
widening of PP could be attributed to excessive wave
reflection. Age relations of PP were paralleled by
forward-wave amplitude (Pf) and characteristic
impedance of the aorta (Zc), which is a major determinant of Pf. The foregoing observations suggest
that age-related differences in PP were attributable
to Pf rather than reflected wave amplitude or timing.
Consistent with this observation, multivariable
models demonstrated that approximately 90% of
variance in PP was attributable to variability in Pf,
with the remainder attributable to relative wave
reflection and timing of the reflected wave [8].
In addition to the strong nonlinearity of age
relations of each of the key hemodynamic measures,
we also observed prominent dissociation of age
relations of CFPWV and Zc. Differing age relations
of CFPWV and Zc could be attributable to regional
heterogeneity in aortic stiffness. Zc is primarily a
measure of proximal aortic properties, whereas
CFPWV summarizes the spatially averaged properties of the descending thoracic and abdominal aorta
as well as the iliac and proximal femoral arteries.
Alternatively, differing behavior of CFPWV and Zc
could be a consequence of aortic remodeling. PWV
and Zc have similar direct relations with aortic wall
stiffness, and both are inversely related to the lumen
diameter. However, Zc has a five-fold greater sensitivity to lumen diameter. Thus, with isolated stiffening of the aortic wall, Zc and PWV will increase in
parallel. In contrast, if the lumen remodels in association with the alterations in stiffness, Zc and PWV
will dissociate and many even change in opposite
directions.
The main load-bearing elements of the aortic
media are the elastic lamellae, which are formed
early in life. After the development of the aortic
lamellae has completed in early childhood, the gene
program for elastic fiber production is silenced
[10,11]. Therefore, subsequent dramatic alterations
in the aortic dimensions in response to somatic
growth and weight gain represent the remodeling
of a fixed pool of elastin to a larger diameter. Aortic
diameter increases substantially throughout the life
course, particularly in the presence of obesity [12].
Remodeling thins the elastic lamellae and increases
wall tension because of the larger radius, as indicted
by the Law of Laplace [13–15]. As a result, fiber stress
and hence strain will increase, leading to increased
fractional engagement of collagen, which is several
orders of magnitude stiffer than elastin. The associated increase in wall stiffness can increase PWV even
as PP falls because of the extreme inverse sensitivity
of Zc to diameter. Thus, aortic remodeling secondary
to midlife weight gain could stiffen the wall of the
aorta and drive up CFPWV, with no increase or
even a fall in PP. One could speculate that the
recent epidemic of obesity and glucometabolic disorders may have contributed to nonlinear PP–age
relations, with diabetes stiffening the aortic wall and
obesity promoting outward remodeling to a larger
aortic diameter, which may temporarily obscure the
effect of wall stiffness on Zc and PP.
On the basis of hemodynamics, aortic lumen
enlargement seems to approach a limit after midlife
when PP and CFPWV increase in parallel, suggesting
an ongoing increase in aortic wall stiffness with
minimal additional diameter remodeling. The evolution of the aortic root diameter over the adult life
course was evaluated using measures of aortic root
diameter obtained over a 16-year interval in Framingham Offspring Study participants [12]. Aortic
root diameter enlarged over the life course in both
men and women. Additive aortic enlargement was
observed in the presence of hypertension and
obesity. Multivariable models indicated that the
increase in aortic diameter with increasing BMI
was attenuated after the median age (52 years),
suggesting that aortic diameter reserve may have
been depleted because of enlargement early in life.
One could speculate that the relatively rapid onset
of the obesity epidemic over the last 3 decades was
associated with aortic enlargement that initially
reduced Zc, because of the strong inverse relation
to aortic diameter (power of 2.5), and contributed to
the cross-sectional midlife PP nadir as well as the
increase in aortic wall stiffness (higher CFPWV). In
support of this hypothesis, the longitudinal study
found strong inverse relations between aortic
diameter and short-term (4 years) or long-term (16
years) change in PP [12].
Data from the AGES-Reykjavik study has shown
that variable modulation of aortic diameter may
play an important role in the widening of PP after
midlife [16]. Contrary to the traditional view that
higher PP should be associated with aortic dilation,
several studies have found that PP is negatively
related to aortic diameter [17–20]. The hypothesis
that smaller aortic diameter contributes to the
widening of PP was further examined in the
AGES-Reykjavik cohort by using high-resolution
MRI of the thoracic aorta [21 ]. In this older cohort,
we found that higher PP was associated with smaller
aortic diameter along the full length of the thoracic
aorta, suggesting mismatch between diameter
and flow in individuals with the highest PP. In a
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Circulation and hemodynamics
multivariable model, we were able to demonstrate
dissociation between cardiac and aortic adaptations
to hemodynamic load. Higher PP was associated
with a smaller aorta diameter and a larger left
ventricular end-diastolic volume, suggesting that
the heart may have greater ability to remodel in
response to hemodynamic demand, for example, in
order to accommodate a requirement for increasing
cardiac output secondary to increasing adiposity.
The aorta may be more constrained in its ability
to remodel because, as noted above, the number of
elastic lamellae and pool of elastic fibers is determined by genetics and early-life exposures during
childhood [11,22]. As a result, some individuals may
have less remodeling reserve than others, resulting
in accelerated widening of PP as the hemodynamic
demand increases or the aortic wall stiffens in later
life.
Consistent with the foregoing, there are important genetic contributions to CFPWV and PP as
evidenced by the moderate heritability of each
phenotype and the identification of specific genetic
loci based on the genomewide association studies
[23,24]. Endothelial dysfunction may also contribute to aortic stiffness through modulation of aortic
smooth muscle cell tone and stiffness [25 ,26 ]. In
addition, nitric oxide has been shown to modulate
the activity of tissue transglutaminase-2, which is a
cross-linking enzyme found in the aortic wall. Studies have shown that reduced bioavailability of nitric
oxide with age is associated with increased transglutaminase-2 activity and increased cross-linking
of proteins in the wall of the aorta, resulting in
increased aortic stiffness [27].
&
&
NEW INSIGHTS INTO WAVE REFLECTION
A number of recent studies have contributed to our
understanding of the role of wave reflection in
central hemodynamics. As noted earlier, augmentation of the central pressure waveform by premature
return of the reflected wave secondary to increased
PWV was once thought to be a major contributor to
the widening of PP. However, recent work has demonstrated that, whereas amplitude and timing of the
reflected wave are important, the augmentation
index is also heavily dependent on the pattern of
left ventricular ejection and the shape of the forward
and reflected waves [28 ,29 ,30 ].
Conversely, reduction in apparent wave reflection with vasoactive medications was associated
with an unanticipated reduction in stroke volume,
suggesting that preload reduction may diminish the
ability of the heart to generate augmentation [31 ].
Many vasodilators are also venodilators and may
reduce preload. As the end-systolic pressure–volume
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relation is substantially steeper than the end-diastolic
relation, modest venodilation may have a much
larger effect on preload than vasodilation has on
afterload, resulting in a marked reduction in the
augmentation, together with a modest reduction in
stroke volume. This mechanism may contribute to
the substantial reduction in augmentation that is
seen following administration of nitrates, which
are potent venodilators that have only modest effects
on arterial resistance [29 ]. As a result, modulation of
preload with venodilator drugs may provide a novel
approach to reduce central pressure pulsatility.
Modulation of preload rather than peripheral vascular resistance will avoid transmitting potentially
harmful pulsatile energy into the periphery where
it can exacerbate small-vessel damage, as would be
the case with arteriolar dilators.
&&
ARTERIAL STIFFNESS AND
HYPERTENSION: CAUSE OR
COMPLICATION
Though often viewed as a complication, recent
studies provide evidence that arterial stiffness may
precede and contribute to the pathogenesis of
hypertension. Using data from a nonhypertensive
subgroup of the Framingham Offspring cohort,
Kaess et al. [32 ] demonstrated that higher aortic
stiffness, assessed as greater Pf amplitude or higher
CFPWV, was a risk factor for BP progression and
incident hypertension during 7 years of follow-up.
In contrast, when the model was reversed, no BP
measure entered the model for follow-up CFPWV
once baseline CFPWV was considered, providing
strong support for the hypothesis that aortic stiffness is a cause rather than a complication of hypertension. A recently reported mouse model of aortic
stiffness produced by a high-fat, high-sucrose diet
demonstrated similar temporal relations between
aortic stiffness and hypertension [33 ]. Several
studies in humans have shown that increased aortic
stiffness can precede the development of hypertension [32 ,34–37], and others have suggested
that the relation may be bidirectional [38–40].
A traditional view of the pathogenesis of hypertension posits initiation of the disease by an increase
in cardiac output that may be a consequence of
various lesions in sodium handling, hyperactivity
of the renin–angiotensin system or the sympathetic
nervous system, or other causes [41]. In this paradigm, the increase in cardiac output triggers secondary changes in resistance vessel structure and
function, a progressive increase in peripheral resistance, and a fixed elevation of mean arterial pressure.
To evaluate this potential mechanism, we defined
reference values (95th percentile) for key central
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Arterial stiffness: insights from Framingham and Iceland Mitchell
hemodynamic measures in healthy participants less
than 50 years of age in the Framingham Offspring
and Third Generations cohorts [8]. We then
examined the prevalence of high values in the full
cohort. We found a modest prevalence of elevated
cardiac output (7%) and peripheral resistance (28%).
In contrast, prevalence of high CFPWV (>8.1 m/s)
was substantial (69%). In light of our findings that
elevated CFPWV is associated with increased risk for
incident hypertension and CVD, it seems that aortic
stiffness and pulsatile load, rather than mean pressure and steady-flow load, may contribute substantially to the burden of hypertension and CVD,
particularly after midlife [7,32 ].
Although additional work will be required in
order to clarify the predominant directionality of
longitudinal relations between arterial stiffness and
hypertension, it is clear that hypertension is very
commonly associated with increased aortic stiffness
and that stiffness complicates the attempts to control BP. The overwhelming majority of cases with
uncontrolled hypertension have persistent (mostly
isolated) SBP elevation, meaning that failure to
control BP represents failure to control PP and hence
failure to control aortic stiffness [42]. Although
this observation gives cause for concern, it also
represents an opportunity because we have never
really tried to control PP or stiffness. All drugs currently approved to treat hypertension were designed
and approved based on their ability to reduce mean
arterial pressure. The epidemiology of uncontrolled
hypertension provides an urgent public health
imperative to refocus our efforts in order to define
and implement interventions that target prevention
or amelioration of abnormal arterial stiffness and
increased PP.
&&
ARTERIAL STIFFNESS AND TARGET
ORGAN DAMAGE
Hypertension and arterial stiffening are associated
with an increased risk for damage in various target
organs, including the heart, brain, and kidneys.
Effects on the heart are largely attributable to excessive load or ischemia because of atherosclerosis or
small-vessel disease. Excessive pulsatile load is
associated with left ventricular hypertrophy and
impaired diastolic relaxation, which may contribute to the link between arterial stiffness and heart
failure with preserved systolic function [43]. Excessive aortic stiffness and high levels of pressure and
flow pulsatility are particularly deleterious in highflow organs such as the brain [44,45 ] and kidneys
(AGES-II) [46 ,47 ]. Aortic stiffening is generally
associated with minimal change or even a reduction
in the stiffness of muscular arteries [8,48]. The
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&&
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resulting ‘impedance matching’ between aorta
and muscular arteries reduces wave reflection and
therefore facilitates transmission of potentially
harmful pulsatile energy into the peripheral vascular bed [44,46 ,47 ]. In addition, high-flow organs
are necessarily low impedance, meaning that
more of the pulsatility transmitted into the main
conduit vessels supplying the organ will penetrate
into the microcirculation, where it can cause damage and remodeling that may impair microvascular
function. The combination of BP lability [49] and
blunted microvascular reactivity [50] in individuals with stiff arteries may predispose to repeated
episodes of ischemia and tissue damage leading to
functional consequences, such as a reduction in
cognitive scores [44,45 ] or glomerular filtration rate
[34,35].
&&
&&
&
ARTERIAL STIFFNESS AND
CARDIOVASCULAR DISEASE RISK
CFPWV has emerged as the gold-standard measure
of aortic stiffness and a powerful new noninvasive
tool for risk stratification. Using data from the
Framingham Heart Study, we demonstrated that
CFPWV reclassified risk in a model that considered
standard CVD risk factors, including SBP [7]. A
recent individual participant meta-analysis of 16
studies and 17 635 participants with 1785 major
CVD events confirmed the ability of CFPWV to
reclassify risk [6 ]. The hazard ratio associated with
CFPWV was particularly high in younger participants, suggesting that CFPWV may be an effective
tool for early screening before potentially irreversible changes in arterial structure have occurred.
Numerous studies have demonstrated that
higher PP is associated with increased risk
[51–55], although it is difficult to demonstrate
that PP reclassifies risk in a model that includes
SBP because SBP and PP are highly correlated. Nevertheless, Franklin et al. [56] were able to demonstrate
that PP and mean arterial pressure in a dualcomponent model stratified risk better than individual BP components and, in contrast to SBP and
DBP, had readily interpretable linear relations with
risk. Elucidation of hypertension pathophysiology
and treatment will be facilitated by the consideration of the separate roles played by mean arterial
pressure and PP, which are key components of BP
that have markedly different anatomic and physiologic determinants.
Much has been written in recent years regarding
the potential prognostic implications of central
pressure compared with peripheral PP for risk stratification. Arguments generally were based on the
not unreasonable assumption that central pressure
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Circulation and hemodynamics
better reflects local load on the heart, brain and
kidneys, and therefore should be a better marker
of risk. However, regardless of whether the absolute
values differ, central and peripheral pressures are
very highly correlated (R 2 > 0.9) [57]. Thus, it will
be difficult to demonstrate that either measure is
superior to the other as a predictor of risk. In
addition, the SphygmoCor device, which many
studies have used to estimate central pressure from
a radial pressure waveform by using a generalized
transfer function, is known to utilize a faulty
calibration procedure that results in substantial
underestimation of central pressure and hence overestimation of the apparent difference between
central and conventional BP [58 ,59]. We evaluated
the direct measures of central pressure based on
carotid tonometry in the Framingham Heart Study,
and did not find any incremental value of central
pressure in a model that included standard risk
factors and arm SBP [7]. In light of these observations, it seems that focusing efforts on improved
awareness of the importance of conventional PP
and CFPWV rather than the potential differences
between central and peripheral pressure would be
reasonable.
&
CONCLUSION
Arterial stiffness research has progressed remarkably
over the last decade and has emerged as an area of
interest across multiple medical specialties. Essentially, all tissues in the body are perfused and therefore potentially susceptible to the adverse effects of
vascular dysfunction and excessive pressure pulsatility. The contribution of stiffness to pathogenesis,
complications, and refractoriness to conventional
treatment of hypertension underscores an important opportunity for the focused discovery of novel
interventions that prevent or ameliorate aortic
stiffness.
Acknowledgements
None.
Financial support and sponsorship
Sources of funding: Work presented in this review
performed at the NHLBI Framingham Heart Study
was supported by the NHLBI (NHLBI/NIH Contract
#N01-HC-25195) and the Boston University School of
Medicine and by HL076784, G028321, HL070100,
HL060040, HL080124, HL071039, HL077447,
HL107385, and 2-K24-HL04334. Work presented in
this review performed at the AGES-Reykjavik Study was
supported by the National Institutes of Health (contract
N01-AG-12100); the National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic
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Heart Association); the Althingi (the Icelandic Parliament); and a grant from the National Institutes of
Health, National Heart, Lung and Blood Institute (grant
number HL094898).
Conflicts of interest
Disclosures: G.F.M. is the owner of Cardiovascular
Engineering, Inc., a company that develops and manufactures devices to measure vascular stiffness, serves as a
consultant to, and receives honoraria from, Novartis and
Merck, and is funded by the research grants HL094898,
DK082447, HL107385, and HL104184 from the
National Institutes of Health.
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