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which is used to directly measure the regional stiffness, While there is no non-invasive technique available to dir-
is generally accepted as the simplest, most robust, repro- ectly measure central PP, the most widely used approach
ducible and non-invasive method of detecting arterial is to measure the brachial PP by a sphygmomanometer
stiffness.13 Aortic PWV is the most interesting parameter and then apply the transfer function. However, the
since the aorta makes the largest contribution to the premise of using the transfer function is that the
buffering function and is responsible for most of the characteristics of the vascular system between the two
pathophysiological effects of arterial stiffness.12 measuring sites are the same in all individuals and under
Therefore, the measurement of aortic PWV (mainly all conditions. Apparently, this is not true since vascular
carotid-femoral PWV) was used in numerous clinical dimension depends on body size, and vascular properties
studies and has emerged as golden measuring criteria of vary with arterial pressure, with age and with treatment.
arterial stiffness in adults.13 The 2013 European guide-
lines for the management of hypertension and cardio- Measurement of arterial diameter change with respect to
vascular disease prevention in clinical practice even the distending pressure
recommended that aortic PWV be used to assess target Unlike PWV, which is the measurement of regional arter-
organ damage.14 The limitations of PWV measurement ial stiffness in a certain segment, the measurement of
should be mentioned here. It remains difcult to accur- changes in arterial diameter and volume can help evalu-
ately record the femoral pressure wave in participants ate the elasticity of the local artery. Echo tracking system
with peripheral artery disease, and obesity effects the or MRI is performed to acquire local stiffness index like
absolute value of PWV by overestimating the distance.13 compliance, distensibility, Youngs elastic modulus and
Cardio-ankle vascular index (CAVI), one of the PWV incremental elastic modulus. Compliance is dened as
measurement modications and derived from arterial the change in arterial volume relative to change in pres-
stiffness index , was introduced by Japanese experts to sure while distensibility is analogous to compliance but
obtain arterial stiffness not affected by blood pressure after normalisation of arterial size. The curvilinear rela-
(BP) at a measuring time; thus permits for the rst time tionship between pressure and diameter is approximated
to analyse the effect of antihypertension drugs on arter- with a logarithmic transformation, resulting in the
ial property.15 CAVI exhibited reproducibility among index reecting the stiffness.
various vascular diseases.10 16 However, the limitations of However, the pressurediameter or pressurevolume
CAVI should also be concerned. CAVI cannot be mea- relations depend both on the stiffness of the vessel wall
sured accurately in patients with aortic stenosis, periph- and on the vessel geometry including artery size and
eral arterial disease or atrial brillation.17 CAVI usually wall thickness.21 Besides, it requires a high degree of
evaluates the vascular condition of large arteries.18 In technical expertise and takes longer than measuring
addition, the mixture of functional and anatomical PWV. This method is applied more in mechanistic ana-
concept also limits its clinical application. lyses than in epidemiological studies.13
factors could break the synthesis/degradation balance inextensible.21 32 Therefore, arterial stiffness increases at
and raise the ratio of collagen/elastin, thus increasing a higher BP even without structural change.
arterial stiffness.24
Cross-links between collagen and elastin in the arterial
HAEMODYNAMIC PATHOGENESIS SECONDARY TO
wall are signicant in providing elasticity and strength to
ARTERIAL STIFFNESS
the arteries. Owing to the glycation of proteins, espe-
Among the various models that applied to the circulatory
cially collagen, advanced glycation end products (AGEs)
system for a better understanding of haemodynamics, the
are formed, which create excessive cross-links between
propagative model based on a viscoelastic tube hypothesis
collagen and consequently induce arterial stiffness.25
is the most acceptable one.12 In this model, the elastic
AGEs could also inuence the stiffness of the artery wall
properties of the tube allow the generation of a forward
by the receptor-mediated endothelial dysfunction and
pressure wave, which travels along the tubes. On the
inammation process. From a prospective study con-
other hand, the numerous branch points and high resist-
ducted in patients with early rheumatoid arthritis, arter-
ance of the tubal end favour the wave reection and gen-
ial stiffness was improved greatly after 12-month
erate retrograde waves. In healthy participants, reected
treatment of anti-inammation.26
waves arrive at the central aorta during the diastole phase,
Smooth muscle cell hypertrophy: Alteration in mechanical
contributing to the secondary uctuation of the pressure
aortic wall properties accompany with reduction in com-
waveform, which benets the coronary perfusion.
pliance and distensibility preceded the development of
With increased arterial stiffness, the forward and
hypertension in spontaneously hypertensive rats.27 While
reected wave travel more rapidly along the arterial tree,
there was no signicant difference in collagen content
leading to an earlier arrive in late phase of systole.
between young spontaneously hypertensive rats and
Therefore, the reected wave amplies systolic BP and
normotensive rats, the media thickness and cross-
PP, increases the after load and may lead to ventricle
sectional area were signicantly larger in hypertensive
hypertrophy in the long run. A raised PP damages small
rats. Vascular smooth muscle cell hypertrophy, which is
arteries in peripheral organs, thus in turn inducing
mainly responsible for media thickness, participated in
arterial stiffness.
the development of arterial stiffness.
Increased arterial stiffness could also promote exces-
sive ow pulsatility into small vascular beds. Unlike most
Vascular function
vascular beds which are protected by intense vasocon-
Endothelial dysfunction: Endothelial dysfunction embodies
striction upstream, the brain is more susceptible to pres-
its indispensable role in vascular disease by releasing
sure and ow pulsatility.33 34 This haemodynamic stress,
vasoactive substances. Nitric oxide (NO) has a vasodila-
pulsatile pressure or BP variability can cause a tsunami
tory effect and exhibits antiatherogenic property
effect towards cerebral parenchyma.35 This might help
through inhibition of vascular smooth muscle cell prolif-
explain how aortic stiffness damages microvasculature
eration.28 Blocking endothelium-derived NO synthesis
and causes dysfunction.36 37
resulted in higher arterial stiffness.29 Impaired endothe-
lial function was independently and inversely related to
PWV, AIx and central PP as shown in the large-scale ARTERIAL STIFFNESS: A PREDICTOR OF STROKE
study among healthy participants.5 In fact, there might An indirect clue for the inuence of arterial stiffness on
exist a vicious circle between endothelial dysfunction stroke comes from early cross-sectional studies. Patients
and arterial stiffness, that is, endothelial dysfunction with cardiovascular risk factors or vascular diseases such
could aggravate structural stiffening and, in turn, worsen as coronary heart disease and end-stage renal disease
endothelial function.24 had higher arterial stiffness than did the control
Smooth muscle tone: Smooth muscle tone modulates the group.38 39 The rst study on arterial stiffness in patients
artery elasticity. Vasodilators decrease the smooth muscle with stroke evaluated vascular stiffness by calculating
tone, cause a reduction of wave reection and raise the index . Index was signicantly greater in patients with
distensibility.30 Vasoconstrictors such as angiotensin II, stroke than in the control group, indicating that aortic
on the other hand, lead to loss of elasticity in the vessel stiffness was independently associated with ischaemic
wall.31 The endothelial dysfunction interacts with stroke.40 Later, more and more large casecontrol
impaired muscle tone via these released vasoactive sub- studies conrmed that greater arterial stiffness was
stances in the progression of elasticity alteration. common in patients with stroke.41 42 Owing to the cross-
sectional nature of these studies, it was impossible to
Blood pressure conclude that vascular stiffness was predictive of stroke.
Arterial stiffness depends on cyclic strain of the arterial Later longitudinal studies demonstrated that vascular
wall, mainly the cyclic change of BP. At a low BP level, stiffness was an independent predictor of cardiovascu-
the elastin controls the composite behaviour and the lar and all-cause mortality in patients with hyperten-
vessel wall is relatively extensible, while at a high BP sion, early-stage renal disease and in the elderly
level, the collagen with stiffer property is increasingly population.4345 However, stroke was only discussed as
important and then the vessel wall becomes one of the clinical end points until Laurent et al46 rst
investigated the association of vascular stiffness and fatal alterations secondary to arterial stiffness should be high-
stroke occurrence in a cohort survey. After an average lighted. Raised PP induces arterial remodelling,
7.9 years follow-up of middle-aged patients with essential increases wall thickness, promotes the development of
hypertension, Laurent et al found that a 1-SD elevation plaque and atherosclerosis, and eventually lead to
(4 cm/s) in PWV was associated with a 72% higher risk rupture or ulceration of atherosclerotic plaques. Besides,
of fatal stroke. High PWV remained signicantly predict- increased aortic pulsatility may also transmit through
ive of stroke death after adjustment for classical cardio- stiffen large vessels to the cerebral microvasculature. As
vascular risk factors. Other researchers assessed its the central artery stiffen, the capacity to regulate the
predictive value in the elderly and general popula- pulsatile ow is reduced, which leads to progressive
tion.6 47 Data from two recent meta-analyses suggest that impedance matching between the aorta and peripheral
the assessment of aortic or carotid stiffness could arteries. Such impedance cause a decrease in the reec-
both improve the prediction of stroke beyond other con- tion coefcient and thereby facilitates the penetration of
ventional risk factors.48 49 In addition, aortic stiffness excessive pulsatile energy into the periphery.54 To make
could predict the prognosis of ischaemic stroke.7 50 it worse, the vascular resistance of the brain is relatively
Carotid-femoral PWV measured 1 week after stroke was low; therefore, the pulsatility of pressure and ow
signicantly associated with a 90-day functional outcome extend well into this organ. This special input imped-
valued by the modied Rank Scale in patients.7 ance of the brain provides an interpretation for how
As to different subtypes of stroke, vascular stiffness arterial stiffness damages the cerebral microvasculature
seems to have different predictive value.8 9 51 Stroke is a and causes impaired cognition function.33 51 54
heterogeneous disease due to its varied pathophysiology Furthermore, the measured higher aortic stiffness may
in each subtype. Patients with lacunar stroke tended to reect parallel structural changes in the intracerebral
have a higher PWV compared with large artery athero- vasculature, including elastic bres broken down, bro-
sclerosis, cardioembolic and cryptogenic stroke.51 sis, calcications, medial smooth muscle necrosis and
Increased arterial stiffness with greater ow pulsatility diffusion of macromolecules into the arterial
into a cerebral small vessel may contribute to the patho- wall.55 Finally, the classical vascular risk factors or vascu-
genesis of lacunar stroke, thus resulting in the differ- lar diseases such as hypertension, atherosclerosis, coron-
ence. Another study demonstrated that aortic stiffness ary heart disease and early-stage renal disease, which are
index was higher in patients with cerebral infarction associated with and even probably promoted by arterial
than in those with a transient ischaemic attack, implying stiffness, are also risk factors for ischaemic stroke.
that cerebral infarction is associated with a more
advanced degree of atherosclerotic process than transi-
ent ischaemic attack.9 Larger studies that evaluate the THE DE-STIFFENING THERAPY AND STROKE PREVENTION
relationship between vascular stiffness and each subtype It has aroused enormous interest whether the reduction
stroke are imperative to help clarify the direct inter- on arterial stiffness can translate into real clinical bene-
action in pathogenesis and provide specic insights into ts on stroke management. De-stiffening therapy
efcient stroke prevention. emerges as a promising strategy to decrease stroke
In recent years, high resolution MRI provides a incidence or mortality and improve functional progno-
unique tool to study the relationship between vascular sis. On the basis of numerous clinical trials, antihyper-
stiffness and neuroimagical changes relevant to the tension drugs are successful at reducing BP and
recurrence or severity of stroke. Cerebral small vessel stiffness.5658 However, it is difcult to separate the effect
disease (SVD), which can increase the risk of stroke, is of intervention on BP reduction alone from their direct
linked to arterial stiffness.35 36 52 53 A study of 1282 effect on the property of the vessel wall. It is of utter-
patients with acute ischaemic stroke or transient ischae- most importance to break the vicious circle between
mic attack showed that brachial-ankle PWV was signi- arterial stiffness and raised PP. Targeting structural
cantly associated with both acute and chronic cerebral factors in vascular signalling remains largely unexplored,
SVD markers including acute lacunar infarct, chronic yet progression should not be ignored. Exercise training
lacunar, white matter hyperintensity, deep cerebral is another effective non-pharmacological method in
microbleeding.52 In the general elderly population of attenuating arterial stiffness.
the Rotterdam scan study, higher PWV was also related
to larger white matter lesion volume, but not to lacunar Pharmacological interventions
infarcts or microbleeding.53 Vascular stiffness and cere- Antihypertension drugs: The most important mechanism
bral SVD could share a common pathophysiological of antihypertension drugs improving arterial stiffness is
mechanism involving vascular injury. the efcacy in lowering BP.59 For the same BP reduction,
antihypertension drugs which improve arterial stiffness
to the greatest extent should be privileged. The
MECHANISM OF ARTERIAL STIFFNESS DURING STROKE BP-independent effect comes from the alteration on
A variety of mechanisms could interpret the association arterial function, structure or a combination of both.
between arterial stiffness and stroke. Haemodynamic Antihypertension drugs with vasodilation activity such as
ACE inhibitor (ACEI), angiotensin receptor blocker with vasodilation activity such as nebivolol and carvedilol
(ARB), calcium channel blocker (CCB) and some display the ability to decrease arterial stiffness, but need
-block (BB) have shown advantage in ameliorating to be further investigated with large-scale prospective
arterial stiffness.60 61 Most of the de-stiffening strategy trials.80 81
preferred the administration of RAAS inhibitors com- Antihyperlipidaemic agents: The data on statins are some-
bined with a CCB or a diuretic.59 what conicting.82 83 A systemic review of nine trials with
ACEI/ARB: Among all classes of the antihypertension 471 participants disproved the effect of statins on redu-
drugs, the RAAS inhibitors are generally recognised to cing arterial stiffness, but this conclusion might relate to
be superior to others in reducing arterial stiffness.56 62 63 the methodological limitation that the included trials
The most probable explanation lies in the probrotic only studied aortic or peripheral elasticity at a time.82 A
action of the RAAS. Owing to the antibrotic potency of recent clinical study, which was designed to measure
RAAS inhibitors, the extracellular matrix in the vascular both aortic PWV and AIx at the end of a 26-week
wall is reversed, which nally translates into a change in follow-up, supported the role of statins in ameliorating
mechanical property of the vessel.64 In addition, ACEI stiffness through anti-inammatory and antiproliferative
could modulate endothelial function via releasing brady- properties.83 The percentage reduction in PWV by u-
kinin and NO.65 66 Numerous studies including both vastatin was associated with that of serum C reactive
long-term ones (such as the REASON trial, the protein independent of the lipid-lowering effect.84
ADVANCE trial) and short-term to medium-term ones Other drugs: Other drugs that target vascular signalling
showed a reduction of arterial stiffness when ACEI or in arterial stiffness development have achieved some
ARB was used.6769 When comparing ARB to ACEI, progression. MMP inhibitors include endogenous tissue
taking valsartan and captopril, for example, could inhibitors and pharmacological inhibitors such as zinc
equally reduce PWV as well as AIx.70 A combination of chelators, doxycycline and marimastat, of which only
ACEI and ARB proved to achieve an even greater effect doxycycline is approved by the Food and Drug
on PWV reduction in patients with chronic kidney Administration (FDA).85 In two-kidney one clip hyper-
disease.71 Clinical trials also conrmed the efcacy of tensive rats, doxycycline (30 mg/kg per day, 4 weeks)
RAAS inhibitors in improving patient survival and redu- successfully prevented surgery-induced increases in sys-
cing cardiovascular events.72 73 The PRORESS trial tolic BP and MMP-2 levels, reduction in endothelium-
(n=6105) demonstrated that after a 4-year follow-up, the dependent vasodilation and vascular hypertrophy.86
ACEI regime reduced the risk of recurrent stroke by However, in spontaneously hypertensive rats, though
28% among participants with previous stroke or transi- structural alteration was ameliorated after 6 months
ent ischaemic attack.72 treatment of doxycycline, arterial pressure, PWV and left
CCB: CCB also proved to lower PWV and AIx, but to a ventricular function were unaffected.87 The efcacy of
lesser extent than RAAS inhibitors did.57 74 75 The doxycycline and other MMP inhibitors in reducing arter-
largest amount of evidence came from trials evaluating ial stiffness needs to be studied by different measure-
amlodipine.57 76 A combination of CCB and ARB had ments and in different animal models.
an advantage over the combination of diuretics and AGEI which can prevent AGE cross-linking and AGE
ARB for less side effects and more arterial stiffness breaker which can break the AGE cross-links were found
improvement.74 75 to attenuate arterial stiffness by interfering the arterial
Diuretic: Although the combination of diuretics and remodelling in animal experiments.88 89 Alagebrium
ACEI/ARB has been merged as one of the most common chloride (also known as ALT-711), a novel non-enzymatic
regimes in treating hypertension, the role of diuretics on breaker of AGE, reduced AIx in patients with isolated sys-
treating arterial stiffness has not been well explored.58 77 tolic hypertension and such effect was related to
A 4-week study demonstrated that hydrochlorthiazide improved endothelial function.90 However, the study
failed to decrease PWV and AIx in spite of a reduction in enrolled only 13 patients and the therapy lasted for only
brachial BP, which imply no favourable effect of diuretics 8 weeks. Later, in a randomised trial, a 1-year administra-
on arterial stiffness beyond BP reduction.76 tion of ALT-711 failed to affect arterial stiffness or endo-
BB: BB is less valuable in reducing arterial stiffness, thelial function.91 Despite the promising effect in
probably because it reduces BP by lowering the cardiac reversing ventricular stiffness, the efcacy of AGEIs and
output, which instead increases periphery resistance and AGE breakers in alleviating arterial stiffness needs long-
the wave reection. BB is far beyond homogeneous, and term and high qualied research.92
the effect of arterial stiffness by BB could be either
favourable or unfavourable. A recent meta-analysis Exercise training
reported that BB increased AIx, whereas all other antihy- Arterial stiffness increasing with ageing was less pro-
pertension drugs decreased AIx.78 Furthermore, another nounced in physically active men and women.93 94
meta-analysis from 13 randomised controlled trials Several studies have shown the efcacy of aerobic exer-
suggested that BB is inferior to prevent stroke by report- cise in preventing age-related arterial stiffness in healthy
ing that the relative risk of stroke was 16% higher by BB individuals and reversing arterial stiffness in patients
than other kinds of antihypertension drugs.79 Novel BBs with vascular risk factors as well.9597 Aerobic exercise