Nephrol Dial Transplant (2002) 17: 1713–1724
Tony Raine Memorial Lecture
Arterial structure and function in end-stage renal disease
Gérard M. London, Sylvain J. Marchais, Alain P. Guerin, Fabien Metivier and Hassan Adda
Nephrology Department, Manhès Hospital, Fleury-Mérogis, France
On October 14, 1995, Professor A. Raine (St
Bartholomew’s Hospital, London) died at the young
age of 46 years. He was a fascinating man who combined
a rigorous scientific approach with clinical acumen. He
excelled in the fields of hypertension research and
nephrological research. He was an inspired investigator
whose untimely death is mourned by many colleagues in
European nephrology.
NDT commemorates the outstanding contributions of
our former subject editor in the field of hypertension by
a contribution bearing on the major research topic of
the late Professor Raine, i.e. the interrelation of kidney
and blood pressure.
Introduction
Epidemiological studies have shown that damage of
large conduit arteries is a major contributing factor
to morbidity and mortality in patients with chronic
kidney disease and in those with end-stage renal
disease (ESRD) [1]. Atherosclerosis, a primary intimal
disease characterized by the presence of plaques and
occlusive lesions, is the most frequent underlying cause
of these complications, but many vascular complications arise in uraemic patients in the absence of
clinically significant atherosclerotic disease [2,3]. Atherosclerosis represents only one form of structural
response to metabolic and haemodynamic alterations
which interfere with the ‘natural’ process of ageing
[4–6]. The spectrum of arterial alterations in ESRD is
broader, including non-occlusive arterial remodeling
accompanying the growing haemodynamic burden,
and humoral abnormalities associated with chronic
uraemia (Fig. 1) [7,8]. The consequences of these
alterations are different from those attributed to the
presence of atherosclerotic plaques.
Arterial remodeling and arterial function:
basic concepts
Arterial remodeling
Professor Anthony Raine 21.7.49–14.10.95.
Correspondence and offprint requests to: Gérard M. London, MD,
Hôpital Manhès, 8 Grande Rue, Fleury-Mérogis, 91712 Ste
GenevièveudesuBois, France. Email: [email protected]
#
An arterial wall alters its structure and function in
response to direct injury and atherogenic factors or
to changes in haemodynamic burden (Fig. 2) [9]. The
structural modifications induced by haemodynamic
alterations are changes in arterial lumen anduor arterial
wall thickness due to activation, proliferation and
migration of smooth muscle cells, and rearrangements
of cellular elements and extracellular matrix of the
vessel wall [9–13].
The mechanical signals for arterial remodeling associated with haemodynamic overload are the cyclic
2002 European Renal Association–European Dialysis and Transplant Association
1714
G. M. London et al.
Fig. 3. Schematic representation of mechanical stresses in blood
vessels.
Fig. 1. Schematic representation of pathogenic factors associated
with arterial disorders in chronic renal failure. CRF, chronic renal
failure.
Fig. 2. Schematic representation of the spectrum of large artery
remodeling. Pressure overload is characterized by wall hypertrophy
and increased wall-to-lumen ratio, while flow goes along overload
with a proportional increase of the arterial diameter and wall
thickness. Atherosclerosis is characterized by the development of
plaques.
tensile stress anduor shear stress (Fig. 3) [12–14]. While
acute changes in tensile or shear stress induce transient
adjustments in vasomotor tone [15,16], chronic alterations of mechanical forces lead to changes in the geometry and composition of the vessel walls that may be
considered adaptive responses to long-lasting changes
in blood flow anduor pressure [11,17–20].
The characteristics of arterial remodeling depend
largely on the nature of haemodynamic stimuli applied
to the vessel and on the presence of an intact endothelium [19,20]. Blood pressure is the principal determinant of arterial wall stretch and tensile stress.
According to Laplace’s law, tensile stress (s) is directly
proportional to arterial transmural pressure (P) and
radius (r), and inversely proportional to arterial wall
thickness (h) according to the formula: ssPruh. In
response to increased blood pressure or arterial radius,
tensile stress is maintained within the physiological
range by thickening of the vessel wall with normal
internal diameter. Blood flow alterations result in
changes in shear stress—the dragging frictional force
[21]. Shear stress (t) is directly proportional to blood
flow (Q) and blood viscosity (g) and inversely proportional to the radius (r) of the vessel, according to the
formula: tsQgupr3 (Fig. 3). Experimental and clinical
data indicate that acute and chronic augmentations of
arterial blood flow induce proportional increases in the
vessel lumen, whereas decreasing flow reduces arterial
inner diameter [10,22,23]. An example of flow-mediated
remodeling associates arterial dilation and sustained
high blood flow after the creation of an arteriovenous
fistula [18]. In this situation, the lumen diameter
increases to maintain shear stress within physiological
limits. Increased arterial inner diameter is usually
accompanied by arterial wall hypertrophy and increased
intima-media cross-sectional area (following increases
in the radius and wall tension) since changes of shear
stress and tensile stress are interrelated because any
modification of arterial radius caused by alterations in
blood flow and shear stress induces changes in tensile
stress.
The process of transforming mechanical forces into
remodeling of vascular system implies that there are
‘sensors’ that detect and transmit physical forces to
effector cells. Endothelial cells are strategically situated
at the blood–vessel wall interface and are the principal
candidates for the role of such sensors [24,25]. This
mechanosensor activation results in the transduction
of physical stimuli into a biochemical signal affecting arterial function through the generation of vasoactive substances [nitric oxide (NO), prostacyclin,
endothelins, etc.], the expression of adhesion molecules, the activation and release of metalloproteinases
[26–31], and the activation of transforming growth
factors [32–35]. The presence of the endothelium is a
prerequisite for normal vascular adaptation to chronic
changes in blood flow, and experimental data indicate that flow-mediated arterial remodeling can be
decreased by inhibiting NO synthase [20,36].
Arterial structure is also altered in response to direct
injury and atherogenic factors [37–39]. Atherosclerosis,
characterized by the presence of plaques, is primarily
an intimal disease, focal and patchy in its distribution, occurring preferentially in medium-sized conduit arteries like epicardial coronary arteries, femoral
and iliac arteries, infrarenal aorta, carotid bulb and
cerebral arteries, and usually sparing muscular type
arteries in the arms, internal mammary and other
Arterial structure and function in ESRD
arteries [39]. Mechanisms of atherogenesis are complex and include smoking, lipid disturbances, thrombogenesis, production of vasoactive substances, growth
factors and mediators of inflammation. Tensile stress
and shear stress also influence the natural history of
atherosclerosis [37,40]. Evidence that enhanced tensile
stress is relevant to the pathogenesis of atherosclerosis
comes from the following observations: atherosclerotic
plaques are virtually confined to systemic arteries
where tensile stress is high, and are absent from the
venous system [41]; atherosclerosis develops in autogenous venous bypass grafts, but can be prevented by
applying a rigid external support to counteract the
increased transmural pressure in the graft [40]; in aortic
coarctation, atherosclerosis is accelerated in arteries
cephalad to the coarctation, while it is decreased in
arteries caudal to the coarctation [41]. The role of
shear stress is demonstrated by the predilection of
atherosclerosis for certain sites, such as ostia, branching points, bifurcations, bending or pronounced
arterial tapering [42– 46]. These sites are characterized
by flow pattern and shear stress disturbances, for
example, low average shear stress or secondary and
turbulent flows with variable shear stress over the
cardiac cycle [44,45]. While it was initially thought that
atherogenesis was the consequence of injury evoked by
high shear stress [45], it was later demonstrated that
atherosclerosis is uncommon in sites with high shear
stress, such as at flow dividers on the inner aspects of
arteries downstream from flow dividers or on the outer
aspect of an arterial bend [44,46–48]. In these locations, the endothelial cells are aligned in the direction
of flow, thereby decreasing the effective resistance
to friction and ‘autoregulating’ shear stress [47]. The
increase of shear stress promotes the secretion and
synthesis of NO [16], prostacyclin [27], and antithrombotic and antigrowth factors that mediate atheroprotection [25], and survival of endothelial cells, which
then become more adherent to the intima and less
permeable to the entry of lipoproteins and monocytes
[49,50]. At sites of low shear stress or turbulent flow
(characterized by flow reversal and time-averaged
shear stress approaching 0), endothelial cells secrete
prothrombotic and progrowth factors, and trigger
endothelial apoptosis [51]. Moreover, blood is in
contact with the endothelium for longer periods of
time, thereby prolonging particle residence time at the
blood–vessel wall interface, thus favouring enhanced
interaction between blood and atherogenic factors,
and facilitating the diffusion of lipids or macromolecules and migration of inflammatory cells across the
endothelium [48,50].
Arterial function
Conduit function of arteries. The conduit function is
to supply an adequate blood flow to peripheral
tissues and organs in accordance with their metabolic
needs. Conduit function efficiency is the consequence
of the width of the arteries and the very low resistance of large arteries to flow. The conduit function
1715
is highly efficient and can accomodate increases
in the flow to some tissues, like muscle, by perhaps
10-fold. This physiological adaptability is mediated
through acute changes of arterial flow velocity anduor
diameter. Diameter changes are dependent on the
endothelium, which responds to alterations in shear
stress [16,24]. The acute endothelium-dependent vasodilation is limited in several clinical conditions including atherosclerosis [52], hypertension [53], cardiac
failure [54], hypercholesterolaemia [55], diabetes [56],
menopause [57] and ageing [58]. Under conditions
of long-term flow overload, the arterial diameters
are enlarged and baseline arterial conductance is increased [10,18]. The principal long-term alterations
of conduit function occur through narrowing or
occlusion of arteries with restriction of blood flow
and resulting ischaemia or infarction of downstream
tissues. Atherosclerosis is the most common disease
that disturbs conduit function. Owing to the large
luminal area of conduit arteries, basal blood flow
remains unchanged until the lumen diameter is narrowed by 50%. Beyond 70–80% reduction of the
lumen diameter (critical stenosis), basal blood flow is
reduced, as is the ability to increase flow during
activity [21].
Cushioning (dampening) function of arteries. The role
of arteries is also to dampen the pressure and flow
oscillations resulting from intermittent ventricular
ejection and to transform the pulsatile flow of arteries
into the steady flow required in peripheral tissues and
organs [21]. During systolic contraction, ;40% of
stroke volume is forwarded directly to peripheral
tissues, while the remainder is stored in capacitive
arteries (mainly aorta and elastic-type arteries).
Approximately 10% of the energy produced by the
heart is diverted for the distension of arteries and
‘restored’ during diastole to recoil the aorta, squeezing the stored blood forward into the peripheral
tissues, thereby ensuring continuous perfusion of
organs and tissues. As the energy produced by the
heart should serve principally for tissue perfusion,
the part of energy used for arterial distension and
recoil should be as low as possible. Therefore, the
arterial wall must be distensible, i.e. for a given volume change (stroke volume), the developed pressure
(pulse pressure) should be as low as possible. The
efficiency of the conduit function depends on the viscoelastic properties of arterial walls and the geometry
of the arteries, including their diameter and length
[21]. The viscoelastic property is best described in
terms of stiffness, which expresses the relationship
between pressure response (DP) and change in volume
(DV ). Stiffness represents the instantaneous slope
of the pressure–volume relationship (SsDPuDV )
(Fig. 4). Because the arterial wall is composed of a
‘mixture’ of smooth muscle cells, fibroblasts and connective tissue, containing elastin and collagen fibres,
the pressure–volume relationship is non-linear. At a
low distending pressure, the tension is borne by elastin fibres, whereas at a high distending pressure, the
1716
Fig. 4. Representation of pressure–volume relationships. Note that
stiffening could be due to position on the curve with stiffness
increasing with pressure, or to changes in viscoelastic properties
(shift to the left with an increase in Einc-incremental elastic modulus).
tension is predominantly borne by less extensible collagen fibres and the arterial wall becomes stiffer. This
arrangement is advantageous because it prevents
arterial blood from pooling at high pressure and protects arteries from high pressure-induced rupture. The
distribution of elastin and collagen differs between
central and peripheral arteries. The collagenuelastin
ratio increases from the aorta towards peripheral
arteries whose stiffness is higher than that of the
central arteries. To facilitate comparisons of viscoelastic properties of structures with different initial
dimensions, stiffness can be expressed relative to the
initial volume as DPVuDV where V is the initial
volume. In contrast to stiffness which provides information about the ‘elasticity’ of the artery as a hollow
structure, the elastic incremental modulus (Einc) provides direct information on the intrinsic elastic properties of the materials that compose the arterial wall
independent of vessel geometry. An increased Einc is
characteristic of stiffer biomaterials and is responsible
for the leftward shift of the pressure–volume curve
(Fig. 4) [21]. The stress applied to arterial segments
(DP) is the pulse pressure. Owing to the inhomogeneity of the viscoelastic properties of successive arterial
segments and the effect of arterial wave reflections
(see below), pulse pressure and systolic pressure are
amplified from the aorta to the peripheral arteries
[59–61]. To determine the elastic properties of arterial
segments accurately, the ‘local’ pulse pressure must
be measured and taken into consideration. Arterial
stiffness can be evaluated by ultrasonography or
by the measure of the pulse wave velocity (PWV)
over a given arterial segment [8,62]. PWV increases
with arterial stiffness [62,63], according to the
Moens–Koerteweg formula PWV2sEinchurD, where
Einc is incremental modulus, h is wall thickness, D is
the artery diameter and r is the density. The principal ‘visible’ consequences of arterial stiffening are
an increase in systolic pressure and a decrease in
diastolic pressure with resulting high pulse pressure
[21]. Pulse pressure depends on the interaction
between LV ejection (stroke volume) and the physical
G. M. London et al.
properties of the arterial system that influence pulse
pressure by two mechanisms. First, the direct mechanism involves the generation of a higher pressure wave
by the LV ejecting blood into a stiff arterial system,
and decreased diastolic recoil resulting in lowered
diastolic pressure. Secondly, the indirect mechanism
acts via the influence of increased arterial stiffness on
PWV and the timing of incident and reflected pressure waves [21,63–67]. Ejection of blood into the
aorta generates a pressure wave that is propagated
to other arteries throughout the body. This forwardtravelling (incident) pressure wave is reflected at any
point of structural and functional discontinuity in the
arterial tree, thereby generating a reflected (‘echo’)
wave travelling backwards towards the ascending
aorta. Incident and reflected pressure waves interact
constantly and are summed-up in the measured pressure wave. The final amplitude and shape of the
measured pressure wave is determined by the phase
relationship (the timing) among the component
waves [21,60–65]. The timing of incident and reflected
pressure waves depends on PWV, the traveling distance of pressure waves, and the duration of LV ejection [65,66]. The shape and amplitude of measured
pulse pressure waves depend on the site of pressure
recording in the arterial tree [66,67]. Peripheral
arteries are close to reflection sites, and the incident
and reflected waves in these arteries are in phase and,
thus, produce an additive effect. The ascending aorta
and central arteries are distant from reflecting sites
and, depending on the PWV and arterial length, the
return of the reflected wave is variably delayed and
thus the incident and reflected waves are not in
phase. In young human subjects with distensible
arteries and low PWV, the reflected waves affect central arteries during diastole after LV ejection has
ceased. This timing is desirable, since the reflected
wave causes an increase in ascending aortic pressure
during early diastole and not during systole, resulting
in aortic systolic and pulse pressures which are lower
than in peripheral arteries (only mean blood pressure
is almost constant throughout the arterial system)
[59–66]. This situation is physiologically advantageous since the increase in early diastolic pressure
has a boosting effect on coronary perfusion, without
increasing LV afterload. The desirable timing is disrupted by increased PWV due to arterial stiffening.
With increased PWV, the reflecting sites appear
‘closer’ to the ascending aorta and the reflected
waves occur earlier, being more closely in-phase with
incident waves in this region. The earlier return means
that the reflected wave affects the central arteries
during systole rather than diastole, thus amplifying
aortic and LV pressures during systole and reducing
aortic pressure during diastole. In this situation, the
pulse and systolic pressure gradients along the arterial tree tend to disappear, resulting in temporal
equalization of peripheral and aortic pressures.
Increased arterial stiffness is deleterious to LV function. By favouring early wave reflections, arterial
stiffening increases peak- and end-systolic pressures
Arterial structure and function in ESRD
Fig. 5. Correlation between aortic stiffness (PWV) and left ventricular mass index in ESRD patients (adapted from London et al. [77]).
Fig. 6. Correlation between wave reflection and left ventricular mass
index in ESRD patients (London et al., personal unpublished data).
in the ascending aorta, increasing pressure load and
myocardial oxygen consumption and decreasing the
diastolic blood pressure as a determinant of coronary
perfusion and blood flow distribution. Canine studies
have shown that aortic stiffening directly decreases
subendocardial blood flow despite an increased mean
coronary flow, and that chronic aortic stiffening
reduces cardiac transmural perfusion and aggravates
subendocardial ischaemia [68]. Furthermore, increased
systolic blood pressure induces myocardial hypertrophy (Figs 5–6), and impairs diastolic myocardial
function and LV ejection [69,70]. In addition,
increased systolic blood pressure and pulse pressure
accelerate arterial damage, increasing the fatigue of
biomaterials, degenerative changes and arterial stiffening, thereby potentiating the process [39]. Although
arterial stiffness is responsible for the acceleration
of pressure wave transmission, the intensity of wave
reflection is dependent on the reflective properties of
the vascular tree (reflectance) that could be altered
independently of arterial stiffening. Reflectance
depends on the impedance mismatches of successive
arterial segments, their branching angles, the vasomotor tone and geometric properties of microvascular
1717
network, and on the body shape responsible for more
or less pronounced spatial dispersion of pressure wave
[21,39].
The dampening function of the arterial tree is altered
primarily during the ageing process and in conditions
associated with ‘sclerotic’ remodeling of arterial walls,
i.e. associated with increased collagen content and
modifications of extracellular matrix (arteriosclerosis)
[6,70–73]. Arteriosclerosis is primarily manifest as
medial degeneration that is generalized throughout
the thoracic aorta and central arteries, causing dilatation, diffuse hypertrophy and stiffening of the arteries
[4,5,21,73]. Arteriosclerosis is sometimes considered to
be a ‘physiological’ ageing phenomenon, resulting in
diffuse fibroelastic intima thickening, increased medial
ground substance and collagen, and fragmentation
of elastic lamellae with secondary fibrosis and calcification of the media [4–6,71–73]. Age-related arterial
alterations leading to stiffening are heterogeneous,
being more pronounced in the aorta and central,
elastic-type, capacitative arteries than in the peripheral
muscular-type limb arteries [62].
Taken together, atherosclerosis is a disorder that
typically disturbs conduit function, while arteriosclerosis does not alter it under basal metabolic conditions.
However, in Western populations, these two conditions frequently coexist since both progress with ageing
and share several common pathogenic mechanisms,
which sometimes make the distinction difficult. Atherosclerosis in ESRD patients was the subject of several
recent reviews; therefore, in the present article we shall
focus on alterations of arterial stiffening in uraemic
patients.
Arterial stiffness, blood pressure and cardiovascular
disease in ESRD
The arterial system of patients with chronic renal
failure and ESRD patients undergoes remodeling that
is characterized by dilatation and, to a lesser degree,
arterial intima-media hypertrophy of central, elastictype, capacitative arteries, and isolated wall hypertrophy of peripheral muscular-type conduit arteries
[7,8,74–76]. In ESRD patients, this remodeling is associated with arterial stiffening due to alterations of the
intrinsic properties of arterial wall materials (Einc)
including those arteries free of atherosclerosis, such as
upper arm arteries [7,8,77–80].
Large arteries, like the aorta or common carotid
artery, are enlarged in ESRD patients in comparison
with age-, sex- and pressure-matched control subjects.
Arterial enlargement is already observed at the onset of
dialysis, suggesting that arterial remodeling takes place
early in the course of renal failure. The internal dimensions of large arteries are influenced by many factors.
Several factors, for example age, sex or mean blood
pressure, are non-specific for ESRD patients, while
others, such as high blood flow velocity and systemic
blood flow rate, are more specific for this patient
population (Fig. 7) [8]. In ESRD patients, chronic
volumeuflow overload (anaemia, arteriovenous shunts,
1718
Fig. 7. Correlation between left ventricular outflow velocity and
common carotid artery diameter in ESRD patients (London et al. [8]).
sodium and water retention) creates conditions for
arterial remodeling [8]. The intima-media thickness
of elastic-type arteries is proportional to changes
in diameter, with similar wall-to-lumen ratio, while
muscular-type arteries are characterized by wall hypertrophy and increased wall-to-lumen ratio [8,75]. This
heterogeneity is related to a predominance of flowrelated remodeling in central arteries under conditions
of combined pressure and flow overload [81]. According to Laplace’s law, arterial wall hypertrophy could
be considered a response to increased tensile stress,
and when blood pressure increases, regardless of
the internal radius, the wall-to-lumen ratio should
increase in order to normalize tensile stress [21]. This
increase was observed in non-uraemic populations
but not in ESRD patients whose wall-to-lumen ratio
in large conduit arteries was not related to pressure
changes [80]. The difference between the observed
relationships suggests that conduit arteries could have
limited capacity to hypertrophy in response to a
combined flow and pressure load. This possibility was
documented by Savage et al. [82] and Konings et al.
[83], who showed that their ESRD patients had
no arterial wall thickening. The altered hypertrophic
response could be due to qualitative alterations of
biomaterials present in ‘uraemic vasculopathy’. Arterial distensibility is ‘pressure-dependent’ [21] and, in
essential hypertensive patients, the decreased arterial
distensibility is due to higher distending blood pressure
rather than to arterial wall thickening and modifications in intrinsic biomaterial stiffness [84,85]. When
adjusted for differences in blood pressure (i.e. under
isobaric conditions), the arterial distensibility anduor
elastic modulus of essential hypertensive subjects are
more distensible (in muscular conduit arteries) or
similar (in elastic capacitive arteries) compared with
those observed in normotensive control subjects
[84,85]. This concept is different from the observation
made in ESRD patients, in whom common carotid
artery stiffness is increased in comparison to age- and
blood pressure-matched non-uraemic subjects [8,75].
G. M. London et al.
In ESRD patients, arterial hypertrophy is accompanied by alterations in the intrinsic elastic properties
of the vessel wall (increased Einc) that contribute
to creating and amplifying the pressure load. This
modification affects elastic and muscular-type arteries,
including arteries free of atherosclerosis like the radial
artery [75]. The observation that the incremental
modulus of elasticity is increased in ESRD patients
strongly favours altered intrinsic elastic properties
or major architectural abnormalities like those seen
in experimental uraemia and the arteries of uraemic
patients, namely fibroelastic intimal thickening,
increased extracellular matrix and high calcium
content with extensive medial calcifications [86–88].
Finally, the presence of generalized endothelial
dysfunction in uraemic patients probably also contributes substantially to arterial alterations in ESRD
patients. As shown experimentally by Lévy and colleagues [89,90], the endothelium influences the mechanical and geometric properties of large arteries,
and removing the endothelium causes an increase in
arterial diameter. In ESRD patients, large artery alterations are associated with decreased post-ischaemic
arterial vasodilatation and decreased flow-debt repayment, suggesting a relationship between arterial
modifications and endothelial dysfunction [91–96].
An association between arterial remodeling and
functional alterations with lipid abnormalities is not
obvious and was found only irregularly. London et al.
[77] and Saito et al. [78] reported an inverse relationship between aortic PWV and HDL cholesterol.
Burdick et al. [97] and Nishizawa et al. [98] described
a positive relationship between carotid intima-media
thickness and IDL or LDL cholesterol. The most
frequently observed factors associated with arterial
stiffening in ESRD seem to be alterations in calcium
and phosphate metabolism. Experimental studies
suggest that some of the effects of renal failure on
arterial remodeling and increased fibrogenesis depend
on the permissive action of parathyroid hormone
[99]. In chronic haemodialysis patients, aortic PWV
was found to be associated with mediacalcinosis of
conduit arteries and increased calcium phosphate
product [77,78]. Kawagishi and colleagues [74]
reported that a high phosphorous level was associated
with carotid artery intima-media thickening, while
increased serum PTH was a risk factor for increased
wall thickness of femoral arteries. Studying renal
transplant recipients, Barenbrock and co-workers
[100] observed an association between high PTH
levels and decreased common carotid artery distensibility. Recent data indicate that mediacalcosis and
extensive calcifications of the arterial tree are the
dominant factor accounting for the increased arterial
stiffening [101].
Consequences of arterial stiffening in ESRD patients
Pathophysiological consequences. The pathophysiological consequences of arterial stiffening and wave
reflections are those already described, i.e. increased
Arterial structure and function in ESRD
1719
ventricular afterload associated with ventricular hypertrophy, decreased subendocardial perfusion and
increased mechanical fatigue of arteries.
The clinical consequences. Arterial stiffening is associated with changes in blood pressure profile, characterized by isolated increase in systolic pressure anduor
increased pulse pressure. Increased pulse pressure
can result from increased systolic pressure as well as
from decrease diastolic pressure which is typical for
advanced arteriosclerosis and is responsible for the
diastolic pressure stabilization or decline observed
after the age of 60 [102]. In the general population,
the pulse pressure is an independent cardiovascular
risk factor, observed principally in older subjects
)50 years old [102–105]. The reason is that systolic
pressure as well as pulse pressure result from the
interaction between cardiac factors (stroke volume,
ejection velocity) and the opposition to LV ejection.
Pulse pressure can also increase due to increased
stroke volume (as observed for example in trained
athletes with spontaneous bradycardia and high
stroke volume and is not associated with higher risk).
The risk associated with high pulse pressure is
observed when the increase in pulse pressure is associated with arterial stiffening. Recent epidemiological
studies have shown that pulse pressure is associated
with risk of death in patients undergoing haemodialysis [106,107]. In early renal disease patients,
Levin et al. [108] have shown that increased systolic
blood pressure is an independent predictor of left
ventricular hypertophy and its progression over time
(odds ratio of 1.11 for each 5-mm Hg increase).
Increased arterial stiffness of elastic type arteries is
associated with reduced creatinine clearance and
observed already in subjects with mild-to-moderate
impairment of renal function [109], and in patients
with chronic renal failure [83]. In ESRD patients,
LVH is closely related to systolic or pulse pressure
[8,66,77]. Arterial stiffness and early wave reflection
are the principal determinants of systolic and pulse
pressures in ESRD patients and are associated with
LVH [77] and its progression over time [110].
While in the past, the consequences of arterial
stiffness for patient outcome have not been directly
evaluated, a recent study demonstrated that arterial
stiffening and increased wave reflections are per se
independent predictors of all-cause and cardiovascular
death in ESRD patients as well as in the general population. Blacher and colleagues [111] applied logistic
regression and Cox analyses to various parameters
of a cohort of 241 subjects with ESRD and showed
aortic PWV to be an independent and significant
predictor of all-cause and cardiovascular mortality.
After adjustment for all risk factors (age, pre-existing
cardiovascular disease, blood pressure, anaemia,
LV hypertrophy, etc.), the odds ratio for PWV
()1227 cmus) was 4.4 [confidence interval (CI):
2.3–8.5] for all-cause mortality and 5 (CI: 2.3–10.9)
for cardiovascular mortality (Fig. 8). Similar results
were observed by Shoji et al. [112] in diabetic patients
Fig. 8. Probability of survival in haemodialysis patients according to
aortic PWV (Blacher et al., [111]).
Fig. 9. Probability of survival according to the response of aortic
PWV to antihypertensive treatment. Patients who responded to a
decrease in blood pressure by a decrease of PWV (negative DPWV)
had a significantly better prognosis (Guérin et al. [124]).
with ESRD. In that study it was demonstrated that the
influence of arterial stiffening on mortality outweighed
the role of diabetes. Finally, Laurent et al. [113] showed
that aortic PWV was an independent predictor of
all-cause and cardiovascular mortality in the general
population. PWV is a complex parameter integrating
arterial geometry and intrinsic elastic properties as
described by the Moens–Korteweg equation (see
above). Based on Cox analyses, Blacher and colleagues
[114] showed that the principal factor associated with
PWV as a predictor of cardiovascular and all-cause
mortality in ESRD was increased elastic modulus.
The latter modulus is associated with extensive arterial
calcifications which are also a strong predictor of
mortality in ESRD patients [115]. As already mentioned, increased vascular reflectance influences wave
reflections independently of arterial stiffness. In
ESRD patients, more marked effects of wave reflections
are associated with cardiovascular and all-cause
mortality independently and in parallel with arterial
stiffening [116].
1720
G. M. London et al.
Fig. 10. Illustration of mean blood pressure (MBP) and aortic PWV changes according to outcome in ESRD patients. In patients who
survived after a mean follow-up of 5 years the aortic PWV decreased in parallel with blood pressure. In patients who died, despite a similar
blood pressure effect, aortic PWV continued to increase (Guérin et al. [124]).
Therapeutic interventions on arterial stiffness and their
impact on patient outcome. Epidemiological studies
have shown that left ventricular hypertrophy and
arterial stiffening are tightly associated and that
both are independent cardiovascular risk factors. An
improvement of arterial stiffening should be one of
the major objectives in the prevention and treatment
of cardiovascular complications in ESRD. Dialysis
by itself does not increase arterial distensibility [117],
and some studies indicate that arterial function
worsens with time on dialysis [101,118,119].
We know from studies in essential hypertensive,
non-uraemic subjects that long-term antihypertensive
therapy induces reverse arterial remodeling with
improvement of the arterial viscoelastic properties
[120]. During recent years, a few controlled studies
were aimed at examining the effect of antihypertensive
drugs on the function of large arteries in ESRD
patients on intermittent haemodialysis therapy. It
has been shown that long-term treatment with antihypertensive drugs effectively lowered blood pressure,
and significantly decreased aortic PWV and wave
reflections [121–123]. The antihypertensive drugs
decreased aortic PWV to a large extent in response
to blood pressure lowering as such. This blood pressure dependency of arterial stiffness offers the possibility to investigate whether the regression of arterial
stiffness has a favourable effect on long-term patient
outcome. This possibility was studied in a follow-up
study by Guérin et al. [124] in 150 haemodialysis
patients whose blood pressure was decreased by association of ‘dry weight’ adjustment and antihypertensive
drugs. The results showed that, in patients whose PWV
decreased in parallel with blood pressure, the survival
was much better than in those ESRD patients whose
PWV was insensitive to blood pressure decrease
(Figs 9 and 10). The blood pressure sensitivity of
arterial stiffening was also associated with a decrease in
left ventricular hypertrophy, which by itself favourably
influenced survival in ESRD patients [125]. The
effects of stiffness attenuation and regression of left
ventricular hypertrophy were independent of blood
pressure changes as such. The same study showed that
the prescription of the ACE inhibitor perindopril
was associated, independently of changes in PWV
or blood pressure, with a decreased relative risk of
cardiovascular mortality of 0.19 (95% CI: 0.14–0.43).
As already mentioned, extensive calcifications of the
arterial tree are associated with increased stiffness,
non-response to antihypertensive agents and increased
risk of death [101,115]. Vascular calcifications are the
consequence of an active ‘osteogenic’ process in the
vessel wall and are associated with several factors
including hyperphosphataemia and possibly a positive
calcium balance (frequently associated with adynamic
bone disease owing to oversuppression of hyperparathyroidism) [101,126,127]. Recent studies have
challenged the current practice of controlling hyperphosphataemia with calcium-containing binders, and
have shown that there is a significant association
between arterial calcification score and the amount of
calcium ingested [101,126]. These associations should
be confirmed. Of note, a recent study using the noncalcium-containing compound sevelamer has shown
that the administration of this compound, but not that
of calcium binders, can prevent the progression of
arterial calcifications in dialysis patients, as detected by
electron beam computed tomography [128].
Conclusions
The vascular complications in ESRD are ascribed to
two different, although associated mechanisms, namely
atherosclerosis and arteriosclerosis. Arteriosclerosis is
characterized by diffuse dilation and hypertrophy of
large conduit arteries and stiffening of arterial walls
and represents one clinical form of an accelerated
ageing process. These alterations are associated with
several haemodynamic changes characteristic of ESRD,
such as flowuvolume overload and increased circumferential tensile stress due to increased arterial diameters
anduor intra-arterial pressure. As a result of these
Arterial structure and function in ESRD
arterial changes, the systolic pressure is abnormally
increased in ESRD patients, while the diastolic pressure is usually within the normal range or even lower.
The main adverse effects of arterial stiffening are:
(i) an elevated LV afterload with development of
LV hypertrophy and increased myocardial oxygen
demand; and (ii) altered coronary perfusion and blood
flow distribution with relative subendocardial ischaemia. Epidemiological studies have demonstrated the
impact of arterial abnormalities on cardiovascular
disease evolution and identified arterial remodeling
and stiffening as independent predictors of overall and
cardiac mortality in ESRD patients.
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