From the Department of Internal Medicine and INSERM (U337), Broussais
Hospital, Paris (M.E.S., R.A.), and Manhès Center, Fleury Merogis
(G.M.L.), France; and Alton Ochsner Medical Foundation, New Orleans, La
(E.D.F.).
Correspondence to Professeur Michel Safar, Médecine Interne 1, Hôpital Broussais, 96 rue Didot, 75674, Paris, Cedex 14, France.
Abstract
Abstract—The most classic hemodynamic concept
explaining the increased mean arterial pressure in
hypertension reflects an increased total peripheral
resistance dynamically and an increased wall-to-lumen ratio to suppress
smaller arteries. However, a more current consideration takes into
account not only that steady component but also the pulsatile component
of blood pressure, a point that importantly modifies the traditional
hemodynamic definition. Whereas mean
arterial pressure is almost constant along the
arterial tree, the pulse pressure increases markedly from
the more central to the peripheral arteries, indicating
that in vivo each artery should be characterized according to its own
blood pressure curve. This important concept implies major
modifications in the methods used to investigate the relationships
between mechanical factors and large artery structure and function. It
therefore seems reasonable that in hypertension the large arteries
should no longer be considered as passive conduits but rather in terms
of their active behavioral response to the mechanical forces to which
they are subjected. New investigational aspects in hypertension
therefore now involve not only genetic, cellular, and molecular
mechanisms but also transductional hemodynamic
mechanisms reflecting changing patterns in the extracellular matrix
that influence structural remodeling of the
vessels.
Early studies concerned with the
hemodynamics of hypertension concentrated on the
regulation of cardiac output, fluid volumes, and vascular
resistances.1 These investigations indicated the
importance of the vascular wall, including that of
veins.1 2 3 Freis1 emphasized aortic
stiffness, and Tarazi et al4 suggested measuring this
stiffness using the ratio of pulse pressure to stroke volume. However,
more recent studies concerned with large arteries in hypertension have
focused on 3 more recent observations. First, older subjects with
isolated systolic hypertension differed from younger ones in
having a higher total peripheral resistance,5
but when they had the same MAP and total peripheral
resistance, there was less systemic arterial
compliance.6 Second, the acute administration of the
antihypertensive agent dihydralazine to hypertensive patients
reduced MAP and brachial artery diameter. In contrast, the
antihypertensive drug diltiazem, causing the same fall in MAP in these
subjects, produced an increased brachial artery diameter. This
important difference suggested active changes in smooth muscle tone in
the conduit vessel wall.7 Third, prolonged
antihypertensive therapy affects various hypertensive conduit arteries
differently, since stroke is more readily and effectively prevented
than target organ events in other vascular territories, such as the
coronary circulation (even at the same reduction in
arterial pressure).8
The earlier investigations of large arteries were focused mainly on
invasive pulsatile arterial
hemodynamics.9 Thus, the definitions of
vascular impedance and wave reflection required more sophisticated
mathematical approaches, and these studies were focused on patients
with cardiac problems. However, in 1970, O'Rourke10
applied the concept of PP transmission to patients with hypertension,
and the relevance of this approach to the study of large arteries in
hypertension and of antihypertensive drugs provided novel approaches to
cardiovascular pharmacology and
therapeutics.11 Finally, the introduction of ultrasonic
devices in recent years has been a major advance, since it permits a
new and dynamic analysis of arterial compliance and
distensibility in animals and humans in vivo.12 13 14
It is now appropriate to suggest that the concept of
arterial stress should be introduced into the area of
hemodynamics of hypertension. This aspect of
arterial function is perhaps as important as increased
vascular resistance. This review has two objectives: (1) to emphasize
the importance of large arteries in our understanding of the
epidemiology and management of clinical
hypertension and (2) to demonstrate that knowledge of pulsatile
arterial hemodynamics is a necessary means
for better understanding the current aspects of molecular biology and
genetics in hypertension.
Pulse Pressure and the Definition of Hypertension
Computer analyses have shown that the arterial
pressure curve may be divided into two components: a steady component,
the MAP, and a pulsatile component, the PP (which is the difference
between the systolic and diastolic
pressures).15 Epidemiological studies have recently
emphasized the relevance of this description. Whereas MAP is an
independent cardiovascular risk factor for any
cardiovascular disorder, including those affecting the
brain, heart, and kidney, the arterial PP provides an
independent predictor of cardiovascular risk for the
heart, particularly for the prediction of myocardial
infarction.16 17 18 19
PP is a very complex parameter. Whereas MAP remains fairly
constant throughout the length of the arterial tree, PP is
much higher in the peripheral than in the central arteries
because of a significant increase in systolic pressure and a
small fall in diastolic pressure. The aortic pressure curve
is considered to be the sum of an incident pressure wave that is
propagated at a given velocity (PWV) along the arterial
tree and a reflected wave which travels backward from the
peripheral reflecting sites toward the ascending aorta and
the heart. These incidents and reflected waves interact constantly
along conduit vessels, the lumen diameter and compliance of which are
gradually reduced from central to peripheral arteries.
Consequently, each artery is characterized by its own pressure curve
and associated with its own mechanical consequences. The brachial blood
pressure curve is only one of the curves that describe the
arterial pressure in the entire circulation.
The amplification of the PP in the upper limbs is greatly influenced by
the duration of the ventricular ejection period and
therefore by heart rate.10 Thus, in conditions associated
with tachycardia, an elevated brachial arterial
pressure, particularly increased systolic pressure,
overestimates pressure levels in the aorta and more central arteries.
This pattern may be one of the major factors explaining the
significance of borderline or white coat hypertension.
On the other hand, the PP gradient along the entire
arterial tree tends to disappear with age, due to a greater
increase in the aortic PP with age than in the peripheral
PP.15 This most likely is due to an early return of the
backward pressure wave toward the heart in the elderly because of the
increase in the velocity of the aortic pulse wave with age. As the
reflected pressure wave returns during the systolic component
of the arterial pressure curve in older persons, it
amplifies the aortic systolic pressure; this factor increases
the end-systolic stress and serves to promote the further
development of ventricular hypertrophy. This
mechanism also helps to alter the elastic recoil of the aorta and to
decrease the diastolic pressure, thus tending to impair
coronary perfusion. These are some important reasons why
increased PP (due to an increased systolic pressure and a
decreased diastolic pressure) can be a strong predictor for
coronary heart disease and myocardial infarction. For the same
reasons, some trials of antihypertensive drugs were not as effective in
demonstrating reduction of morbidity and mortality of coronary
heart disease as for stroke8 20 ; the criterion of entry
into such therapeutic trials was primarily diastolic
pressure, and the populations studied did not include hypertensive
patients with the major coronary risks (ie, those with
increased systolic and low diastolic
pressures20 ). This important hemodynamic
point was emphasized by the Systolic Hypertension in the
Elderly study, in which isolated systolic hypertension was the
only criterion of entry, and drug treatment resulted in significant
reductions in coronary events.21
Finally, these aspects of PP amplification show the need to encourage
the use of new mechanical tools for describing
cardiovascular risk in
epidemiology. Not only must the heights of
systolic, diastolic, and mean arterial
pressures be considered, but also several additional
parameters describing the arterial wall
mechanics (eg, aortic PP, PP amplification, PWV, incremental elastic
modulus, and the timing of wave reflections). Similarly, it will be
important for us to include the major features of PP amplification in
any future guidelines for the clinical management of hypertension.
Indices of Arterial Stiffness
Ultrasound Techniques
Using in vivo carotid artery preparations of normotensive WKY and
SHR,24 the static hypertensive pressure-diameter curve is
shifted toward higher values of diameter, indicating that arteries from
normotensive and hypertensive animals differ in their structure and/or
smooth muscle tone. However, at any given transmural pressure, the
vessels can be stressed by applying a sinusoidal mechanical signal and
measuring the change in diameter, thus leading to a dynamic
pressure-diameter curve. One major characteristic of the dynamic curves
is that their slope is always lower than that of the corresponding
static curve.24 Bergel25 found this to be so
for various arterial segments in vitro. This finding is not
surprising, since the wall of any viscoelastic material, whether of
physical or biological origin, has less time to reach its maximum
potential strain when the stress is sinusoidal than it does in static
tests. Thus, the ratio between the static and dynamic compliances
provides a useful index of the viscosity of the arterial
wall.
The frequency dependence of dynamic compliance has been recognized
recently in vivo in normotensive rats. Atrial pacing has been used to
show that the frequency dependence predominates on the elastic carotid
artery, but it cannot be observed on the muscular femoral
artery.26 Finally, a clinical application of interest was
obtained in a study on large populations of normotensive and
hypertensive subjects in which there was a significant statistical
association between reduced carotid distention (or increase in PWV) and
high heart rate.27 Because tachycardia is a
strong predictor of cardiovascular
mortality,28 the statistical association between increased
arterial stiffness and increased heart rate provides an
interesting link between cardiac rhythm, cardiovascular
risk, and alterations in conducting vessels.
Measurements of PWV
Cross-sectional studies have shown that changes in PWV point to
arterial changes independent of age and
arterial pressure in several circumstances. First, patients
with end-stage renal disease have higher PWV (aorta, upper and lower
limbs) than gender-matched control subjects of the same age and
arterial pressure.30 Second, the
polymorphism of the AT1 receptor gene for
angiotensin II was associated with significantly higher
values of aortic PWV in hypertensive patients having the cc
allele than in patients (with the same arterial
pressure) having the aa and ac
alleles.31 Third, PWV may be increased in hypertensive
patients with normalized arterial pressure receiving
chronic antihypertensive drug therapy.32
Longitudinal studies have shown that PWV is poorly influenced by
arterial pressure reduction in the arms and
legs.22 However, changes in aortic PWV are much more
influenced by arterial pressure, even though they may be
partly independent. This has been shown during pregnancy33
or after the administration of certain pharmacological
agents.22 Finally, the major finding supporting the
clinical relevance of arterial stiffness is the recent demonstration
that in patients with end-stage renal disease, carotid elastic modulus
was an independent predictor of cardiovascular
mortality, a point clearly shown during this
workshop.34
Accumulation of Aortic Collagen and Arterial Stiffness
The major structural change in the artery wall associated with
increased arterial stiffness relates to increased collagen
content. Because collagen turnover is slow, it is difficult to
determine the contribution of collagen changes to the viscoelastic
properties of the hypertensive arterial wall in vivo.
Preventive (but not therapeutic) protocols have been developed recently
in hypertensive rats35 that may permit assessment of the
relationships between the aortic wall collagen content, increased
sodium intake, and the role of the renin-angiotensin
system.
Increased sodium intake leads to ventricular and aortic
hypertrophy in genetic hypertension in rats and to further
development of extracellular matrix.36 37 38 Although
changes in arterial structures are associated with an
increase in blood pressure in Dahl salt-sensitive rats,39
there was no substantial change in intra-arterial blood
pressure in the cases of SHR-SP or stroke-resistant
SHR.36 37 38 Moreover, excess dietary sodium intake in both
the hypertensive and normotensive rats was associated with increased
left ventricular mass without an increase in
pressure.37 A reduced sodium intake or administration of
diuretics such as indapamide, chlorothiazide,
or even spironolactone40 41 42 reversed vascular
hypertrophy and collagen accumulation in SHR and in SHR-SP
in the absence of substantial changes in blood pressure. Determinations
of nonmuscular myosin and EA III fibronectin in SHR-SP rats showed that
increased sodium intake was associated with a loss of the contractile
phenotype of vascular smooth muscle, independent of
arterial pressure changes.40 Investigations of
pulsatile arterial hemodynamics in SHR and
SHR-SP (under high sodium diet) suggest that the isobaric
distensibility was identical in the 2 strains, whereas there was less
vessel hypertrophy and collagen accumulation in SHR,
suggesting that these rats had a stiffer wall material.38
There was a parallel occurrence between the incidence of
cerebrovascular accidents and the degree of sodium intake in SHR-SP,
although blood pressure remains unchanged and the stiffness of wall
material under high sodium diet is reduced in comparison with
SHR.38 40 41 These findings suggest that a reduced
stiffness of the vascular wall material, possibly of genetic origin
(but influenced by increased sodium intake), played a role in the
incidence of strokes in SHR-SP independent of blood pressure.
Chronic inhibition of ACE decreased the accumulation of aortic collagen
in SHR independently of any change in blood pressure.35
This is not influenced by bradykinin blockade and is paralleled by
a decrease in ACE in the vascular wall but not in the plasma. Studies
on cultures of vascular smooth muscle cells have indicated that
angiotensin II stimulates collagen
synthesis.43 In vivo studies using selective blockade of
AT1 receptors in SHR clearly indicate that the accumulation
of collagen in the aorta is influenced by the blockade of this
receptor.44 We noted earlier that aortic PWV is critically
increased in hypertensive patients having the cc allele
of the AT1 receptor gene for angiotensin
II.31 Inhibition of ACE not only decreased
arterial pressure in these hypertensive patients but also
markedly and selectively decreased aortic PWV.45 Much work
remains to determine the links between arterial stiffness,
accumulation of aortic or ventricular collagen, sensitivity
to sodium, and activation of the renin-angiotensin
system.
Endothelium, Arterial Remodeling,
and Laplace Law
Many studies carried out on hypertensive rats and humans have
demonstrated abnormalities in resistance vessel structure associated
with an increased reduction in media-to-lumen ratio.46
Although these findings have been of great interest, the measurement
methods suffer from several limitations.47 A wire myograph
generally has been used to study small arteries, and some of the
conditions determined by this device are artificial, since the
endothelial surface is exposed to the wire pressure and
the vessel geometry is altered. The vessel shortens, so measurements of
the media cross-sectional area may not reflect the values before
experimental dissection. In contrast, large conduit arteries have
several methodological advantages over small arteries for hypertension
studies.22 First, operation blood pressure can be
determined in vivo at the exact site where the arterial
vessel is studied. Second, the viscoelastic properties of the
arterial wall may be evaluated transcutaneously by
ultrasound techniques under conditions of
physiological blood flow, shear stress, smooth
muscle tone, and endothelial function. Third, the
arterial intima-media thickness may also be measured in
vivo in hypertensive humans,48 49 allowing calculation of
circumferential wall stress and incremental elastic modulus. Finally,
interactions between shear stress, circumferential stress, and
arterial remodeling may be extensively studied in vivo.
Arteries are capable of structural and functional changes in response
to alterations within their milieu or to changes in
hemodynamic variables. Vascular remodeling may be
considered as an adaptive process in response to long-lasting changes
in arterial blood flow and/or pressure, whose ultimate
effect tends to be maintenance of the constancy of tensile
and/or shear stresses. The changes in shear and tensile stresses are
interrelated, since any change in arterial radius produced
by alterations in blood flow and shear stress induces changes in
tensile stress (unless the pressure varies in the opposite direction).
The geometric characteristics of vessel remodeling depend in large part
on the type of hemodynamic stimuli applied to the
vessel, as well as on the presence of intact
endothelium. Experimental and clinical data indicate
that acute and chronic augmentation in arterial blood flow
induces proportional increase in the luminal area of the vessel,
whereas the decrease in flow reduces arterial
diameter.50 The most classic example of flow-mediated
remodeling includes arterial dilation associated with
sustained high blood flow after creation of arteriovenous
fistula.51 Increase in arterial diameter is
usually accompanied by an increase in tensile stress, one of the major
determinants of vascular geometry and structure.
In hypertension, the effects of tensile stress are mediated by two
mechanisms: an increase in intra-arterial pressure and a
distention on the arterial diameter. According to the
Laplace theorem, where wall stress is proportional to radius (R) and
intra-arterial pressure (P) and inversely proportional to
wall thickness, arterial wall hypertrophy
serves as a compensatory mechanism to the increase of the PR
product. Clinical and experimental studies in hypertensive animals
and humans have shown that this purely mechanical aspect of the law of
Laplace is not observed in vivo in the sense that there is little
(central arteries) or no (peripheral arteries) increase in
diameter, thereby causing a decreased wall-to-lumen
ratio.22 46 47 48 49 50 51 Because hypertensive large arteries are
hypertrophied and the external tension is higher than the internal,
this could prevent an increased arterial diameter. Another
possibility is that altered endothelial function may
keep arterial diameter constant through changes in shear
stress and/or release of vasoactive compounds. An example of this
possibility is given in the early phase of development in SHR, during
which a transient increase in cardiac output and carotid blood flow has
been reported.52 53 Because there is no parallel increase
in diameter of the carotid artery during this phase, and because this
alteration occurs despite the increase in blood pressure, it has been
suggested that the transient change in flow might prevent the
pressure-induced increase in diameter through the mechanism of flow
dilation (or constriction).52 Finally, this mechanism has
two characteristics: (1) it might help to maintain wall tension with a
smaller hypertrophy than expected from the effect of purely
mechanical factors and (2) it requires the presence of an intact
endothelium.52
Experimental studies have demonstrated that endothelium
plays an important and active role both in vascular remodeling and in
the control of the viscous and elastic properties of the
arterial wall.54 55 Studying the effect of
endothelium removal on carotid arterial
compliance, Levy and collaborators54 56 have shown that
stripping the endothelial layer induces an increase in
compliance and diameter. This suggests that endothelial
cells act on the wall of arteries to keep the compliance within a given
required level. While it has been shown repeatedly that decreased
compliance has a negative impact on the left ventricular
function and coronary perfusion, the abnormal increase in
capacitive properties of the arterial system could in
theory also produce negative effects on cardiovascular
function. Under normal conditions, only 40% to 50% of blood ejected
from the left ventricle is stored in capacitive arteries during the
systolic interval. An abnormal increase in compliance could be
responsible for an exaggerated arterial blood pooling
during systole. This would produce alterations in PP transmission with
decreased PWV and lengthening of the transmission of pressure head to
peripheral circulation. Under this condition, the
displacement of the blood column in the arterial tree would
be more dependent on a direct "pushing" effect of stroke volume,
abnormally increasing the inertial component of cardiac workload. On
the other hand, Boutouyrie et al55 have shown that
destruction of endothelial layer is responsible for a
huge increase in the viscosity of arterial wall, increasing
the hysteresis of the arterial pressure-diameter
relationship. This finding has two theoretical consequences: (1) to
increase the capacity for blood pooling during the
diastolic interval, thus altering the arterial
recoil and diastolic runoff, and (2) to increase the
dissipation of energy transmitted by the heart in an inefficient way.
Finally, the combined effects of endothelial
dysfunction and altered viscoelastic properties of arteries are to
increase arterial blood volume during all phases of cardiac
cycle, to increase the inertial component of afterload, and finally to
increase the total cardiac workload.
In the past, endothelium was considered mainly as an
interface between blood flow and vascular smooth muscle. We must now
consider that the endothelium plays an active role as
an interface between pulsatile blood pressure and diameter. In
short-term situations, the increase in diameter after
endothelium denudation clearly shows that
vasoconstrictive compounds of
endothelial origin are involved.54 Such
compounds remain as yet unidentified, although they are not inhibited
by indomethacin.56 In long-term
situations, endothelium-induced structural change is a
relevant possibility, since endothelial denudation is
associated with a higher increase in wall thickness in younger rats
with genetic hypertension than in controls, a process that is not
observed in older rats.57 In the case of large arteries in
hypertension, it is difficult to determine the relative contribution of
growth and antigrowth factors of endothelial or smooth
muscle origin in the mechanism of the Laplace law equilibrium. In
parallel, we still need to know whether these alterations of conduit
arteries are the initial events of future hypertensive
complications.
Selected Abbreviations and Acronyms
Acknowledgments
This study was performed with the help of INSERM (Institut
National de la Santé et de la Recherche Médicale, Paris),
GPH-CV, and the French Society of Hypertension, the Ministry of
Research and Association Claude Bernard (Assistance Publique de Paris),
and a grant from the European Community (Biomed). We thank Anne Safar
for preparing the manuscript and Dr Owen Parkes for checking the
English text.
Received January 28, 1998;
first decision March 25, 1998;
accepted April 3, 1998.
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© 1998 American Heart Association, Inc.
Third Workshop on Structure and Function of Large
Arteries: Part I
Recent Advances on Large Arteries in Hypertension
Key Words: hemodynamics • transduction • arteries • vessels • vascular remodeling
Ultrasound measurements have resulted in the development of
dynamic indices of arterial stiffness in recent
years.22 23 This method has provided information that is
very different from the static indices that are obtained by in vitro
studies of arterial segments.23 However,
little has been done to differentiate between the relevance of static
and dynamic pressure-diameter relationships of large conduit
vessels.
Because the ultrasound techniques used to evaluate
arterial stiffness take a long time to perform, a great
deal of work has been done on PWV measurements in the territories of
the aorta and the upper and lower limbs in which computerized automatic
procedures provide an adequate reproducibility.29 PWV is
strongly influenced by age and arterial pressure,
particularly in the aorta. Thus, statistical adjustments are needed for
its interpretation. According to the Moens-Korteweg equation, PWV is
influenced by 2 factors, the vascular geometry and the viscoelastic
properties of the wall material, that act independently of age and
blood pressure.15
ACE
=
angiotensin-converting enzyme
AT1
=
angiotensin type 1 receptor
MAP
=
mean arterial pressure
PP
=
pulse pressure
PWV
=
pulse wave velocity
SHR
=
spontaneously hypertensive rats
SHR-SP
=
stroke-prone SHR
WKY
=
Wistar-Kyoto rats
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