Endothelial Function Is Associated With Pulse Pressure,Pulse
Wave Velocity, and Augmentation Index in
Healthy HumansCarmel M. McEniery, Sharon Wallace, Isla S.
Mackenzie, Barry McDonnell, Yasmin,
David E. Newby, John R. Cockcroft, Ian B. Wilkinson
AbstractArterial stiffness is an independent predictor of
mortality and is regulated by a number of factors,
includingvascular smooth muscle tone. However, the relationship
between endothelial function and definitive measures of
arterialstiffness and wave reflections has not been described in
healthy individuals. Therefore, we tested the hypothesis
thatendothelial function is inversely correlated with aortic pulse
wave velocity (PWV), central pulse pressure, andaugmentation index
in healthy individuals. Peripheral and central pulse pressure and
augmentation index weredetermined at rest, and global endothelial
function was measured using pulse wave analysis and administration
ofsublingual nitroglycerin and inhaled albuterol. Aortic PWV was
also determined at baseline in a subset of 89 subjects.In a
separate group of subjects (n89), aortic PWV was measured and
brachial artery flow-mediated dilatation assessedas a measure of
conduit artery endothelial function. Global endothelial function
was significantly and inverselycorrelated with aortic PWV (r0.69;
P0.001), augmentation index (r0.59; P0.001), and central
(r0.34;P0.001) and peripheral pulse pressure (r0.15; P0.03).
Moreover, there was a stronger correlation betweencentral rather
than peripheral pulse pressure. After adjusting for potential
confounders, global endothelial functionremained independently and
inversely associated with aortic PWV and augmentation index. There
was also a significant,inverse relationship between conduit artery
endothelial function and aortic PWV (r0.39, P0.001), which
remainedindependent after adjusting for confounding factors. In
healthy individuals, a decline in endothelial function isassociated
with increased large artery stiffness, wave reflections, and
central pulse pressure. (Hypertension. 2006;48:602-608.)
Key Words: nitric oxide endothelium-derived factors blood
pressure pulse arteries
Endothelial dysfunction, characterized by a reduced
bio-availability of endothelium-derived NO, is an importantstep in
the progression of atherosclerosis. Indeed, resistancevessel,1
conduit artery,2 and coronary3,4 endothelial dysfunc-tion
independently predict all-cause and cardiovascular mor-tality. A
number of risk factors for cardiovascular disease,including age,5
hypertension,1 obesity,6 hypercholesterol-emia,7 diabetes,8 and
smoking,9 are associated with systemicendothelial dysfunction.
Interestingly, these risk factors arealso associated with increased
elastic artery stiffness,10,11which is itself an important
predictor of outcome in a numberof patient groups.1215 Removal of
the vascular endotheliumalters arterial stiffness in animal
models,16 and we havedemonstrated recently that blocking NO
synthesis increaseslocal arterial stiffness,17,18 suggesting that
endothelium-derived NO contributes to the regulation of large
arterystiffness in vivo.
Support for this hypothesis stems from the observation
thatbrachial artery pulse pressure, a surrogate measure of
largeartery stiffness, correlates with coronary19 and
resistancevessel20 endothelial function in hypertensive patients
andcontrols. However, direct evidence of a relationship
betweenendothelial function and more definitive measures of
arterialstiffness is largely limited to studies in patients with
cardio-vascular disease and risk factors,2126 and the
relationshipbetween endothelial function and aortic
(carotidfemoral)pulse wave velocity (PWV), the current
gold-standardmeasure of stiffness, in healthy normotensive
individuals,who are free of the potentially confounding influence
ofcardiovascular disease, has not been well-described. More-over,
as we27 and others28 have shown previously, brachialpulse pressure
does not always provide an accurate indicationof central pulse
pressure, and the relationship between endo-thelial function and
central pulse pressure is unclear. This is
Received May 25, 2006; first decision June 16, 2006; revision
accepted July 24, 2006.From the Clinical Pharmacology Unit (C.M.M.,
S.W., I.S.M., Y., I.B.W.), University of Cambridge, Addenbrookes
Hospital, Cambridge, United
Kingdom; Department of Medicine (D.E.N.), University of
Edinburgh, Edinburgh Royal Infirmary, Edinburgh, United Kingdom;
and the Department ofCardiology (B.M., J.R.C.), Wales Heart
Research Institute, Cardiff, United Kingdom.
Correspondence to Carmel M. McEniery, University of Cambridge,
Addenbrookes Hospital, Box 110, Cambridge CB2 2QQ, United Kingdom.
2006 American Heart Association, Inc.Hypertension is available
at http://www.hypertensionaha.org DOI:
likely to be important clinically, because the left
ventricle,kidney, and brain are influenced by central, not
peripheralpulse pressure,29,30 and central pulse pressure is a
strongerpredictor of all-cause mortality in patients with
cardiovascu-lar disease.31 To our knowledge, there are no data
describingthe relationship between endothelial function and
centralpulse pressure, PWV, and augmentation index (AIx) in alarge
group of healthy individuals.
We hypothesized that global endothelial function, whichincludes
conduit and resistance vessel endothelial function, isassociated
with aortic wall properties and wave reflection.Therefore, the aim
of this study was to test this hypothesis ina group of healthy
individuals using a validated, noninvasivemethod with which to
assess endothelial function32,33: pulsewave analysis coupled with
the administration of the endo-thelium-dependent 2 adrenoceptor
agonist albuterol and theendothelium-independent vasodilator
nitroglycerin (NTG).To confirm our findings, we also examined the
relationshipbetween arterial stiffness and flow-mediated
dilatation, awidely used technique to assess conduit vessel
endothelialfunction, in a separate group of healthy
MethodsSubjectsIn all, 309 healthy volunteers, across a wide age
range (18 to 81years), were recruited from a community-based
volunteer database.All of the subjects were free of cardiovascular
disease, risk factors,and medication. Approval for the study was
obtained from the localresearch ethics committee, and written
informed consent obtainedfrom each participant.
HemodynamicsBrachial blood pressure was recorded in duplicate in
the nondomi-nant arm using a validated oscillometric
sphygmomanometer (HEM705-CP, Omron Corp).34 Radial artery waveforms
were recordedwith a high-fidelity micromanometer (SPC-301, Millar
Instruments).A validated transfer function35,36 was then used to
generate acorresponding central aortic pressure waveform
(SphygmoCor, At-Cor Medical) as described previously.37 From this,
mean arterialpressure (MAP) and heart rate (HR) were determined
using theintegral software. Augmentation index, an estimate of
systemicarterial (elastic plus muscular) stiffness,38 was
calculated as thedifference between the second systolic peak and
inflection point,expressed as a percentage of the central pulse
pressure. The aorticPWV was measured using the same device by
sequentially recordingECG-gated carotid and femoral artery
waveforms, as describedpreviously.37
Assessment of Global Endothelial FunctionGlobal endothelial
function was assessed by determining the changein AIx in response
to the administration of NTG and albuterol.32,33Briefly, a 500-g
tablet of NTG (Cox) was placed under the tonguefor 3 minutes and
then removed, and hemodynamic recordings weremade 3, 5, 10, 15, 20,
and 30 minutes after NTG administration. Atleast 30 minutes after
NTG, albuterol (Allen and Hanburys) wasgiven by inhalation with a
spacer device (2200 g), and hemody-namic recordings were made 5,
10, 15, and 20 minutes after albuteroladministration. The response
to NTG or albuterol was defined as themaximum change in AIx after
drug administration, and globalendothelial function was defined as
the ratio of the change inalbuterol relative to NTG. Therefore, a
reduction in the albuterol:NTGratio (ie, less fall in AIx with
albuterol compared with NTG) isindicative of worse endothelial
Assessment of Conduit ArteryEndothelial FunctionConduit artery
endothelial function was determined by recording thediameter
changes in the brachial artery to increased blood flowgenerated
during reactive hyperemia (flow-mediated dilatation) andNTG.
Briefly, the brachial artery was identified using high-resolution
vascular ultrasound (Acuson XP 128/10) with a 7- to10-MHz linear
array transducer. A B-mode image of the artery wasscanned in a
longitudinal section 5 to 10 cm above the antecubitalfossa and
updated from the R wave of an ECG. End-diastolic imagesof the
vessel were then acquired every 3 seconds and stored offlinefor
later analysis using edge detection software (Brachial
Tools).Images were recorded for 1 minute before a pressure cuff,
around theforearm distal to the elbow, was inflated above
suprasystolic pres-sure for 5 minutes. After deflation of the cuff,
the increase in bloodflow was measured (reactive hyperemia) along
with the change invessel diameter (endothelium-dependent
dilatation), which was mea-sured for a further 5 minutes. NTG (25
g) was then administeredsublingually, and the changes were measured
over a period of 5minutes (endothelium-independent dilatation).
Flow-mediated andNTG-mediated dilatation were defined as the
maximal percentagechanges in vessel diameter after reactive
hyperemia and administra-tion of NTG, respectively.
ProtocolAll of the studies were conducted in a quiet,
temperature-controlledroom (222C). Heart rate, blood pressure, and
arterial waveformswere all recorded in duplicate.
Study 1 Assessment of Global Endothelial FunctionIn 220
individuals, 3 sets of recordings were made during a 30-minute
period of supine rest, with the last taken as baseline. Global
TABLE 1. Clinical Characteristics and Baseline
HemodynamicResponses of Subjects
BStudy 1, Subset
Age, y 4517 4820 4116
Gender, male/female 132/88 48/41 41/48
Height, m 1.720.09 1.710.10 1.710.11
Weight, kg 76143 7513 7416
BMI, kg/m2 25.54.2 25.43.7 25.04.4
Total cholesterol, mmol/L 4.161.15 4.900.83 4.940.91
Triglycerides, mmol/L 1.360.35 1.440.96 1.390.93
Glucose, mmol/L 4.970.85 4.900.80 4.901.26
Peripheral SBP, mm Hg 12116 12516 11912
Peripheral DBP, mm Hg 7010 698 728
Peripheral PP, mm Hg 5112 5613 4710
Central SBP, mm Hg 10817 11017 10711
Central DBP, mm Hg 7110 708 738
Central PP, mm Hg 3711 4012 348
MAP, mm Hg 8711 8711 889
HR, bpm 659 6310 6310
Augmentation index, % 1516 1816 1613
Aortic PWV, m/s 8.313.65 7.371.75
Cigarette smokers, n 40 7 11
Column A refers to all subjects included in study 1
(NTG/albuterol). ColumnB refers to those individuals in study 1 in
whom aortic PWV was measured atbaseline. Column C refers to those
individuals included in study 2. SBPindicates systolic blood
pressure; DBP, diastolic blood pressure; PP, pulsepressure.
McEniery et al Endothelial Function and Arterial Stiffness
endothelial function was then assessed. In a subset of 89
individuals,aortic PWV was measured at baseline, before the
Study 2 Assessment of Conduit ArteryEndothelial FunctionIn a
separate group of individuals (n89), conduit artery
endothelialfunction was assessed after baseline measurements of
blood pressureand aortic PWV.
In all of the subjects, 10 mL of blood were then drawn from
theantecubital fossa into plain tubes. The samples were centrifuged
at4C (4000 rpm for 20 minutes) and the serum separated and storedat
80C for subsequent analysis. Cholesterol, triglycerides, andglucose
were determined using standard methodology in an accred-ited
Statistical AnalysisDifferences in the response to NTG and
albuterol (study 1) orflow-mediated and NTG-mediated dilatation
(study 2) were analyzedusing paired Student t tests. Stepwise
multiple regression analyses
were then conducted using SPSS software (version 11.0).
Variablesfor the stepwise linear regression model were chosen based
onunivariate correlation analyses and those variables known or
thoughtto be associated with arterial stiffness, from published
observations.All of the values represent meanSD, and a P0.05 was
consideredsignificant. R2 change indicates the percentage change
ResultsThe baseline characteristics of the subjects studied are
shownin Table 1. The mean ages of the groups were similar:
4517years (study 1), 4820 years (study 1 subset), and 4116years
Study 1: Global Endothelial FunctionAdministration of NTG and
albuterol caused a significant fallin AIx of 146% (P0.001) and 85%
(P0.001),respectively (Figure 1). Importantly, there were no
Figure 1. Example of peripheral andcentral pressure waveforms at
baselineand after NTG and albuterol.
604 Hypertension October 2006
MAP or HR in response to either drug. With univariateanalyses,
endothelial function was most strongly correlatedwith aortic PWV
(r0.69; P0.001; Figure 2A), AIx(r0.59; P0.001), and age (r0.56;
P0.001). Similarrelationships were observed when these analyses
were per-formed separately in younger and older individuals basedon
the median age of the group (45 years). When theseanalyses were
performed on the whole group, using theresponses to albuterol and
NTG separately rather than as aratio, only the response to
albuterol remained significantlycorrelated. There was also a
significant correlation betweenendothelial function and central
pulse pressure (r0.34;P0.001) and, to a lesser extent, peripheral
pulse pressure(r0.15; P0.03). Other variables that were
significantlyassociated with endothelial function were total
cholesterol(r0.37; P0.001) and body mass index ([BMI] r0.18;P0.01).
When all of these parameters were included in astepwise multiple
regression model to examine the majorindependent determinants of
endothelial function, togetherwith gender, low-density lipoprotein
cholesterol, triglycer-ides, and smoking, only age and BMI remained
significantlyassociated. When this analysis was repeated using the
re-sponse to albuterol, again only age and BMI remained
sig-nificantly associated. Baseline values of AIx or PWV did
notenter either model.
To determine whether global endothelial function influ-ences
aortic PWV and AIx, stepwise multiple regressionmodels were
constructed for each parameter to control forpossible confounding
variables (Table 2). Aortic PWV wasindependently and positively
associated with age and bloodglucose level and negatively with
endothelial function. Aug-mentation index was also independently
and positively asso-ciated with age and MAP and negatively
associated withendothelial function, height, and HR. When the same
regres-sion models were constructed using the response to
albuteroland NTG separately, the response to albuterol
remainedindependently associated with both aortic PWV and AIx,
whereas the response to NTG was not significantly associ-ated.
In post hoc analyses, exclusion of smokers did notmeaningfully
alter any of the regression models.
Subjects were then stratified into quartiles of age andglobal
endothelial function to examine the interaction be-tween each
parameter and aortic stiffness (Figure 3). For agiven quartile of
age, aortic PWV increased as endothelialfunction declined and vice
Study 2: Conduit Vessel Endothelial FunctionThe mean baseline
artery diameter was 4.030.78 mm beforeinflation of the forearm
occlusion cuff and 3.990.79 mmbefore the administration of NTG (P
not significant). Themaximal change in diameter was 5.803.03% after
ischemiaand 9.595.08% after NTG. There was a significant andinverse
correlation between flow-mediated dilatation andaortic PWV (r0.39;
P0.001; Figure 2B), which re-mained independent even after
correcting for confoundingvariables (Table 2).
DiscussionAortic stiffness is an independent predictor of
all-cause andcardiovascular mortality in selected patient
groups.1215 Phys-iologically, the stiffness of the large arteries
depends on 3main factors: structural elements within the arterial
wall, suchas elastin and collagen; distending pressure; and
vascularsmooth muscle tone. Changes in smooth muscle tone alterthe
distribution of forces within the arterial wall,
providingfunctional regulation of arterial stiffness. We have
shownrecently in both animals17 and humans18 that the
endotheli-um-derived vasodilator NO contributes to the regulation
oflocal conduit artery stiffness in vivo. The aim of the
currentstudy was to investigate the relationship between
endothelialfunction and large artery stiffness and associated
wavereflection characteristics in a group of healthy
individuals.Our major findings were that global endothelial
functioncorrelates more strongly with central rather than
Figure 2. The relationship between global endothelial function
(ratio of the response to albuterol to NTG) and aortic PWV (A) and
con-duit artery endothelial function (flow-mediated dilatation) and
aortic PWV (B).
McEniery et al Endothelial Function and Arterial Stiffness
pulse pressure and is independently and inversely correlatedwith
aortic PWV (a measure of large artery stiffness) and AIxas measured
by AIx. In addition, we found that aortic PWVwas significantly and
inversely correlated with flow-mediateddilatation in the brachial
artery, which is an established andwidely used measure of conduit
artery endothelial function.Together, these data suggest that
endothelial function is animportant determinant of central
hemodynamics and largeartery stiffness and lend further support to
the importance ofNO in the regulation of large artery stiffness in
Previous studies indicate that peripheral pulse
pressure,frequently considered as a surrogate measure of large
stiffness, is associated with arteriolar endothelial
dysfunctionand conduit artery endothelial dysfunction in
hypertensiveanimals39 and patients40 and coronary endothelial
dysfunctionin hypertensive and normotensive individuals
undergoingdiagnostic angiography.19 A number of other studies
havedescribed a relationship between various indices of
arterialstiffness and endothelial dysfunction in selected
patientgroups.2125 However, these studies require invasive
proce-dures and/or highly specialized equipment and
operators.Moreover, only a limited number of studies assessed
aorticPWV, the current gold-standard measure of large
arterystiffness, and wave reflection characteristics.
Furthermore,many of the patients studied had 1 cardiovascular
riskfactor, and, to our knowledge, no previous data have
exploredthe relationship among arterial stiffness, wave
reflections,and endothelial function in a sufficiently large group
In the current study, global endothelial function, whichincludes
conduit and resistance vessel endothelial function,was assessed
using a previously validated,6,32,33 noninvasivemethod, which
couples the technique of pulse wave analysiswith the administration
of a 2-adrenoceptor agonist as anendothelium-dependent vasodilator
and NTG as an endothe-lium-independent NO donor. This technique is
reproducibleand correlates with the response to acetylcholine and
sodiumnitroprusside in the forearm vascular bed, assessed
usingvenous occlusion plethysmography.32 Global
endothelialfunction, obtained using the above technique, was
inverselyassociated with peripheral pulse pressure, but there was
amuch stronger correlation with central pulse pressure, whichis a
better surrogate measure of central artery stiffness and
leftventricular afterload and is a stronger predictor of
TABLE 2. Stepwise Linear Regression Analyses
Parameter Regression Coefficient SE P R 2 Change (%)
Variables excluded: gender, BMI, total cholesterol,HR, MAP, and
triglycerides (R 20.81, P0.001)
Age 0.120 0.012 0.667 0.001 75
Global endothelial function 2.221 0.590 0.258 0.001 4
Glucose 0.574 0.230 0.125 0.015 2
Variables excluded were gender, total cholesterol,smoking, and
BMI (R 20.69; P0.001)
Age 0.446 0.050 0.478 0.001 57
Global endothelial function 8.177 1.630 0.239 0.001 5
Height 0.336 0.072 0.195 0.001 3
HR 0.308 0.067 0.181 0.001 3
MAP 0.230 0.065 0.164 0.001 1
Variables excluded: MAP, gender, BMI, totalcholesterol, HR,
smoking, baseline arterial diameter,and NTG-mediated vasodilatation
(R 20.21; P0.01)
Endothelial function 0.221 0.076 0.362 0.01 14
Age 0.030 0.014 0.259 0.05 7
Figure 3. Influence of age and endothelial function on
aorticPWV. Endothelial function refers to the ratio of response
toalbuterol versus NTG, with quartile 4 representing superior
andquartile 1 representing inferior endothelial function. There
wereno individuals in the highest quartile of age in whom
endothelialfunction was also in the highest quartile.
606 Hypertension October 2006
mortality in patients with cardiovascular disease than
periph-eral pressure.31 Moreover, we have shown previously
thatassessing peripheral pulse pressure does not always provide
areliable estimate of central (aortic) pulse pressure.27,41
To explore further the relationship between endothelialfunction
and large artery stiffness and wave reflection, wealso assessed
aortic PWV, which provides a robust measureof arterial
stiffness,29,42 and AIx, which provides a compositemeasure of
elastic plus muscular artery stiffness and wavereflection.38 Both
of these indices are independent predictorsof cardiovascular risk
in selected patient populations. Globalendothelial function was
significantly and negatively corre-lated with aortic PWV and AIx.
However, both indices areinfluenced by a number of factors, and to
control for potentialconfounding influences, a multiple regression
model wasconstructed for each parameter, including known or
likelydeterminants of arterial stiffness and wave reflection.
Asexpected, age was independently associated with aortic PWV,but
there was also an independent, negative association withglobal
endothelial function, indicating that as endothelialfunction
declined, the aortic PWV increased. Indeed, thisassociation was
evident within each quartile of age in thepresent study. In
addition, plasma glucose concentration wasalso independently
associated with aortic PWV, suggestingthat even in healthy
individuals, glucose tolerance mayinfluence arterial stiffness.
Concerning AIx, age, gender,height, HR, and MAP were all
independently associated, inline with previously published
findings.27,43,44 However,global endothelial function emerged as an
additional, inde-pendent determinant of AIx, suggesting that a
decline inendothelial function in smaller, preresistance arteries
maylead to enhanced wave reflection and a rise in AIx.
We also determined the relationship between aortic PWVand
another, widely used method of assessing endothelialfunction,
flow-mediated dilatation in the brachial artery (conduitartery
endothelial function), in a separate group of healthyindividuals.
Flow-mediated dilatation emerged as a significantand independent
determinant of aortic PWV, suggesting that asconduit artery
endothelial function declines, large artery stiffnessincreases.
Although flow-mediated dilatation is known to corre-late with
invasively measured coronary endothelial
function,45ultrasound-based measures of endothelial function
requirehighly specialized equipment and operators, making them
un-suitable for inclusion in large-scale population studies. In
con-trast, PWA coupled with administration of NTG and
albuterolprovides a simple and repeatable method with which to
assessglobal endothelial function in large numbers of patients.
Never-theless, the observed relationship between flow-mediated
dila-tation and aortic PWV in the current study confirms our
findingsusing NTG and albuterol and lends further support to
ourhypothesis that endothelial function is associated with
LimitationsAlthough global endothelial function was associated
witharterial stiffness, aging also exerts a marked effect on
bothparameters, and the cross-sectional nature of the current
studylimits our ability to infer a causal relationship.
Therefore,further studies are required to determine whether a
endothelial function per se leads to arterial stiffening.
Also,we did not observe any independent relationship
betweencholesterol and arterial stiffness, which is perhaps
surprisingin light of previously published work from our
laboratory11and others,46 but may reflect the a priori exclusion of
PerspectivesNO is a potent antiatherogenic molecule, and the
importanceof endothelial function as a surrogate marker of risk
hasbecome increasingly recognized following the results ofstudies
in which endothelial dysfunction predicts all-causeand
cardiovascular mortality.1,3,4 Arterial stiffening is
alsoassociated with a number of adverse hemodynamic
effects,including a rise in central pulse pressure, as observed in
thecurrent study, leading to increased cyclic stress on the
arterialwall, increased left ventricular afterload, and decreased
myo-cardial perfusion. Interestingly, conditions associated
withendothelial dysfunction, such as aging, smoking,
hypercho-lesterolemia, hypertension, and diabetes, are also
associatedwith increased arterial stiffness,79 suggesting that
impairedNO bioavailability may be the link. Therefore, a
morethorough understanding of the relationship among
endothelialfunction, arterial stiffness, and wave reflections may
promotebetter risk stratification and targeting of therapies,
particu-larly those that restore NO bioavailability.
ConclusionsEndothelial function and large artery stiffness are
indepen-dent determinants of all-cause and cardiovascular
mortality.The results of the current study demonstrate that even
inhealthy individuals, a decline in global endothelial function
isassociated with increased aortic stiffness (PWV) and AIx.
Inaddition, we have also shown that global endothelial
functioncorrelates more strongly with central, rather than
peripheralpulse pressure. These data suggest that large artery
stiff-ness and central hemodynamics are influenced by
endothelialfunction and support our previous findings describing
theimportance of NO in the regulation of large artery stiffness
invivo. Therefore, therapeutic strategies that restore NO
bio-availability may reduce arterial stiffness and its
Sources of FundingThis research was supported by the British
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