endothelial function is associated with pulse pressure,pulse wave velocity, and augmentation index...

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. [email protected]

2006 American Heart Association, Inc.Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000239206.64270.5f

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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 individuals.

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 function.

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

Parameter

AStudy 1(n220)

BStudy 1, Subset

(n89)

CStudy 2(n89)

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 603

endothelial function was then assessed. In a subset of 89 individuals,aortic PWV was measured at baseline, before the administrationof NTG.

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 laboratory.

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 for eachparameter.

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 2).

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 changes in

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 versa.

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 peripheral

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).


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 vivo.

Previous studies indicate that peripheral pulse pressure,frequently considered as a surrogate measure of large artery

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 ofhealthy individuals.

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 all-cause

TABLE 2. Stepwise Linear Regression Analyses

Parameter Regression Coefficient SE P R 2 Change (%)

Aortic PWV

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

Augmentation index

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

Aortic PWV

Variables excluded: MAP, gender, BMI, totalcholesterol, HR, smoking, baseline arterial diameter,and NTG-mediated vasodilatation (R 20.21; P0.01)

Conduit artery

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.


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 largeartery stiffness.

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 decline in

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 patientswith hypercholesterolemia.

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 adversecardiovascular consequences.

Sources of FundingThis research was supported by the British Heart Foundation.

DisclosuresNone.

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endothelial function is associated with pulse pressure,pulse wave velocity, and augmentation index...

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