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Comparison of the Relation ofTriglyceride-Rich Lipoproteins and

Muscular Artery Compliance inHealthy Women Versus Healthy Men

Ngoc-Anh Le, PhD, W. Virgil Brown, MD, Warren W. Davis, MD,David M. Herrington, MD, MHS, Lori Mosca, MD, PhD, Shunichi Homma, MD,

Barry Eggleston, Howard J. Willens, MD, and Jeffrey K. Raines, PhD

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o determine whether structural features or concentra-ions of plasma lipoproteins are predictive of arterialompliance in healthy women versus healthy men, co-orts of 111 men and 112 women with a wide range of0-year risks for coronary artery disease were selectedsing assessments based on the Framingham Hearttudy. Age ranges were restricted to 35 to 69 years foren and 45 to 79 years for women. Lipid-loweringrugs or any evidence of vascular disease was cause forxclusion. Fasting lipoprotein analysis and arterial com-liance measurements in thigh and calf were completed

n all patients. Plasma triglyceride levels were the most

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tcEpCnimdpDtwSwmt.virgil.brown@med.va.gov.

2005 by Excerpta Medica Inc. All rights reserved.he American Journal of Cardiology Vol. 95 May 1, 2005

owerful predictor of compliance in women. Weakerut significant relations were observed between plasmaon–high-density lipoprotein cholesterol, apolipopro-ein-B, and apolipoprotein-CIII. In contrast, the only sig-ificant predictor of compliance in men was bodyeight. Thus, the major lipid predictors of arterial stiff-ess in women are concentrations of triglyceride-rich

ipoproteins. These results are consistent with previousndings that triglyceride measurements are more stronglyelated to clinical vascular events in women than inen. �2005 by Excerpta Medica Inc.

(Am J Cardiol 2005;95:1049–1054)

e recently demonstrated that compliance of thelarge muscular arteries in the thigh and calf

orrelates with the number of stenotic coronary ves-els1 and the wall area of the abdominal aorta aseasured by magnetic resonance imaging.2 We also

ocumented that the Framingham risk score3 corre-ates with this measurement of arterial stiffness in thehighs and calves of men and women.2,4 In this study,e investigated the relations between compliance in

high and calf arteries with a series of quantitativelasma lipoprotein measurements, including apoli-oproteins. For this purpose, we recruited a cohort ofealthy men and women who were documented not toave clinical vascular disease.

ETHODSPatient cohort: The protocol for the study was ap-

roved by the institutional review boards at each studyite. The intent of this study was to relate potentialipoprotein predictors in healthy men and women toeasurements of the early (subclinical) phase of vas-

ular disease manifest by arterial compliance abnor-

rom the Atlanta Veterans Affairs Hospital and Emory University Schoolf Medicine, Atlanta, Georgia; the Wake Forest University Medicalenter, Winston-Salem, North Carolina; the Columbia Universityedical Center, New York, New York; Rho, Inc., Chapel Hill, Northarolina; and the University of Miami Medical Center, Miami,lorida. This study was funded in part by grants from Vasocor, Inc.,oston, Massachusetts, and Credit First Suisse, New York, New York.anuscript received September 29, 2004; revised manuscript re-

eived and accepted December 27, 2004.Address for reprints: W. Virgil Brown, MD, Atlanta VAMC Mail

ode 111, 1670 Clairmont Road, Decatur, Georgia 30033. E-mail:

alities. Men (35 to 69 years old) and women (45 to9 years old) were recruited into 3 groups of �40atients per group with predicted 10-year risks of10%, 10% to 20%, or �20% according to theethod of Wilson et al4 as derived from the Framing-

am Heart Study cohort. Patients who had type 2iabetes mellitus were assigned to group 3.5 Evidencef vascular disease in any arterial distribution or use ofipid-lowering drugs was cause for exclusion. Of thenitial 262 patients who were recruited, 33 were ex-luded due to recent use of lipid-lowering drugs. Sixubjects who had abnormalities discovered duringreadmill stress testing for electrocardiographic orentricular wall motion abnormalities (on echocardi-graphy) were also excluded. These exclusions left11 women and 112 men for data analysis.

Laboratory analysis: At the initial visit, medical his-ory, physical examination, and blood analyses wereompleted for 269 patients after an 8-hour fast. Themory Lipid Research Laboratory (Atlanta, Georgia)erformed all plasma lipoprotein analyses on a BeckmanX7 chemistry autoanalyzer (Beckman Coulter Diag-ostics, Fullerton, California). Levels of total triglycer-des and cholesterol were determined by enzymaticethods (Beckman Coulter Diagnostics) and direct high-

ensity lipoprotein (HDL) and direct low-density li-oprotein cholesterol by homogeneous assays (Equaliagnostics, Exton, Pennsylvania). Plasma concentra-

ions of apolipoprotein-B (apo-B) and lipoprotein(a)ere determined by immunoturbidimetry (DiaSorin,tillwater, Minnesota) and that of apolipoprotein-C-IIIas determined by another immunoturbidimetricethod (Wako Chemicals). Triglyceride-rich lipopro-

eins were isolated by preparative ultracentrifugation at a

10490002-9149/05/$–see front matterdoi:10.1016/j.amjcard.2004.12.057

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ensity of 1.020 g/ml (Beckman Coulter). Plasmaevels of high-sensitivity C-reactive protein were mea-ured with an ULTRA-CRP assay (Polymadco, Inc.,ortlandt Manor, New York), and homocysteine wasetermined by fluorescence polarization immunoassayAbbott IMx Analyzer).

Exercise electrocardiography/echocardiography: Allubjects underwent transthoracic echocardiographyerformed according to guidelines of the American

IGURE 1. To determine peripheral arterial compliance, cuff pressn an instantaneous basis. During early diastole the system rapid

ects the cuff volume by 0.65 ml of air, which produces a step dectantaneous cuff pressure. The maximum pressure change in the cycle is also measured (Pm). By knowing Pcal, Pm, and the expanossible to calculate the maximum volume change (Vm) associatedycle.

TABLE 1 Clinical Characteristics of Subjects by Gender

GenderAge(yrs)

Systolic BP(mm Hg)

Diastolic BP(mm Hg)

Weight(kg)

BoMInd

(kg/

Women 61 � 9 135 � 21 75 � 12 71 � 14 27Men 54 � 9 129 � 17 76 � 10 85 � 14 27Gender

comparison(p value)*

�0.001 0.05 0.31 �0.001 0.

*Wilcoxon’s 2-sample t test.BP � blood pressure.

TABLE 2 Traditional Lipid Analysis of Subjects by Gender

Gender

TotalCholesterol

(mg/dl)HDL-Cholesterol

(mg/dl)LDL-Cholesterol

(mg/dl)

NonChole

(mg

Women 204 � 34 53 � 14 131 � 32 151Men 192 � 36 43 � 11 129 � 35 149Gender

comparison(p value)*

0.03 �0.001 0.61 0.

*Wilcoxon’s 2-sample t test.LDL � low-density lipoprotein.

ociety of Echocardiography6 before and after tread- r

050 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 95

mill exercise using Bruce’s protocoland were analyzed for segmentalwall motion abnormalities at the Col-lege of Physicians and Surgeons,Columbia University (New York,New York). Significant electrocar-diographic changes (�1 mm of STdepression) or segmental wall mo-tion abnormalities were cause forexclusion.

Measurement of arterial compli-ance: Peripheral arterial compliancewas assessed with a fully automatedcomputer-controlled air plethysmo-graph (Vasogram). The device con-sists of an air pump, a calibrationchamber, and a high-resolution pres-sure transducer.1–3 Special bloodpressure cuffs are placed at the thighand calf, and measurements at theselevels are taken independently.1–3 Acontinuous tracing of the pulse vol-ume is recorded (Figure 1) as thecuff pressure is increased. The max-imum volume change under the cuffis calculated and normalized to apulse pressure of 50 mm Hg(MaxV50) and measured in millili-ters. Higher MaxV50 measure-ments correspond to more compli-ant arteries. Three measurements ofcompliance were made �1 weekapart, and the results were aver-aged. The correlation between pairedmeasurements of calf and thighMaxV50 values obtained during thefirst and second visits were 0.77 ml(p �0.0001) and 0.79 ml (p�0.0001), respectively.1

Statistical analysis: Simple de-scriptive statistics were used to de-scribe the characteristics of the studypopulation. Wilcoxon’s 2-sampletest was used to compare genderswith respect to study variables.Spearman’s correlation coefficients,scatterplots scatteroverlaid with sim-ple linear regression lines, and 95%confidence intervals of the meanwere used to measure the linear re-lations between anthropometric andlipid variables and mean arterial

ompliance. Gender-specific multivariable regressionodeling was used to identify lipid and other hema-

ologic predictors that might explain significantmounts of additional variation in mean arterial com-liance after accounting for statistically significantnthropometric and traditional lipid predictors. First,he statistically significant anthropometric and tradi-ional lipid predictors of mean arterial complianceithin each gender were found using multivariable

(Pc) is measuredxtracts and rein-se (Pcal) in in-for the cardiac

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ntry was a p value of 0.05). The result was a set of 4ender-specific minimal models for calf and thighean arterial compliance measurements that included

nly anthropometric and traditional lipid predictorsith a significance level �0.05. The possible predic-

or set was expanded to include advanced lipid andther hematologic variables. With this expanded pre-ictor set, stepwise model selection was used to iden-ify any additional predictors of mean arterial com-liance after adjusting for the variables contained inhe minimal models. The p value criterion for entrynto the stepwise selection process was 0.10 andhat for staying in the model was 0.05. To assess themportance of any additional predictors that re-ained after stepwise model selection, minimalodel R2 values, change in R2 in relation to mini-al model R2 values, and accompanying p valuesere computed.

All statistical analyses were performed with SAS.02 (SAS Institute, Cary, North Carolina). Data wereransferred electronically from each clinical site,tored, and analyzed by staff at Rho, Inc. (Chapel Hill,orth Carolina).

ESULTSThe clinical characteristics of men and women are

resented in Table 1. The women were older (6 years)y design to help compensate for their delayed onsetf coronary artery disease. However, the Framinghamisk score in women was 9.6 � 6.7% per decade,hich was significantly lower than the score in men

12.9 � 8.8% per decade). The men were heavier thanhe women, but no difference in body mass index wasound. Systolic blood pressure was higher but dia-tolic pressure was lower in women.

Women had significantly higher levels of totalholesterol due entirely to the expected higher level ofDL cholesterol (Table 2). A higher level of apoli-oprotein-AI was consistent with this finding (Table 3).lasma levels of triglycerides did not differ, but theontent of apolipoprotein-CIII per apolipoprotein-Bapolipoprotein-CIII/apolipoprotein-B ratio) in triglyc-ride-rich lipoprotein particles (�1.020 g/ml) wasower in women. Levels of low-density lipoproteinholesterol and total apolipoprotein-B and low-densityipoprotein size were not significantly different be-ween men and women. Levels of high-sensitivity-reactive protein were higher in women but those ofomocysteine were similar to those in men.

Patients’ measurements of MaxV50 in calvesnd thighs versus weight are shown in Figure 2. Inen, the correlation coefficient for MaxV50 in the

alf (r � 0.45, p �0.001) was 2 times that in womenr � 0.21, p � 0.03). The MaxV50 value as mea-ured in the thigh also correlated with weight inen (r � 0.23, p � 0.02) but not in women.ecause MaxV50 is designed to be an index ofbsolute volume change with each pulse wave, it isot surprising that the larger legs of larger subjectsould manifest a larger pulse volume wave. Ac-

ordingly, multivariate analysis conducted for other

PREVENTIVE CARDIOLOGY/TRIGLYCERIDE-RICH LIPOPROTEINS AND MUSCU

T G W M G

LAR ARTERY COMPLIANCE BY GENDER 1051

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ariables was done after adjusting for body weight,xcept for female thigh (see the following).

In univariate analysis, highly significant decreasesn the MaxV50 measured at the calf (r � �0.30, p �.001) and thigh (r � �0.39, p �0.001) was associ-ted with increasing levels of triglycerides in womenFigure 3). In women, apolipoprotein-B and non-HDLlso correlated negatively with MaxV50 in the thighnd calf (Table 4). Total apolipoprotein-CIII relatednversely to MaxV50 in the thigh (r � �0.21, p �.03), but no significant correlation was found in thealf. The relations for women with correlation co-fficients �0.15 and a p value �0.05 at the thigh oralf are shown in Figure 4. Total cholesterol methese criteria but must be considered of marginalignificance because multiple comparisons wereade in this analysis. In men, there were no signif-

cant relations between triglyceride levels (Figure) and other lipoprotein measurements. High-sensi-ivity C-reactive protein was inversely but weaklyelated (r � �0.21, p � 0.02) to compliance only athe calf and only in men.

Results of multivariate analysis of the relations be-ween MaxV50 and the various anthropometric and lipidarameters as predictors are presented in Table 5. Theinimal model adjusted for the correlation between

ody weight and the compliance measurements at thehigh and calf in men and only in the calf in women.

ith only weight adjustment as the minimal model inen, adding apolipoproten-CIII provided slight im-

IGURE 2. Plot of patients’ compliance measurements (MaxV50)ersus subjects’ weight in kilograms for the (A) thigh and (B) calfn women and for the (C) thigh and (D) calf in men. Standardegression lines and 95% confidence intervals are shown. Onlyhe thigh data are significant in women (r2 � 0.044), whereashe thigh (r2 � 0.20) and calf (r2 � 0.05) are significant in men.

rovement in predicting MaxV50 at the calf (but not at p

052 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 95

he thigh). No other parameters added predictive value inhe men. In women, the minimal model for the calf basedn physical and traditional lipid parameters includedeight and triglyceride levels, the strongest of the cor-

elates in univariate analysis. With this model, levels ofpolipoprotein-B, apolipoprotein-CIII/apolipoprotein-Batio (see Discussion) in triglyceride-rich particles, andomocysteine added predictive value. These additional

IGURE 3. Patients’ compliance measurements (MaxV50) in theA) thigh and (B) calf in women and the (C) thigh and (D) calf inen versus fasting triglyceride levels (milligrams per deciliter).tandard regression lines and 95% confidence intervals arehown.

IGURE 4. Spearman’s correlation coefficients for relations be-ween various lipoprotein measurements and Max V50 at thehigh (black bars) and calf (gray bars) in women. Only thoseeasurements with a value >0.15 are included. The p value for

ach relation is presented in Table 4. Chol � cholesterol; CIII �polipoprotein-CIII; NonHdl � non-HDL; TG � triglycerides.

arameters increased the R2 value from 0.16 to 0.31 at

MAY 1, 2005

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he calf. At the thigh, only the apolipoprotein-CIII/apo-ipoprotein-B ratio added predictive value to the minimalodel, which included only triglycerides. Thus, apoli-

oprotein-CIII/apolipoprotein-B ratio was a significant

TABLE 4 Univariate Correlations With Compliance

Variable n

Calf MaxV50*

R2 p Value

WomenApo AI 109 �0.04 0.65 �Apo B 110† �0.24† 0.01† �Cholesterol 110 �0.18 0.05 �Hcy 110 �0.01 0.91HDL cholesterol 110 0.15 0.13CRP 110 0.002 0.99LDL cholesterol 110 �0.07 0.44 �Lp(a) 110 0.01 0.89Non-HDL cholesterol 110† �0.20† 0.04† �Triglycerides 110† �0.23† 0.02† �Weight 111† 0.23† 0.02†

Apolipoprotein CIII 110 �0.10 0.31 �LDL diameter 110 0.05 0.64Apo CIII/apo-B ratio‡ 104 �0.06 0.53 �

MenApo-AI 104 �0.13 0.19Apo-B 104 0.14 0.15Cholesterol 107 �0.03 0.72 �Hcy 106 �0.04 0.72 �HDL cholesterol 107 �0.14 0.16CRP 106† �0.21† 0.02† �LDL cholesterol 107 �0.10 0.30Lp(a) 107 �0.08 0.40 �Non-HDL cholesterol 107 0.03 0.75 �Triglycerides 106 �0.01 0.98 �Weight 111† 0.43† �0.001†

Apo-CIII 106 �0.10 0.31 �LDL diameter 106 �0.05 0.61ApoCIII/apoB ratio‡ 98 0.12 0.24

*Spearman’s correlation coefficient is shown with p values for compliance atmethod provides for assessment of p values in nonparametric data.

†Parameters with correlations �0.2 and p values �0.05 at the thigh and cal‡Ratio in isolated triglyceride-rich lipoproteins (d �1.019 g/ml).apo � apolipoprotein; Lp(a) � lipoprotein (a); other abbreviations as in Tabl

TABLE 5 Relation of Compliance and Various Parameters in MuAnalysis*

Variables inMinimalModel

R2 ofMinimalModel

AdditionalSignificantVariables

Calf Weight 0.20 Apo-CIIIMaxV50 in menCalf Weight/TG 0.16 Apo-B, apo-CIII/

apo-B, HcyMaxV50 in womenThigh Weight/BMI 0.10 NoneMaxV50 in menThigh TG 0.15 Apo-CIII/apo-BMaxV50 in women

*The minimal model in women for MaxV50 recorded at the thigh included plafor Max V50 at the calf included body weight and plasma TG. In men, the mweight at the calf and weight and BMI at the thigh. Those additional meaindependently to the strength of the correlation with vascular compliance are shoand at the 2 anatomic locations.

BMI � body mass index; TG � triglycerides. Other abbreviation as in Tables

redictor of decreased compliance at the thigh and calf i

PREVENTIVE CARDIOLOGY/TRIGLYCERIDE-RICH LIPOPROTEIN

only after adjusting for total triglycer-ides. Neither non-HDL cholesterol nortotal apolipoprotein-B added to thepredictive value when triglycerideswere considered, which is consistentwith their known relation to eachother, probably as components ofvery low-density lipoproteins and in-termediate-density lipoproteins.

DISCUSSIONThe method of measuring com-

pliance at the thigh and calf used inthis study has been shown to pre-dict the extent of coronary arterydisease measured by angiography2

and the wall area of the abdominalaorta as assessed by magnetic res-onance imaging.3 In 2 previousstudies that included �350 patientseach, the relations between the Fra-mingham risk calculations (usingclassic risk factors) and MaxV50measurements were found to behighly significant, with partial R2

values of 0.19 for the thigh and0.17 for the calf.3,5 These studiesincluded patients who had provedvascular disease and variable risksover a wide age range. Previousinvestigators have also found thatvarious measurements of arterio-sclerotic disease correlate with de-creased compliance as assessed byother methods, such as ultrasoundtechniques, pulse velocity, andpulse-wave analysis.7–13 It is note-worthy that these techniques tendto depend primarily on propertiesof the thoracic aorta rather than onthose of muscular arteries. Theseare research techniques that requirehighly trained personnel. Thepresent device is applicable in anoutpatient setting and can be usedby staff members who have mini-mal training.

The work described in this studywas done to determine whether pa-tients who had a range of classicrisk factors but no clinical evidenceof vascular disease would show re-lations between lipoprotein param-eters and the stiffness of thigh orcalf arteries as measured by this airplethysmographic device. The studydesign allowed comparison of co-

orts of women and men of equivalent size and com-arable risk as calculated by the Framingham riskunctions. The most striking finding in this study washe very strong and independent relation between fast-

gh MaxV50*

p Value

2 0.807† 0.005†

9 0.048 0.407 0.081 0.891 0.898 0.381† 0.03†

1† 0.008†

1 0.961† 0.031 0.990 0.32

7 0.514 0.702 0.883 0.753 0.757 0.081 0.962 0.832 0.867 0.455† 0.007†

7 0.459 0.386 0.53

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nce in the arteries of the thigh and that separatelyeasured in the calf of women. This relation inomen appears to be confirmed by significant corre-

ations of MaxV50 in the thigh and calf with non-HDLholesterol and with total plasma apolipoprotein-B.lasma apolipoprotein-CIII, another indicator of in-reased triglyceride-rich lipoproteins,14 also corre-ated with decreased compliance in thighs of women.one of these relations were detected in men. Other

tudies have reported stronger relations in women thann men between plasma triglycerides and the incidenceor prevalence) of vascular disease. This has beenound in the Framingham Heart Study,15 theROCAM study in Europe,16 the Evans County Study

n Georgia,17 the Lipid Research Clinic Follow-uptudy,18 a meta-analysis of community studies andlinical trials,19 and, more recently, the Third Nationalealth and Nutrition Examination Survey.20 The weak

orrelation between HDL cholesterol and low-densityipoprotein size was surprising because these measure-ents tend to be inversely related to triglyceride con-

entrations. This finding may be due to the smallumbers of subjects in this study compared with theommunity-based datasets that have defined these re-ations. Enrichment of apolipoprotein-C III in apoli-oprotein-B–containing lipoproteins has been foundo be a risk factor for vascular disease in cohorts ofatients in clinical trials whether treated with placebor cholesterol-lowering drugs.21–23

Our data differ from previous measurements ofascular compliance, because subjects’ ages did notave a strong correlation with MaxV50 at the calf orhigh. In previous measurements of compliance, theelation between wall stiffness and increased pulseelocity has been the most common assessment.7–10

he length of the thoracic aorta is the major contrib-tor to the distance over which this velocity is mea-ured. The alteration of this very elastic tissue withge may be a strong determinant of these results,hereas the specific assessment of muscular arteries

MaxV50), such as those in the thigh and calf, mayespond differently to aging.

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atterns. Am Heart J 1989;118:234–247.2. London GM, Marchais SJ, Safar ME, Genest AF, Guerin AP, Metivier F,hedid K, London AM. Aortic and large artery compliance in end-stage renal

ailure. Kidney Int 1990;37:137–142.3. Lehmann ED, Riley WA, Clarkson P, Gosling RG. Non-invasive assessmentf cardiovascular disease in diabetes mellitus. Lancet 1997;350(suppl 1):14–19.4. Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with defi-iency of apolipoprotein C-III and A-I: evidence that apolipoprotein C-III inhibitsipoprotein lipase in vivo. J Clin Invest 1986;78:1287–1295.5. Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J986;112:432–437.6. Assmann MD, Schulte H. Relation of high-density lipoprotein cholesterol and

riglycerides to incidence of atherosclerotic coronary artery disease (the PROCAMxperience). Am J Cardiol 1992;70:733–737.7. Heyden S, Heiss G, Hames CG, Bartel AG. Fasting triglycerides as predictorsf total and CHD mortality in Evans County, Georgia. J Chron Dis 1980;33:75–282.8. Criqui MH, Heiss G, Cohn R, Cowan LD, Suchindran CM, Bangdiwala S,ritchevsky S, Jacobs DR Jr, O’Grady HK, Davis CE. Plasma triglyceride levels

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