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Association of obesity and metabolicsyndrome with the severity and outcome of

intermittent claudicationJonathan Golledge, MChir, MA, FRCS, FRACS,a,b Anthony Leicht, PhD,c Robert G. Crowther,

BSc(hons),c Paula Clancy, PhD,a Warwick L. Spinks, PhD,c andFrancis Quigley, MS,b Townsville,

Queensland, Australia

Background: Obesity is recognized as an independent predictor of coronary artery disease; however, its importance inperipheral arterial disease is less clear. The aim of this study was to assess the association between obesity and the severityand outcome of intermittent claudication.Methods: This study was a prospective cohort study based at a tertiary referral center. Sixty patients with intermittentclaudication selected for conservative treatment were assessed for obesity and metabolic syndrome by using the InternationalDiabetes Federation definition. Other risk factors, including diabetes, hypertension, smoking history, serum lipids, adipocy-tokines, and C-reactive protein, were measured by clinical and bloodassessment. Obesity and metabolic syndrome were relatedto the severity of peripheral arterial disease, defined by ankle-brachial pressure index and graded treadmill measured maximum

walking distance (MWD) and initial claudication distance, by using multiple linear regression analysis allowing for traditionalatherosclerotic risk factors. Patients were followed up for 24 months, and combined outcome was reported in terms of death,

cardiovascular events, or requirement for revascularization. The effect of obesity and metabolic syndrome on outcome wasinvestigated by using Kaplan-Meier and Cox proportional hazard analysis.Results:Obesity and serum adiponectin were independently associated with the severity of peripheral arterial diseasemeasured by ankle-brachial pressure index (P .03 and .001), initial claudication distance (P .009 and .03), and MWD(P .001 and .04). Metabolic syndrome was independently associated only with MWD (P .02). By 24 months,outcome events occurred in 37% 7% and 43% 9% of patients with metabolic syndrome or obesity, respectively,compared with 0% and 11% 6% of those without these diagnoses. Waist circumference independently predicted thelikelihood of outcome events (relative risk, 1.16; 95% confidence interval, 1.08-1.26; P< .001).

Conclusions: These findings, if confirmed in other cohorts, suggest the importance of treating obesity in patients withintermittent claudication. Serum adiponectin concentrations may be an important guide to the efficacy of treatment inpatients with intermittent claudication and obesity. ( J Vasc Surg 2007;45:40-6.)

The increasing incidence of obesity has focused re-search on this modifiable risk factor for cardiovasculardisease.1,2There is particular interest in a constellation ofrisk factors associated with obesity, known as the metabolicsyndrome, that are thought to result from insulin resis-tance.3Some, but not all, studies suggest an independentassociation between obesity or metabolic syndrome andcoronary events.4-7 Because peripheral arterial disease iscommon in patients with diabetes mellitus, it is not surpris-ing that metabolic syndrome has been particularly linkedwith lower limb artery disease.8,9In animal models, obesityhas been specifically linked with impaired limb blood

flow.

10

The interpretation of studies of obesity and meta-

bolic syndrome is complicated by the use of a number ofdifferent definitions and evidence; depending on whichcriteria are used, the outcome varies.4,11Two large popu-lation studies found no association between body massindex and symptomatic or asymptomatic lower limb arterydisease.12,13In one of these studies in which 708 men wereexamined, a waist-hip ratio above the median was indepen-dently associated with peripheral arterial disease at an oddsratio of 1.7.13These findings support studies of coronaryartery disease indicating that abdominal girth is a muchmore important risk factor for vascular disease than bodymass index.4It has been suggested that screening patients

with demonstrated vascular disease for obesity and meta-bolic syndrome may identify high-risk subgroups to directintensive treatment.14Few studies have examined the effectof obesity and metabolic syndrome on the outcome inpatients with existing peripheral arterial disease. In thisstudy, we assessed the prevalence of metabolic syndromeand obesity in a cohort of patients with intermittent clau-dication. We used girth measurements and the Interna-tional Diabetes Federation definition of metabolic syn-drome.15We assessed two hypotheses: (1) that obesityand/or metabolic syndrome is associated with more severeintermittent claudication and (2) that obesity and/or met-abolic syndrome is associated with a poorer prognosis dur-

From the Vascular Biology Unita and Institute of Sport and Exercise

Science,c James Cook University, and the bTownsville Hospital.

J.G. and A.L. contributed equally to this work.

Supported by funding from the National Health and Medical Research

Council (279408/379600), National Institutes of Health (R01

HL080010-01), and James Cook University.

Reprint requests: Jonathan Golledge, MChir, MA, FRCS, FRACS, The

Vascular Biology Unit, James Cook University, Townsville, Queensland

4811, Australia (e-mail: [email protected]).

CME article

0741-5214/$32.00

Copyright 2007 by The Society for Vascular Surgery.

doi:10.1016/j.jvs.2006.09.006

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ing follow-up, as evidenced by more frequent cardiovascu-lar or revascularization events.

METHODS

Patients. Approval for this study was provided by theethics committees of the Townsville Hospital, the MaterHospital, and James Cook University. In this prospectivestudy, we consecutively assessed patients with symptomaticperipheral arterial disease referred to the Townsville Hos-pital.Patients were initially assessed by a consultant vascularsurgeon to identify those with intermittent claudicationsecondary to peripheral arterial disease. Intermittent clau-dication was defined by an appropriate history, a positiveEdinburgh claudication questionnaire response, and anankle-brachial pressure index (ABPI) less than 0.9.16Pa-tients with critical ischemia (rest pain or tissue loss) ornonvascular symptoms were excluded. Because only pa-tients with lifestyle-limiting intermittent claudication arereferred to the vascular clinic, all patients underwent a

computed tomographic angiogramto assess whether endo-vascular therapies were feasible. Because the second aim ofthis study was to assess the association between obesity andcardiovascular or revascularization events, patients selectedfor endovascular or open vascular surgery were excluded.The remaining patients who had intermittent claudicationand were selected for medical treatment were eligible forthe study. Medical treatment consisted of advice on exer-cise, smoking cessation, and control of cardiovascular riskfactors under the supervision of a cardiovascular physician.As a result, 10 and 6 patients were started on treatment fordiabetes and dyslipidemia, respectively. The patients haddetailed further assessment, including recording of medical

history, examination, blood, and imaging findings.Clinical definitions. Hypertension was defined by

systolic blood pressure of 130 mm Hg or higher, diastolicblood pressure of 85 mm Hg or higher, or previouslydiagnosed and treated high blood pressure.15Diabetes wasdefined by a fasting blood glucose of 7.0 mmol/Lor higheror, for patients with fasting glucose between 6.1 and 6.9mmol/L, a positive oral glucose tolerance test.17Cigarettesmoking classification was based on a history as currentsmokers (smoked within the last month), ex-smokers(given up for more than 1 month), and never-smokers.Ischemic heart disease was defined by a history of myocar-dial infarction, angina, or coronary revascularization. Cere-

brovascular disease was defined by a history of stroke,transient ischemic attack, or cerebral revascularization.Dyslipidemia was defined according to the European JointSociety of Cardiologists criteria as total cholesterol of 4.5mmol/L or higher, low-density lipoprotein 2.5 mmol/Lor higher, or current lipid-lowering treatment.18

Blood analysis. Blood was collected after an over-night fast and assessed for full blood count, urea andelectrolytes, glucose, cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein, andC-reactive protein (CRP), as previously described.19

Blood glucose was measured by the glucose oxidasemethod, lipids by automatedenzymaticmethods, and CRP

by particle-enhanced turbidimetry (Roche Diagnostics,Basel, Switzerland).19Serum was stored at 80C for laterbatch assessment of adiponectin, leptin, and resistin con-centrations by using enzyme-linked immunosorbent assay(R&D Systems). Intra-assay and interassay coefficients of

variation for these assays are between 3% and 6% in ourlaboratory.Assessment of obesity and metabolic syndrome.

On entry into the study, patients weight, height, and waistand hip circumference were measured in accordance withguidelines of the International Society for the Advance-ment of Kinanthropometry.20The percentage body fat wasmeasured by bioelectrical impedance scales (TBF 521;Tanita Corporation of America, Arlington Heights, Ill).21

Body mass index was calculated as weight in kilogramsdivided by height in meters squared. Obesity and metabolicsyndrome were defined by using the International DiabetesFederation classification, which uses varying waist circumfer-

ences fordifferentpopulations. In our study, because patientswereof European origin,we defined obesity as a waist circum-ference of 94 cm or greater for men and 80 cm or greater inwomen.15Metabolic syndrome was diagnosed when obesitywas present in addition to two of the following: fasting trig-lycerides 1.7 mmol/L or more or specific treatment to de-crease triglycerides; HDL less than 1.03 mmol/L in men orless than 1.29 mmol/L in women or specific treatment toincrease HDL; hypertension; fasting glucose 5.6 mmol/L ormore; or treated diabetes mellitus.15

Objective assessment of peripheral vascular disease.

A consultant vascular surgeon documented the presence ofperipheral pulses and reviewed the computed tomographicangiogram. The site of arterial occlusions or stenosesgreater than 50% was documented from the angiogram,and the peripheral vascular disease was recorded as aor-toiliac, infrainguinal, or combined. ABPI measurementswere performed by a qualified sonographer. Participantsrested supine for 10 minutes before measurement of theABPI. The ABPI was calculated by measuring the systolicblood pressure at the ankle (taking the highest of either thedorsalis pedis or posterior tibial arteries) with a handheldbidirectional Doppler scanner (MD6; D.E. Hokanson Inc.,Bellevue, Wash, USA) and then dividing that value by thesystolic blood pressure in the brachial artery.22Larger sphyg-momanometer cuffs were used in obese patients. Treadmillassessment wasalsoperformed. Patientswere initially familiar-ized with walking on the treadmill by a practice session.Maximum walking distance (MWD) and initial claudicationdistance (ICD) were subsequently measured during a gradedtreadmill test.23The treadmill test commenced at 3.2 km/hand anincline of0%, and the incline was increased by2%every2 minutes until voluntaryexhaustion or maximal claudicationpain.24

Follow-up. Patients were followed up at 3, 6, 12, 18,and 24 months. Notes were flagged to identify eventsoutside the review visits. The following end points werenoted: death, myocardial infarction, stroke, and coronaryor peripheral revascularization.

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Statistical analysis. Data were recorded in a spread-sheet (Excel; Microsoft, Redmond, Wash) and transferredto a statistical package for analysis (SPSS 12.0; SPSS Inc,Chicago, Ill). Initially the relationships between waist cir-cumference, waist-hip ratio, and circulating adipocytokinesand ABPI, ICD, and MWD were assessed. To investigatethe independent association of obesity and metabolic syn-drome with the severity of intermittent claudication, mul-tiple linear regression analysis was performed by using thedependent variables ABPI, ICD, or MWD and the covari-ants age, sex, smoking history, diabetes, hypertension, anddyslipidemia (the last three criteria were not included inmetabolic syndrome analyses because these are part of the

diagnostic criteria). The influence of obesity or metabolicsyndrome on combined end points during follow-up wasassessed with Kaplan-Meier analysis. Because all eventsoccurred in patients with metabolic syndrome, we used asurrogate marker of obesityie, waist circumferencetoperform a Cox proportional hazard analysis allowing forother determinants of cardiovascular events (age, sex,smoking, diabetes, hypertension, and dyslipidemia).

RESULTS

Characteristics of patients in relation to obesity andmetabolic syndrome. Between June 2003 and June2005, 60 patients were entered into the study, of whom 48

were defined as obese and 44 as having metabolic syn-drome. The characteristics of patients in relation to

whether they were obese or had metabolic syndrome are

illustrated inTable I.

Relationship between obesity or metabolic syn-

drome and severity of peripheral arterial disease.

Waist-hip ratio, but not waist circumference, was correlated

with the severity of peripheral arterial disease as assessed by

ABPI (r 0.41; P .001;Fig,a), but not by MWD (r 0.18; P .17)or ICD (r 0.21; P .10). The severity of

peripheral arterial disease by all three different defini-

tions was correlated with serum adiponectin concentra-

tions (Fig,b-d). Allowing for other known determinants

of atherosclerosis, obesity was independently associatedwith the severity of lower limb artery disease (Table II).

Metabolic syndrome was associated with the severity of

intermittent claudication as defined by MWD only (stan-

dardized coefficient 0.343;P .02), allowing for age,

sex, and smoking history. The adipocytokines adiponectin

and leptin were strongly associated with ABPI after adjust-

ment for traditional cardiovascular risk factors (Table III).

Serum adiponectin was also weakly independently associ-

ated with MWD (standardized coefficient 0.277;P .04) and ICD (standardized coefficient 0.292;P .03).

Effect of obesity and metabolic syndrome on inter-

Table I. Characteristics of patients with intermittent claudication in relation to obesity and metabolic syndrome

Variable Overall

Obesity Metabolic syndrome

Present Absent Present Absent

n 60 48 12 44 16Age (y) 67.3 7.8 68.40 7.41 63.00 8.34 68.70 7.67 63.50 7.20Male 30 28 2 28 2Current smoker 18 12 6 12 6Ex-smoker 28 28 0 28 0Nonsmoker 14 8 6 4 10Diabetes mellitus 22 19 3 19 3Hypertension 46 38 8 34 12IHD 18 15 3 15 3CVD 8 6 2 6 2Waist circumference (cm) 94.71 13.97 99.55 10.02 75.32 10.23 100.87 9.41 77.75 9.80Waist-hip ratio 0.901 0.091 0.928 0.071 0.795 0.084 0.939 0.064 0.798 0.072BMI (kg/m2) 28.37 4.39 29.86 3.22 22.40 3.27 30.17 3.19 23.43 3.36% Fat 33.21 7.22 36.11 6.42 30.11 6.82 34.10 7.40 30.78 6.27Cholesterol (mmol/L)* 4.99 1.12 4.97 1.16 5.07 0.99 4.94 1.20 5.13 0.87Triglyceride (mmol/L) 1.75 0.98 1.88 1.03 1.23 0.51 1.96 1.04 1.18 0.46HDL (mmol/L)* 1.45 0.43 1.41 0.45 1.58 0.30 1.39 0.46 1.61 0.27

LDL (mmol/L)* 2.77 1.03 2.73 1.03 2.94 1.04 2.69 1.07 2.99 0.91CRP (mg/L) 4.56 7.13 5.31 7.79 1.63 1.68 5.59 8.07 1.78 1.69Lowest ABPI 0.61 0.14 0.58 0.13 0.70 0.08 0.58 0.14 0.67 0.08MWD (m) 425.54 279.90 371.85 232.28 640.24 356.11 373.44 237.19 568.79 342.08ICD (m) 219.71 214.20 182.67 186.12 367.87 261.04 190.30 191.57 300.57 256.40Adiponectin (g/mL) 10.15 3.17 9.40 2.81 13.14 2.86 9.71 2.73 11.37 4.00Leptin (ng/mL) 83.25 94.08 90.99 101.25 52.28 48.60 87.95 105.03 70.32 54.32Resistin (ng/mL) 20.61 19.50 21.40 21.37 17.46 8.57 21.92 22.15 17.00 8.39

IHD,Ischemic heart disease;CVD,cerebrovascular disease;BMI,body mass index; HDL,high-density lipoprotein;LDL,low-density lipoprotein;CRP,

C-reactive protein;ABPI,ankle-brachial pressure index;MWD,maximum walking distance;ICD,initial claudication distance.

Shown are numbers or mean SD.

*To convert to mg/dL, multiply by 38.67.To convert to mg/dL, multiply by 88.57.


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mediate outcome. Patients were followed up for a mini-mum of 12 months unless they experienced a terminalevent. Three patients died 15, 21, and 22 months afterentry into the study. Although no autopsies were per-

formed, the deaths were all believed to be secondary tocardiac events. Twelve further cardiovascular events oc-curred. Four patients had nonfatal myocardial infarctions,and one was treated by a coronary artery bypass graft.Three

Fig. Scatterplots showing the relationship between waist-hip ratio or serum adiponectin and the severity of lower limbartery disease. Waist-hip ratio was correlated with ankle-brachial pressure index (ABPI)(a,r 0.41;P .001).Serum adiponectin was correlated with ABPI (b, r 0.31;P .01), maximum walking distance(MWD)(c, r 0.26;

P .04), and initial claudication distance(ICD)(d,r 0.36;P .005).

Table II. Multiple regression models relating traditional risk factors and obesity to severity of peripheral arterial disease

PAD measure

ABPI ICD MWD

Standardized coefficient* Pvalue Standardized coefficient* Pvalue Standardized coefficient* Pvalue

Age 0.057 .70 0.172 .28 0.003 .99Female sex 0.157 .30 0.057 .72 0.203 .18

Smoking 0.160 .31 0.151 .36 0.346 .03Diabetes 0.364 .003 0.168 .19 0.169 .15Hypertension 0.215 .09 0.140 .29 0.228 .07Dyslipidemia 0.066 .58 0.070 .58 0.028 .81Obesity 0.279 .03 0.370 .009 0.435 .001

PAD,Peripheral arterial disease;ABPI,ankle-brachial pressure index;ICD,initial claudication distance;MWD,maximum walking distance.

Overall model: ABPI, F 3.52,P .004; ICD, F 2.35,P .03; MWD, F 0.69,P .003.

*Reduction in the severity of PAD per unit change in factor or compared with subjects without the factor.




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patient experienced minor strokes, and one subsequently

underwent a carotid endarterectomy. Two patients devel-oped critical lower limb ischemia and required open arterialreconstruction (aortic bypass and femoropopliteal bypass).Three patients had deterioration of their intermittent clau-dication and underwent peripheral revascularization. ByKaplan-Meier analysis at 24 months, the incidence of car-diovascular events was 37.2% 7.4% and 42.8% 9.1% inpatients with metabolic syndrome and obesity, respectively,compared with 0% and 11.2% 6.1% in patients withoutthese diagnoses. Because no event occurred in patientswithout metabolic syndrome, it was problematic to relateobesity and metabolic syndrome independently to cardio-vascular outcome. We therefore used waist circumference

as a continuous variable and performed Cox proportionalhazard analysis. Waist circumference was independentlyassociated with an increased risk of cardiovascular events(Table IV).

DISCUSSION

The incidence of obesity is increasing, and there is nowgreater focus on this risk factor as a cause of coronary arterydisease.1-6Lower limb artery disease is present in approxi-mately 10% of the population over 60 years old, but incomparison with ischemic heart disease, it is poorly inves-tigated.25The importance of obesity in the developmentand progression of peripheral arterial disease has received

relatively little attention. The recent American task forcepractice guidelines for the management of patients withperipheral arterial disease did not consider obesity as atreatable cause of lower limb artery disease.26Some, butnot all, studies have correlated obesity with the presence oflower limb artery disease, particularly when obesity isdefined by abdominal girth measurements.7-9,12-14,27,28

However, there are few investigations of how obesity af-fects the severity and outcome of lower limb artery disease.

This study suggests the importance of obesity in pre-dicting more severe lower limb artery disease and worseoutcomes during follow-up in patients with intermittentclaudication. Obesity independently predicted more severeintermittent claudication as assessed by ABPI, ICD, orMWD (Table II). Metabolic syndrome was associated onlywith MWD. The most important finding of this study wasthe poor outcome of patients with obesity or metabolicsyndrome during intermediate-term follow-up. All the pa-tients who had a cardiovascular event during follow-up had

metabolic syndrome.Although as a result of this disparity itwas not possible to include metabolic syndrome in a Coxproportional hazard analysis, we did assess the independentassociation between waist circumference and outcomeevents (Table IV). This analysis demonstrated an importantassociation between larger waist circumference and in-creased outcome events.

The correlation between serum adiponectin and allthree measures of the severity of peripheral arterial diseasesuggests that this adipocytokine plays an important role inthe poor prognosis associated with obesity in patients withlower limb ischemia (Fig). Both adiponectin and leptinwere particularly associated with ABPI after adjustment for

other cardiovascular risk factors. Serum adiponectin levelshave been previously negatively correlated withcoronaryartery disease severity and progression.29,30 Recently,Iwashima and colleagues31 reported an association be-tween ABPI and serum adiponectin, although the investi-gators did not perform any functional tests of peripheralarterial disease. In animal models, adiponectin has beendemonstrated to protect against the development of ath-erosclerosis.32Several mechanisms have been suggested forthis protective effect, including inhibition of thrombusformation and inflammation.33-35

Interpretation of this study must take into accountseveral limitations.Indeveloping thisstudy,webelievedthatit

was important to enter a homogenous group of patientsie,patients with intermittent claudication planned to be treatedconservatively. These tight entry criteria and the detailednumber of investigations performed restricted the samplesize. It will be important to confirm our findings in a largercohort. We also plan to extend the follow-up for this groupto assess whether the identified differences persist in thelong term. We defined outcome in this study in terms of theclinical end points death, cardiovascular events, and revas-cularization. Most events during follow-up (10/15) werecardiovascular events. Five additional patients required re-vascularization for the development of critical ischemia(n 2) or worsening intermittent claudication (n 3).

Table III. Multiple regression model relating traditionalrisk factors and adipocytokines to ABPI

Variable Standardized coefficient* Pvalue

Age 0.293 .04

Female sex 0.303 .11Smoking 0.202 .18Diabetes 0.138 .24Hypertension 0.128 .27Dyslipidemia 0.037 .74Adiponectin 0.506 .001Leptin 0.589 .001Resistin 0.101 .39

ABPI,Ankle-brachial pressure index.

Overall model: F 5.04;P .001.

*Change in ABPI per unit change in factor or compared with subjects

without the factor.

Table IV. Predictors of outcome events

Variable Relative risk 95% CI Pvalue

Age (per 1 y) 1.03 0.92-1.14 .62Female sex 0.25 0.06-1.14 .07Smoking 5.11 1.30-39.86 .02Diabetes 5.64 1.36-23.38 .01Hypertension 1.32 0.21-8.50 .77Dyslipidemia 1.20 0.70-1.40 .99Waist (per 1 cm) 1.16 1.08-1.26 .001

CI,Confidence interval.

Overall model: 2 32.4;P .001.




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Decisions to perform revascularization in patients withintermittent claudication can be influenced by factors un-related to the progression of peripheral arterial disease: eg,the type of arterial occlusive lesion. However, because mostoutcome events in this study were unrelated to revascular-ization for intermittent claudication, we do not believe thatthese factors altered our results. Ideally, other measures ofoutcome, such as health-related quality of life or objectiveassessments of peripheral arterial disease, would have beenvaluable to assess.36

In conclusion, the findings of this study suggest thatobesity and metabolic syndrome predict poor outcome forpatients with peripheral vascular disease. Interventions totarget this problem in patients with lower limb arterydisease are required.

We thank R. Kerr, K. Sangla, S. Glanville, and the staffof the Townsville Hospital Vascular Out-Patients for theirhelp with this study.

AUTHOR CONTRIBUTIONS

Conception and design: JG, AL, WLS, FQAnalysis and interpretation: JG, ALData collection: JG, AL, RGC, PCWriting the article: JGCritical revision of the article: JG, AL, RGC, PC, WLS, FQFinal approval of the article: JG, AL, RGC, PC, WLS, FQStatistical analysis: JGObtained funding: JG, AL, WLSOverall responsibility: JG

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Submitted Aug 2, 2006; accepted Sep 1, 2006.

COLLECTIONS OF PAPERS

On the Web version of the Journal, selected articles have been grouped together for the convenience of thereaders. The current collections include the following:

American Board of Vascular SurgeryEditorial CommentsHistoryReporting StandardsTechnical Notes

Basic Science ReviewsGuidelinesLifeline Research Meeting AbstractsReviews



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